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H&D > Wk 8 TBL 6 Hypersensitivity Reactions > Flashcards

Wk 8 TBL 6 Hypersensitivity Reactions Flashcards

1
Q

9 Type II HS reactions to know

A
  1. Autoimmune hemolytic anemia
  2. Erythroblastosis fetalis
  3. Goodpasture
  4. Graves Disease
  5. Guillain-Barre
  6. Myasthenia Gravis
  7. Pemphigus vulgaris
  8. Pernicious anemia
  9. Rheumatic Fever
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2
Q

3 Type III HS reactions to know

A
  1. Post streptococcal glomerulonephritis
  2. Systemic lupus erythematosus
  3. Serum sickness
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3
Q

10 Type IV hypersensitivity reactions

A
  1. Celiac
  2. Contact Dermatitis
  3. DMT1 (Type I diabetes)
  4. GVHD
  5. Hashimoto’s thyroiditis
  6. Inflammatory bowel disease (Crohn’s, UC)
  7. Multiple Sclerosis
  8. PPD test
  9. Psoriasis
  10. Rheumatoid arthritis
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4
Q

2 Hypersensitivity reactions that are maybe type IV

A
  1. Ankylosing spondylitis
  2. Reactive arthritis
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5
Q

What is the target for HS and sx of rheumatic fever?

A

Strep pyogenes antibodies cross-react to mitral valve antigens

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6
Q

What are 2 types of tolerance with regards to the adaptive IS?

A
  1. Central tolerance in the thymus
  2. Peripheral tolerance - circulating T cells
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7
Q

What is central tolerance?

A

In thymus, negative selection of self-reactive T-cells

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8
Q

What happens to negatively selected T cells in the thymus?

A
  1. apoptosis
  2. differentiation into Treg
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9
Q

What is peripheral tolerance?

A

Circulating T cells see activated DCs w/ costimulatory signal 2 -> T cell activation

In settings w/o inflammation, immature DCs w/o signal 2 present to T cells -> T cell death, anergy (unable to respond to signals)

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10
Q

What happens to Tregs that converted from self-reactive T cells?

A

Either:
1. Interact w/ immature DCs
2. Convert activated DCs into regulatory DCs
3. Can produce immunosuppressive cytokines: IL-10, TGFbeta

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11
Q

What are 2 immunosuppressive cytokines?

A

IL-10 and TGFbeta
-suppress T cell activation

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12
Q

Treg fxns

A
  1. Develop in thymus and circulate to suppress autoimmune responses
  2. Induced during immune responses and suppress immunopathology (out of control immune responses)
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13
Q

What regulates Tregs?

A

Trascription factor FoxP3

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14
Q

What happens if FoxP3 is mutated?

A

Lead to IPEX (immunodysregulation polyendocrinopathy enteropathy X-linked syndrome)
=autoimmune disease in multiple organs

-complete loss of FoxP3 fxn not observed, but -> overwhelming autoimmunity and death in experimental animals

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15
Q

What happens when tolerance breaks down?

A

Hypersensitivity reactions

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16
Q

What are hypersensitivity reactions?

A

Immune responses that damage human tissues
-can be response to foreign antigens (penicillin -> RBC destruction)
-response to self antigens (autoimmunity)

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17
Q

What are the 4 types of hypersensitivity reactions?

A
  1. Type I: Mediated by IgE (ie allergic rxns) - mast cells
  2. Type II: Mediated by IgG (cell-associated antigens)
  3. Type III: Mediated by IgG:antigen immune complexes
  4. Type IV: Mediated by T cells (helper that releases IFN gamma or TNF or by CTLs)

-it multiple can play role together

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18
Q

Why do tolerance mechanisms break down?

A
  1. Genetics (HLA, sex, genes assoc w/ immune regulation)
    -most immune-mediated diseases driven by complex genetics
    -some autoimmune driven by single gene, usually centrally involved in immune tolerance: CTLA-4, PD-1, FoxP3, AIRE
  2. Environmental factors - smoking, weight, age, diet, etc
  3. infectious history - similarity b/w foreign and self antigens - molecular mimicry
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19
Q

What is the strongest locus assoc w/ autoimmune diseases?

A

HLA

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20
Q

HLA-B27 associated diseases

A

MHC Class I
Psoriasis
Ankylosing spondylitis
IBD
Reactive arthritis

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21
Q

What specifically mediates Type II hypersensitivity?

