Pathology

Question 1

45 year old woman suffers from difficulty walking. Spinal cord shows symmetric myelin layer vacuolization and axonal degeneration involving the posterior columns and lateral corticospinal tracts. What is causing this patient’s condition?

Answer 1

1. “Subacute combined degeneration” due to abnormal myelin synthesis associated with Vitamin B12 deficiency.
2. Damage to the dorsal columns leads to b/l loss of position and vibration sensation (sensory ataxia)
3. Damage to b/l lateral corticospinal tracts leads to UMN signs (spastic paresis, hyperreflexia, +Babinski).
4. Axonal degeneration of peripheral nerves can cause numbness or paresthesias.
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Question 2

Adenoma to carcinoma sequence

Answer 2

1. Inactivation of APC (tumor suppressor gene on chromosome 5) in normal colonic epithelium leads to hyperproliferation.
2. Methylation abnormalities and COX-2 overexpression lead to adenomatous polyps, premalignant lesions with dysplastic mucosa.
3. Additional mutations in K-ras (activation), DCC (inactivation), and p53 (inactivation) lead to further accumulations of genetic abnormalities, which can transform into carcinoma.
4. Accumulation of gene mutations in a stepwise progression to adenocarcinoma is called the “adenoma-to-carcinoma sequence.”
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Question 3

Increased activity of which enzyme is most likely to promote recurrent adenoma development?

Answer 3

Cyclooxygenase-2 (COX-2). Increased activity of COX-2 occurs in some forms of colon adenocarcinoma and in inherited forms of polyposis. Patients taking aspirin (a COX inhibitor) regularly have been shown to have lower incidence of adenomas compared to general population.

Question 4

Gliosis

Answer 4

1. Universal response of CNS to severe damage, involving proliferation of astrocytes (glial hyperplasia) in an area of neuron degeneration leading to a glial scar compensating for volume loss after neuronal death.
2. Proliferating astrocytes have large vesicular nuclei with prominent nucleoli, and contain many fibrils and glycogen granules.
3. After neuronal death, astrocytic processes form a closely connected firm meshwork called a gliotic scar.
4. Shrunken and deeply eosinophilic neurons (red neurons) undergo cell death and are phagocytosed by microglia.
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Question 5

Bilateral ovarian masses removed from a 55 year old Caucasian woman show poorly differentiated cells heavily loaded with mucus

Answer 5

Krukenberg tumor- metastatic gastric adenocarcinoma to the ovarian stroma characterized by mucin-producing, signet-ring neoplastic cells. Can also occur in association with breast, pancreas, or gallbladder primary cancers. Most common type of metastatic ovarian cancer. Breast cancer metastasis to the ovary estimated 6-28% of patients, but most common neoplastic source associated with Krukenberg tumor is stomach.

Question 6

Virchow’s node

Answer 6

Metastasis of gastric carcinoma from gastric wall to the left supraclavicular sentinel node. Frequently the first clinical manifestation of occult gastric cancer.

Question 7

Sister Mary Joseph nodule

Answer 7

Metastasis of gastric carcinoma to periumbilical region resulting in a subcutaneous mass. If gastric carcinoma left untreated/undiagnosed can cause extensive peritoneal seeding and widespread metastasis to liver and lungs.

Question 8

Cell cycle checkpoints

Answer 8

1. G1 (synthesis of RNA, protein, lipid, carbohydrate) to S (DNA replication) phase
2. G2 (ATP synthesis) to M (mitosis) phase
3. Checkpoints are regulated by cyclins and cyclin-dependent kinases (CDKs) that screen for DNA damage or abnormalities.
4. Cells with normal DNA are allowed to proceed, cells with damaged DNA trigger DNA repair mechanisms, and if DNA damage is too substantial to be repaired, p53 (“molecular policeman”) signals BAX, which inactivates Bcl-2, causing cytochrome C to leak from mitochondria and activate apoptosis (caspases).
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Question 9

Retinoblastoma protein (Rb)

Answer 9

1. Nuclear phosphoprotein (Rb) that regulates G1–>S checkpoint by binding the E2F transcription factor necessary for transition to S phase.
2. E2F is released when Rb is phosphorylated (inactivated) by cyclinD/CDK4 complex.
3. Inactive (hyperphosphorylated) Rb protein releases E2F, allowing cell to proceed through G1–>S checkpoint.
4. Activated (hypophosphorylated) Rb binds E2F, preventing cell cycle progression.
5. Abnormal phosphorylation of Rb results in permanent Rb inactivation, allowing for constitutively free E2F, thereby allowing cells (even those with damaged DNA) to proceed through G1–>S checkpoint and uncontrolled growth.
6. Mutations of Rb protein linked to retinoblastoma, osteosarcoma, breast adenocarcinoma, SCC of the lung, and bladder carcinoma.
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Question 10

Zollinger-Ellison syndrome

Answer 10

Gastrin hypersecretion induces parietal cell hyperplasia, causing visible enlargement of gastric rugal folds on endoscopy. Increased gastric acid secretion caused by excess gastrin causes PUD, hearburn, and diarrhea. Gastrin not only stimulates HCl secretion from parietal cells in fundus/body of the stomach but also has a trophic effect on them.

Question 11

Secretin

Answer 11

Produced by S cells of small intestine. Increases bicarbonate production by pancreas and leads to secretion of watery, alkaline pancreatic juice. Also inhibits gastric acid secretion and stimulates pyloric sphincter contraction.

Question 12

Serotonin

Answer 12

Primarily found in enterochromaffin cells of GI tract, CNS, and platelets. In GI tract, helps to regulate intestinal secretions and peristalsis.

Question 13

Somatostatin

Answer 13

Somatostatin (growth hormone-inhibiting hormone) is secreted by D cells of pancreatic islets and GI mucosa. Has multiple inhibitory effects over GI tract, including decreasing motility, gastrin secretion, pancreatic endocrine/exocrine secretion, and absorption of nutrients.

Question 14

Transforming growth factor alpha (TGF-α)

Answer 14

Potent stimulator of epithelial growth, secreted by carcinomas, macrophages, and epithelial cells.

Question 15

Menetrier disease

Answer 15

Overproduction of TGF-α resulting in mucosal-cell hyperplasia with gastric fold enlargement. However, condition causes hypoplasia of parietal/chief cells, resulting in glandular atrophy with reduced gastrin secretion.

Question 16

Nests of polygonal cells with Congo red-positive deposits in a neck mass

Answer 16

Medullary thyroid carcinoma (MTC) is characterized by extracellular deposits of amyloid formed by calcitonin secreted from neoplastic parafollicular C-cells. Amyloid stains with Congo red.

Question 17

Neck mass with histology of branching structures with interspersed calcified bodies

Answer 17

Well-differentiated papillary thyroid cancer. Papillary structure with calcifications (psammoma bodies) and large, ground glass, grooved nuclei. Follicular hyperplasia with tall cells is variant of papillary thyroid cancer found in older individuals, more invasive than classic well-differentiated papillary thyroid cancer.

Question 18

Neck mass with sheets of uniform cells forming small follicles

Answer 18

Presence of colloid-containing microfollicles suggests benign follicular adenoma. Sometimes, benign follicular adenoma can be difficult to distinguish from well-differentiated follicular thyroid cancer, which can also have appearance of normal thyroid follicles. Tip-off is that capsular and vascular invasion only occurs with carcinoma.

Question 19

Neck mass with pleomorphic giant cell nests with occasional multinucleated cells

Answer 19

Large pleomorphic giant cells seen in anaplastic thyroid cancer.

Question 20

Most common predisposing condition for native valve infective endocarditis in developed nations

Answer 20

Mitral valve prolapse (with or without mitral regurgitation), responsible for approximately 25-30% of cases of IE in developed nations. Mitral valve is the most common valve affected by infective endocarditis. Microscopic deposits of platelets and fibrin occur spontaneously in individuals with valvular disease 2/2 endocardial injury from turbulent blood flow. These deposits become colonized by microorganisms during episodes of transient bacteremia. Other common factors are valvular sclerosis and mechanical valves.

Question 21

Most important form of acquired heart disease in children and young adults in developing countries.

Answer 21

Rheumatic heart disease. Remains a frequent cause of IE in developing nations.

Question 22

Adverse effect of high concentrations of oxygen therapy given for neonatal respiratory distress syndrome?

Answer 22

Retinopathy of prematurity (retrolental fibroplasia). Retinal damage 2/2 neonatal oxygen supplementation. Temporary local hyperoxia in the retina is thought to induce up-regulation of proangiogenic factors such as VEGF upon return to room air ventilation. Retinal vessel neovascularization and possible retinal detachment with blindness may result.

Question 23

Non-atrophic chronic gastritis

Answer 23

Most often due to H. pylori infection, which primarily affects the antrum but with time may spread to involve the gastric body. Inflammatory infiltrate is primarily composed of neutrophils in the acute phase, but may be characterized by lymphocytes, lymphoid follicles, and plasma cells in chronic H pylori gastritis.

Question 24

Pathogenesis of centriacinar emphysema associated with chronic smoking

Answer 24

Oxidative injury to the respiratory bronchioles by cigarette smoke activates resident alveolar macrophages followed by inflammatory recruitment of neutrophils into the affected airspaces. Infiltrating neutrophils and activated alveolar macrophages release proteases (eg, elastase, cathepsins, MMPs) that degrade the ECM and generate oxygen free radicals that impair the function of protease inhibitors (eg, A1AT). Protease-antiprotease imbalance leads to acinar wall destruction and irreversible airspace dilation.

Question 25

Club cells

Answer 25

aka Clara cells. Nonciliated, secretory constituents of terminal respiratory epithelium. Secrete club cell secretory protein and surfactant components. Help to detoxify inhaled substances by cytochrome P450 mechanism.

Question 26

Type I pneumocytes

Answer 26

Make up over 95% of the inner epithelial lining of the alveoli, these cells are destroyed by acinar wall damage that occurs in emphysema.

Question 27

Wernicke's aphasia

Answer 27

Wernicke= Word salad. Receptive aphasia (may be fluent aphasia). Impairment in verbal/written language comprehension as well as repetition. Often produced by a lesion in Wernicke's area (located in the auditory association cortex within the posterior portion of superior temporal gyrus, usually in the left temporal lobe), which is supplied by the inferior terminal MCA branches. Superior division of the MCA supplies Broca's area.

Question 28

Inhibin B

Answer 28

Hormone secreted from Sertoli cells. Stimulated by FSH, and has negative feedback inhibition of FSH release from anterior pituitary. Sertoli cells are present within the seminiferous tubules of the testes. In patients with 1 testicle, mass of Sertoli cells greatly reduced and circulating levels of inhibin B are likely to be low. Low inhibin B will not adequately inhibit FSH secretion, and thus FSH levels will tend to be elevated in males with 1 testicle. Male patient of any age who has only 1 testes requires further evaluation as there is increased cancer risk.

Question 29

Gonadotropin regulation in males

Answer 29

Pulsatile secretion of GnRH from hypothalamus stimulates release of FSH and LH, which are produced by gonadotroph cells of anterior pituitary. "L"H stimulates release of testosterone from "L"eydig cells of testes. LeyDIG cells DIG testosterone. F"S"H stimulates release of inhibin B from "S"er"T"oli cells of "S"eminiferous "T"ubules. Testosterone has negative feedback inhibition of LH and GnRH secretion. Inhibin B suppresses FSH secretion. Dihydrotestosterone and DHEA also cause LH feedback inhibition.

