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Immunopathy Flashcards

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1
Q

Components of innate immunity

A
  1. Barriers (skin)
  2. Phagocytes
  3. NK cells
  4. Dendritic cells
  5. Complement
  6. Normal flora
  7. Chemicals (lysosyme, acute phase proteins, lactic acid,cytokines, complement)
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2
Q

Components of Adaptive Immunity

A
  1. T cells
  2. B cells
  3. APCs
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3
Q

Organs of innate vs adaptive immunity

A

Innate:

  • mucosa
  • skin
  • liver (source of acute phase proteins/complement)
  • bone marrow (source of cells)

Adaptive:

  • Bone marrow
  • THymus
  • Lymph nodes
  • Spleen
  • MALTs
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4
Q

Cytokines of Innate immunity

A

IL-1,6,8,10,12,17

TNF alpha and beta

IFN alpha and beta and gamma

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5
Q

Cytokines of Adaptive immunity and cells from which they are released

A

IL-1, 4, 5, 13

Produced by activated T cells

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6
Q

Cytokines of Hematopoiesis

A

IL-3, 7

GM-CSF

G-CSF

M-CSF

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7
Q

Function of IL-1

A

Innate immunity:

  • Cell activation
  • Fever
  • Acut phase proteins
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8
Q

Function of IL-6

A

Innate Immunity

  • Fever
  • Produce Actue phase proteins
  • Activates B and T cells

Released after IL-1 and TNF

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9
Q

Function of IL-8

A

Innate immunity

  • Neutorphil chemotaxis
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10
Q

Function of IL-10 and cells from which it is released

A

Innate immunity: **Induces Humoral Immunity**

  • Suppresses CMI-promoting cytokines (IL-2, 4, 5, 13 I think)
  • Stimulates Th2 differentiation (humoral immunity)

Released from:

  • Treg cells
  • APCs
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11
Q

Function of IL-12 and cells from which it is released

A

Innate Immunity: **Induces Cellular Immunity**

  • activates NK cells
  • Activates Tc cells
  • TH1 polarization (cellular immunity)

Released from:

  • APCs
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12
Q

Function of IL-17 and cells from which it is released

A

Innate Immunity **Proinflammatory**

  • activates neutrophils, fibroblasts, keratinocytes

Released from:

  • TH17 cells
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13
Q

Function of TNF alpha/beta

A

Innate Immunity

  • Like IL-1
  • Chemokine production from macrohpages and endothelial cells
  • Induces class I expression
  • Stimulates tissue factor expression (coagulation cascade)

Other: (TNF-alpha only)

  • Cachexia (mm wasting)
  • Inhibits myocardial contraction and smooth muscle tone –> Hypotension and possible shock
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14
Q

Function of IFN-alpha and -beta

A

Innate Immunity: **anti-viral**

  • Increase class I expression
  • Promotes Th1 polarization
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15
Q

Function of IFN-gamma and cells from which it is released

A

Innate Immunity: **promotes CMI**

  • Class I and II expression
  • Promotes IgG class switch
  • Promotes CMI

Released by:

  • Th1
  • NK cells
  • Tc cells
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16
Q

Function of IL-2 and cells from which it is released

A

Adaptive immunity

  • T cell maturation
  • Activates Tc and NK cells

Released by:

  • activated T cells
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17
Q

Function of IL-4 and cells from which it is released

A

Adaptive Immunity:

  • Promotes IgE isotype switching
  • Activates mast cells and eosinophils
  • Suppresses macrophages

Released by:

  • Activated T-cells
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18
Q

Function of IL-5 and cells from which it is released

A

Adaptive Immunity:

  • Promotes IgA isotype switching
  • Eosinophil maturation

Released by:

  • Activated T cells
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19
Q

Function of IL-13 and cells from which it is released

A

Adaptive Immunity:

  • Promotes IgE production
  • Inhibits proinflammatory cytokine synthesis
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20
Q

Function of IL-3 and cells from which it is released

A

Hematopoiesis:

  • B cell and granulocyte maturation

Released by:

  • T cells
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21
Q

Function of IL-7 and cells from which it is released

A

Hematopoiesis:

  • B and T cell maturation

Released by:

  • fibroblasts
  • bone marrow stromal cells
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22
Q

Function of GM-CSF

A

Hematopoiesis:

Maturation of:

  • Eosinophil
  • neutrophil
  • Monocyte
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23
Q

Function of G-CSF

A

Hematopoiesis:

  • Neutorphil maturation
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24
Q

Function of M-CSF

A

Hematopoiesis:

  • Monocyte maturation
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25
Function of Regulatory cytokines: TGF-beta and IL-10
Inhibit activities of: * Th1 * Th2 * Th17
26
MHC Class I 1. Cell types expressing it 2. Gene clusters and chromosome 3. Structure 4. Size of peptide binding 5. Endogenous/Exogenous pathogens
1. Nucleated cells and platelets 2. Chromosome 6; gene clusters A, B, C 3. Polymorphic alpha chain (3 regions), non-polymorphic ß2 microglobulin 4. binds peptides w/8-10 aa 5. Endogenous
27
MHC Class II 1. Cell types expressing it 2. Gene clusters and chromosome 3. Structure 4. Size of peptide binding 5. Endogenous/Exogenous pathogens
1. APCs 2. Chromosome 6, DP, DQ, DR 3. Polymorphic Alpha and beta chain 4. 10-35 aa 5. Exogenous
28
What is the inheritance pattern of MHC?
* They are inherited intact from each parent * Genes are codominant
29
What HLA alleles are expressed in SLE?
DR2 and DR3
30
What HLA alleles are expressed in RA?
DR4
31
What HLA alleles are expressed in MS?
DR3, DR4, B7
32
What HLA alleles are expressed in Type 1 Diabetes?
DR3, DR4, B8
33
What HLA alleles are expressed in Ankylosing Spondylitis?
B27
34
During antigen processing in the Class I pathway, where do Ag and receptor associate?
In the ER | (intracellular pathogens)
35
During antigen processing in the Class I pathway, where do Ag and receptor associate?
In Vesicles | (Exogenous pathogens)
36
Response of Ag binding to TLRs
37
Which TLR binds lipopeptides?
TLR 1
38
Which TLR binds peptidoglycan, lipoteichoic acid, fungal wall components?
TLR 2
39
Which TLR binds dsRNA from viruses?
TLR 3
40
Which TLR binds LPS?
TLR 4
41
How to distinguish NK cells from T cells?
NK don't have TCR/CD3 complexes NK has Fc receptor CD16
42
What is the role of CD16 in NK cells?
It is the Fc receptor Function: Antibody-dependent cell-mediated cytotoxicity (ADCC)
43
What are the inhibitory receptors present on NK cells and what do they engage?
Receptors: * CD 94 * Killer cell Ig-like receptors Engage Clss I proteins on normal cells
44
What do activating receptors of NK cells bind?
Infected or tumor cells
45
Which cytokines enhance NK activity? From which cell type are they secreted?
Enhanced by: * IL-12 (promotes IFN-gamma) * IL-15 (proliferation) * IFN-gamma * IL-1 * IL-2 IL-12 and -15 are secreted by macrophages
46
How do NK cells lyse targets?
Perforin and granzymes --\> apoptosis
47
Function of NKT cells and Ag type recognized
Kill cells expressing lipid Ags and promote CMI/Ab production Ags: lipid/glycolipid Ag
48
Cellular vs Humoral immunity summary
49
Th1 cells * What cytokine induces polarization? * What cytokines are released? * What type of immunity is stimulated?
* What cytokine induces polarization? * IL-12 * What cytokines are released? * IL-2 * TNFß * IFN-gamma * What type of immunity is stimulated? * CMI
50
Th2 Cells * What cytokine induces polarization? * What cytokines are released? * What type of immunity is stimulated?
* What cytokine induces polarization? * IL-10 * What cytokines are released? * IL-4, IL-13 --\> IgE * IL-5 --\> IgA * IFN-gamma --\> IgG * What type of immunity is stimulated? * Humoral Immunity
51
Ig that functions as the B cell Ag receptor
IgM
52
Ig that can cross the placenta and is found in breast milk
IgG
53
IgG isotype that cannot opsonize
IgG2
54
Ig that is monomeric or pentameric, can opsonize and activate complement
IgM
55
Ig that gives mucosal immunity
Dimeric IgA (secretory)
56
Ig in which most are bound to mast cells
IgE
57
Where is MALT located? (tissue levels and organs)
Tissues: * Lamina propria * Submucosa Organs: * Tonsils * Adenoids, Peyer's patches
58
Characteristic cells of MALT
M cells: mediate Ag entry Plasma cells: secrete IgA
59
Free cells of MALT
* Lamina propria lymphocytes (activated CD4 cells) * B cells/Plasma cells (secrete IgA) * Transepithelial lymphocytes (CD8)
60
What percentage of WBCs are lymphocytes?
25-30%
61
Where do NKT cells mature?
Thymus
62
Cell surface proteins on B cells: 1. Adhesion 2. Signal Transduction 3. Ag Presenting 4. Ag Processing
1. Adhesion * ICAM 1 (bind LFA--1 on T cells) * LFA3 (binds CD2 on T cells 2. Signal Transduction * CD40 (binds CD40L on T cells) * B7 (binds CD28 on T cells) * CD21 (complement receptor) 3. Ag Presenting * MHC II 4. Ag Processing * Fc receptors
63
Cytokines produced by Regulatory B cells
* IL-10 * Supress CMI cytokines * TGF-ß * Inhibit Th1, Th2, Th17 Function: Suppress CMI
64
Cytokines produced by Effector B cells (Be)
* Be-2 cells * IL-2, 4, 6, and TNF-alpha * Activate Tc, NK cells, mast cells, eosinophils, B and T cells * Be-1 cells * IL-12, IFN-gamma, TNF-alpha * Activate Tc cells, Th1 polarization, promote CMI Overall function: stimulate CMI
65
Cytokines that stimulate B cell maturation
IL-3 IL-7
66
Cytokines that stimulate T cell maturation
IL-2 IL-7 Thymic Hormones
67
TCR accessory molecules
CD3 and zeta
68
Cell surface proteins on T cells: 1. TCR 2. Adhesion molecules
1. TCR * CD3 * zeta * CD28 (costimulatory, binds CD80 (B7) on APCs) * CD154 (CD40 L) (binds CD40 on APC) 2. Adhesion * CD2 (binds LFA-3 on APCs) * LFA-1 (binds ICAM-1 on APCs and endothelium)
69
Th1 cells 1. Stimulatory cytokines 2. Inhibitory Cytokines 3. cytokines secreted 4. Function
1. Stimulatory cytokines * IL-12 * IFN-gamma 2. Inhibitory Cytokines: * IL-4 (stimulate Th2) * IL-10 (Stimulate Th2) * IL-13 (secreted by Th2) 3. cytokines secreted * TNFß, IFN-gamma 4. Function * Promote CMI and isotype switch to IgG 1 and 3 (opsonization)
70
Th2 cells 1. Stimulatory cytokines 2. Inhibitory cytokines 3. cytokines secreted 4. Function
1. Stimulatory cytokines * ​​IL-4 * IL-10 2. Inhibitory cytokines * IL-12 (stimulates Th1) 3. cytokines secreted * IL-4, 5, and 13 4. Function * B cell proliferation * Isotype switch * IL-4 and 13: IgE * IL-5: IgA
71
Th17 cells 1. Stimulatory cytokines 2. cytokines secreted 3. Function
1. Stimulatory cytokines * ​​IL-1 * IL-6 * TGF-ß 2. cytokines secreted * ​​IL-17 * IL-22 3. Function * IL-17: recruitment and survival of neutrophils * IL-22: activates keritinocytes/fibroblasts (secrete IL-6 and IL-8) * Tissue inflammation
