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Flashcards in Immunopathy Deck (229):
1

Components of innate immunity

  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)

2

Components of Adaptive Immunity

  1. T cells
  2. B cells
  3. APCs

3

Organs of innate vs adaptive immunity

Innate:

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

Adaptive:

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

4

Cytokines of Innate immunity

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

TNF alpha and beta

IFN alpha and beta and gamma

5

Cytokines of Adaptive immunity and cells from which they are released

IL-1, 4, 5, 13

Produced by activated T cells

6

Cytokines of Hematopoiesis

IL-3, 7

GM-CSF

G-CSF

M-CSF

7

Function of IL-1 

Innate immunity:

  • Cell activation
  • Fever
  • Acut phase proteins

8

Function of IL-6

Innate Immunity

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

Released after IL-1 and TNF

9

Function of IL-8

Innate immunity

  • Neutorphil chemotaxis

10

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

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

11

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

Innate Immunity:  **Induces Cellular Immunity**

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

Released from:

  • APCs

12

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

Innate Immunity  **Proinflammatory**

  • activates neutrophils, fibroblasts, keratinocytes

Released from:

  • TH17 cells

13

Function of TNF alpha/beta

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

14

Function of IFN-alpha and -beta

Innate Immunity: **anti-viral**

  • Increase class I expression
  • Promotes Th1 polarization

15

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

Innate Immunity:  **promotes CMI**

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

Released by:

  • Th1
  • NK cells
  • Tc cells

16

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

Adaptive immunity

  • T cell maturation
  • Activates Tc and NK cells

Released by:

  • activated T cells

17

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

Adaptive Immunity:

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

Released by:

  • Activated T-cells

18

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

Adaptive Immunity:

  • Promotes IgA isotype switching
  • Eosinophil maturation

Released by:

  • Activated T cells

19

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

Adaptive Immunity:

  • Promotes IgE production
  • Inhibits proinflammatory cytokine synthesis

20

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

Hematopoiesis:

  • B cell and granulocyte maturation

Released by:

  • T cells

21

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

Hematopoiesis:

  • B and T cell maturation

Released by: 

  • fibroblasts
  • bone marrow stromal cells

22

Function of GM-CSF 

Hematopoiesis:  

Maturation of:

  • Eosinophil
  • neutrophil
  • Monocyte

23

Function of G-CSF

Hematopoiesis:

  • Neutorphil maturation

24

Function of M-CSF

Hematopoiesis:

  • Monocyte maturation

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

136

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

137

What is pictured?

Type II Primary Membranoproliferative GN

Intramembranous immune deposits

138

What is pictured?

Type I Primary Membranoproliferative GN

Subendothelial IC deposits

139

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

140

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

141

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

142

CMI mechanism

143

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

144

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

145

Cytokines that induce Tc maturation

  1. Bind Class I MHC w/IL-2 and IFN-gamma: becomes cytolytic
  2. IL-12: Increases cytolytic activity

146

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

147

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

148

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

149

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 

150

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

151

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

152

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

153

What are the most likely infections in Prolonged Imunodeficiency?

  1. CMV (overall)
  2. Adenovirus (children)

154

What are the most common diseases that recur after a kidney transplant?

Membranous GN

Membranoproliferative GN

155

Types of rejection in kidney transplant

  1. Acute Cellular
  2. Acute Humoral
  3. Chronic Rejection
    • fibrosis
    • Mononuclear infiltrate
    • Tubular atrophy

156

Characteristics of Chronic rejection in Heart Transplant

  • Arteriopathy = narrowing of lumen
    • Intimal proliferation
    • Distal epicardial and intramyocardial coronary artery branches

157

Common recurrent disease in heart transplants?

Accelerated atherosclerosis

158

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

159

Common Recurrent disease in Liver Transplant

  1. Hep B
  2. Hep C

160

Characteristics of Post-transplantation Lymphoproliferative Disorder (PTLD)

  • EBV-induced B cell Proliferation
  • Associated with immunosuppression

161

What are long term complications in transplantation?

  1. Post-transplantation lymphoproliferative disorder
  2. leukemia
  3. Hodgkin's and non-Hodgkin's lymphomas
  4. Infection

162

Function of AIRE 

(Autoimmune Regulatory Protein)

  • stimulates expression of peripheral Ags in thymus for (+)/(-) selection (central tolerance)

163

Characteristics of Autoimmune Polyendocrine Syndrome

  • Cause
  • Affected systems

  • Cause:
    • mutation of AIRE (central tolerance)
  • Affected systems:
    • Endocrine
    • Skin

164

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)

165

What is epitope spreading?  What does it cause?

  • constant exposure of different, normally hidden, epitopes due to tissue damage
  • Causes autoimmune disease

166

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

167

What is the pathogenesis of Lupus?