Question 30

Zona glomerulosa

Answer 30

1. Think "GFR" and "It gets sweeter as you go deeper." 2. CHOLESTEROL ---> PREGNENOLONE (CYP11A1) 3. PREGNENOLONE ---> PROGESTERONE (3-beta-hydroxysteroid dehydrogenase) 4. PROGESTERONE ---> 11-DEOXYCORTICOSTERONE (weak MC) (21-hydroxylase) 5. DEOXYCORTICOSTERONE ---> CORTICOSTERONE (weak GC) (11-beta-hydroxylase) 6. CORTICOSTERONE ---> ALDOSTERONE (aldosterone synthase) * *****************************

Question 31

Zona fasciculata

Answer 31

1. CHOLESTEROL ---> PREGNENOLONE (CYP11A1) 2. PREGNENOLONE ---> 17-OH-PREGNENOLONE 3. (17-α-hydroxylase) 4. PREGNENOLONE ---> PROGESTERONE 5. (3-beta-HSD) 6. PROGESTERONE ---> 17-OH- PROGESTERONE 7. (17- α-hydroxylase) 8. 17-OH-PREGNENOLONE ---> 17-OH- PROGESTERONE 9. (3-beta-HSD) 10. 17-OH- PROGESTERONE ---> 11-DEOXYCORTISOL 11. (21-hydroxylase) 12. 11-DEOXYCORTISOL ---> CORTISOL 13. (11-beta-hydroxylase) * *****************************

Question 32

Zona reticularis

Answer 32

1. CHOLESTEROL ---> PREGNENOLONE (CYP11A1) 4. PREGNENOLONE ---> PROGESTERONE 5. (3-beta-HSD) 2. PREGNENOLONE ---> 17-OH-PREGNENOLONE 3. (17-α-hydroxylase) 6. PROGESTERONE ---> 17-OH- PROGESTERONE 7. (17-α-hydroxylase) 8. 17-OH-PREGNENOLONE ---> 17-OH- PROGESTERONE 9. (3-beta-HSD) 10. 17-OH-PREGNENOLONE ---> DHEA 11. (17, 20-lyase) 12. 17-OH- PROGESTERONE ---> ANDROSTENEDIONE 13. (17,20-lyase) 14. DHEA ---> ANDROSTENEDIONE 15. (3-beta-HSD) 16. DHEA and Androstenedione are converted to testosterone in peripheral tissues. * *****************************

Question 33

Primary hyperaldosteronism

Answer 33

1. Etiology: 60% bilateral adrenal hyperplasia, unilateral aldosterone-producing adrenal adenoma (Conn's syndrome) 2. Sx: Hypertension (2/2 Na+ retention, may present with headaches and blurred vision), hypokalemic alkalosis (2/2 excess K+ and H+ urinary excretion, may present with muscle weakness and paresthesias) 3. Dx: Elevated plasma aldosterone, low plasma renin activity, aldosterone remains elevated following oral saline load. * *****************************

Question 34

Aldosterone escape

Answer 34

"Aldosterone escape" limits/prevents edema and hypernatremia in primary hyperaldosteronism. Increased aldosterone secretion from the adrenal leads to increased Na+ reabsorption (and decreased H+ and K+ reabsorption), and therefore hypertension and increased blood volume. The increased blood volume leads to increased renal blood flow, increased GFR, and increased atrial natriuretic peptide (ANP) secretion, which combined all lead to increased Na+ excretion by the kidney, thus resetting the sodium homeostasis set point, causing hypervolemia and hypertension without hypernatremia or edema.

Question 35

What structures traverse the cribiform plate?

Answer 35

CN I olfactory bundles

Question 36

What structures traverse the optic canal?

Answer 36

CN II, ophthalmic artery, central retinal vein

Question 37

What structures traverse the superior orbital fissure?

Answer 37

CN III, IV, VI (innervate ocular muscles), V1 (branch of CN V), ophthalmic vein, sympathetic fibers

Question 38

What structures traverse the foramen rotundum?

Answer 38

CN V2 (maxillary)

Question 39

What structures traverse the foramen ovale (skull)?

Answer 39

CN V3 (mandibular)

Question 40

What structures traverse the foramen spinosum?

Answer 40

Middle meningeal artery and vein

Question 41

What structures traverse the internal acoustic meatus?

Answer 41

CN VII, VIII

Question 42

What structures traverse the jugular foramen?

Answer 42

CN IX, X, XI, jugular vein

Question 43

What structures traverse the hypoglossal canal?

Answer 43

CN XII

Question 44

What structures traverse the foramen magnum?

Answer 44

Spinal roots of CN XI, brain stem, vertebral arteries

Question 45

Vernet syndrome

Answer 45

1. Jugular foramen syndrome 2/2 lesions of the jugular foramen such as tumors, trauma, infection. 2. Characterized by CN IX, X, and XI dysfunction: 3. Loss of taste from posterior 1/3 of tongue (CN IX) 4. Loss of gag reflex (CN IX, X) 5. Dysphagia (CN IX, X) 6. Dysphonia/hoarseness (CN X-recurrent laryngeal) 7. Soft palate drop with deviation of uvula toward normal side (CN X) 8. SCM and trapezius muscle paresis on side of lesion (CN XI) * *****************************

Question 46

Lesion at cerebellopontine angle

Answer 46

Eg, vestibular schwannoma. Typically cause sensorineural hearing loss and tinnitus due to CN VIII dysfunction.

Question 47

Renin-angiotensin-aldosterone system (RAAS)

Answer 47

Regulates arterial bp and sodium/fluid content in the body. In response to hyponatremia, hypovolemia, or hypotension, renin is released from the kidneys, converting angiotensinogen to angiotensin I. ACE converts angiotensin I to angiotensin II. Ang II increases aldosterone secretion from the adrenal cortex, which leads to sodium retention in collecting tubules of kidneys. Ang II is also a potent vasoconstrictor, thus increasing SVR and arterial BP.

Question 48

What are the negative feedback mechanisms of angiotensin II?

Answer 48

1. Elevated Ang II stimulates angiotensin receptors on JGA cells to inhibit renin release. 2. Elevated BP and sodium levels secondary to ang II eventually decrease renin release via intrarenal baroreceptors and macula densa pathways. * *****************************

Question 49

What are the effects of ACE inhibitors on the RAAS system?

Answer 49

1. Decrease Angiotensin II (blocking arteriolar vasoconstriction and aldosterone secretion) 2. Decrease Aldosterone 3. Increase renin (feedback loop) 4. Increase Angiotensin I (feedback loop) 5. Increase bradykinin (ACE is responsible for bradykinin breakdown, thus ACE-Is cause increased bradykinin) * *****************************

Question 50

Atrial natriuretic peptide (ANP)

Answer 50

ANP is a polypeptide hormone secreted by atrial cardiomyocytes in response to atrial stretch, which is indicative of systemic volume expansion. ANP lowers BP through peripheral vasodilation, natriuresis, and diuresis. ANP is inactivated by neprilysin.

Question 51

Organs affected by ANP

Answer 51

1. Kidney: ANP dilates afferent arterioles, increasing GFR and urinary excretion of sodium and water. Also ANP limits sodium reabsorption in proximal tubule and inner medullary collecting duct and inhibits renin secretion. 2. Adrenal gland: ANP restricts aldosterone secretion, leading to an increase in sodium and water excretion by the kidneys. 3. Blood vessels: ANP relaxes vascular smooth muscle in arterioles and venules, producing vasodilation. It also increases capillary permeability, leading to fluid extravasation into the interstitium and a decrease in circulating blood volume. ANP mediates these changes by binding to the natriuretic peptide receptor on cell membranes, activating Guanylate Cyclase and forming cyclic GMP. ******************************

Question 52

Cardiovascular dysphagia

Answer 52

Uncommon. Usually the result of left atrial enlargement as the left atrium is located posteriorly, and directly overlies the esophagus. LAE most commonly occurs in the setting of mitral stenosis and left ventricular failure.

Question 53

Congenital bilateral absence of the vas deferens (CBAVD)

Answer 53

CFTR gene mutations (CF) are the most common cause of CBAVD. Patients with CBAVD have azoopermia and infertility but normal levels of FSH, LH, testosterone and normal spermatogenesis. CFTR mutations are likely responsible for abnormal development of Wolffian structures. Will also see hx of recurrent pneumonia, digital clubbing, and pancreatic insufficiency with CF.

Question 54

Aspirin Exacerbated Respiratory Disease (AERD) aka aspirin-intolerant asthma

Answer 54

1. AERD (Samter's Triad) is a chronic medical condition seen in 10% of asthmatic adults that consists of: 2. Asthma 3. Recurrent rhinosinusitis with nasal polyps 4. Aspirin-induced bronchospasm and sensitivity to other NSAIDs * *****************************

Question 55

Nasal Polyp

Answer 55

Protrusion of edematous inflamed nasal mucosa usually 2/2 repeated bouts of rhinitis

Question 56

Child with nasal polyps

Answer 56

Test for Cystic Fibrosis

Question 57

Adolescent male presenting with profuse epistaxis

Answer 57

Angiofibroma- benign tumor of nasal mucosa composed of large blood vessels and fibrous tissue, classically seen in adolescent males, very rare in females

Question 58

Chinese adult with enlarged cervical LNs, bxp shows keratin + cells in a background of lymphocytes

Answer 58

Nasopharyngeal carcinoma- a malignant tumor of nasopharyngeal epithelium associated with EBV infection, classically seen in African children or Chinese adults. Bxp reveals pleomorphic keratin-positive epithelial cells (poorly differentiated squamous cell carcinoma) in a background of lymphocytes. Often presents with involvement of cervical LNs.

Question 59

Child presents with high fever, sore throat, drooling and dysphagia, muffled voice, inspiratory stridor.

Answer 59

Acute epiglottitis- usually 2/2 H influenzae type B, especially in non-immunized children

Question 60

Child presents with a hoarse, "barking" cough and inspiratory stridor

Answer 60

Laryngotracheobronchitis (croup)- usually 2/2 parainfluenza virus

Question 61

Vocal cord nodule

Answer 61

Nodule on true vocal cord, usually b/l and secondary to excessive vocal cord use. Composed of degenerative (myxoid) connective tissue. Presents with hoarseness, resolves with resting of voice.

Question 62

Benign tumor of the vocal cord

Answer 62

Laryngeal papilloma- papillary tumor 2/2 HPV 6 and 11. Usually single in adults and multiple in children.

Question 63

Laryngeal carcinoma

Answer 63

SqCC arising from the epithelial lining of the vocal cord. | RFs= alcohol and tobacco, rarely can arise from a laryngeal papilloma (HPV 6, 11)

Question 64

Mechanism of pleuritic chest pain

Answer 64

Nerves that innervate the pleura are sensitized by bradykinin and PGE2, that are generated by inflammatory response of pneumonia. Pleura is stretched when patient breathes in, causing pain.