72
Cytokines that stimulate Tc cell development
* IL-2 * IFN-gamma
73
Cytokines released by Treg cells
* IL-10 * inhibits IL-12 to block Th1 development and CMI * TGF-ß * Inhibits T cell and macrophage activation * IgA production * Stimulates tissue repair (angiogenesis, connective tissue)
74
Percent of WBCs that are Monocytes/macrophages
1-6%
75
Cell surface proteins on Macrophages: 1. Ag processing 2. Receptors
1. Ag processing * MHC I and II * C3b receptor (opsonization) * LFA-1 (binds ICAM-1 on other cells) 2. Receptors: * CD14 (binds LPS-binding protein) * TLRs * Mannose receptors (bind PAMPs) * Hormone receptors
76
Functions of Macrophages
1. Ag processing 2. Control Th1 and Th2 polarization * Secrete IL-12 for Th1 * Secrete IL-10 for Th2 3. CMI 4. Delayed-type hypersensitivity (DTH) 5. Tissue damage/reorganization/healing
77
Interdigitating Dendritic Cells
* After Ag encounter, migrate to draining node where they mature * Express high MHC lvls for Ag presentation Summary: 1. MHC I and II 2. APCs 3. Migratory
78
Follicular Dendritic cells
* Express only MHC I * Not APCs * Non-migratory (stay in 1º and 2º follicles of lymph nodes, spleen and mucosal tissue) * Function: hold immune complexes in mucosal tissue
79
Characteristics of Type I Hypersensitivity 1. Mediated by which Ig? 2. Response by which cell type? 3. Which type of antigen?
1. IgE 2. Th2 3. Soluble
80
In Type 1 sensitivity, which cytokines are released to activate the sequence?
* IL-4: * IL-10: (-) CMI * IL-13: (-) CMI * IL-9: activates mast cells IgE isotype switching, Ab production
81
Cell types associated with Local Type I Rxns and Diseases
* Cells: Mast Cells * Diseases: 1. Utricaria 2. Allergic Rhinitis 3. Asthma 4. Atopic dermatitis 5. Food allergy
82
Cell types associated with Systemic Type I Rxns and Diseases
* Cell Types: Mast cells and Basophils * Diseases: anaphylaxis
83
Mucosal vs Connective Tissue Mast Cells * Products * Granule contents * Location
Mucosal Mast Cells * Products: LTs and PGs (mostly PGD2); Tryptase and chymase * Granules: Chondroitin sulfate * Location: Submucosa of Respiratory tract and Intestines Connective Tissue Mast Cells * Products: PGD2, Tryptase * Granules: Heparin * Location: Skin and Intestines
84
Mast cell activation and Degranulation mechanisms (Picture)
85
Mast cell activation and Degranulation mechanisms (Explanation)
1. PIP2 --\> DAG and Ca2+ --\> PKC --\> Phosphorylates myosin --\> granule-membrane fusion and release 2. High Ca2+ lvls and MAP kinase --\> PLA2 --\> hydrolyses PC to arachidonic Acid 1. AA + COX = PG 2. AA + Lipoxygenase = LT 3. MAP Kinase + G protein --\> adenylate cyclase --\> increased cAMP --\> PKA --\> (-) degranulation Summary: Ca2+ causes degranulation and PG/LT synthesis; cAMP causes inhibition of degranulation
86
Primary Mediators of Type I Rxns
1. Histamine 2. Chemotactic factors (eosinophils and neutrophils) 3. Heparin/Chondroitin sulfate (storage matrices) 4. Proteases (tryptase and chymase) 5. TNF-alpha 6. IL-6
87
H1 vs H2 receptors
1. H1 Receptors * Increased vascular permeability (bronchial endothelial cells) * **Smooth mm contraction** * Increased mucus production 2. H2 Receptors * Smooth mm relaxation (vascular smooth mm) * **Vasodilation** * Increased vascular permeability * Increased mucus production
88
Function of tryptase and chymase
Tryptase * From both mucosal and connective tissue mast cells * Bronchial hyperresponsiveness Chymase * Connective tissue mast cells * Increased mucus production
89
What are the secondary mediators of Type I Rxns?
1. LTs: LTC4, LTD4, LTE4 2. PGs: * PGD2 * PGE2 3. Cytokines * IL-1, IL-6, TNF-alpha: Anaphylaxis/inflammation * IL-4 and -13: Th2 activity * IL-3, -5, GM-CSF: Eosinophil activity * Platelet activating factor: increased venule permeability
90
LT receptors: LT1 vs LT2
LT1 * Increased vascular permeability * Bronchoconstriction LT2 * Endothelial activation * Macrophage activation * Chemokine release
91
Biphasic response of Type I Hypersensitivity: Components of each phase
Phase I: Primary mediators (Histamine, Heparin/Chondroitin Sulfate, Typtase, chymase) Phase II: Secondary mediators, Esosinophils, neutrophils
92
Characteristics of Anaphylaxis
Systemic, non-atopic Type I Rxn * Skin: Pruritus, erythema, Urticaria, angioedema * Vacular: Hypotension and shock * Respiratory: Bronchial obstruction from edema, bronchospasm, hyperexcretion of mucus * Blood: DIC
93
What is pictured? In what reaction can it be present?
Pulmonary Edema Anaphylaxis, Type I Rxn
94
What is pictured? What type of reaction is it?
Urticaria Local non-atopic Type I Rxn
95
What is pictured? What type of reaction is it?
Angioedema (usually involved deep dermis) Local non-atopic Type I Rxn
96
Diagnostic Tests for Type I rxn
1. RIST (sandwich ELISA for IgE concentration) 2. RAST (normal ELISA for specific IgE to allergens): in vitro
97
Define Atopy
An inherited abnormal state of hypersensitivity to an allergen with hyper-reactive target tissues Serum IgE often elevated but not diagnostic
98
Define Peak expiratory flow rate (PEFR)
Brief, forceful exhalation reduced PEFR indicates airway narrowing
99
Define Spirometry
Measures Forced expelled volume (FEV) Indicates extent of airway obstruction
100
Location and Clinical Manifestation of Allergic Rhinitis
Locations: nasal mucosa and conjuctiva Clinical Manifestations * Pale, swollen nasal mucosa with watery secretions * Pruritic, hyperemic conjuctivae * Paroxysmal sneezing * Allergic shiners (lwr eyelid ecchymoses from eye rubbing) * Nasal crease (from nose wiping)
101
Extrinsic vs Intrinsic Asthma * Serum tests * Results of skin test * Family History
Extrinsic: response to allergens * IgE and allergen-related * Elevated serum IgE * Skin tests positive * Family history Intrinsic: Vagal response to irritants * Normal serum IgE * Eosinophilia * Skin test negative * No family history
102
