Immune overview, autoimmunity, and primary immune deficiencies Flashcards Preview

FPP_MSS > Immune overview, autoimmunity, and primary immune deficiencies > Flashcards

Flashcards in Immune overview, autoimmunity, and primary immune deficiencies Deck (114)
1

Th1: cytokines produced

IFN-gamma

2

Th2: cytokines produced

IL-4, IL-5, IL-13

3

Th17: cytokines produced

IL-17, IL-22, chemokines

4

IFN-gamma and IL-12 induce what Th subtype?

Th1

5

IL-4 induces what Th subtype?

Th2

6

TGF-beta, IL-6, IL-1, and IL-23 induce what Th subtype?

Th17

7

Th1: immunologic reactions triggered

1. macrophage activation 2. stimulation of IgG 3. antibody production

8

Th2: immunologic reactions triggered

1. IgE production 2. activation of mast cells 3. activation of eosinophils

9

Th17: immunologic reactions triggered

1. recruitment of neutrophils 2. recruitment of monocytes

10

Th1 is used by the host to defend against what?

intracelluar microbes

11

Th2 is used by the host to defend against what?

helminthic parasites

12

Th17 is used by the host to defend against what?

extracellular bacteria, fungi

13

Th1: role in disease

immune-mediated chronic inflammatory diseases (often autoimmune)

14

Th2: role in disease

allergies

15

Th17: role in disease

immune-mediated chronic inflammatory diseases (often autoimmune)

16

Describe each of the four major Ig subtypes

1. IgM: low affinity, activates the classical complement pathway 2. IgG: neutralizes microbes and toxins, opsonizes antigens, activates classical complement pathway, responsible for antibody-dependent cellular cytotoxicity (ADCC) 3. IgA: mucosal transport, neutralizes mucosal microbes and toxine 4. IgE: ADCC of parasites, responsible for allergy reaction (mast cell degranulation)

17

Name the three complement pathways and what is responsible for activating them

1. Classical pathway: IgM and IgG 2. Alternative pathway: C3b 3. Lectin pathway: mannose-binding lectin (MBL)

18

All complement pathways converge on what?

Activation of C5-C9, forming the membrane attack complex (MAC)

19

Describe APECED

Autoimmune polyendocrinopathy candidiasis ectodermal dystropy (APECED): Cause: AIRE gene defect -> example of failure of central tolerance Autoimmune adrenal and parathyroid disease Can also induce autoimmune hypothryroidism, hypogonadism, vitiligo, and pernicious anemia Also associated with fungal infections (candidiasis)

20

APECED is caused by what?

AIRE gene defect -> thymic medullary cells do not express self-antigen -> self-reactive T-cells are not deleted (failure of central tolerance)

21

Name the major clinical features of APECED

1. bradycardia, hypotension (salt craving) 2. bronzed skin 3. thrush in mouth 4. abnormal nails

22

Lab findings of APECED

1. low cortisol 2. low calcium, low PTH 3. hyponatremia, hypocalcemia, hyperkalemia

23

Describe ALPS

Autoimmune lymphoproliferative syndrome (ALPS): Cause: mutations in Fas or FasL -> example of failure of peripheral tolerance Widespread lymphadenopathy, splenomegaly, and autoimmune cytopenias (hemolytic anemia and thrombocytopenia). High IgG, IgA, and IgM common Increased percentages of double-negative T-cells

24

Clinical features of ALPS

1. Pallor 2. diffuse lymphadenopathy 3. splenomegaly

25

Lab findings of ALPS

1. hypergammaglobulinemia 2. Coomb's positive hemolytic anemia 3. Flow cytometry shows increase double-negative T-cells

26

ALPS is caused by what?