Question 65

Most common causes of lobar pneumonia

Answer 65

``` Streptococcus pneumoniae (95%) Klebsiella pneumoniae (5%)- has a thick mucoid capsule ```

Question 66

Gross phases of lobar pneumonia

Answer 66

1. Congestion- congested vessels and edema 2. Red hepatization- exudate, neutrophils, and hemorrhage filling the alveolar air spaces, giving normally spongy lung a solid consistency 3. Gray hepatization- due to degradation of RBCs within the exudate 4. Resolution- regeneration of lining of alveolar air sacs via type II pneumocytes (lung stem cells) * *****************************

Question 67

Bronchopneumonia

Answer 67

Scattered patchy consolidation centered around bronchioles; often multifocal and bilateral

Question 68

Most common causes of bronchopneumonia

Answer 68

1. Staphylococcus aureus 2. Haemophilus influenzae 3. Pseudomonas aeruginosa 4. Moraxella catarrhalis 5. Legionella pneumophila * *****************************

Question 69

2nd most common cause of secondary pneumonia

Answer 69

Staphylococcus aureus- often complicated by abscess or empyema (bronchopneumonia)

Question 70

Common cause of secondary pneumonia and pneumonia superimposed on COPD

Answer 70

H. influenzae (bronchopneumonia)

Question 71

Pneumonia in a CF patient

Answer 71

Pseudomonas aeruginosa (bronchopneumonia)

Question 72

Community acquired pneumonia or pneumonia superimposed on COPD

Answer 72

Moraxella catarrhalis (bronchopneumonia)

Question 73

Pneumonia transmitted from a water source, intracellular organism that is best visualized by silver stain

Answer 73

Legionella pneumophila (bronchopneumonia)

Question 74

Most common cause of CAP

Answer 74

Streptococcus pneumoniae, also most common cause of secondary pneumonia, usually seen in middle-aged adults and elderly

Question 75

Pneumonia often seen in malnourished and debilitated individuals, especially elderly in nursing homes, alcoholics, diabetics

Answer 75

Klebsiella pneumoniae, thick mucoid capsule results in gelatinous sputum (currant jelly), often complicated by abscess

Question 76

Complications of Mycoplasma pneumoniae

Answer 76

1. Autoimmune hemolytic anemia 2/2 IgM antibodies against I antigen on RBCs- cold agglutinins 2. Erythema multiforme * *****************************

Question 77

Most common cause of atypical pneumonia

Answer 77

Mycoplasma pneumoniae- usually affects young adults in college or military. Not visible on gram stain b/c no cell wall.

Question 78

Second most common cause of atypical pneumonia in young adults

Answer 78

Chlamydia pneumoniae

Question 79

Most common cause of atypical pneumonia in infants

Answer 79

Respiratory syncytial virus (RSV)

Question 80

Atypical pneumonia in post-transplant patient on immunosuppressive therapy

Answer 80

Cytomegalovirus (CMV)

Question 81

Atypical pneumonia in elderly, immunocompromised, and those with preexisiting lung disease

Answer 81

Influenza virus. Also increases risk for superimposed S aureus or H influenzae bacterial pneumonia

Question 82

Atypical pneumonia with high fever

Answer 82

Coxiella burnetii- Q fever; seen in farmers and veterinarians as Coxiella spores are deposited on cattle by ticks or are present in cattle placentas.

Question 83

How is Coxiella burnetti different from other rickettsial organisms?

Answer 83

1. Causes pneumonia 2. Does not require arthropod vector for transmission as survives in highly heat-resistant endospores 3. Does not produce a skin rash * *****************************

Question 84

Causes of aspiration pneumonia

Answer 84

Most often due to anaerobic bacteria in the oropharynx (eg, Bacteroides, Fusobacterium, Peptococcus) or Klebsiella.

Question 85

Patient presents with 4 days of cramping abdominal pain and feeling weak for the past 2 weeks. He is an industrial laborer with no PMH or allergies. His peripheral blood smear shows basophilic stippling on a background of hypochromic microcytic anemia.

Answer 85

Lead poisoning (plumbism). In US, lead poisoning is typically seen in children ingesting lead-containing paint chips, but can also occur in adults. Affected individuals are usually miners or industrial workers (especially in battery manufacturing) who inhale lead particles while working. Adults with lead poisoning present with weakness, abdominal pain, and constipation. In severe cases, may present with headache, cognitive sx, peripheral neuropathy. On exam, may have blue "lead lines" at junction of teeth and gingivae. Diagnostic finding on peripheral smear is coarse basophilic stippling of RBCs on a background of hypochromic microcytic anemia.

Question 86

Classic peripheral blood smear in someone with lead poisoning

Answer 86

1. Diagnostic finding on peripheral smear is coarse basophilic stippling of RBCs on a background of hypochromic microcytic anemia. 2. Basophilic stippling results from abnormal degradation of ribosomal RNA due to lead-induced inhibition of a nucleotidase. 3. Hypochromic microcytic anemia results from inhibition of ALAD and Ferrochelatase with resultant reduced heme for production of RBCs (sideroblastic anemia). Net effect is decreased hemoglobin synthesis. * *****************************

Question 87

Aortic stenosis (AS)

Answer 87

An AS murmur is a systolic ejection-type crescendo-decrescendo murmur that starts after S1 following the opening of the aortic valve and typically ends before the A2 component of S2. Intensity of AS murmur is directly related to the magnitude of the left ventricle to aorta pressure gradient. The maximum pressure difference between the LV and aortic pressure tracings corresponds to the peak intensity of a cardiac murmur during auscultation.

Question 88

Syringomyelia

Answer 88

1. Central cystic dilation (syrinx) within cervical (typically C8-T1) spinal cord that slowly enlarges causing damage to the ventral white commissure (crossing pain and temperature fibers) and anterior horns. 2. Damage to crossing fibers of lateral spinothalamic tracts causes b/l loss of pain and temperature sensation in a cape-like distribution. 3. Involvement of anterior horn motor neurons causes flaccid paralysis and atrophy of intrinsic hand muscles. 4. Further expansion within cervical cord can produce lower extremity weakness and hyperreflexia by affecting lateral corticospinal tracts as well as loss of position and vibration senses in feet due to involvement of posterior columns. 5. Scoliosis (kyphosis) can occur 2/2 paresis of paravertebral muscles. 6. Presents with chronic loss of upper extremity pain and temperature sensations, upper extremity weakness and hyporeflexia, lower extremity weakness and hyperreflexia (UMN signs), and kyphoscoliosis. * *****************************

Question 89

Pathogenesis of pulmonary hypertension 2/2 hypertensive heart disease (LVH)

Answer 89

Hypertensive heart disease is the most common cause of LV diastolic dysfunction. It's characterized by concentric LV hypertrophy and decreased LV diastolic compliance. Higher diastolic filling pressures are needed to maintain SV and CO. This increase in pressure is transmitted backward to the LA and pulmonary veins, leading to pulmonary venous congestion, which increases pulmonary capillary and arterial pressure. These high pressures in the lung vasculature result in endothelial damage and capillary leakage of serum proteins. This leads to decreased production of nitric oxide (vasodilator) and increased production of endothelin (vasoconstrictor) by the dysfunctional epithelium, resulting in increased vascular tone. Remodeling of the pulmonary vasculature over time with increased smooth muscle cell proliferation (medial hypertrophy) and collagen/elastin deposition (intimal thickening and fibrosis).

Question 90

Precipitating factors of G6PD deficiency hemolytic anemia

Answer 90

1. Infections 2. Drugs- dapsone, antimalarials, sulfonamide antibiotics (TMP-SMX); oxidative stress 3. Diabetic ketoacidosis 4. Favism (ingestion of fresh fava beans) * *****************************

Question 91

Lingual thyroid

Answer 91

Failure of migration of the thyroid gland can cause a lingual thyroid, which can present as a base of tongue mass. Surgeons should be careful when removing any mass along the thyroglossal duct's path as the mass could be the only thyroid tissue present. Clinical features of hypothyroidism in children: lethargy, feeding problems, constipation, macroglossia, umbilical hernia, large fontanels, dry skin, hypothermia, prolonged jaundice.

Question 92

How does ionizing radiation therapy work?

Answer 92

Ionizing radiation (eg, gamma rays, x-rays) induces DNA damage through DNA double-strand breaks (fractures) and formation of oxygen free radicals, which cause cellular and DNA damage. There is an initial plateau of cell survival with increasing radiation dose, but after a certain point there is a rapid increase in cell death, leading to a characteristic cell death curve for ionizing radiation. Ionizing radiation has a higher energy than UV radiation (which leads to formation of pyrimidine-pyrimidine dimers), leading to more cell damage. The effect of ionizing radiation is most pronounced in malignant cells as they are rapidly dividing and less able to repair DNA damage. Epithelial surfaces (eg, bowel mucosa, skin) are also severely affected as they are rapidly dividing.

Question 93

How do alkylating cancer agents work?

Answer 93

Induce DNA cross-linking

Question 94

Type I collagen

Answer 94

1. Skin (dermis) 2. Bone 3. Tendons 4. Ligaments 5. Dentin 6. Cornea 7. Blood vessels 8. scar tissue (primary collagen in mature scars). 9. Defect in Type I collagen in Osteogenesis imperfecta, autosomal dominant disorder that presents with easily fractured bones and blue sclera. 10. Most abundant type of collagen in the body. * *****************************

Question 95

Type II collagen

Answer 95

Cartilage, vitreous humor, nucleus pulposus

Question 96

Type III collagen

Answer 96

1. Skin 2. Lungs 3. Intestines 4. Blood vessels 5. Bone marrow 6. Lymphatics 7. Granulation tissue (1-2 week old scar) 8. Defects in Type III collagen in Ehlers-Danlos syndrome (type 3 and 4) * *****************************

Question 97

Type IV collagen

Answer 97

Basement membrane. Defect in Type IV collagen gene causes Alport syndrome.

Question 98

Evolution of a myocardial scar under light microscope: 0-4 hours after MI

Answer 98

No visible change

Question 99

Evolution of a myocardial scar under light microscope: 4-12 hours after MI

Answer 99

Wavy fibers with narrow, elongated myocytes

Question 100

Evolution of a myocardial scar under light microscope: 12-24 hours after MI

Answer 100

Myocyte hypereosinophilia with pyknotic (shrunken) nuclei

Question 101

Evolution of a myocardial scar under light microscope: 1-3 days after MI

Answer 101

Coagulation necrosis (loss of nuclei and striations) with prominent neutrophilic infiltrate

Question 102

Evolution of a myocardial scar under light microscope: 3-7 days after MI

Answer 102

Disintegration of dead neutrophils and myofibers with macrophage infiltration at border areas

Question 103

Evolution of a myocardial scar under light microscope: 7-10 days after MI

Answer 103

Robust phagocytosis of dead cells by macrophages with the beginning formation of granulation tissue at margins

Question 104

Evolution of a myocardial scar under light microscope: 10-14 days after MI

Answer 104

Well-developed granulation tissue (type III collagen) with neovascularization

Question 105

Evolution of a myocardial scar under light microscope: 2wk-2mo after MI

Answer 105

Progressive Type I collagen deposition and scar formation. Fibrosis continues until about 2 months after infarction resulting in a dense collagenous mature scar composed primarily of Type I collagen.

Question 106

Fibronectin

Answer 106

Large glycoproteins produced by fibroblasts and some epithelial cells. Binds to integrins, matrix collagen, and glycosaminoglycans (GAGs), serving as mediator of normal cell adhesion and migration. Integrin-mediated adhesion of cells to basement membrane and ECM involves the binding of integrins to fibronectin, collagen, and laminin.

Question 107

Vertical transmission of HIV-1

Answer 107

1. Oral thrush, interstitial pneumonia, and severe lymphopenia during the first year of life are consistent with mother-to-child vertical transmission of HIV-1. 2. Risk of HIV infection in an infant born to an HIV+ mother who received no prenatal ART can be as high as 35%, where as ART during pregnancy reduces the risk to 1-2%. 3. All pregnant women with HIV should take ART regardless of their CD4 count or viral load. 4. Avoid efavirenz or other drugs with an associated teratogenic risk. 5. ART should be continued as long as women are breastfeeding. 6. Infant should receive several weeks of zidovudine prophylaxis. * *********************************