Characteristics of Early bronchial reaction in asthma and mediator cells
* Mast cells and eosinophils * Smooth mm contraction * Vasodilation * Edema * Increased mucous production
103
Characteristics of Late bronchial reaction in asthma and mediator cells
* Eosinophils and neutrophils * Cough produces thick sputum * Thick mucus plugs * smooth muscle hyperplasia and hypertrophy, eventual lumen obstruction (chronic)
104
What is pictured? In which illness is it associated?
Inflammed bronchus of Late Asthmatic Reaction * Thickened basement membrane (left arrow) * Smooth muscle hyperplasia (Bottom arrow) * Increased mucus (top arrow)
105
Characteristics of atopic dermatitis
* Elevated serum IgE * Staph infections common * Acute lesions * vesicular, erythematous, pruritic * weeping and crusting with itching * On **face** and **flexor** regions * Chronic lesions * Dry and scaly * Epidermal hyperplasia and hyperkeratosis
106
What is pictured?
Atopic Dermatitis
107
In Type II Hypersensitivity, 1. What types of Ig are involved? 2. What type of antigen?
1. IgG, IgM 2. bound to cell or matrix \*Causes cellular dysfunction
108
What is MCV?
Mean Corpuscular Volume: Size of RBCs If high = Macrocytic If low = Microcytic
109
What does hemoglobin measure?
Oxygen carrying capacity of the blood
110
What does hematocrit measure? How is it calculated?
Oxygen carrying capacity of the blood Hct% = (RBC count x MCV) / 10
111
Characteristics of hemolytic anemia | (blood labs, symptoms)
Blood: 1. Increased Hemoglobin 2. Bilirubinemia 3. **reticulocytosis** 4. **Spherocytosis** Clinical Symptoms: 1. Jaundice 2. Splenomegaly (filtering RBCs) 3. Fever (platelet release of chemokines upon lysis)
112
What is the process that leads to reticulocytosis in hemolytic anemia?
Decreased O2 in kidney --\> Increased erythropoietin (EPO) --\> erythroid hyperplasia --\> reticulocytosis
113
Erythroblastosis Fetalis 1. Type of hemolytic anemia 2. Associated Ig 3. Treatment 4. Prevention
1. Warm 2. IgG (can cross placenta) 3. Transfusions during third trimester 4. anti-Rh Ab to mother w/i 72 hours after birth of first child Type II Hypersensitivity
114
Ig associated with: 1. Erythroblastosis Fetalis 2. Autoimmune cold HAs 3. Secondary cold HAs 4. Paroxysmal cold HAs
1. IgG 2. IgM 3. IgM 4. IgG
115
Characteristics of Immune thrombocytopenia 1. Ig 2. Counts 3. Clinical features
* Anti-platelet IgG * \<100,000 * Features: * Echymoses and petechiae * Nose bleeds * Hemorrhagic bullae * Anemia (blood loss) * Fever/chills (mediators released following lysis) Type II Hypersensitivity
116
Anti-GBM Nephritis * Type of Hypersensitivity * To what does the Ab bind? * What are the clinical manifestations? * What is the pathological change?
* Type II Hypersensitivity * Ab to type IV collagen of GBM * Acute Nephritic Syndrome 1. Macroscopic hematuria 2. Proteinuria 3. Retention of H2O and Na+ * Edema * HTN * Rapidly Progressive (crescentic) Glomerulonephritis (RPGN) 1. GBM ruptures 2. Crescents of parietal cells 3. Bowman space obliterated
117
Goodpasture's Syndrome * Type of Hypersensitivity * To what does the Ab bind? * What are the clinical manifestations? * What is the pathological change?
* Type II * ABM and GBM * Pulmonary Symptoms/pathology * occurs first 1. Hemoptysis (Pulmonary hemorrhage 2. Dyspnea * Renal Symptoms/pathology * Rapidly Progressive Glomerulonephritis * GBM ruptures (hematuria, proteinuria) * Crescents of parietal cells * Bowman space obliterated
118
Myasthenia Gravis * Type of Hypersensitivity * To what does the Ab bind? * What are the clinical manifestations? * What is the pathological change?
* Type II * ACh receptors (increases endocytosis of receptors) * Clinical: * Muscle weakness * Occurs with Thymoma (thymic hyperplasia) * Path: * Damage to postsynaptic membrane
119
Grave's Disease * Type of Hypersensitivity * To what does the Ab bind? * What are the clinical manifestations? * What is the pathological change?
* Type II * TSH receptor; stimulates production of thyroid hormone * Path/Clinical: * Epithelial hyperplasia (goiter) * Ophthalmopathy involving periorbital edema early followed by fibrosis (bug eyes)
120
Bullous Pemphigoid * Type of Hypersensitivity * To what does the Ab bind? * What are the clinical manifestations? * What is the pathological change?
* Type II * adhesion protiens at dermal-epidermal junction * Path/Clinical * Dermal-epidermal separation by eosinophils/lymphocytes * Fluid-filled blisters
121
Pemphius Vulgaris * Type of Hypersensitivity * To what does the Ab bind? * What are the clinical manifestations? * What is the pathological change?
* Type II * epidermal cell adhesion molecules * Path/Clinical * Acantholysis (lysis of intercellular adhesion sites) * Flaccid blisters that rupture and crust over
122
Pernicious Anemia * Type of Hypersensitivity * To what does the Ab bind? * What are the clinical manifestations? * What is the pathological change?
* Type II * Auto-Abs: * Block binding of B12 to intrinsic factor * Block binding of intrinsic factor to ileal cells * Path: * parietal cell-specific CD4 T cells * Loss of parietal cells * reduced IF * Reduced Acid * Auto-Abs: * reduced IF and B12 * Megaloblastic anemia from imparied hemopoeisis * Clinical: * Bone marrow hypercellular * Gastritis * Demylination with spastic paraparesis
123
What is pictured?
Megaloblastic anemia, Megaloblasts, associated with Pernicious anemia
124
What is pictured?
Spherocytosis, associated with Hemolytic anemia
125
Acute Rheumatic Fever/Heart disease * Type of Hypersensitivity * To what does the Ab bind? * What are the clinical manifestations? * What is the pathological change?
* Type II * ABs to S pyogenes cross-react with heart * **Aschoff's** nodules * inflammatory cells/giant cells surrounding fibrous necrosis * Rheumatic valvular disease (**vegetations**) * cause **murmur** * Exudative inflammation * pericarditis, myocarditis, endocarditis * **Polyarthritis** (neutrophils) * Sydenham's **Chorea** (limbs, facial mm)
126
What is pictured?