Mutations in Fas or FasL -> failure of peripheral tolerance

27

Describe IPEX

Immune dysregulation, polyendocrinopathy, X-linked (IPEX): Due to mutation in Foxp3 gene (loss of Treg cells) Requires bone marrow transplant -> deadly otherwise Affects boys in infancy Hypergammaglobulinemia Presents with IBD, severe eczema and food allergies, T1DM, thyroiditis, autoimmune hemolytic anemia, thrombocytopenia

28

Clinical features of IPEX

1. Diffuse eczematous rash 2. Cachexia 3. Pallor

29

Lab findins for IPEX

1. Hypergammaglobulinemia 2. Coomb's positive hemolytic anemia 3. IgE ~14,000IU/dl (nl < 200) 4. positive skin allergy test to all (most) foods 5. low serum albumin, iron deficiency 6. hyperglycemia, glucosuria, low insulin

30

Treg cells express which gene?

Foxp3

31

What is the Foxp3 gene?

Expressed in Treg cells. It is mutated in IPEX syndrome.

32

Which gene family is most frequently associated with autoimmune disease?

HLA

33

Ankylosing spondylitis is strongly associated with which MHC allele?

HLA-B27

34

Which MHC allele is frequently associated with a wide variety of autoimmune disorders, including: RA, T1DM, pemphigus vulagaris?

HLA-DR4

35

Name the 4 types of hypersensitivity reactions:

Type 1: immediate sensitivity (IgE-mediated) Type 2: antibody-mediated Type 3: immune-complex-mediated Type 4: delayed-type hypersensitivity (T-cell mediated)

36

Allergic rhinits, asthma, eczema, and food allergies are ell examples of what type of hypersensitivity reaction?

Type 1

37

Type 1 hypersensitivity is mediated by what?

IgE

38

Myasthenia gravis and Graves disease are examples of what type of hypersensitivity?

Type 2

39

A multinucleate cell found an an inflamed muscle is called a(n)

Aschoff body

40

What are the criteria for Acute Rheumatic Fever?

J(heart)NES criteria: J = Joints (heart) = heart (carditis) N = nodules E = erythema marginatum S = sydenham's chorea 2 major or 1 major + 2 minor criteria + supporting evidence of preceding GAS infection major: carditis, polyarthritis, sydengam's chorea, erythema marginatum, subQ nodules minor: fever, arthralgia, elevated acute phase reactants, prolonged PR interval

41

Acute rheumatic fever is caused by what?

Molecular mimicry of heart muscle by S. pyogenes virulence factors (M proteins) following GAS infection

42

Treatment for ARF

Penicillin prophylaxis

43

ARF is what type of hypersensitivity reaction?

Type 2

44

Goodpasture's syndrom is what type of hypersensitivity reaction?

Type 2

45

Name treatment options for type 2 hypersensitivity reactions

1. Non-life-threatening: high dose IVIG, corticosteroids, Rituximab 2. Life-threatening: plasmapheresis

46

Type 3 hypersensitivity is mediated by what?

Immune complexes (Ab:Ag)

47

Systemic Lupus Erythematosus is an example of what type of hypersensitivity?

Type 3

48

What are the 11 criteria for SLE? How many of them must be present for Dx of SLE?

At least 4 of 11 criteria must be met for Dx: 1. malar rash 2. discoid rash 3. photosensitivity 4. oral/nasal ulcers 5. arthritis 6. serositis 7. cerebritis (including seizures) 8. nephritis 9. ANA 10. Ab to dsDNA or Anti-Sm 11. Autoimmune cytopenias (ITP, AIHA)

49

Immune complexes generated in SLE primarily affect what tissues/organ systems?

1. Kidney 2. Joints 3. Skin

50

Early-onset SLE is associated with what?

Early complement defects (C1q, C2, C4)

51

SLE: antibody specificity and major clinicopathologic manifestations

1. DNA, nucleoproteins, others ("anything") 2. nephritis, arthritis, vasculitis

52

Polyarteritis nodosa: antibody specificity and major clinicopathologic manifestations

1. Hepatitis B virus (due to chronic HepB infection) 2. Vasculitis

53

Poststreptococcal glomerulonephritis: antibody specificity and major clinicopathologic manifestations

1. Streptococcal wall antigens 2. nephritis

54

Serum sickness: antibody specificity and major clinicopathologic manifestations

1. Various protein antigens 2. Systemic vasculitis, nephritis, arthritis

55

Arthus reaction: antibody specificity and major clinicopathologic manifestations

1. Various protein antigens 2. Cutaneous vasculitis

56

What is the Arthus reaciton?