Question 108

Filtration fraction (FF)

Answer 108

FF = GFR/RPF. I.e., Fraction of plasma flowing through the glomeruli that is filtered across the glomerular capillaries into Bowman's space or the ratio between GFR and renal plasma flow (RPF). RPF is used to calculate FF rather than renal blood flow (RBF) b/c RBF contains the volume of blood occupied by RBCs, a volume unavailable for filtration across the glomerular capillaries.

Question 109

Renal plasma flow (RPF)

Answer 109

RPF quantifies the volume of plasma that is able to pass through the glomerular capillaries more accurately than RBF. Can be calculated via this equation: RPF = RBF * (1 - Hematocrit)

Question 110

Chloride shift (in RBCs)

Answer 110

Carbon dioxide produced by tissue respiration enters RBCs and is hydrated by carbonic anhydrase to form carbonic acid (H2CO3), which undergoes spontaneous conversion to bicarbonate ions and H+. Many of the bicarbonate ions diffuse out of the RBC into the plasma. To maintain electrical neutrality, chloride ions diffuse into the RBC to take their place. This "chloride shift" is the cause of high RBC chloride content in venous blood. Some of the CO2 is carried by Hb as a carbamate (15%).

Question 111

Northern blot

Answer 111

Detects target mRNA in a sample to assess gene expression. Best method for determining whether a gene is being expressed is to analyze for presence of its mRNA with a Northern blot. Components of the unknown sample are separated by size and charge via gel electrophoresis. The resultant bands are then blotted onto a nitrocellulose membrane and incubated with a labeled hybridization probe or antibody to identify the specific mRNA molecule of interest.

Question 112

Southern blot

Answer 112

1. Technique used to detect target DNA mutations. 2. DNA extraction from individual's cells. 3. Restriction endonuclease digestion of DNA sample into fragments. (Endonuclease creates restriction fragments from a region containing gene of interest). 4. Gel electrophoresis to separate various sizes and charges of DNA fragments; larger fragments move slowly and shorter fragments move faster. 5. Resultant bands are then blotted onto a nitrocellulose membrane and incubated with a labeled hybridization DNA probe (single-stranded segment of labeled DNA complementary to gene of interest) to identify target gene. * *********************************

Question 113

Western blot

Answer 113

Detects target protein in a sample. Components of the unknown sample are separated by size and charge via gel electrophoresis. The resultant bands are then blotted onto a nitrocellulose membrane and incubated with a labeled hybridization probe or antibody to identify the specific protein of interest.

Question 114

Southwestern blot

Answer 114

Detects DNA-bound proteins in a sample. Components of the unknown sample are separated by size and charge via gel electrophoresis. The resultant bands are then blotted onto a nitrocellulose membrane and incubated with a labeled hybridization probe or antibody to identify the specific protein of interest.

Question 115

ELISA (enzyme-linked immunosorbent assay)

Answer 115

Commonly used to measure the amount of a protein in body fluids. Eg, to measure plasma insulin levels.

Question 116

Diabetic nephropathy histology

Answer 116

1. Mesangial expansion 2. GBM thickening 3. Glomerular sclerosis 4. If nodular glomerular sclerosis, Kimmelstiel-Wilson lesion, which consists of dense hyaline deposits and more commonly arises in the glomerular arterioles. * *****************************

Question 117

Cardiac tissue conduction velocity

Answer 117

1. From fastest to slowest conduction velocity: 2. Purkinje system 3. Atrial muscle 4. Ventricular muscle 5. AV node 6. "Park AT VENTure AVenue" mnemonic 7. Conduction is slowest within the AV node to delay depolarization impulse by 0.13s to allow adequate time for ventricular filling following atrial contraction. * *****************************

Question 118

Left atrium near openings of pulmonary veins

Answer 118

Proximal portions of pulmonary veins contain myocardial tissue that functions like a sphincter during atrial systole. Tissue has different electrical properties than surrounding atrial myocytes and is prone to causing premature atrial contractions and atrial fibrillation.

Question 119

Osteosarcoma

Answer 119

1. Area of mixed lysis and sclerosis with focal periosteal elevation and reactive new bone formation on xray 2. Bone tumor most often associated with Paget's disease of the bone 3. Arises in femur, tibia, humerus, etc. 4. Radiographic findings= destruction of normal trabecular bone pattern, mixed radiodense and radiolucent areas, periosteal new bone formation, lifting of cortex, Codman's triangle, and adjacent soft tissue ossification in "sunburst" pattern. * *****************************

Question 120

Radiographic findings of avascular necrosis

Answer 120

Crescent sign, indicating subchondral collapse

Question 121

Renal osteodystrophy

Answer 121

1. Damage to the bone 2/2 chronic renal failure. There are 4 bony diseases associated with advanced chronic renal failure: 2. Secondary hyperparathyroidism --> hypocalcemia due to decreased 1-alpha-hydroxylation of vitamin D by proximal renal tubule cells and hyperphosphatemia b/c kidney cannot excrete phosphate. Extra phosphate in the blood binds Ca++, thus decreasing free Ca++. Decrease in free Ca++ leads to elevated PTH in blood. 3. Osteomalacia --> inability to mineralize osteoid made by osteoblasts 2/2 decreased calcium concentration. 4. Osteitis fibrosa cystica --> PTH levels increase 2/2 decreased Ca++ levels. High levels of PTH cause activation of osteoclasts, leading to resorption of Ca++ from bone and cyst formation with reactive fibrosis, eventually leading to "burn out" bone. 5. Mixed uremic osteodystrophy --> both increased turnover (osteoclastic bone resorption) with abnormal mineralization (osteomalacia) 6. Osteoporosis- leeching out of calcium from bone slowly over time. Metabolic acidosis (2/2 inability to secrete acid from kidneys) leads to buffering against bone, causing demineralized trabecular bone. 7. Adynamic bone --> acellularity * *****************************

Question 122

3 theories of endometriosis

Answer 122

1. Retrograde menstruation 2. Lymphatic/vascular spread 3. Coelomic metaplasia * *****************************

Question 123

Most common sites of endometriosis

Answer 123

1. Ovaries 2. Cul-de-sac 3. Posterior broad ligaments 4. Uterosacral ligaments 5. Uterus 6. Fallopian tubes 7. Sigmoid colon 8. Appendix 9. Round ligaments * *****************************

Question 124

DNA laddering

Answer 124

A laboratory phenomenon used to identify apoptotic cells and distinguish them from necrotic cells. During karyorrhexis, endonucleases degrade DNA into fragments that are multiples of 180 base pairs; these fragments are equally spaced on gel electrophoresis giving the appearance of a ladder.

Question 125

Psoriasis

Answer 125

1. Due to keratinocyte proliferation 2. Associated with HLA-C 3. Koebner's phenomenon- lesions arise in areas of trauma/scrape 4. Histology shows acanthosis (epidermal hyperplasia), parakeratosis (hyperkeratosis of stratum corneum with retention of keratinocyte nuclei), Munro microabscesses (neutrophils in SC), and thinning of epidermis above elongated dermal papillae leading to Auspitz sign when scale picked off. 5. Tx corticosteroids, UVA light with psoralen. * *****************************

Question 126

Lichen planus

Answer 126

1. Pruritic, planar, polygonal, purple papules often with reticular white lines on surface (Wickham striae) 2. Wrists, elbows, oral mucosa 3. Histology shows inflammation of dermal-epidermal junction with 'saw-tooth' appearance of dermal papillae 4. Assoc with chronic hepatitis C * *****************************

Question 127

Pemphigus vulgaris

Answer 127

1. IgG anti-desmoglein antibodies 2. Type II hypersensitivity reaction 3. Destruction of desmosomes between stratum spinosum keratinocytes = acantholysis 4. Suprabasal blisters (skin and oral mucosa bullae) 5. Basal layer cells remain attached via hemidesmosomes leading to "tombstone appearance" 6. Thin-walled bullae rupture easily (Nikolsky sign) 7. Immunofluorescence highlights IgG surrounding keratinocytes in 'fish net' pattern. * *****************************

Question 128

Bullous pemphigoid

Answer 128

1. IgG antibody against hemidesmosome components (BP180) 2. Autoimmune destruction of hemidesmosomes btw basal cells and underlying basement membrane 3. Subepidermal blisters of the skin, but oral mucosa spared 4. Entire epidermis separated from dermis, leading to tense bullae that do not rupture easily 5. Clinically milder than pemphigus vulgaris 6. Immunofluorescence highlights IgG along basement membrane (linear pattern) * *****************************

Question 129

Dermatitis herpetiformis

Answer 129

1. Autoimmune deposition of IgA at tips of dermal papillae 2. Pruritic vesicles and bullae grouped (herpetiform) 3. Strongly associated with celiac disease, resolves with gluten-free diet 4. IgA antibodies are against gluten components and cross-react with reticulin fibers that attach BM to dermis * *****************************

Question 130

Erythema Multiforme (EM)

Answer 130

1. Hypersensitivity reaction most commonly associated with HSV infection; also Mycoplasma infection, drugs (eg, penicillin, sulfonamides), autoimmune d/o (eg, SLE), or malignancy. 2. Targetoid rash and bullae--> target appearance 2/2 central epidermal necrosis surrounded by erythema. 3. EM with oral mucosa/lip involvement and fever = Stevens-Johnson syndrome (SJS) 4. Toxic epidermal necrolysis (TEN) is a severe form of SJS characterized by diffuse sloughing of skin, resembling a large burn, typically due to adverse drug reaction. * *****************************

Question 131

T regulatory cells

Answer 131

1. CD4+, CD25+, FoxP3+ 2. CD25 = IL-2R on T reg cells. T regs depend on IL-2 for growth and survival. 3. Polymorphisms in CD25 are associated with autoimmunity--> MS, DM type II * *****************************

Question 132

CD34

Answer 132

Hematopoeitic stem cells are CD34+

Question 133

CD28

Answer 133

1. CD28 is present on T-cells. 2. Binds B7 on MHC II antigen presenting cells. 3. B7 on APC, CD28 on CD4+ T-cell; 28/4 = 7 * *****************************

Question 134

IL-2

Answer 134

T-cell growth factor and CD8+ T-cell activator. Secreted by Th1 CD4+ cells when activated by APCs presenting antigen. Provide second signal for CD8+ T-cells to be activated (1st signal is MHC Class I presentation of intracellular antigen).

Question 135

CD95

Answer 135

1. CD95 = Fas receptor = binds FasL (Fas ligand) 2. Mediates cell apoptosis in immature T-cells during negative selection. * *****************************

Question 136

3 ways to activate caspases

Answer 136

1. Intrinsic mitochondrial pathway: Decreased Bcl2 expression leads to cytochrome C leaking out of the mitochondrial membrane to activate caspases. 2. Extrinsic receptor pathway: FasL binds Fas receptor (CD95) on target cell, activating caspases (eg, negative selection of thymocytes in thymus) vs. TNF binding TNF receptor on target cell, activating caspases. 3. Cytotoxic CD8+ T-cell mediated pathway: perforins secreted by CD8+ T cells create pores in membrane of target cell. Granzyme from CD8+ T cell enters pores and activates caspases (eg, CD8+ T-cell killing of virally infected cells). 4. Caspases activate proteases and endonucleases to mediate apoptosis. * *****************************

Question 137

Which cells recognize MHC class I and class II? Which cells present MHC class I and II?

Answer 137

1. CD4+ cells bind Class II MHC with their TCR complex 2. CD8+ cells bind Class I MHC with their TCR complex 3. 4 x 2 = 8 and 8 x 1 = 8. 4. TCR complex = T-cell receptor + CD3 4. Antigen presenting cells (APCs) express MHC class II. 5. All nucleated cells and platelets express MHC class I. RBCs do not express MHC Class I. * *****************************

Question 138

CD14

Answer 138

Co-receptor for TLR4 (toll-like receptor 4) on macrophages. Recognizes lipopolysaccharide (a pathogen-associated molecular pattern [PAMP]) on the outer membrane of gram - bacteria. TLR activation results in activation of NF-kappa-beta, a nuclear transcription factor that activates immune response genes.

Question 139

CD40

Answer 139

Present on B-cells. Binds CD40L (ligand) on T-helper CD4+ cells. If CD40 mutated, patients have IgM syndrome. T-helper cell mediates isotype switching and B-cell maturation to plasma cells.

Question 140

CD55

Answer 140