Aschoff body, associated with Acute Rheumatic fever
127
Characteristics of Type III Hypersensitivity
* Ab types: IgG, IgM * Immune complex formation, inflammation, tissue damage
128
What is the Arthus reaction?
* Model that explains how immune complexes initiate tissue damage * Immune complexes form * Acomplement activated * Mast cells degranulate * Result: * Vasculitis * Erythema * Edema * Hemorrages
129
Polyarteritis Nodosa * Type of Hypersensitivity * Onset * What are the clinical manifestations? * What is the pathological change?
* Type III * Onset: with infections (HBV, TB, Strep) * Systemic vasculitis that spares pulmonary circulation * Morphology * Necrotizing inflammation * Mixed infiltrate * Fibrinoid necrosis causes vessel wall thickening and occlusion of lumen --\> ischemia * \*\*\***All stages of inflammation occur at same time**\*\*\* * Clinical manifestations: associated with low O2
130
What is pictured?
Polyarteritis nodosa vasculitis w/ occlusion and necrosis of wall
131
Serum Sickness * Type of Hypersensitivity * Onset * What are the clinical manifestations?
* Type III * Onset: follows large dose of high molecular weight compound * Symptoms: 1. Pruritic rash first 2. fever 3. arthritis 4. myalgia 5. GN 6. lymphadenopathy 7. splenomegaly
132
Immue Complex Glomerulonephritis * Type of Hypersensitivity * Common finding of group * Pathogenesis * Clinical Syndromes
* Type III * Granular IC deposits * Path: Either * In situ rxn of Ab w/ Ag * Deposition of circulating IC * Clinical: * Nephritic syndrome (mild proteinuria (\>150mg) * Nephrotic syndrome (extensive proteinuria (\>3.5g) and hematuria
133
Acute Diffuse Proliferative GN * Type of Hypersensitivity * Onset * What is the pathological change? * What are the clinical manifestations?
* Type III, IC-GN * Onset * Post-infectious (strep) * Non-infectious (lupus) * Path: * Diffuse Hypercellularity * Subepithelial deposits = humps * Granular deposits w/immunofluorescence * Clinical: * Children, post-Inf: nephritic syndrome (hematuria, RBC casts, hypocomplementemia) * Others: RPGN/Chronic GN
134
Rapidly Progressive (crescentic) GN * Type of Hypersensitivity * Onset * What is the pathological change? * What are the clinical manifestations?
* Type III, IC-GN * immune-mediated * Path: * Subepithelial ICs * GBM thickened and ruptured * Clinical: * Allows inflammatory cells in urinary space (appear in urine?)
135
Membranous GN * Type of Hypersensitivity * Onset * What is the pathological change? * What are the clinical manifestations?
* Type III, IC-GN * Autoimmune, drug induced, tumor Ags, lupus * Path: * Subepithelial deposits as "spikes" * Thickened, irregular GM that grows over deposits * Universal GBM thickening = "wire loops" * Clinical: * Nephrotic syndrome * Hematuria
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Membranoproliferative GN * Type of Hypersensitivity * Onset * What is the pathological change? * What are the clinical manifestations?
* Type III, IC-GN * Onset: * Type I Primary: Subendothelial immune deposit, mesangial immune deposit * Type II Primary: Intramembranous immune deposit * Secondary: Subendothelial deposits caused by infection/autoimmune disease/neoplasm * Path: * Hypercellularity * GBM thickened with "double contour" * Cell components occur between GBMs "interposed mesangial cell process" * Clinical: * Nephritic or nephrotic syndrome
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What is pictured?
Type II Primary Membranoproliferative GN Intramembranous immune deposits
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What is pictured?
Type I Primary Membranoproliferative GN Subendothelial IC deposits
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What is the difference between type I and type II primary membranoproliferative GN?
Type I: * Subendothelial immune deposits; mesangial immune deposits Type II: * Intramembranous immune deposits
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Two types of Type IV Hypersensitivity (explanation)
Delayed Type Hypersensitivity (DTH) * Kills extracellular microbes * Th1 secrete IFN-gamma to activate Macrophages * Th17 secrete IL-17 and -22 Stimulate neutrophils, fibroblasts, keratinocytes Cell-Mediated Immunity (CMI) * Kills intracellular microbes (viruses) and tumor cells * Th1 secretes IFN-gamma and IL-2 --\> activate Tc and NK cells
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DTH mechanism
Tuberculin-type Hypersensitivity reaction 1. _Sensitization_: initial recognition, produces **memory** Th1 cells 2. _Elicitation phase_: 2nd encounter, **Induration** (vasc. perm. and leakage of fibrinogen 3. Resolution/Chronic inflammation * **Granuloma** formation (epithelioid) and healing by **Fibrosis**
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CMI mechanism
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Allergic Contact Dermatitis
* Type IV DTH hypersensitivity * Elicitation: basophils, eosinophils, monocytes * Symptoms: * Acute: highly pruritic vesicular rash * Chronic: Pruritic, crusty rash * Diagnosis: Patch test * Treatment: corticosterioids
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Mechanisms of cytotoxicity (Tc cells)
1. Granzyme/perforin - apoptosis or necrotic cell lysis 2. Fas Ligand (Tc) - Fas - Apoptosis 3. TNF-ß (lymphotoxin) (Tc) - Apoptosis
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Cytokines that induce Tc maturation
1. Bind Class I MHC w/**IL-2** and **IFN-gamma**: becomes cytolytic 2. **IL-12**: Increases cytolytic activity
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Direct vs Indirect pathway of graft rejection
Direct: * react to MHC on donor cells * Donor dendritic cells most important (MHC I and II, B7) Indirect: * Donor Ag presentation by recipient's dendritic cells
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Characteristics of Hyperacute Graft rejection * Time frame * Cause * Result
* w/i minutes to hours * Pre-existing Abs to MHC or mismatched blood type * Damaged endothelium * **thrombosis** * infarction