A Type 3 hypersensitivity reaction following intradermal injection of an antigen. Produces local vasculitis due to deposition of IgG:Ab immune complexes, which in turn recruit PMNs and local mast cell degranulation. Sometimes associated with vaccines.

57

List the two major processes behind Type 4 hypersensitivity reactions

1. Delayed-type hypersensitivity (Th1 delayed-type hypersensitivity and Th17-mediated inflammatory reaction) 2. T-cell-mediated lysis

58

Rheumatoid arthritis is an example of what type of hypersensitivity reaction?

Type 4

59

What are the three main inflammatory cytokines released by monocytes and macrophages?

IL-1, IL-6, TNF

60

True or false: B-cells may be involved in the Type 4 hypersensitivity response

True

61

What type of hypersensitivity reaction is Dermatomyositis?

Type 4

62

Clinical manifestations of Dermatomyositis

1. Heliotropic rash 2. Gottron's papules (scaly rashes, PIP joints and hands) 3. Proximal muscle weakness 4. Capillary changes (dilation, dropout hemorrhage -> especially apparent on nail beds) 5. High AST/ALT

63

Dermatomyositis vs. Polymyositis

Dermatomyositis: Perifascicular atrophy: CD4/B/PC/MP-mediated infarct of tissue due to microvascular injury and compensatory capillary dilation Polymyositis: diffuse muscle fiber death due to CD8-mediated attach of muscle fibers

64

T1DM: hypersensitivity type?

Type 4 - pancreatic islet antigens

65

Rheumatoid arthritis: hypersensitivity type?

Type 4 - unknown joint antigen

66

Multiple sclerosis: hypersensitivity type?

Type 4 - CNS myelin proteins

67

Inflammatory bowel disease: hypersensitivity type?

Type 4 - unknown intestinal antigen

68

Tuberculosis: hypersensitivity type?

Type 4 - microbial proteins

69

Name the disease associated with the following autoimmune mechanisms/antigens: 1. auto-reactive T-cells and activated macrophages that specifically de-myelinate CNS motor and sensory neurons 2. Autoantibodies directed against platelets 3. antibodies to Schwann cell membranes with ascending paralysis 4. Auto-antibodies against thyroglobulin leading to thyroid inflammation and hypothyroidism 5. Enteropathy related to gluten in food

1. Multiple sclerosis 2. Thrombocytopenia 3. Guillain-Barre Syndrome 4. Hashimoto's thyroiditis 5. Celiac disease

70

Name the disease associated with the following autoimmune mechanisms/antigens: 1. Antibodies against dsDNA, histones, and other nuclear proteins -> nephritis, cerebritis, serositis, dermatitis, etc 2. Autoantibodies against joint antigens 3. Autoantibodies to myosin following infection with GAS (especially joints and heart)

1. Systemic lupus erythematosus 2. Rheumatoid arthritis 3. Rheumatic fever

71

Allergy is also known as what?

Type 1 hypersensitivity reaction

72

Name 4 main suspicion criteria for primary immune deficiency (PID)

1. Too may infections (i.e. >2 pneumonias, etc) 2. Weird infections (pneumocystis) 3. Infections in weird places (liver, lung abscesses) 4. Early-onset autoimmunity

73

Describe the major features of the following complement defects: 1. Early (C2, C4) 2. Late (C5-C9) 3. C3

1. Sinopulmonary infections, increased susceptibility to S. pneumoniae and H. Influenzae, autoimmune disease (SLE, glomerulonephritis) 2. defective MAC, increase Neisseria infections (increased susceptibility to meningitis, but more likely to survive) 3. Severe pyogenic infections

74

Workup: complement deficiency

CH50: 0 = deficient, >1 = consumption AH50 for rare alternative pathway defect

75

Complement deficiency first presents at what life stage?