Decay Accelerating Factor (DAF) - present on all blood cells from myeloid lineage (RBC, WBC, platelets), inhibiting complement C3 convertase from destroying cells. Anchored by GPI to cell membrane. Deficiency in linker molecule (GPI) leads to complement-mediated lysis of RBCs and paroxysmal nocturnal hemoglobinuria.

Question 141

Dialysis-associated amyloidosis

Answer 141

1. Beta2-microglobulin deposits in joints in patients on dialysis. (localized amyloidosis) 2. Beta-2-microglobulin provides structural support for MHC class I. Beta-2-microglobulin not filtered well form blood in dialysis and deposits in joints. * *****************************

Question 142

Medullary carcinoma of thyroid

Answer 142

Calcitonin (produced by tumor C-cells) deposits within the tumor. FNA shows tumor cells in a background of amyloid. (localized amyloidosis)

Question 143

Amylin

Answer 143

Resistance to insulin in skeletal muscle and adipocytes of patients with NIDDM leads to the pancreas secreting excess insulin. Byproduct of insulin production is amylin, which deposits in the islets of the pancreas. Form of localized amyloidosis.

Question 144

Senile cardiac amyloidosis

Answer 144

Non-mutated serum transthyretin deposits in the heart. Serum transthyretin is the 2nd most common protein in the blood and over long periods of time can deposit in the heart. Usually asymptomatic. Present in over 25% of individuals over 80 years old. (localized amyloidosis)

Question 145

Familial amyloid cardiomyopathy

Answer 145

Mutated serum transthyretin deposits in the heart, leading to restrictive cardiomyopathy and congestive heart failure. 5% of AA carry mutated gene. (localized amyloidosis)

Question 146

Primary amyloidosis

Answer 146

Systemic deposition of AL amyloid, which is derived from immunoglobulin light chain. Associated with plasma cell dyscrasias such as multiple myeloma, with overproduction of light chains, which can become misfolded and deposit in tissues.

Question 147

Secondary amyloidosis

Answer 147

Systemic deposition of AA amyloid, which is derived from serum amyloid-associated protein (SAA). SAA is an acute-phase reactant that is increased in chronic inflammatory states (eg, SLE, RA, Crohn's, UC), malignancy, and Familial Mediterranean Fever. Increased SAA can convert into AA and deposit in tissues.

Question 148

Familial Mediterranean Fever (FMF)

Answer 148

FMF is an AR disorder that occurs in persons of Mediterranean origins 2/2 dysfunction of neutrophils. Presents with episodes of fever and acute serosal inflammation, mimicking appendicitis, arthritis, myocardial infarction. High SAA during attacks deposits as AA amyloid in tissues.

Question 149

Systemic amyloidosis

Answer 149

Amyloid is a misfolded protein that deposits in extracellular space in beta-pleated sheet. Congo red staining and apple green birefringence. Classic findings are nephrotic syndrome as kidney is the most common organ involved. Restrictive cardiomyopathy or arrhythmia if amyloid deposits in heart. Tongue enlargement, malabsorption (bowel wall thickening 2/2 amyloid), hepatosplenomegaly. Dx requires tissue bxp (usually abdominal fat pad and rectum are easily accessible for bxp). Damaged organs must be transplanted.

Question 150

Arachidonic acid metabolites

Answer 150

1. Phospholipase A2 releases arachidonic acid from the phospholipid cell membrane. AA is acted upon by cyclooxygenase (COX) or 5-lipoxygenase (5-LPO). 2. COX produces prostaglandins PGD2, PGE2 (mediates fever and pain), and PGI2, leading to vasodilation of arterioles and increased vascular permeability of the post-capillary venule. 3. 5-LPO produces leukotrienes LTB4 (attracts and activates neutrophils), LTC4, LTD4, LTE4, which are the slow reacting substances of anaphylaxis, mediating vasoconstriction, bronchospasm, and increased vascular permeability. * *****************************

Question 151

What mediates fever and pain in inflammation?

Answer 151

1. PGE2 --> fEver and pain are mediated by PGE2 2. Bradykinin mediates pain 3. PGE2 and bradykinin sensitize sensory nerve endings, predisposing to pain. 4. Pyrogens from bacteria cause macrophages to release IL-1 and TNF, which increase COX activity in perivascular cells of hypothalamus. Increased PGE2 raises temperature set point. * *****************************

Question 152

What are the mediators of the delayed response of anaphylaxis?

Answer 152

The delayed response of anaphylaxis involves production of arachidonic metabolites LTC4, LTD4, and LTE4, which mediate vasoconstriction, bronchospasm, and increased vascular permeability, thus maintaining the acute inflammatory response (histamine granules released from mast cells). Essentially they contract smooth muscle in the blood vessels, smooth muscle in the bronchioles, and the pericytes in the post-capillary venules, which have the contractile fxn of smooth muscle and open up space in between endothelial cells, leading to vascular permeability.

Question 153

What are the four main mediators that attract and activate neutrophils?

Answer 153

1. LTB4 2. C5a 3. IL-8 4. Bacterial products * *****************************

Question 154

What activates mast cells?

Answer 154

Mast cells are widely distributed throughout connective tissue. They are activated by (1) tissue trauma, (2) complement proteins C3a and C5a, or (3) cross-linking of cell-surface IgE by antigen.

Question 155

Hageman factor

Answer 155

Hageman factor is Factor XII. It's an inactive pro-inflammatory protein produced in the liver. Factor XII is activated by exposed subendothelial collagen, and in turn activates coagulation and fibrinolytic systems, complement, and the kinin system. Kinin cleaves high-molecular weight kininogen (HMWK) to bradykinin, which mediates vasodilation, increased vascular permeability, and pain. Plays an important role in DIC caused by severe gram negative sepsis.

Question 156

What are the pathways that activate inactive complement precursors?

Answer 156

1. Classical pathway: C1 binds IgG or IgM that is bound to antigen. "GM makes CLASSIC cars." 2. Alternative pathway: microbial products or surface molecules directly activate complement C3. 3. Mannose-binding lectin (MBL) pathway: MBL binds to mannose (or other sugars) on microorganisms and activates complement C1-like complex. 4. All pathways results in production of C3 convertase (mediates C3-->C3a and C3b), C3b produces C5 convertase (mediates C5-->C5a and C5b). C5b complexes with C6-C9 to form the membrane attack complex (MAC), which lyses microbes by creating a hole in the cell membrane. 5. C5a is a chemotactic for neutrophils and a mast cell activator. 6. C3b is an opsonin for phagocytosis, tagging cells/organisms for phagocytosis. * *****************************

Question 157

Azotemia

Answer 157

Accumulation of nitrogenous waste products in the blood, leading to an elevation in BUN

Question 158

Neutrophil invasion into inflamed tissue (aka Leukocyte adhesion cascade)

Answer 158

1. Step 1- Margination: vasodilation slows blood flow in postcapillary venules, leading cells to marginate from the center of flow to the periphery. Additionally, increased vascular leakage leads to hemoconcentration and decreased wall shear stress. 2. Step 2- Rolling: histamine mediates P-selectin release from Weibel-Palade bodies, TNF and IL-1 upregulate E-selectin on endothelium. E- and P-selectins loosely bind sialyl Lewis X and PSGL-1 (sialylated glycoproteins) on neutrophils, causing slow rolling of neutrophils along vessel wall. 3. Step 3- Adhesion (and Crawling): TNF and IL-1 also upregulate ICAM and VCAM on endothelium. C5a and LTB4 upregulate integrins on neutrophils. Sampling of chemokines secreted from inflamed tissue activates these interns by inducing a conformational change needed to bind. Interactions between CAMs on endothelium and CD18 β2-integrins (Mac-1 and LFA-1) allows for firm adhesion of leukocytes to BV endothelium. 4. Step 4- Transmigration and chemotaxis: neutrophils are attracted by bacterial products, IL-8, C5a, and LTB4. Transmigrate across endothelium of postcapillary venules and move towards chemoattractants. Neutrophils migrate by squeezing in between endothelial cells via integrin attachments to PECAM-1 (platelet endothelial cell adhesion molecule), which are found primarily at peripheral intercellular junctions of endothelial cells. 5. Step 5- Phagocytosis: enhanced by opsonins (IgG, C3b). Pseudopods extend from leukocytes to form phagosomes, which are internalized and merge with lysosomes to produce phagolysosomes. 6. Step 6- Destruction of phagocytosed material: O2-dependent killing is most effective mechanism. HOCl (bleach) generated by oxidative burst (NADPH oxidase) in phagolysosomes. O2-independent killing less effective than O2-dependent killing and occurs via enzymes present in leukocyte secondary granules (eg, lysozyme in macrophages, major basic protein in eosinophils). 7. Step 7- Resolution: neutrophils undergo apoptosis and disappear w/i 24 hours after resolution of inflammatory stimulus. * *****************************

Question 159

O2-dependent killing

Answer 159

1. O2 -----------> O2* (NADPH oxidase, uses NADPH) 2. O2*----------> H2O2 (superoxide dismutase) 3. H2O2-------> HOCl (myeloperoxidase) 4. MPO is a blue-green heme-containing pigment that gives sputum its color. * *****************************

Question 160

Outcomes of macrophage presence in acute inflammation

Answer 160

1. Resolution and healing: M0s secrete anti-inflammatory cytokines (IL-10 and TGF-beta) 2. Continued acute inflammation: M0s recruit additional neutrophils by secreting IL-8 with persistent pus formation. 3. Abscess: continued acute inflammation surrounded by fibrosis, M0s mediate fibrosis via fibrogenic growth factors and cytokines. 4. Chronic inflammation: M0s present antigen (MHC class II) to activate CD4+ helper T-cells and promote chronic inflammation. * *****************************

Question 161

CD4+ T-cell activation

Answer 161

1. Extracellular antigen is phagocytosed, processed, and presented by APCs on MHC Class II. 2. TCR complex (TCR and CD3) recognizes antigen presented on MHC Class II and binds. 3. B7 (CD80/86) on APC (eg, M0s) binds CD28 on CD4+ T-helper cell, providing a 2nd activation signal. 4. After activation signal, APC secretes either IL-12 or IL-4 to differentiate T-helper cell into Th1 or Th2. 4. Activated CD4+ T helper cells secrete cytokines that promote inflammation in 2 subsets: 5. Th1 CD4+ cells: secrete IFN-gamma, IL-2 6. Th2 CD4+ cells: secrete IL-4, IL-5, IL-10, IL-13 * *****************************

Question 162

What cytokines do Th1 CD4+ cells secrete and what are their role?

Answer 162

1. IFN-gamma: stimulates macrophages, promotes B-cell class switching from IgM to IgG, inhibits Th2 cell phenotype and promotes Th1 phenotype. 2. IL-2: T-cell growth factor and CD8+ T-cell activator * *****************************

Question 163

What cytokines do Th2 CD4+ cells secrete and what are their role?

Answer 163

1. IL-4: promotes B-cell class switching to IgE and IgG 2. IL-5: promotes B-cell class switching to IgA, eosinophil chemotaxis and activation, promotes maturation of B-cells to plasma cells. 3. IL-10: inhibits Th1 phenotype, attenuates inflammatory response. 4. IL-13: also promotes B-cell class switching to IgE * *****************************

Question 164

CD8+ cytotoxic T-cell activation

Answer 164

1. Intracellular antigen (derived from proteins in cytoplasm) is processed and presented on MHC Class I. 2. IL-2 from CD4+ Th1 cells provides 2nd activation signal. 3. Cytotoxic killing occurs via secretion of perforin and granzyme. Perforin creates pores that allow granzyme to enter target cell, activating apoptosis. 4. CD8+ cells can also express FasL, which will bind to Fas on target cells and activate apoptosis. * *****************************

Question 165

B-cell activation

Answer 165

1. Immature B-cells produced in BM and undergo Ig rearrangements to become naive B cells that express IgM and IgD. 2. B-cell activation occurs via Ag binding by surface IgM and IgD, resulting in maturation to IgM or IgD secreting plasma cells. 3. B-cell presents Ag to CD4+ helper T cells via MHC class II. CD40 receptor on B cells binds CD40L on helper T cell, providing second signal. Th1 CD4+ cell then secretes IL-4 and IL-5, mediating B-cell isotype switching, hypermutation, and maturation to plasma cells. * *****************************

Question 166

Granuloma

Answer 166

1. An aggregation of "epitheloid histiocytes" (activated M0s with abundant pink cytoplasm) usually surrounded by giant cells and a rim of lymphocytes. 2. Noncaseating granulomas lack central necrosis (eg, reaction to foreign material, sarcoidosis, beryllium exposure, Crohn's disease, cat scratch disease (stellate-shaped noncaseating granulomas in neck). 3. Caseating granulomas exhibit central necrosis and are characteristic of tuberculosis and fungal infections. * *****************************

