1
Q
Define Humoral Immunity and what is it activated by.
A
- Humoral immunity: antibody responses that act to inactivate microorganisms
- Activated by both T-helper cells and microorganisms themselves (+ products)
2
Q
What are the two ways that B-Cell Activation occurs and what are the activation stages??
A
- T-dependent pathway (shown in picture)
- T-independent pathway
- Activation Stages
- Contact and regcognition of microorganism
- Activations signals through BCR via T-helper
- Antibody Secretion
- Isotype Switching
- Affinity Maturation
3
Q
What is the antigen receptor-mediated signal transduction in B lymphocytes?
- What transcription factors are activated?
A
- Signal transduction activated via phosphorylation of Ig-alpha and Ig-beta – co-stimulatory motifs
- Phorsphorylation cascade leads to activation of transcription factors: Myc, NFAT, NF-(kappa)B, and AP-1
- B-cells can also be activated via toll-like receptors (TLRs) or the complement pathway
4
Q
What are the five consequences of Ig-mediated B-cell activation?
A
- Clonal expansion
- Ability to respond to cytokines produced by helper T cells
- Interaction with helper T cells
- Migration from follicle to T-Cell zone
- Early phase of humoral immune response via secretion of ABs
5
Q
Define isotype in terms of B-cells.
- What process allows for the production of isotypes?
- What is the chain order?
A
- Isotype: heavy chain variations of Igs
- Happens via class-switching, which is regulated by CD40/CD40L
- Chain Order: VDJ – MDGEA (aka Dr. Gea)
- VDJ hypermutations are conserved during class-switching so antigen specificity is preserved
6
Q
Define affinity maturation and what enzyme catalyzes this process?
A
- Affinity maturation: random hypermutations that lead to stronger affinity against antigens via AID
7
Q
Define plasma cell, in terms of B-Cells.
A
- Plasma cell: B-cells that act as antibody secreting factories
8
Q
For T-dependent antigens:
- Primary or secondary response?
- What do they recognize?
- Does affinity maturation occur?
- Are they short-lived or long lived?
- Class switching and hypermutation?
A
- T-dependent antigens
- Secondary response
- Recognizes proteins (linear epitope)
- B-cell acts like APC to create peptide + MHC Class II
- T-helper cell recognizes peptide + MHC Class II and activates B-cell somatic hypermutations and class-switching
- Affinity maturation (see board drawing)
- Long-lived
9
Q
For T-independent antigens:
- Primary or secondary response?
- What do they recognize?
- Does affinity maturation occur?
- Are they short-lived or long lived?
- Class switching and hypermutation?
A
- T-independent antigens
- Primary response
- Recognizes polymeric structures (conformational epitope)
- No need for T-cell activation process – only IgM antibodies produced to label organisms for degradation
- No affinity maturation (see board drawing)
- No class switching/hypermutation
- Short-lived
10
Q
For Primary B-cell response:
- Is it the first exposure or second exposure?
- Is it slower or faster than secondary?
- Is it facilitated via T-dependent or T-independent?
- What B-cells does it utilize?
A
- Primary B-cell response
- First exposure to microorganism/antigen
- Slower, less specific, and in smaller magnitude than 2º
- T-independent response (mainly IgM)
- Utilizes marginal B-cells (in lymph tissue) and B-1 B-cells (in periphery)
11
Q
For Secondary B-cell response:
- Is it the first exposure or second exposure?
- Is it slower or faster than primary?
- Is it facilitated via T-dependent or T-independent?
- What B-cells does it utilize?
A
- Secondary B-cell response (recall response)
- Second exposure to microorganism/antigen
- Faster, more specific, and in greater magnitude due to memory B-cells from 1º
- T-dependent response (increase in IgG and other class-switches)
- Utilizes follicular B-cells (undergo class-switching in germinal centers of lymph nodes)
12
Q
How does negative feedback of B-cells occur?
- What cells facilitate this process?
- What cytokines are released by this cell?
A
- Negative feedback
- T regulatory cells release cytokines that deactivate all lymphocytes
- Cytokine released: IL-10 by T-cells activates ITIM, which blocks signal transduction
13
Q
What are the 3 clinical outcomes of patients with B-cell abnormalities?
A
- Three clinical outcomes of patients with B-cell abnormalities
- Defect in B-cell development
- Excess IgA production
- X-linked hyper IgM
14
Q
What are the three mechanisms used by secreted antibodies to combat infections?
A
- Neutralization of microbes/toxins
- Opsonization and phagocytosis
- Antibody-dependent cellular cytotoxicity
15
Q
What are the 4 isotypes of antibodies and what are their functions?