Auto-Abs from:

  1. Failure of peripheral tolerance
  2. Dysfunctional Tregs

168

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

169

Characteristics of Mesangial GN

  • Mesangial proliferation w/IC deposits
  • mild symptoms: Nephritic

170

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

171

Characteristics of Chronic Discoid Lupus

  • Skin lesions w/o systemic symptoms
  • ANA w/o anti-dsDNA

172

Characteristics of Subacute Cutaneous Lupus 

  • Skin lesions w/o systemic symptoms
  • ANA w/o anti-dsDNA

173

Drug-induced Lupus

  • Multiple organs affected
    • Not CNS or kidney

174

Differential Diagnosis with positive Anti-nuclear Ab test?

CREST:

  • Calcinosis
  • Raynaud's 
  • Esophageal motility disorder
  • Sclerodactyly (scleroderma)
  • Telangiectasia (dilation of vessels)

And LUPUS

175

What auto-Ab causes a positive Coombs test?

Anti-RBC Ab

176

What allele increases risk of developing rheumatoid arthritis?

HLA-DRB1

177

Symptoms of Rhematoid arthritis

  1. Symmetric stiffness (starts in small joints)
  2. Rheumatoid nodules
  3. Vasculitis
  4. Lung: pneumonitis/pleurisy

178

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

180

What is Mixed Connective Tissue Disease?

Coexistence of SLE, polymyositis, RA and systemic sclerosis

181

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

182

What is CREST syndrome?

Calcinosis

Raynauds

Esophageal dysmotility

Sclerodactyly

Telangiectasia (vessel dilation)

183

Ab present in Limited scleroderma

anti-centromere Ab

184

Antibody present in Diffuse Scleroderma

anti-Scl 70 (DNA topoisomerase)

185

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

186

Primary Immunologic Deficiency Syndromes

  • Cause
  • Common symptoms

  • Cause: Genetic
  • Common symptoms:
    1. skin lesions
    2. chronic diarrhea
    3. impaired growth
    4. failure to thrive

187

Markers for B and T cells in counting

B cells: CD 19, 20, sIg

T cells: CD 2, 3, 5

188

What does a positive DTH skin test mean?

CMI anergy

189

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)

192

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

193

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

194

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

195

Cause of MHC Class I deficiency

defect in TAP2

196

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

197

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

199

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

201

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

202

Common Variable ID

  • Type of immunodeficiency
  • Cells present
  • Symptoms
  • Treatment

  • B cell immunodeficiency
  • No plasma cells
  • Symptoms:
    • Recurrent sinopulmonary infection
    • Ig lvl < 300

203

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

204

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

205

Hereditary angioedema

  • Type of immunodeficiency
  • Deficiency

  • Complement Deficiency
  • C1INH deficiency

206

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

208

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

209

Pathogenesis of HIV infection

Primary target: mucosal CD4 T cells

210

Mechanisms of CD4 loss in HIV

211

Patient presents with fever, lymphadenopathy, and rash.  CD4 counts <800.  What does he have?

Stage I HIV: Acute infection

212

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

213

Patient presents with opportunistic infections and CD4 count <200.  What does he have?

Stage 3 AIDS: Crisis phase

214

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

217

Characteristics of Primary (immunocytic) amyloidosis

  • Amyloid protein
  • Major organ affected

  • Ig/AL light chains (AL amyloid)
    • from neoplastic plasma cells
  • Affects heart

218

Amyloid protein associated with Secondary (reactive) amyloidosis

Serum amyloid-associated protein A

(AA amyloid)

Secondary to chronic inflammation

219

Characteristics of Heriditary (familial) amyloidosis

  • Amyloid protein
  • Major organ affected

  • Mutant Transthyretin (TTR)
  • Affects Heart

220

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

221

Characteristics of Senile amyloidosis

  • Deposit
  • Major organ affected

  • Normal transthyretin (TTR)
  • Major organ: Heart
    • CHF
    • Ventricular dysfunction
    • Valvular insufficiency
    • Ischemia

222

Amyloid protein build-up associated with long-term dialysis?

ß2 microglobulin

223

Amyloid protein associated with Alzheimer's disease

ß-amyloid (Aß)

224

Name the disease:

Bence Jones proteins

AL protein

Primary (immunocytic) amyloidosis

associated with plasma cell dyscrasias, such as multiple myloma

225

Disease associated with secondary (reactive) amyloidosis

RA

(chronic inflammation, cellular necrosis)

226

Where does ß2 microglobulin deposit in hemodialysis-associated amyloidosis?

Joints and bones

227

Characteristics of Familial Mediterranean Fever

  • amyloid deposit
  • symptoms

  • Deposit
    • AA protein
  • Symptoms
    • Fever
    • serosal inflammation (pleura, peritoneum, synovial membranes)

228

Characteristics of Familial amyloid polyneuropathies

  • Deposit
  • Symptoms

  • Deposit:
    • Mutant transthyretin deposits in nerves
  • Symptoms:
    • progressive peripheral and autonomic neuropathy

229

Amyloid protein associated with Isolated atrial amyloidosis

ANF