Question 167

Steps of granuloma formation

Answer 167

1. M0s process and present antigen via MHC class II to CD4+ helper T cells. (B7 and CD28 provide 2nd signal). 2. Interaction leads to M0s secreting IL-12, which induces CD4+ helper T cell to differentiate into Th1 subtype. 3. Th1 cells secrete IFN-y, which converts M0s to epithelioid histiocytes and giant cells. 4. Th1 secrete IL-2, which activates and promotes growth of CD8+ T-cells. 5. Same process in both caseating and non-caseating granulomas. * *****************************

Question 168

Severe Combined Immunodeficiency (SCID)

Answer 168

1. Defective cell-mediated (T-cell) and humoral (B-cell) immunity with various etiologies. 2. Cytokine receptor defects - cytokine signaling necessary for proliferation and maturation of B and T cells. 3. Adenosine deaminase (ADA) deficiency - ADA necessary to dominate adenosine and deoxyadenosine for excretion as waste products in the urea cycle; buildup of adenosine and deoxyadenosine is toxic to lymphocytes. 4. MHC class II deficiency - MHC class II is necessary for CD4+ helper T cell activation and cytokine production. 5. SCID is characterized by susceptibility to fungal, viral, bacterial, and protozoal infections, including opportunistic infections and live vaccines. 6. Tx is sterile isolation and stem cell transplantation (hematopoietic stem cells can regenerate cells without ADA deficiency/ MHC class II deficiency) * *****************************

Question 169

X-linked agammaglobulinemia

Answer 169

1. Bruton's agammaglobulinemia, x-linked disorder 2. Complete lack of immunoglobulin due to disordered B-cell maturation. 3. A mutated Bruton tyrosine kinase (BTK gene) prevents pre- and pro-B cells from maturing to naive B cells, therefore preventing their eventual maturation to plasma cells. 4. Presents after 6 months of life (maternal IgG antibodies protect during first 6 months) with recurrent bacterial, enterovirus (eg, polio, coxsackievirus), and Giardia lamblia infections. 5. Absent B cells in peripheral blood, decreased Ig of all classes. Absent/scanty LNs and tonsils. 6. Lack of IgG leads to inability to opsonize bacteria properly. Lack of IgA leads to inability to protect against mucosal infections of the IG tract (such as enterovirus or Giardia) 7. Live vaccines (eg, polio) must be avoided. * *****************************

Question 170

Common Variable Immunodeficiency (CVID)

Answer 170

1. Low immunoglobulin due to B-cell (produce Ig) or helper T-cell defects (CD4+ T-cell required to make IL-4 and IL-5 to produce Ig and mature B-cells to plasma cells). 2. Increased risk for bacterial, enterovirus, Giardia lambda infections, usually in late childhood. May be asymptomatic. 3. Increased risk for autoimmune disease and lymphoma. * *****************************

Question 171

IgA deficiency

Answer 171

1. Most common immunoglobulin deficiency disorder 2. Low serum and mucosal IgA 3. Increased risk for mucosal infection, especially viral, however, most patients are asymptomatic. 4. Associated with Celiac disease (HIGH YIELD) * *****************************

Question 172

Hyper-IgM syndrome

Answer 172

1. Characterized by elevated serum IgM levels, due to mutated CD40L (on Th2 cells) or CD40 receptor (on B cells). 2. Second signal cannot be delivered to T-helper cells during B-cell activation. IL-4 and IL-5 are not produced by Th2 cell, which are necessary for Ig class switching. 3. Results in low IgA (predisposing to mucosal infections), low IgE, and low IgG, resulting in recurrent pyogenic infections due to poor opsonization, especially at mucosal sites. 4. However, primary method for activating B-cells remains intact, where IgM on immature B-cell encounters antigen and is activated to create an IgM plasma cell. 5. Therefore, high IgM serum levels and low IgA, IgE, IgG. * *****************************

Question 173

Wiskott-Aldrich Syndrome

Answer 173

1. Rare x-linked recessive mutation of Wiskott-Aldrich Syndrome protein (WASp) gene, which codes for a cytoplasmic protein expressed exclusively in hematopoietic cells that functions in cytoskeleton polymerization and signaling. 1. Wiskott-Aldrich triad = thrombocytopenia (petechiae on skin, mucosal membrane bleeding, epistaxis, bloody diarrhea), eczema, and immunodeficiency (variety of recurrent infections due to defective cellular (T) and humoral (B) immunity). 2. Recurrent bacterial infections develop by three months. 3. Enlargement of the spleen not uncommon, b/c spleen must destroy defective small platelets. 4. Majority of WAS children develop at least one autoimmune disorder, and cancers (mainly lymphoma and leukemia) develop in up to a third of patients. 5. Bleeding is a major cause of death. * *****************************

Question 174

C5-C9 complement deficiencies

Answer 174

Increased risk for Neisseria infection

Question 175

C1 inhibitor deficiency

Answer 175

1. Results in hereditary angioedema, which is characterized by edema of the skin (especially periorbital) and mucosal surfaces. 2. C1 inhibitor helps control C1. If deficient, C1 is over activated leading to over activation of complement, which leads to vasodilation, edema and vascular permeability. * *****************************

Question 176

Lymph node drainage of: 1. Head and neck 2. Lungs 3. Trachea and esophagus 4. Upper limb, breast, skin above umbilicus 5. Liver, stomach, spleen, pancreas, upper duodenum 6. Lower duodenum, jejunum, ileum, colon to splenic flexure 7. Colon from splenic flexure to upper rectum 8. Lower rectum to anal canal above pectinate line, bladder, vagina (middle third), cervix, prostate 9. Testes, ovaries, kidneys, uterus 10. Anal canal (below pectinate line), skin below umbilicus (except popliteal area), scrotum, vulva 11. Dorsolateral foot, posterior calf

Answer 176

1. Cervical LNs: drains head and neck 2. Hilar LNs: lungs 3. Mediastinal LNs: trachea and esophagus 4. Axillary LNs: upper limb, breast, skin above umbilicus 5. Celiac LNs: liver, stomach, spleen, pancreas, upper duodenum 6. Superior mesenteric LNs: lower duodenum, jejunum, ileum, colon to splenic flexure 7. Inferior mesenteric LNs: colon from splenic flexure to upper rectum 8. Internal iliac LNs: lower rectum to anal canal above pectinate line, bladder, vagina (middle third), cervix, prostate 9. Para-aortic LNs: testes, ovaries, kidneys, uterus 10. Superficial inguinal LNs: anal canal (below pectinate line), skin below umbilicus (except popliteal area), scrotum, vulva 11. Popliteal LNs: dorsolateral foot, posterior calf * *****************************

Question 177

Lymphatic drainage?

Answer 177

1. Right lymphatic duct drains right side of body above diaphragm. 2. Thoracic duct drains everything else into junction of left subclavian and internal jugular vein. * *****************************

Question 178

Which part of the LN enlarges in an extreme cellular immune response (eg, viral infection)?

Answer 178

1. Paracortex 2. Houses T cells. Region of cortex between follicles and medulla. 3. Not well developed in DiGeorge syndrome patients. * *****************************

Question 179

Where are reticular cells and macrophages located in the lymph node?

Answer 179

Located in the medullary sinuses of the medulla. Communicate with efferent lymphatics.

Question 180

Splenic sinusoids

Answer 180

Long, vascular channels in red pulp with fenestrated "barrel hoop" membrane. Reticular fibers hold "barrels" together. RBCs squeeze through fenestrations.

Question 181

Post splenectomy

Answer 181

1. Decreased IgM, decreased complement activation, decreased C3b opsonization, increased susceptibility to encapsulated organisms. 2. Howell-Jolly bodies (nuclear remnants) 3. Target cells 4. Thrombocytosis (loss of sequestration and removal) 5. Lymphocytosis (loss of sequestration) * *****************************

Question 182

Encapsulated organisms

Answer 182

1. Please SHINE my SKiS: 2. Pseudomonas aeruginosa 3. Streptococcus pneumoniae 4. Haemophilus Influenzae type b 5. Neisseria meningitides 6. Escherichia coli 7. Salmonella 8. Klebsiella pneumoniae 9. Group B Streptococci * *****************************

Question 183

Where are T-cells, B-cells, and M0s located in the spleen?

Answer 183

1. T-cells are located within the Periarteriolar Lymphatic Sheath (PALS) in the white pulp. 2. B-cells are located within follicles in the white pulp. 3. Macrophages and specialized B-cells are located within the marginal zone, between the red and white pulp. This is where APCs capture blood-borne antigens for recognition by lymphocytes. M0s removed encapsulated bacteria in spleen. * *****************************

Question 184

Thymus

Answer 184

1. Located in anterosuperior mediastinum. 2. Site of T-cell differentiation and maturation. 3. THymus derived from THird pharyngeal (branchial) pouch. 4. Cortex is dense with immature T cells, medulla is pale with mature T cells and Hassall corpuscles containing epithelial reticular cells. 5. Hypoplastic in DiGeorge syndrome and SCID. 6. Enlarged in myasthenia gravis. * *****************************

Question 185

Innate immunity

Answer 185

1. Neutrophils, macrophages, monocytes, dendritic cells, NK cells (lymphoid origin), complement 2. Nonspecific response to pathogens. Occurs within minutes to hours. 3. Lysozyme, complement, C-reactive protein (CRP), defense's. 4. TLRs recognize Pathogen-Associated Molecular Patterns (PAMPs) such as LPS (gram - bacteria), flagellin (bacteria), nucleic acids (viruses) * *****************************

Question 186

Adaptive immunity

Answer 186

1. T cells, B cells, circulating antibodies 2. Variation through V(D)J recombination during lymphocyte development. 3. Highly specific response, refined over time, memory response faster and more robust. 4. Immunoglobulins 5. Memory cells = activated B and T cells; subsequent exposure to a previously encountered antigen creates a stronger, quicker immune response * *****************************

Question 187

Major Histocompatibility Complex (MHC) class I

Answer 187

1. MHC Class I encoded by HLA genes: HLA-A, HLA-B, HLA-C loci 2. Bind TCR complex (TCR + CD3) and CD8 3. Expressed on all nucleated cells (+ platelets). Not expressed on RBCs. 4. Present endogenously synthesized antigens (eg, virus) to CD8+ cytotoxic T cells. 5. Antigen peptides loaded onto MHC I in RER after delivery via TAP (transporter associated with antigen processing) 6. α-chain with peptide-binding groove and associated β-2 microglobulin * *****************************

Question 188

Diseases associated with: 1. HLA-A3 2. HLA-B8 3. HLA-B27 4. HLA-C 5. HLA-DQ2/DQ8 6. HLA-DR2 7. HLA-DR3 8. HLA-DR4 9. HLA-DR5

Answer 188

1. HLA-A3: hemochromatosis 2. HLA-B8: Addison disease, myasthenia gravis 3. HLA-B27: Psoriatic arthritis, Ankylosing spondylitis, IBD-associated arthritis, Reactive arthritis (formerly Reiter syndrome): PAIR - aka seronegative arthropathies 4. HLA-C: Psoriasis 5. HLA-DQ2/DQ8: Celiac disease (I 8 2 much gluten at DQ) 6. HLA-DR2: MS, hay fever, SLE, Goodpasture syndrome 7. HLA-DR3: DM type I, SLE, Graves disease, Hashimoto thyroiditis, Addison disease. 8. HLA-DR4: Rheumatoid arthritis, DM type I, Addison disease (there are 4 walls in a "rheum") 9. HLA-DR5: Pernicious anemia (vitamin B12 deficiency), Hashimoto thyroiditis. * *****************************

Question 189

Major Histocompatibility Complex (MHC) class II

Answer 189

1. MHC Class II encoded by HLA genes: HLA-DP, HLA-DQ, HLA-DR loci 2. Bind TCR complex (TCR + CD3) and CD4 3. Expressed on APCs (M0s, dendritic cells) 4. Present exogenously synthesized antigens (eg, bacterial proteins) to CD4+ helper T cells. 5. Antigen loaded following release of invariant chain in an acidified endosome 6. α-chain and β-chain create peptide-binding groove, associated with invariant chain * *****************************

Question 190

Natural killer (NK) cells

Answer 190

1. Use perforin and granzymes to induce apoptosis of virally infected or tumor cells. 2. Lymphocyte members of innate immune system. 3. Enhanced activity by IL-2, IL-12, IFN-α, IFN-β 4. Kill when exposed to nonspecific activation signal on target cell and/or to absence of class I MHC on target cell surface. 5. Kills via antibody-dependent cell-mediated cytotoxicity (CD16 binds Fc region of bound Ig, activating NK cell). * *****************************

Question 191

Positive selection

Answer 191

1. Thymic cortex 2. T cells expressing TCRs capable of binding self-MHC on cortical epithelial cells survive. * *****************************