A
- IgG – neutralizes microbes (too big to enter epithelial barrier) and toxins (prevents engagement with receptors) and triggers opsonization
- IgM – activates classical complement pathway
- IgA – mucosal immunity
- IgE – eosinophil- and mast cell-mediated defense against helminths; allergy
16
Q
What is the role of these complement pathway proteins?
- C3b
- C5b6789
- C5a
- C3a, C4a, C5a
A
- C3b activates macrophages for phagocytosis and opsonization (ROS – NADPH Burst)
- Membrane attack complex (C5b6789) triggers cell lysis by puncturing plasma membrane
- C5a is a chemokine that attracts macrophages and neutrophils to site of infection (follows gradient)
- C3a, C4a, C5a activates basophils and mast cells to release histamine and serotonin → inflammatory response
17
Q
Define opsonization and how does this process occur?
- What receptors are required and what do they bind to?
A
- Opsonization – antibody-mediated phagocytosis that leads to NADPH Burst
- Fc Receptors (FcRs) bind Fc component of ABs to induce pathway
18
Q
Define phagocytosis and how does it occur:
- What receptor is needed and what does it bind to?
A
actin-mediated engulfs foreign objects
- Fc receptor – binds Fc component of AB leading to phagocytosis or activation of cell
19
Q
What is the alternate pathway and how is it initiated?
A
- Alternative pathway
- Initiated via C3 convertase formation in addition to Factor B and D binding
20
Q
What is the classical pathway initiated by?
A
- Classical pathway
- Initiated via antigen-antibody binding
- C1 binds to antibody at the Fc region
21
Q
What is the lectin pathway initiated by?
A
- Lectin pathway
- Initiated via lectin binding mannose residues on foreign cells
22
Q
How is mucosal immunity facilitated?
A
- IgA transport across epithelial barrier to lumen
- IgA dimerizes via linker J chain
- Once secreted into lumen, it binds antigens to inactivate microbes.
23
Q
What are three mechanisms of evasion of humoral immunity by microbes?
A
- Antigenic variation – mutation of antigen-specific sites or variants of surface proteins
- Inhibition of complement pathway – complement-binding proteins expressed by bacteria
- Cell-surface structure for blocking – structures that prevent antibodies from binding (i.e. hyaluronic acid capsules)
24
Q
What are the 5 vaccination types and what are their forms of protection?
A
- Attenuated pathogens
- Antibody response
- Subunit vaccines
- Antibody response
- Conjugate vaccines
- Helper T – Cell dependent antibody response
- Synthetic vaccines
- Antibody Response
- Recombinant viruses and bacteria
- Cell-mediated and humoral immune responses
25
What is paroxysmal nocturnal hemoglobinuria?
* complement-mediated intravascular RBC lysis
* patients may report red or pink urine (from hemoglobinuria)
* Treatment: eculizumab (terminal complement
inhibitor)
26
Early defects in the complement system predispose a patient to:
ICX (immune complex) disease
* Example: Depressed C3 is seen in active Lupus (SLE)
27
Late defects in the complement pathway predispose to:
* Predisposition to Neisseria
* Types of Neisseria
* Meningococcal Meningitis
* Defects in Complement Pathway
* C5b, C6, C7, C8, C9 (any component in MAC)
* Patients with these defects often have reoccurrences because they are unable to use complement pathways to lyse bacteria
28
What type of vaccinations are used to prevent infections? List three vaccines.
* **Bacterial** vaccines must be used to prevent infections
* Haemophilus influenzae, pneumococcal, meningococcal
29
A depressed alternative pathway predisposes to:
* Sepsis
* Defects in C3 ALSO predispose to sepsis
30
For Hereditary Angioedema (HAE),
* What is the Etiology?
* A decrease in what complement protein is seen?
* What sympyoms are seen?
* What is the pathophysiology?
* What is the treatment?
* HAE
* Etiology: decreased C1esterase inhibitor
* Diagnosis: depressed C4 levels
* Systemic swelling
* Contact Pathway: Factor 12 →→→→ bradykinin (all steps are inhibited by C1esterase Inhibitor)
* Increase in bradykinin → vasculature permeability (NO and PGI2) → angioedema
* Treatment: C1esterase Inhibitor
* Epinephrine can only be used histamine-induced angioedema
31
What is the best test for assessing a classical complement deficiency?
* What will the level of this test be if a complement protein is absent?