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Characteristics of Acute Humoral Graft rejection * Time frame * Cause * Result
* Few days to a couple of weeks * Ab to endothelial Ags * Results: * necrotizing vasculitis (**Thickened vessel wall**) * narrowing of the lumen * infarction
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Characteristics of Acute Cellular Graft rejection * Time frame * Cause * Result
* Not stated * T cell infiltrate responding to foreign Abs * Results: * Endothelial injury * Invasion of tubules * Necrosis
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Characteristics of Chronic Graft rejection * Time frame * Cause * Result
* Months to years * Not stated * Results: * Kidney: fibrosis, tubular atrophy * Vasculature: **Intimal fibrosis**, smooth mm proliferation
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Characteristics of Graft vs Host Disease * Most common in which type of transplant? * Cause * Symptoms * Treatment
* Hematopoietic cell transplant * Donor immune cells mount response to recipient * Symptoms: 1. Rash 2. Jaundice (destroys small bile ducts) 3. Bloody diarrhea (mucosal ulceration) * Treatment: 1. Corticosteroids and cyclosporin 2. use of self stem cells
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Characteristics of Host vs Graft Disease * Most common in which type of transplant? * What is it?
* Hematopoietic cell transplant * Residual NK and T cells in recipient attack transplant
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What are the most likely infections in Prolonged Imunodeficiency?
1. CMV (overall) 2. Adenovirus (children)
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What are the most common diseases that recur after a kidney transplant?
Membranous GN Membranoproliferative GN
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Types of rejection in kidney transplant
1. Acute Cellular 2. Acute Humoral 3. Chronic Rejection * fibrosis * Mononuclear infiltrate * Tubular atrophy
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Characteristics of Chronic rejection in Heart Transplant
* Arteriopathy = narrowing of lumen * Intimal proliferation * Distal epicardial and intramyocardial coronary artery branches
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Common recurrent disease in heart transplants?
Accelerated atherosclerosis
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Types of Rejections in Liver transplants and Characteristics
1. Acute cellular * Portal inflammation * Bile duct injury * Endothelial inflammation in portal/central veins 2. Chronic rejection * Arteriopathy
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Common Recurrent disease in Liver Transplant
1. Hep B 2. Hep C
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Characteristics of Post-transplantation Lymphoproliferative Disorder (PTLD)
* EBV-induced B cell Proliferation * Associated with immunosuppression
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What are long term complications in transplantation?
1. Post-transplantation lymphoproliferative disorder 2. leukemia 3. Hodgkin's and non-Hodgkin's lymphomas 4. Infection
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Function of AIRE
(Autoimmune Regulatory Protein) * stimulates expression of peripheral Ags in thymus for (+)/(-) selection (central tolerance)
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Characteristics of Autoimmune Polyendocrine Syndrome * Cause * Affected systems
* Cause: * mutation of AIRE (central tolerance) * Affected systems: * Endocrine * Skin
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Mechanisms of Peripheral Tolerance in self-reactive cells
1. Induced to be **anergic** by Ag-presentation w/o costimulatory signals 2. Suppressed by **T regs** by cytokine secretion (**IL-10**, **TGF-ß**) 3. Removed by **apoptosis** * Persistent activation * Fas-mediated (T regs)
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What is epitope spreading? What does it cause?
* constant exposure of different, normally hidden, epitopes due to tissue damage * Causes autoimmune disease
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Types of auto-Abs present in Lupus, association with active disease
1. Anti-nuclear 2. Anti-dsDNA (Active disease) 3. anti-RBC (+ COOMBS test) 4. anti-phospholipid
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What is the pathogenesis of Lupus?
Auto-Abs from: 1. Failure of peripheral tolerance 2. Dysfunctional Tregs
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Locations of IC deposition and resulting symptoms
1. Skin * Malar rash (butterfly, over nose) * Discoid rash (erythematous raised patches * Photosensitivity 2. Joints * Arthritis (2 or more joints) 3. Kidney * proteinuria * Cellular casts * Mesangial GN * Proliferative GN * Membranous GN 4. Serosal Membranes * Pleruitis * Pericarditis 5. Other: Hematological * Anemia * Leukopenia * Thrombocytopenia * Hypergammaglobulinemia * Hypocomplementemia
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Characteristics of Mesangial GN
* Mesangial proliferation w/IC deposits * mild symptoms: Nephritic
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Focal vs Diffuse proliferative GN
Both: * Endothelial and mesangial proliferation Focal: * \<50% glomeruli affected * Variable symptoms (nephritic or nephrotic) Diffuse: * Most glomeruliaffected * Nephrotic * Subendothelial deposits
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Characteristics of Chronic Discoid Lupus
* Skin lesions w/o systemic symptoms * ANA w/o anti-dsDNA
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Characteristics of Subacute Cutaneous Lupus
* Skin lesions w/o systemic symptoms * ANA w/o anti-dsDNA
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Drug-induced Lupus
* Multiple organs affected * Not CNS or kidney
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Differential Diagnosis with positive Anti-nuclear Ab test?