Question 192

Negative selection

Answer 192

1. Thymic medulla. 2. T cells expressing TCRs with high affinity for self antigens undergo apoptosis. 3. Tissue-restricted self-antigens are expressed in the thymus due to the action of autoimmune regulator (AIRE); deficiency leads to autoimmune polyendocrine syndrome-1 * *****************************

Question 193

Th1 helper T-cell (CD4+)

Answer 193

1. Secrete IFN-y 2. Activates M0s and cytotoxic CD8+ T cells 3. Induced by IFN-y and IL-12 (secreted by APCs) 4. Inhibited by IL-4 and IL-10 (secreted from Th2 cell) * *****************************

Question 194

Th2 help T-cell (CD4+)

Answer 194

1. Secrete IL-4, IL-5, IL-10, IL-13 2. Recruit eosinophils for parasite defense, promote IgE and IgA production by B cells 3. Induced by IL-4 4. Inhibited by IFN-y (secreted from Th1 cell) * *****************************

Question 195

Cytotoxic T cells

Answer 195

1. Kill virus-infected, neoplastic, donor graft cells by inducing apoptosis 2. Release cytotoxic granules containing preformed proteins (eg, perforin, granzyme B) 3. Cytotoxic T cells have CD8, which binds to MHC class I on virus-infected cells. * *****************************

Question 196

Th17 cell

Answer 196

1. Induced by TGF-β and IL-6 2. Secrete IL-17 3. CD4+ T cell * *****************************

Question 197

T regulatory cells

Answer 197

1. Help maintain immune tolerance by suppressing CD4 and CD8 T-cells 2. Identified by expression of CD3, CD4, CD25, and FOXP3 3. Activated regulatory T cells produce anti-inflammatory cytokines (eg, IL-10, TGF-β) * *****************************

Question 198

Fab region of Ab

Answer 198

1. Fragment, antigen binding 2. Unique antigen-binding pocket; only 1 antigenic specificity expressed per B cell (determines idiotype) 3. Contains variable/hypervariable regions, consists of light and heavy chains * *****************************

Question 199

Fc region of Ab

Answer 199

1. Fc region of IgM and IgG fixes complement. 2. Consists of heavy chains only 3. Macrophage binding region 4. C= Constant, carboxy terminal, complement binding, carbohydrate side chains 5. Determines isotype (IgM, IgD, etc.) * *****************************

Question 200

Generation of antibody diversity

Answer 200

1. Antigen independent 2. Random recombination of VJ (light-chain) and V(D)J (heavy-chain) genes 3. Random addition of nucleotides to DNA during recombination by terminal deoxynucleotide transferase (TdT) 4. Random combination of heavy chains with light chains * *****************************

Question 201

Generation of antibody specificity

Answer 201

1. Antigen dependent 2. Somatic hypermutation and affinity maturation of variable region 3. Isotype switching of constant region * *****************************

Question 202

Immunoglobulin subtypes

Answer 202

1. All isotypes can exist as monomers. 2. Mature naive B cells prior to activation express IgM and IgD on surface. 3. Differentiate in germinal centers of LNs by isotype switching (gene rearrangement; mediated by cytokines and CD40L) into plasma cells that secrete IgA, IgE, IgG. * *****************************

Question 203

IgG

Answer 203

1. Main antibody in secondary/delayed response to antigen 2. Most abundant isotype in serum 3. Fixes complement, crosses placenta (providing infants with passive immunity), opsonizes bacteria, neutralizes bacterial toxins and viruses. * *****************************

Question 204

IgA

Answer 204

1. Prevents attachment of bacteria and viruses to mucous membranes. 2. Does not fix complement. 3. Monomer (in circulation) or dimer (with J chain when secreted). 4. Crosses epithelial cells by transcytosis. 5. Produced in GI tract by Peyer's patches and protects against gut infections (eg, Giardia, enterovirus) 6. Most produced antibody overall, but has lower serum concentrations. 7. Released into secretions (tears, saliva, mucous) and breast milk. 8. Picks up secretory component from epithelial cells, which protects Fc portion from luminal proteases. * *****************************

Question 205

IgM

Answer 205

1. Produced in primary/immediate response to an antigen. 2. Fixes complement. 3. Does not cross placenta. 4. Antigen receptor on surface of B cells. 5. Monomer on B cell, pentamer with J chain when secreted. 6. Pentamer enables avid binding to antigen while humoral response evolves. * *****************************

Question 206

IgD

Answer 206

1. Unclear function. 2. Found on surface of many B cells and in serum. * *****************************

Question 207

IgE

Answer 207

1. Binds mast cells and basophils 2. Cross-links when exposed to allergen, mediating immediate type I hypersensitivity through release of inflammatory mediators like histamine. 3. Mediates immunity to worms (helminths) by activating eosinophils. 4. Lowest serum concentration. * *****************************

Question 208

Acute-phase reactants

Answer 208

1. Serum concentrations change significantly in response to inflammation; produced by liver in both acute and chronic inflammatory states. Induced by 1L-6. 2. C-reactive protein 3. Ferritin 4. Fibrinogen 5. Hepcidin 6. Serum amyloid A 7. Albumin (downregulated) 8. Transferrin (downregulated) * *****************************

Question 209

C-reactive protein

Answer 209

Acute-phase reactant upregulated during inflammation that acts as an opsonin. Fixes complement and facilitates phagocytosis. Measured clinically as a sign of ongoing inflammation.

Question 210

Ferritin

Answer 210

Acute-phase reactant upregulated during inflammation. Binds and sequesters iron to inhibit microbial iron scavenging.

Question 211

Fibrinogen

Answer 211

Acute-phase reactant upregulated during inflammation. Coagulation factor, promotes endothelial repair, correlates with ESR.

Question 212

Hepcidin

Answer 212

Acute-phase reactant upregulated during inflammation. Leads to decreased iron absorption by degrading ferroportin and decreased iron release from macrophages. Upregulated in chronic inflammatory states leading to anemia of chronic disease.

Question 213

Serum amyloid A

Answer 213

Prolonged elevation can lead to secondary amyloidosis. Chronically elevated SAA leads to AA deposition in tissues (most often kidneys, heart).

Question 214

Acute-phase reactants that are downregulated during inflammation?

Answer 214

1. Albumin: reduction conserves amino acids for positive acute-phase reactants. 2. Transferrin: internalized by macrophages to sequester iron and inhibit microbial iron scavenging. * *****************************

Question 215

Complement

Answer 215

1. Hepatically synthesized plasma proteins that play a role in innate immunity and inflammation. 2. MAC defends against gram - bacteria. 3. Activated by classic pathway (IgG, IgM), alternative pathway, and mannose-binding lectin (MBL) pathway. 4. C3b = opsonization, helps clear immune complexes 5. C3a, C4a, C5a = anaphylaxis 6. C5a = neutrophil chemotaxis 7. C5b-9 = cytolysis by MAC * *****************************

Question 216

Inhibitors of complement

Answer 216

1. DAF (decay accelerating factor) aka CD55 2. C1 esterase inhibitor 3. Help prevent complement activation on self cells such as RBCs * *****************************

Question 217

Complement disorders

Answer 217

1. C1 esterase inhibitor deficiency: causes hereditary angioedema due to unregulated activation of kallikrein, which increases bradykinin. ACE inhibitors are contraindicated in these patients. 2. C3 deficiency: increases risk of severe, recurrent pyogenic sinus and respiratory tract infections, increased susceptibility to type III hypersensitivity reactions. 3. C5-C9 deficiencies: terminal complement deficiency increases susceptibility to recurrent Neisseria bacteremia. 4. DAF (GPI-anchored enzyme/CD55) deficiency: causes complement-mediated lysis of RBCs and PNH. * *****************************

Question 218

IL-2

Answer 218

IL-2 is secreted by all T cells. Stimulates growth of helper (CD4+), cytotoxic (CD8+), regulatory T cells (CD4+), and NK cells.

Question 219

IL-3

Answer 219

IL-3 is secreted by all T cells. Supports growth and differential of bone marrow stem cells. Functions like GM-CSF.

Question 220

IL-1

Answer 220

IL-1 is secreted by macrophages. Osteoclast-activating factor. Causes fever and acute inflammation. Activates endothelium to express adhesion molecules (ICAM, VCAM). Induces chemokine secretion to recruit WBCs.

Question 221

IL-6

Answer 221

IL-6 is secreted by macrophages. Causes fever and stimulates production of acute-phase reactants (hepcidin, CRP, ferritin, fibrinogen, etc.)

Question 222

IL-8

Answer 222

IL-8 is secreted by macrophages. Major chemotactic and growth factor for neutrophils. "Clean up on IL-8." Neutrophils recruited by M0s to clear infections.

Question 223

IL-12

Answer 223

IL-12 is secreted by macrophages. Induces differentiation of T cells into Th1 cells. Activates NK cells.

Question 224

TNF-alpha

Answer 224

TNF-alpha is secreted by macrophages. Mediates septic shock. Activates endothelium. Causes WBC recruitment, vascular leak. Causes cachexia in malignancy.

Question 225

IFN-y

Answer 225

Interferon-gamma is secreted by NK cells and Th1 cells in response to IL-12 from macrophages. Stimulates macrophages to kill phagocytosed pathogens. Inhibits differentiation of Th2 cells. Activates NK cells to kill virus-infected cells. Increases MHC expression and antigen presentation by all cells.

Question 226

IL-4

Answer 226

IL-4 is secreted by Th2 cells. Induces differentiation of T cells into Th2 cells. Promotes growth of B cells. Enhances class switching to IgE and IgG.

Question 227

IL-5

Answer 227

IL-5 is secreted by Th2 cells. Promotes growth and differentiation of B cells. Enhances class switching to IgA. Stimulates growth and differentiation of eosinophils.

Question 228

IL-10

Answer 228

IL-10 is secreted by Th2 cells. Attenuates inflammatory response. Decreases expression of MHC class II and Th1 cytokines. Inhibits activated macrophages and dendritic cells. Also secreted by regulatory T cells. TGF-beta and IL-10 both atTENuate the immune response.

Question 229

Lactoferrin

Answer 229

Protein found in secretory fluids and neutrophils that inhibits microbial growth via iron chelation.

Question 230

Pyocyanin

Answer 230

Made by Pseudomonas aeruginosa to generate ROS to kill competing microbes.

Question 231

Cell surface proteins present on T cells

Answer 231

1. Helper T cells (Th1, Th2): CD4+, CD40L, TCR (binds Ag-MHC II complex), CD3 (associated with TCR), CD28 (binds B7 on APC) 2. Cytotoxic T cells: CD8+, TCR, CD3, CXCR4/CCR5 (co-receptors for HIV) 3. Regulatory T cells: CD4+, CD25, FoxP3 * *****************************

Question 232

Cell surface proteins present on B cells

Answer 232

1. Ig (binds antigen) 2. CD19 3. CD20 4. CD21 (receptor for EBV): "You can drink Beer at the Bar when you're 21." B cells, Epstein-Barr virus, CD21. 5. CD40 (binds CD40L on Th cells) 6. MHC II * *****************************

Question 233

Cell surface proteins present on M0s

Answer 233

1. CD14 (co-receptor with TLR4 for PAMPs) 2. CCR5 (HIV receptor) 3. MHC II 4. B7 (CD 80/86) 5. Fc and C3b receptors (enhanced phagocytosis) * *****************************

Question 234

Cell surface proteins present on NK cells

Answer 234

1. CD16 (binds Fc of IgG) 2. CD56 (unique marker for NK) * *****************************

Question 235

Anergy

Answer 235

State during which a cell cannot become activated by antigen. T and B cells become anergia when exposed to antigen without costimulatory signal (signal 2). Another mechanism of self-tolerance (in addition to negative selection).

Question 236

Antigenic variation

Answer 236

1. Salmonella (2 flagellar variants) 2. Borrelia recurrentis aka relapsing fever 3. N gonorrhoeae (pilus protein) 4. Influenza, HIV, HCV 5. Trypanosomes 6. Mechanisms for variation include DNA rearrangement and RNA segment reassortment (eg, influenza major shift) * *****************************

Question 237

Passive immunity

Answer 237

1. Receiving preformed antibodies 2. Rapid 3. Short life span of antibodies (half-life = 3 weeks) 4. IgA in breast milk, maternal IgG crossing placenta, antitoxin, humanized monoclonal antibody 5. Given after exposure to Tetanus toxin, Botulinum toxin, HBV, Varicella, Rabies virus, unvaccinated patients are given preformed antibodies (passive): "To Be Healed Very Rapidly" 6. Combine passive and active immunizations can be given for hepatitis B or rabies exposure * *****************************

Question 238

Live attenuated vaccine

Answer 238