* CH50 Test
* If a complement component is absent, the CH50 level will be zero; if one or more components of the classical pathway are decreased, the CH50 will be decreased because lysis in the assay will not occur
32
Primary Immunodeficiencies
4 classes
1. Phagocyte dsyfunction
2. B-cell Disorders
3. T-cell Disorder
4. B and T cell Disorders
33
Defects in Phagocyte Dsyfunction
3 Types
1. Chronic Granulomatous Disease
2. Leukocyte Adhesion Defects (LAD)
3. Chediack-Higashi Syndrome
34
Defects in B Cell Development and Function
3 Types
1. X-Linked Gamma Agammaglobulinemia
2. Selective IgA Deficiency
3. Common Variable Immunodeficiency (CVID)
35
Defects in T Cell Development and Function
2 Types
1. DiGeorge syndrome
2. Hyper IgE
36
Defects in T and B Cell Development and Function
4 Types
1. Wiskott-Aldrich Syndrome
2. Hyper-IgM Syndromes
3. SCID
4. Ataxia-Telangiectasia
37
Secondary (Acquired) Immunodeficiency
One example.
HIV/AIDS
38
**Chronic Granulomatous Disease**
Etiology
Pathphysiology
Symptoms/Clinical Charcaterisitcs
Diagnosis
* Etiology: mutations in phagocyte oxidase (NADPH Burst)
* Pathophysiology: inability to kill phagocytosed microbes
* Symptoms: recurrent infections
* Diagnosis: NBT Tests (histological view of macrophage activity)
39
**Leukocyte Adhesion Defects (LAD) (3 types)**
Etiology
Pathphysiology
Symptoms/Clinical Charcaterisitcs
* Overall pathophysiology: failure to recruit leukocytes to sites of infection
* Symptoms: leukocytosis and recurrent infections early in life
* Types
* Type I
* Etiology: mutation in CD18 gene → defect in integrin
* Diagnostic characteristics: delayed umbilical cord separation
* Type II
* Etiology: abnormality in fucosylation (glycosylation of sialyl Lewis X) → defect in sialyl Lewis X → required for leukocyte-endothelium binding
* Diagnostic characteristics: severe mental/growth retardation
* Type III
* Etiology: mutation in KINDLIN-3 gene → defective platelet aggregation
* Diagnostic characteristic: excessive bleeding
40
**Chediack-Higashi Syndrome**
Etiology
Pathphysiology
Symptoms/Clinical Charcaterisitcs
* Etiology: mutation in LYST gene
* Pathophysiology: defective phagosome-lysosome fusion
* Symptoms: recurrent infections and giant lysosomes in leukocytes
* Diagnostic characteristic: albinism
41
**Defects in TLR Pathways**
Etiology
Pathphysiology
Symptoms/Clinical Charcaterisitcs
* TLR3 mutations →→ herpes simplex encephalitis
* NEMO (NF-kB Essential Modulator) → ectoderm defects → lack of sweating
42
**Severe Combined Immunodeficiencies (SCID)**
**(4 Types)**
Etiology
Pathphysiology
Symptoms/Clinical Charcaterisitcs
* Pathophysiology: impaired T cell development with or without impaired B cell or NK cell development
* Symptoms:
* Infections by live attenuated vaccines (chicken pox, MMR)
* Skin rash via maternal graft (graft-versus-host reaction)
* Diagnosis: TREC Assay (absence of TREC = absence of T cells = SCID)
* Types
* DiGeorge Syndrome
* Etiology: 22q11 deletion
* Diagnostic characteristics: defective parathyroid glands/thymus and facial deformities
* ADA Deficiency (adenosine deaminase)
* Etiology: mutation in adenosine deaminase (purine salvage pathway)
* Diagnostic characteristics: reduction of lymphocyte numbers
* X-linked SCID
* Etiology: mutations in interleukins
* Absence of V(D)J Recombination
* Etiology: mutations in NHEJ pathway → lack of specificity for epitopes
43
**X-Linked Gamma Agammaglobulinemia**
Etiology
Pathphysiology
Symptoms/Clinical Charcaterisitcs
* Etiology: mutations in Bruton Tyrosine Kinase
* Pathophysiology: failure of B cell maturation past pre-B
* Diagnostic characteristic: no germinal centers in lymph nodes
44
**Selective IgA Deficiency**
Etiology
Pathphysiology
Symptoms/Clinical Charcaterisitcs
* Pathophysiology: IgA deficiency (important in mucosal regions)
* Symptoms: increased incidence of respiratory and GI infections
45
**Common Variable Immunodeficiency (CVID)**
Etiology
Pathphysiology
Symptoms/Clinical Charcaterisitcs
* Pathophysiology: low IgG, IgA, IgM
* Diagnostic characteristics: low IgG leads to impaired antibody response to vaccines
46
**X-Linked Hyper-IgM Syndrome**
Etiology
Pathphysiology
Symptoms/Clinical Charcaterisitcs