CREST: * Calcinosis * Raynaud's * Esophageal motility disorder * Sclerodactyly (scleroderma) * Telangiectasia (dilation of vessels) And LUPUS
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What auto-Ab causes a positive Coombs test?
Anti-RBC Ab
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What allele increases risk of developing rheumatoid arthritis?
HLA-DRB1
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Symptoms of Rhematoid arthritis
1. Symmetric stiffness (starts in small joints) 2. Rheumatoid nodules 3. Vasculitis 4. Lung: pneumonitis/pleurisy
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Pathology of Rheumatoid Arthritis
1. Rheumatoid factors initiate IC formation in synovium * IgMs to Fc of IgG or anti-citrullinated peptide Ab * due to defective CD4+CD25+ Tregs 2. Th17 cells release IL-17: neutrophil recruitment 3. Th1 cells activate macrophages * by secretion of IL-1 and TNF-alpha, PGE2 and LTB4 4. IL-1 and TNF-alpha activate synovial cell proliferation 5. Osteoclasts resporb bone 6. Synovium thickens and connective tissue **pannus** replaces cartilege
179
Sjogren's Syndrome * Pathology * Clinical Symptoms
* Pathology * CD4 cells and Igs reactive to glands * Lymphocytic infiltrate (B cells, plasma cells, CD4) * Hyperplasia of duct lining occludes duct * Fibrosis, atrophyof acini, replacement of parynchyma with fat * Clinical Symptoms * Chronic dry eyes (assess with Schirmer test) * Dry mouth (difficulty swallowing, fissures, caries) * enlargement of salivary glands
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What is Mixed Connective Tissue Disease?
Coexistence of SLE, polymyositis, RA and systemic sclerosis
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Progressive Systemic Sclerosis (scleroderma) * Pathology * Clinical Symptoms
* Pathology * Collagen-vascular disease * fibrosis in skin and other organs * Clinical Symptoms * Raynaud's * Cutaneous fibrosis * Symptoms of DIffuse Scleroderma * Skin * Connective dissue infiltration * GI = malabsorption syndrome * joints = arthritis * Lungs = pulmonary fibrosis * Heart = cardiac arrhythmia * CREST Syndrome
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What is CREST syndrome?
Calcinosis Raynauds Esophageal dysmotility Sclerodactyly Telangiectasia (vessel dilation)
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Ab present in Limited scleroderma
anti-centromere Ab
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Antibody present in Diffuse Scleroderma
anti-Scl 70 (DNA topoisomerase)
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Polymyositis-Dermatomyositis * Pathology * Clinical Symptoms
* Pathology * Increased MHC I and II on skeletal muscle cells * atrophy and necrosis * Dermatitis from IC-mediated vasculitis * Clinical Symptoms 1. Symmetric proximal mm weakness/pain 2. Muscle enzymes in blood 3. Creatine in Urine 4. Rash and photosensitivity 5. Hypergammaglobulinemia * Rheumatoid factor or anti-nuclear Abs
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Primary Immunologic Deficiency Syndromes * Cause * Common symptoms
* Cause: Genetic * Common symptoms: 1. skin lesions 2. chronic diarrhea 3. impaired growth 4. failure to thrive
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Markers for B and T cells in counting
B cells: CD 19, 20, sIg T cells: CD 2, 3, 5
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What does a positive DTH skin test mean?
CMI anergy
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What does a positive NBT test mean? What does a negative and positive result look like?
Positive test: * blue-black * functional NADPH oxidase Negative test: * yellow
190
What does the flow cytometric assay of dihydrorhodamine test?
NADPH oxidase activity (replaces NBT test)
191
Defect and genetic cause of X-linked SCID
* Defect * No T or NK cells * Non-functional B cells * Cause: * IL2 receptor gamma chain * \*\*IL-7 receptor (T cell maturation)
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Chronic Granulomatous Disease * Type of Immunodeficiency * Molecular defect * Symptoms * Treatment
* Intrinsic Phagocyte deficiency * Molecular defect: * Defective NADPH oxidase complex * No ROIs * Symptoms: * lymphadenopathy * skin lesions * sinopulmonary infections * Treatment: * IFN-gamma
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Defect and cause of Wiskott-Aldrich syndrome
* Defect: * defective B and T cells * Cause: * WAS gene defect * codes for signal transduction in hematopoietic stem cells
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X-linked agammaglobulinemia * Type of Immunodeficiency * Defect * Cause * Symptoms
* B cell immunodeficiency * Defect * Failure of B cells to mature * **\*\*No B, Normal T** * Cause * defective B cell **tyrosine kinase** gene (**BTK**) * Symptoms: * Recurrent infections: eye, ear, teeth, rash * Ig \< 250 * Treatment: IV Ig
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Cause of MHC Class I deficiency
defect in TAP2
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Type 1 leukocyte adhesion deficiency * Type of Immunodeficiency * Defective molecules * Symptoms
* Phagocyte deficiency * Defective molecules * LFA-1 * Mac-1 (CR3) * Symptoms: * Defective chemotaxis/cytotoxicity * recurrent skin, vaginal, sinopulmonary infections
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Autosomal SCID * Causes * Cells absent
* Causes: 1. Adenosine deaminase deficiency * ​​(-) ribonucleotide reductase --\> (-) lymphoid stem cell development 2. Purine nucleoside phosphorylase deficiency 3. Recombination-activating gene (RAG) mutations 4. Jak3 defects * Cells absent: * B and T cell maturation inhibited
198
What is the cause of Common variable immunodeficiency?
failure of B cell differentiation into plasma cells
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What are selective immunodeficiencies? What is the most common type?
Defects in isotype switching IgA
200
Selective IgA Deficiency * Type of immunodeficiency * Cause * Symptoms