Any age

76

Identify the type of immunodeficiency and the initial screening test(s) that should be used: 1. SCID 2. DiGeorge Syndrome (22q11DS) 3. XLA 4. CVID 5. CGD 6. C2, C5-C9 deficiency

In all cases, get CBC with differential first 1. Combined B cell and T cell deficiency -> flow cytometry, TREC 2. T cell deficiency -> FISH, RT-PCR, or chromosome microarray (preferred) 3. Antibody deficiency -> IgG/A/M/E, antibody titers 4. Antibody deficiency -> IgG/A/M/E, antibody titers 5. PMN (neutrophil) defect -> DHR (preferred) or NBT 6. Complement deficiency -> CH50

77

Describe the etiology of SCID

X-linked is most common (46%). Mutation in the common gamma-chain (gamma-c) of the IL-2 receptor. gamma-c is also a shared component in other IL receptors (IL-4/7/15/21). Effect: T/NK cells not present. B cells present but not functional.

78

Describe the common clinical manifestations of SCID

Pneumonia (P. jiroveci), otitis media, thrush, intractable diarrhea, failure to thrive

79

Describe the treatment for SCID

Bone marrow transplant (100% fatal without treatment). Early treatment (<3mo) associated with 95% survival rate.

80

What is a TREC?

T-cell Receptor Excision Circle (TREC). Measured with qRT-PCR Nonreplicating circular pieces of DNA (cut and spliced out) in naive T-cells generated in the process of making TCRs. TRECs serve as a marker of normal, naive T-cells -> absent in SCID and other forms of T-cell lymphopenia

81

Describe the etiology of DiGeorge Syndrome (22q11DS)

Microdeletion in chromosome 22q11.2 (usually TBX1 gene), resulting in defects in pharyngeal pouches 1-6.

82

What are the major clinical features of DiGeorge Syndrome (22q11DS)?

CATCH22: C = cardiac defects A = abnormal facies T = thymic dysplasia C = cleft palate H = hypocalcemia 22 = 22nd chromosome Also: immunodeficiency and developmental delay w/ low IQ T-cell abnormalities (30%) and Antibody deficiency (15%)

83

Which gene is most commonly associated with DiGeorge Syndrome (22q11DS)?

TBX1

84

Describe diagnostic testing for DiGeorge Syndrome (22q11DS)

Screening recommended for all infants with significant heart defects or unexplained lymphopenia Chromosome microarray (preferred), FISH (older, 15% false negative), RT-QPCR for TBX1 haploinsufficiency (future)

85

What is micrognathia

small chin

86

What are the classic abnormal facies of DGS/22q11DS?

1. Micrognathia 2. Low-set ears 3. fish-shaped mouth

87

XLA (X-Linked Agammaglobulinemia) is due to a defect in which gene?

Btk

88

Describe the etiology of XLA

X-linked agammaglobulinemia: Due to mutations in Bruton's Tyrosine Kinase (Btk) -> results in a failure of differentiation of B-cells -> B cells absent, resulting in severe agammaglobulinemia

89

Describe the major clinical features of XLA

1. Onset in infancy or early childhood 2. Recurrent otitis media, sinusitis, pneumonia 3. Bronchiectasis (if not detected early) Infection with encapsulated bacteria (S. pneumoniae, H. Influenzae) and mycoplasma 4. Severe enteroviral infections 5. IgG/A/M/E deficiency

90

Name the diagnostic labs indicated for detection of XLA

1. CBC diff 2. IgG/A/M/E 3. flow cytometry

91

What is the major cause of death in patients with CVID?

Pulmonary disease (bronchiectasis and interstitial lung disease)

92

How is CVID diagnosed?

1. Decrease IgG (>2 SD below mean) and low IgA and/or IgM 2. flow cytometry to confirm normal B and T cells 3. Exclude secondary immune deficiency in Hx (drugs, lumphoma, protein-losing enteropathy)

93

Describe the major clinical features of CVID

1. Onset at any age 2. Very low IgG and low IgM and/or IgA 2. RTI/GI infections 3. Bad titers with vaccines 4. Neoplasia (including B-cell lymphoma and gastric carcinoma) 5. Autoimmune cytopenias 6. Liver disease (including hepatitis and autoimmune)

94

If a patient presents with low/absent IgA, but normal IgG and IgM, what is the most likely PID diagnosis?