* Etiology: mutations in CD40L (CD154) gene
* Pathophysiology: defect in class-switching; low levels of all Igs except IgM
* Symptoms: severe and frequent infections
47
**Wiskott-Aldrich Syndrome**
Etiology
Pathphysiology
Symptoms/Clinical Charcaterisitcs
* Etiology: mutation in WASP
* Pathophysiology: decreased actin polymerization in cytoskeleton
* Symptoms: skin bleeding
48
**Hyper-IgE Syndromes (HIES)**
Etiology
Pathphysiology
Symptoms/Clinical Charcaterisitcs
* Etiology: dominant negative mutation in STAT3 or recessive mutation in DOCK8
* Symptoms: eczema, eosinophilia, two rows of teeth
49
**X-Linked Lymphoproliferative**
Etiology
Pathphysiology
Symptoms/Clinical Charcaterisitcs
* Etiology: mutation in SLAM, SAP, or XIAP
* Pathophysiology: decreased NK and T cell activation
* Diagnostic characteristics: inability Epstein-Barr virus (EBV)
50
**Ataxia-Telangiectasia**
Etiology
Pathphysiology
Symptoms/Clinical Charcaterisitcs
* Etiology: defect in ATM (DNA repair protein)
* Symptoms: abnormal gait and neurological deficits
51
**HIV**
Etiology
Pathophysiology
Symptoms
* Etiology: virus that interacts with chemokine receptors of CD4+ T Cells
* Pathophysiology: reduction of CD4+ T cell counts
* Acute Phase: momentary spike in viral load and reduction of CD4+ cells
* Chronic Phase: clinical latency and asymptomatic
* AIDs: CD4+ cells less than 200 cells/mm3
* Symptoms: tumors and opportunistic infections
52
Recognize the signs and symptoms of clinical anaphylaxis.
* Constitutional Symptoms
* Urticaria (hives), angioedema (swelling)
* Eyes
* Red, watery eyes
* ENT
* Bluish lips, runny nose
* Cardio
* Increased HR, vasodilation
* Respiratory
* Shortness of breath, wheezing
* Neuro
* Altered mental status, sense of doom, fainting
* GI
* Abdominal pain, vomiting, diarrhea
53
Explain the pathophysiology of an anaphylaxis event.
Type I Reaction Sensitization (onset is seconds to minutes)
Allergen → APC → TH2 cell → activates B Cell → IgE ABs → activates mast cells/basophils → mast cell degranulation → release of histamines, cytokines, leukotrienes, prostaglandins
Food allergy causes this response, but food intolerance just causes pain with no antibody response
54
Relate the leukotriene and prostaglandin pathway to hypersensitivity reactions.
Explian each normal pathway and the end result of each pathway..
* PM FAs → arachidonic acid → PGH2 → PGE2 → PGE2 binds to EP-Rs on mast cells and eosinophils → inhibits inflammatory response
* COX1/COX2 are needed for AA to PGH2
* PM FAs → arachidonic acid → LTX4 (variants of leukotrienes) → inflammation
55
What happens in AERD?
Aspirin Exacerbated Respiratory Disease (AERD)
* If you take aspirin, you get COX blocks → inhibition of PGE2 → increased release of LTs from mast cells → increased inflammatory response
* Diagnostic characteristics: acute dyspnea, nasal polyps and nasal inflammation
* Treatment: aspirin desensitization and “–lukast” drugs (leukotriene modifiers)
56
Identify treatment strategies for anaphylaxis.
Intermuscular injection of epinephrine
Acute symptoms: antihistamines
57
In central T lymphocyte tolerance, when an immature T cell has high affinity for self-antigens, two things can happen:
* Negative selection → deletion
* Development of regulatory T cell → suppression
58
In central B cell tolerance (bone marrow), when immature B cell has high affinity for self-antigens, three things can happen:
* Receptor editing: re-expression of recombinase to create new Ig light chains
* Apoptosis: deletion
* Anergic B cell
59
In peripheral T lymphocyte tolerance, when a mature T cell has high affinity for self-antigens,
* What three things can happen?
* What are the way each of these three things happen?
* Anergy → unresponsive T cell due to
* Signaling block: no co-stimulation
* Binding of inhibitory receptor (PD-L1)
* Suppression by Regulatory T cells
* CD4+ cells that express CD25 and FoxP3 (TFs)
* Secrete IL-10 and TGF-B
* Competes for IL-2
* Apoptosis → deletion
* Via intrinsic signals (with no co-stimulation)
* Via death receptors (FasR)
60
In peripheral B cell tolerance, when a mature B cell has high affinity for self-antigens,
* What three things can happen?