A

IgG

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22
Q

Type II reaction characteristics

A
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23
Q

How do antibodies induce Type II hypersensitivity reactions? 6 mechanisms

A
  1. Cytotoxic mechanism #1: Complement-mediated inflammatory response via classical pathway (C1) ->
  2. Cytotoxic mechanism #2: complement-mediated cell lysis: C5b attracts C6-C9 - MAC formation - pores in cell membrane -> lysis
  3. Cytotoxic mechanism #3: Complement- and IgG-mediated opsonization -> destruction in phagolysosome
  4. Cytotoxic mechanism #4: Antibody-dependent cell-mediated cytotoxicity (ADCC). Mostly mediated by NK cell - expresses Fc gamma receptors that bind IgG specific for RBCs, delivers granzyme B and perforin -> apoptosis
  5. Non-cytotoxic mechanism #1: Autoantibodies become receptor antagonists and block receptor from receiving signal (MG)
  6. Non-cytotoxic mechanism #2: Autoantibodies become receptor agonists and induce a signal (Grave’s Disease)
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24
Q

What happens when the classical complement pathway is activated?

A
  1. C3a &C5a -> vasodilation, neutrophil recruitment and activation
  2. neutrophil degranulation
  3. peroxidases, proteases, and vasodilators
  4. inflammation-induced RBC death
  5. cytopenias: anemia, thrombocytopenia, neutropenia
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25
Q

How is hemolytic hypersensitivity detected in the lab?

A

Direct Coombs Test

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26
Q

How does the direct Coombs test work?

A

Patient RBCs bound to autoantibodies

Add anti-human IgG (Coombs reagent)

->agglutination and precipitation

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27
Q

What diseases does Coombs test detect?

A
  1. Autoimmune hemolytic anemia- Antibodies to RBC antigens
  2. Drug-induced hemolytic anemia - covalent attachment to RBCs, drug-specific IgG (ie penicillin)
  3. Hemolytic disease of the newborn - erythroblastosis fetalis, maternal IgG, Rh-specific
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28
Q

Indirect Coombs test

A

Patient’s serum is incubated w/ lab RBCs expressing known antigens (think A or B)

Incubated w/ Coombs reagent

-> agglutination

Used for ABO blood typing and Rh screening

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29
Q

What type of reaction is Rheumatic heart disease? What happens?

A

Strep pyogenes antibodies cross-react to mitral valve antigens -> mitral valve scarring

Type II

30
Q

What type of rxn is Guillain-Barre Syndrome? What happens?

A

Antibodies bind to the myelin sheath (anti-myelin)
-> loss of muscle fxn
-> respiratory/GI infection

Type II

31
Q

Type and what happens in Goodpasture syndrome?

A

Type II HS

Antibodies bind to glomerular basement membrane (collagen)

32
Q

Pernicious anemia

A

Type II HS rxn

-Abs bind to parietal cells, inhibit intrinsic factor

33
Q

Pemphigus vulgaris

A

Type II HS rxn

Abs bind epidermal cells and disrupt tight junctions -> skin lesions

34
Q

Immune thrombocytopenic purpura

A

Type II HS rxn

Abs bind to platelets

35
Q

What are the 2 noncytotoxic hypersensitivities

A
  1. Autoantibodies become receptor antagonists and block a signal (Myasthenia gravis)
  2. Autoantibodies become receptor agonists and induce induce a signal (Grave’s disease)
36
Q

Myasthenia gravis

A

Type II HS rxn
=AchR block

non-cytotoxic mechanism: anti-acetylcholine receptor antibodies at neuromuscular junction:
-block binding of Ach on muscle receptors from neurons
-loss of Ach muscle surface receptors
-> muscle weakness: eye, face, upper limbs
-> difficulty speaking, chewing, swallowing

37
Q

Grave’s Disease

A

Type II HS rxn
=TSH receptor signaling

Autoantibodies (anti-thyroid stimulating hormone receptor) act as receptor agonists and induce a signal
-agonist = induces receptor signaling

-> hyperthryroidism - increased T, metabolism, bulging eyes

38
Q

Tx of Type II HS rxns

A
  1. IVIg - intravenous non-specific IgG - blocks/inhibits Fc receptors so unable to bind autoantibodies, inhibits phagocytosis & ADCC (antibody-dependent cellular toxicity)
  2. Plasmapheresis - removal of autoantibodies from plasma
  3. Rituximab - deplete B cells: antibody that binds CD20 on B cells, induces apoptosis, and is non-specific
  4. Other immunosuppressive drugs: corticosteroids
39
Q

What mediates Type III HS rxns?

A

IgG
-binds to soluble antigens to form IgG:antigen immune complexes that are not cleared

40
Q

How are Type II and Type III reactions different from each other?