* B cell immunodeficiency * Cause: * Isotype switch failure * Secretion failure * Symptoms: * recurrent infections: * Sinopulmonary * GI * IgA lvls \<5-7mg/dl * No secretory IgA
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Hyper-IgM Syndrome * Type of immunodeficiency\ * Cause * Cell types present * Symptoms
* B cell immunodeficiency * Cause: * T cells fail to produce cytokines for isotype switch * defects in CD40 (B cells) * Defects in CD40L (T cells) * Cells: * Th1 and Th2 defect * Symptoms: * Ab and CMI defeciency * Pyogenic infections * Intracellular microbe infections
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Common Variable ID * Type of immunodeficiency * Cells present * Symptoms * Treatment
* B cell immunodeficiency * No plasma cells * Symptoms: * Recurrent sinopulmonary infection * Ig lvl \< 300
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DiGeorge Syndrome * Type of immunodeficiency * Cause * Symptoms * Treatment
* T cell Immunodeficiency * Cause: * deletion of 22q11 * failure of development of 3rd and 4th pharyngeal pouches * thyroid and parathyroid hypoplasia * Symptoms: * hypocalcemia * congenital heart disease * Chronic infection * T cell deficiency * Treatment: * marrow or stem cell transplant
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Paroxysmal Nocturnal Hemoglobinuria * Type of immunodeficiency * Cause * Symptoms
* Complement deficiency * Cause: * Deficiency in DAF and CD59 (Mac inhibitor) * Symptoms: * pancytopenia: reduction in the number of red and white blood cells, as well as platelets
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Hereditary angioedema * Type of immunodeficiency * Deficiency
* Complement Deficiency * C1INH deficiency
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What type of infections are commonly associated with Complement Immunodeficiency? What is the specific defect involved?
Neisseria infection defects in MAC
207
How is HIV transmitted from mother to fetus?
1. Transplacentally 2. During delivery (most common in US) * give anti-retroviral therapy to mother 3. Breast milk
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What are the envelope proteins of HIV? What are their functions?
1. gp120 * binds CD4 and CCR5 or CXCR4 (initiate entry) 2. gp41 * Induce HIV-host membrane fusion
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Pathogenesis of HIV infection
Primary target: mucosal CD4 T cells
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Mechanisms of CD4 loss in HIV
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Patient presents with fever, lymphadenopathy, and rash. CD4 counts \<800. What does he have?
Stage I HIV: Acute infection
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Patient presents with lymphadenopathy and splenomegaly. Has had a fever and oral infections. CD4 count 200-499/microL. What does he have?
Stage 2 HIV: Chronic phase
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Patient presents with opportunistic infections and CD4 count \<200. What does he have?
Stage 3 AIDS: Crisis phase
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What opportunistic infections occur in stage 2 (chronic phase) HIV?
Oral Infections 1. Oral Candidiasis 2. Oral Hairy cell leukoplakia 3. EBV infection
215
What serologic test can diagnose HIV?
ELISA for IgM to gp24 and gp120 develop 2-8 weeks after infection
216
Staining techniques and results for amyloidosis
1. Congo red stain = RED 2. Polarized light = yellow/green birefringence
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Characteristics of Primary (immunocytic) amyloidosis * Amyloid protein * Major organ affected
* Ig/AL light chains (AL amyloid) * from neoplastic plasma cells * Affects heart
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Amyloid protein associated with Secondary (reactive) amyloidosis
Serum amyloid-associated protein A (AA amyloid) Secondary to chronic inflammation
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Characteristics of Heriditary (familial) amyloidosis * Amyloid protein * Major organ affected
* Mutant Transthyretin (TTR) * Affects Heart
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What disease is associated with deposition of a mutant form of transthyretin (TTR)? Deposition of normal TTR?
Mutant TTR: Hereditary (familial) amyloidosis Normal TTR: senile amyloidosis
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Characteristics of Senile amyloidosis * Deposit * Major organ affected
* Normal transthyretin (TTR) * Major organ: Heart * CHF * Ventricular dysfunction * Valvular insufficiency * Ischemia
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Amyloid protein build-up associated with long-term dialysis?
ß2 microglobulin
223
Amyloid protein associated with Alzheimer's disease
ß-amyloid (Aß)
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Name the disease: Bence Jones proteins AL protein
Primary (immunocytic) amyloidosis associated with plasma cell dyscrasias, such as multiple myloma
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Disease associated with secondary (reactive) amyloidosis
RA (chronic inflammation, cellular necrosis)
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Where does ß2 microglobulin deposit in hemodialysis-associated amyloidosis?
Joints and bones
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Characteristics of Familial Mediterranean Fever * amyloid deposit * symptoms
* Deposit * AA protein * Symptoms * Fever * serosal inflammation (pleura, peritoneum, synovial membranes)
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Characteristics of Familial amyloid polyneuropathies * Deposit * Symptoms
* Deposit: * Mutant transthyretin deposits in nerves * Symptoms: * progressive peripheral and autonomic neuropathy
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Amyloid protein associated with Isolated atrial amyloidosis
ANF
Pathology
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