* What are the ways that these happen?
* Anergy → no co-stimulation with CD40
* Apoptosis → deletion
* Regulation by inhibitory receptors
61
What gene is mutated in IPEX and what is the result of this mutation?
FoxP3 mutation → few to no Tregs produced → increased immune activity
62
What genes have mutations in Autoimmune Lymphoproliferative Syndrome?
Mutations in genes associated with apoptosis (caspases, Fas)
63
What is the difference between an antigen and immunogen?
* Antigen: any substance recognized by AB or T cell
* Immunogen: antigen capable of eliciting response (all antigens are not immunogens)
64
* What is a live, attenuated vaccine?
* Do they require a booster?
* What are some examples of this?
* Infectious agents have reduced virulence due to mutations or genetic engineering
* Give strongest response and longest protection
* Examples: MMR, chickenpox
65
* What is an inactivated vaccine?
* Do they require boosters?
* What is an example?
* Infectious agents have been killed by fixatives or chemicals so they cannot produce proteins or replicate in cells
* Requires boosters
* Safer than attenuated
* Examples: seasonal influenza vaccines
66
* What are subunit vaccines?
* Do they require boosters?
* What are two examples?
* Contain only a “subunit” or portion of an organism
* Requires boosters
* HPV and HepB
67
* What are conjugate vaccines?
* Do they require a booster?
* What are some examples?
* Vaccine against encapsulated bacteria – conjugates polysaccharide + protein carrier (protein carrier is needed to act as peptide in MHC complex because when bacteria is broken down, this protein subunit can be used as peptide)
* Safe because it lacks infectious agent
* Examples: Neisseria meningitidis, H. flu, and streptococcus pneumoniae
68
* What is the role of adjuvants in the success of vaccines?
* What do they activate?
* What are some examples?
* Adjuvant: any substance that enhances the immune response to an antigen with which it is mixed
* Aluminum salts/gels
* Monophosphoryl lipid A
* Activate PRRs (TLRs, NODs)
69
Herd immunity and neutralization are two immune mechanisms that provide protection after vaccination. How does each work?
* Herd immunity: if most of the population is vaccinated, infections do not spread
* Neutralization
* Neutralizing antibodies: binding prevents infections
* Non-neutralizing antibodies: binding does not prevent infection
* Broadly neutralizing antibodies: recognize a non-specific epitope found in multiple subtypes of a pathogen; the antibody can undergo hyper-mutation to become more specific to each pathogen with time
70
* What is a type A drug reaction?
* Is it predictable?
* What is it dependent on?
* How common are these?
* Most adverse reactions
* Predictable – related to the pharmacological action of drug
* Dose dependent
71
* What is a type B reaction?
* Is it predictable?
* How common are they?
* What are three types of type B reactions?
* Unpredictable – unrelated to known pharmacological action of drugs
* Types of type B reaction
* Intolerance – known side effect at lower dose than expected
* Idiosyncratic – based on how patient metabolizes drug
* Hypersensitivity/allergy/immune mechanisms
72
What is the diagnostic test for a type I hypersensitivity reaction?
skin testing
73
What is the diagnostic test for a type II hypersensitivity reaction?
blood smear for hemolysis
74
What is the diagnostic test for a type III hypersensitivity reaction?
check for equal AB/antigen ratio
75
What is the diagnostic test for a type IV hypersensitivity reaction?
CBC
76
* What happens in a type I hypersensitivity reaction?
* What are some common clinical characteristics?
* What activates this response?
* What effector cells respond?
* What are examples of this reaction?
77
What happens in a type II hypersensitivity reaction?
What are some common clinical characteristics?
What activates this response?
What effector cells respond?
What are examples of this reaction?
78
What happens in a type III hypersensitivity reaction?
What are some common clinical characteristics?
What activates this response?
What effector cells respond?
What are examples of this reaction?
79
What happens in a type IVa hypersensitivity reaction?
What are some common clinical characteristics?
What activates this response?
What effector cells respond?
What are examples of this reaction?
80
What happens in a type IVb hypersensitivity reaction?
What are some common clinical characteristics?
What activates this response?
What effector cells respond?
What are examples of this reaction?
81
What happens in a type IVc hypersensitivity reaction?
What are some common clinical characteristics?
What activates this response?
What effector cells respond?
What are examples of this reaction?
82
What happens in a type IVd hypersensitivity reaction?
What are some common clinical characteristics?
What activates this response?
What effector cells respond?
What are examples of this reaction?
SPM
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