1. Microorganism loses pathogenicity but retains capacity for transient growth within inoculated host. 2. Induces cellular and humoral (antibodies) responses. 3. MMR is only live attenuated vaccine given to persons with HIV. 4. Induces strong, often lifelong immunity, but may revert to virulent form. 5. Often contraindicated in pregnancy and immunodeficiency. 6. Live attenuated vaccines: BCG, influenza (intranasal), measles, mumps, rubella, polio (Sabin, OPV), varicella zoster, yellow fever. * *****************************

Question 239

Inactivated vaccine

Answer 239

1. Pathogen inactivated by heat or chemicals. 2. Maintaining epitope structure on surface antigens is important for immune response. 3. Mainly induces humoral response. 4. Safer than live vaccines but weaker immune response; booster shots usually required. 5. Inactivated vaccine: Rabies, Influenza (injection), Polio (Salk), hepatitis A. * *****************************

Question 240

Hypersensitivity types

Answer 240

1. Type I hypersensitivity - Anaphylactic and Atopic 2. Type II hypersensitivity - Cytotoxic (antibody mediated) 3. Type III hypersensitivity - Immune complex 4. Type IV hypersensitivity - Delayed (cell-mediated) 5. ACID * *****************************

Question 241

Type I hypersensitivity reaction

Answer 241

1. Antibody mediated (types I, II, and III HS rxns are all antibody mediated) 2. Anaphylactic and atopic reactions: free Ag cross-links IgE on presensitized mast cells and basophils, triggering immediate release of vasoactive amines that act at postcapillary venules (i.e., histamine). 3. Reaction develops rapidly after Ag exposure b/c of preformed antibody. 4. Delayed response follows due to production of AA metabolites (eg, leukotrienes C4, D4, E4). 5. Skin tests for specific IgE. 6. Allergic and atopic disorders such as allergic rhinitis, hay fever, eczema, hives, asthma. Anaphylaxis from bee sting or food/drug allergies. * *****************************

Question 242

Type II hypersensitivity reaction

Answer 242

1. Type II is cy-2-toxic. 2. Antibody mediated --> IgM, IgG bind to fixed antigen on "enemy" cell, causing cellular destruction via opsonization and phagocytosis, complement or Fc receptor mediated inflammation, or antibody-mediated cellular dysfunction. 3. Disease tends to be specific to tissue or site where antigen found. 4. Ex. acute hemolytic transfusion reactions, autoimmune hemolytic anemia, bullous pemphigoid, erythroblastosis fetalis (hemolytic disease of the newborn), Graves disease, Goodpasture syndrome, Guillain-Barre syndrome, ITP, myasthenia graves, rheumatic fever. * *****************************

Question 243

Type III hypersensitivity reaction

Answer 243

1. Immune complex = 3 things are stuck together: Antibody-Antigen-Complement 2. Immune complex mediated--> antigen-antibody (IgG) complexes activate complement, which attracts neutrophils that release lysosomal enzymes. 3. Associated with vasculitis and systemic manifestations. 4. Ex. Arthur reaction, SLE, polyarteritis nodosa, PSGN, serum sickness. * *****************************

Question 244

Type IV hypersensitivity reaction

Answer 244

1. 4 T's = T cells, Transplant rejections, TB skin tests, Touching (contact dermatitis) 2. Test with patch test, PPD. 3. Delayed T-cell mediated reaction--> sensitized T cells encounter antigen and release cytokines, leading to macrophage activation. 4. Response does not involve antibodies. 5. Cell-mediated reaction and therefore not transferable by serum. 6. Ex. contact dermatitis (eg, poison ivy, nickel allergy), graft-vs-host disease, multiple sclerosis. * *****************************

Question 245

Autoantibody associated with mixed connective tissue disease?

Answer 245

Anti-U1 RNP (ribonucleoprotein)

Question 246

Autoantibody associated with Celiac disease?

Answer 246

IgA anti-endomysial, IgA anti-tissue transglutaminase (anti-TTG)

Question 247

Autoantibody associated with granulomatosis with polyangiitis (Wegener's granulomatosis)?

Answer 247

PR3-ANCA (c-ANCA)

Question 248

Autoantibody associated with Lambert-Eaton syndrome?

Answer 248

V-gated calcium channel antibodies

Question 249

Autoantibody associated with microscopic polyangiitis?

Answer 249

MPO-ANCA (p-ANCA)

Question 250

Autoantibody associated with rheumatoid arthritis?

Answer 250

Anti-cyclic citrullinated protein (anti-CCP), specific compared to rheumatoid factor. Anti-cyclic citrullinated peptide (anti-CCP) antibodies. Tissue inflammation causes arginine residues in proteins to be enzymatically converted into citrulline. Citrullination can significantly alter protein shape, which serves as antigen for an autoimmune response, exaggerated in RA and resulting in high titers of anti-CCP antibodies not present in other inflammatory conditions. Usually measured by ELISA using mixture of CCPs as antigen.

Question 251

Rheumatoid factor

Answer 251

IgM autoantibody that targets Fc region of human IgG, found in 10% of normal people, 80% of people with RA. Non-specific. Diagnostic utility limited by poor specificity as found in approximately 10% of healthy individuals, 30% of patients with SLE and nearly all pts with mixed cryoglobulinemia.

Question 252

Autoantibody associated with eosinophilic granulomatosis with polyangiitis (Churg-Strauss)?

Answer 252

MPO-ANCA (p-ANCA)

Question 253

Autoantibody associated with Graves disease?

Answer 253

Anti-TSH receptor

Question 254

Autoantibody associated with myasthenia gravis?

Answer 254

Anti-ACh receptor

Question 255

Autoantibody associated with Goodpasture syndrome?

Answer 255

Anti-basement membrane (Anti-GBM)

Question 256

Autoantibody associated with antiphospholipid syndrome?

Answer 256

1. lupus anticoagulant 2. Anti-cardiolipin 3. anti-β2-glycoprotein-I 4. Found in patients with SLE and antiphospholipid antibody syndrome (APLS). APLS causes hypercoagulability, paradoxical prolongation of aPTT and recurrent miscarriages/spontaneous abortions. * ***********

Question 257

Autoantibody associated with Sjögren syndrome?

Answer 257

Anti-SSA, Anti-SSB (anti-Ro, anti-La)

Question 258

Autoantibody associated with autoimmune hepatitis (type I)?

Answer 258

Anti-smooth muscle

Question 259

Autoantibody associated with limited scleroderma (CREST)?

Answer 259

Anti-centromere antibodies

Question 260

Autoantibody associated with pemphigus vulgaris?

Answer 260

Anti-desmoglein (anti-desmosome)

Question 261

Autoantibody associated with bullous pemphigoid?

Answer 261

Antihemidesmosome

Question 262

Autoantibody associated with diffuse scleroderma?

Answer 262

Anti-Scl-70 (anti-DNA topoisomerase I)

Question 263

Autoantibody associated with primary membranous nephropathy?

Answer 263

Antiphospholipase A2 receptor

Question 264

Autoantibody associated with pernicious anemia?

Answer 264

Anti-parietal cell

Question 265

Autoantibody associated with SLE (non-specific)?

Answer 265

Antinuclear antibodies (ANA). Nonspecific finding in many connective tissue disorders. ANAs characteristically occur in IgM form in pts with RA but found less frequently than RFs.

Question 266

Autoantibodies associated with SLE (specific)?

Answer 266

Anti-dsDNA, anti-Smith

Question 267

Autoantibody associated with type I DM?

Answer 267

Anti-glutamic acid decarboxylase (GAD-65)

Question 268

Autoantibody associated with drug-induced lupus?

Answer 268

Anti-histone

Question 269

Autoantibodies associated with polymyositis and dermatomyositis?

Answer 269

Anti-Jo-1, anti-SRP, anti-Mi-2

Question 270

Autoantibodies associated with Hashimoto thyroiditis?

Answer 270

Antimicrosomal, antithyroglobulin

Question 271

Autoantibody associated with primary biliary cirrhosis?

Answer 271

Antimitochondrial antibodies

Question 272

Direct vs. Indirect Coombs' test

Answer 272

1. Direct Coombs' test (direct antiglobulin test) : detects antibodies that have adhered to a patient's RBCs (eg, test an Rh+ infant of an Rh- mother, or test for autoimmune hemolytic anemia). 2. RBCs from patient's blood sample are washed (removing patient's own plasma) and then incubated with anti-human globulin ("Coombs reagent"). If this produces agglutination of RBCs, direct Coombs test is positive, a visual indication that antibodies (and/or complement proteins) are bound to the surface of RBCs of patient. 3. Indirect Coombs' test: detects serum antibodies in patient that can adhere to other RBCs (eg, test an Rh- woman for Rh+ antibodies) 4. Serum extracted from patient's blood sample and incubated with RBCs of known antigenicity. If agglutination occurs, indirect Coombs test is positive. Used in prenatal testing of pregnant women and in testing blood prior to a blood transfusion. * *****************************

Question 273

Serum sickness

Answer 273

1. Immune complex disease in which antibodies to foreign proteins (either in antiserum or medications) are produced (takes at least 5 days). 2. Immune complexes form and are deposited in membranes, where they fix complement (leads to tissue damage). 3. More common than Arthus reaction. 4. Most serum sickness is now caused by drugs (not antiserum) acting as haptens. 5. Fever, urticaria, arthralgia, proteinuria, lymphadenopathy occur 5-10 days after antigen exposure. 6. Unlike other drug allergies, which occur very soon after receiving the medication, serum sickness develops 5-14 days after first exposure to a medication. * *****************************

Question 274

Arthus reaction

Answer 274

1. Local subacute antibody-mediated type III hypersensitivity reaction in the skin. 2. Intradermal injection of antigen into a presensitized individual (with circulating IgG) leads to immune complex formation in the skin. 3. Characterized by edema, necrosis, and activation of complement. 4. Arthus reactions have been infrequently reported after vaccinations containing diphtheria and tetanus toxoid. Very rare. 5. Test with immunofluorescent staining. * *****************************

Question 275

Blood transfusion reactions

Answer 275

1. Allergic reaction: type I hypersensitivity reaction against plasma proteins in transfused blood. Urticaria, pruritus, wheezing, fever. Tx with antihistamines. 2. Anaphylactic reaction: severe type I hypersensitivity allergic reaction. IgA-deficient individuals must receive blood products without IgA. Dyspnea, bronchospasm, hypotension, respiratory arrest, shock. Tx with epinephrine. 3. Febrile non-hemolytic transfusion reaction: type II HS reaction. Host antibodies against donor HLA antigens and WBCs. Fever, headaches, chills, flushing. 4. Acute hemolytic transfusion reaction: type II hypersensitivity reaction. Intravascular hemolysis (ABO blood group incompatibility) or extravascular hemolysis (host antibody reaction against foreign antigen on donor RBCs). Fever, hypotension, tachypnea, tachycardia, flank pain, hemoglobinuria (intravascular hemolysis), jaundice (extravascular hemolysis). * *****************************

Question 276

Important differentiating features between colitis-associated carcinoma and sporadic colorectal carcinoma?

Answer 276

1. Colitis-associated carcinoma is more likely to: 2. Affect younger patients 3. Progress from flat and non-polypoid dysplasia; carcinomas tend to be of higher grade or anaplastic. 4. Histologically appear mucinous and/or have signet ring morphology. 5. Develop early p53 mutations and late APC gene mutations, opposite that of sporadic disease 6. Be distributed within the proximal colon (especially wth Crohn's disease or with concurrent primary sclerosing cholangitis) 7. Be multifocal in nature 8. CRC in IBD patients usually develops after 10 years of colitis. Pancolitis associated with the highest risk of CRC. * *****************************

Question 277

Patient being evaluated for persistent cough and pulmonary infiltrate. His blood is added to an anticoagulated tube and placed in ice water. Several minutes late clumping is detected inside the tube, but it rapidly uncoagulates when the tube is warmed by being held. Which organism is most likely responsible?

Answer 277

1. Mycoplasma pneumoniae. 2. Cold agglutinins are antibodies that are produced in response to M. pneumoniae infection. 3. They are directed against antigens in the cell membrane of M. pneumoniae that happen to be homologous antigens that are present on the surface of human erythrocytes. 4. Cold agglutinins cause agglutination (clumping) of RBCs when a sample of blood containing these is chilled. 5. Cold agglutinins are responsible for the transient anemia that can be documented in many patients with a M. pneumoniae infection. 6. Also associated with EBV infection and some heme malignancies. * *****************************

Question 278

Behçet's disease

Answer 278

1. Triad of recurrent aphthous ulcers, genital ulcers, and uveitis. 2. Due to immune complex vasculitis after a viral infection. 3. Etiology unknown. * *****************************