IgA deficiency

95

What treatment is contraindicated with IgA deficiency?

IVIG - because non-IgA immunoglobulins are usually normal

96

What are the major clinical features of IgA deficiency?

(Vast majority of subjets are normal) 1. very low IgA and normal IgG and IgM 2. Increased sinopulmonary and/or GI infections (example: giardia) 3. Increased incidence of atopic disease (coeliac disease and autoimmune disease) 4. False-negative and false-positive diagnostic tests

97

Why does IgA deficiency cause false results on various serum diagnostic tests?

1. False-negative: lack of IgA (IgA Ab to transglutaminase) 2. False-positive: increased incidence of heterophile antibodies (example: pregnancy tests)

98

What is a heterophile antibody?

An antibody that recognizes an antigen different than the one that induced the original immune response Feature of EBV infections

99

Normal IgG/A/M/E with normal T-cell function, but an abnormal response to vaccines (especially polysaccharide (PS) antigens) is indicative of what

Specific Antibody Deficiency

100

Lab evaluation for Ab deficiency: Give the expected findings for each:

  1. B cell numbers
  2. IgG
  3. IgA
  4. IgM
  5. Response to immunization
  • IgA deficiency
  • XLA
  • CVID
  • Steroid-induced hypogammaglobulinemia
  • 5. Specific Ab deficiency

 

Disorder B cell numbers IgG IgA IgM Response to Immunization IgA deficiency nl nl

<10mg/dl

(very low)

nl nl XLA absent/very low <200mg/dl (low) low/not detectable low/not detectable absent CVID normal to low usually <400 mg/dl (low) low (90%) low (70-80%) decreased/absent Steroid-induced hypogammaglobulinemia usually nl usually >400mg/dl slightly reduced slightly reduced blunted, but not absent Specific Ab deficiency nl nl nl nl decreased

101

What is the etiology of Chronic Granulomatous Disease (CGD)?

Impaired bactericidal killing due to a functional abscence of respiratory burst in neutrophils and monocytes

Due to a deficiency of NADPH oxidase. Usually X-linked.

102

What are the major clinical findings of CGD?

  1. Onset by age 2
  2. pneumonia
  3. adenopathy/adenitis/abscesses
  4. hepatic abscess without obvious source
  5. sepsis
  6. osteomyelitis
  7. infection with catalase+ bacteria

103

What type of bacteria are usually found with CGD?

Catalase+ bacteria

examples: S. aureus, serratia, salmonella, nocardia, klebsiella, burkholderia

also fungus: candida, aspergillus

104

How is CGD diagnosed?

Dihydrorhodamine test (DHR)

105

A liver abscess in an infant or young child without an obvious source is usually what disease?

Chronic Granulomatous Disease (CGD)

106

Rolling adhesion of leukocytes is mediated by what?

selectins (E-selectin, P-selectin) on the endothelium and sialyl Lewis (CD15) on leukocytes

107

Tight adhesion is mediated by what?

LFA-1 (CD18/CD11a) with ICAM-1/2

MAC-1 (CD18/CD11b) with ICAM-2

108

In leukocyte adhesion deficiency, are leukocytes abnormally high or abnormall low?

High

109

What are the common clinical findings in Leukocyte Adhesion Deficiency 1 (LAD-1)?

  1. Recurrent pyogenic infections
  2. Delayed umbilical cord detachment
  3. leukocytosis
  4. inability to form pus

110

What treatment(s) is(are) indicated in LAD-1?

  1. Aggressive infection treatment
  2. Bone marrow transplant (severe cases)

111

What is the etology of LAD-1?

Autosomal deficiency of LFA-1/MAC-1 family of integrins -> leading to low to moderate CD11/CD18 expression

Deficiency in adhesion molecules leads to impaired leukocyte trafficking and margination -> PWNs cannot enter sites of injury/infection to form pus

112

What is the molecular difference between LAD-1 and LAD-2?

LAD-1: CD18 deficiency

LAD-2: Fucosylation deficiency

113

What bacteria is especially common in Late Complement (C5-C9) deficiency

Neisseria meningitidis

114

What is the most common Early Complement Deficiency?

C2