A

Both mediated by IgG
1. Type II IgG binds to cell-associated antigens. Type III IgG binds to soluble antigens present at high levels
2. Type II IgG induces complement activation, opsonization, ADCC. Type III immune complexes activate complement in blood vessels, synovial fluid, and glomeruli

41
Q

Describe Type III HS rxns

A
  1. IgG binds to soluble antigens present at high levels to form immune complexes (Ab-Ag) that are not cleared
  2. the immune complexes activate complement in blood vessels, synovial fluid, and glomeruli
  3. complexes precipitate out of solution and accumulate in joints, blood vessel walls and glomeruli due to plasma filtration in the synovial fluid and glomerulus
  4. this complement activity drives vasculitis by recruiting C1, C5a and C3a mediate vasodilation and activate neutrophils
  5. neutrophils degranulate, release cytotoxic granules, ROS -> vascular necrosis vasculitis, rash, fever
  6. The hyperactivation of complement can -> C3 consumption, which is a dx marker for some disease
42
Q

What do Type III HS rxns induce?

A
  1. vasculitis
  2. joint inflammation: arthritis & arthralgias
  3. kidney inflammation: glomerulonephritis, proteinurea, kidney dysfunction
  4. Systemic inflammation - fever
43
Q

What types of genes are Type III hypersensitivities linked to?

A

Genes that
1. regulate immune tolerance
2. maintain normal clearance of immune complexes
3. scavenger genes important for removal of necrotic or apoptotic debris

44
Q

Serum sickness

A

Type III HS rxn

= a response to foreign antibodies
-can be provoked by non-human abs, non-human monoclonal antibodies, anti-thymocyte globulin
-ex. anti-snake venom created as anti-horse B cells (antibodies) that humans launch response to with T cell help to create anti-horse Ig
-> horse anti-venom/anti-horse immune complexes
-> rash, joint pain, fever typically 10-21 days after exposure

45
Q

Tx for serum sickness

A

NSAIDs
anti-histamine
corticosteroids

46
Q

Serum Sickness-like syndrome

A

Drug-induced

-similar signs and symptoms as serum sickness

-10-21 days after drug treatment

-antibiotics: penicillin, cephalosporins, etc

47
Q

What kind of reactions can drugs induce?

A
  1. Type I HS: Penicillin allergic response w/ penicillin-specific IgE
  2. Type II HS: destruction of penicillin-coated RBCs w/ penicillin-specific IgG
  3. Type III HS: Penicillin-induced serum sickness-like syndrome w/ Penicillin/IgG immune complexes
48
Q

Systemic Lupus Erythematosus (SLE)

A

Type III HS

  • we develop variety of antibodies against nuclear proteins:
    1. Anti-ribonucleoprotein (AKA Smith antibodies)
    2. Anti-dsDNA
    3. Anti-nuclear (non-specific) - in SLE and other AI diseases
49
Q

SLE Sx and Tx

A
  1. Skin:
    -Malar rash - facial butterfly
    -Discoid rash
    -Photosensitivity
  2. Kidney:
    -glomerulonephritis
    -proteinuria
  3. Other:
    - migrating arthralgias
    - -mucosa, serosa (ulcers, pleuritis)
    - neurological (seizures, psychosis)

Most common in females of childbearing age
-sx and autoantibodies very variable

Tx: corticosteroids

50
Q

Type III HS Summary

A
51
Q

What mediates Type IV HS reactions?

A

T cells:
Th mediate by releases IFN gamma & TNF

CTL directly mediate tissue damage by killing cells

52
Q

What is PPD?

A

= purified protein derivate
-tests for Mycobacterium tuberculosis antigens
-is a Type IV HS rxn

  1. inject PPD antigens and TB antigens
  2. antigens induce delayed HS rxn
  3. macrophages take up the antigens & release inflammatory cytokines
  4. Causes recruitment of memory Th1 cells specific for TB antigens
  5. Macrophages present antigens to Th1 cells, which make IFN gamma, which activates more macrophages
  6. localized inflammatory response and induration of skin

*If no memory Th1 activation, no induration
=delayed type hypersensitivity (DTH) b/c takes 1-2 days to induce T cell response

53
Q

Contact dermatitis

A

Type IV HS rxn

CD4+ and CD8+ T cells

ie. urushiol (Poison ivy) and Nickel

exposure -> recruit Th1 cells & CTLs that mediate tissue destruction
1. the compounds react w/ self-proteins to induce compound-specific T cell response
2. *Rxn requires prior exposure
3. Th1-mediated inflammation, CTL-mediated killing of keratinocytes, blistering rash

-often called “allergic” contact dermatitis but not an immediate (Type I) HS

54
Q

Rheumatoid arthritis

A

Type IV HS rxn, mostly mediated by Th1 cells

=chronic inflammation in small joints of hands, feet. Larger can also be involved.

-3:1 women:men

-synovial swelling, granulation in joints, rheumatoid nodules, elevated CRP & ESR, fatigue, fever

tx: NSAIDs, corticosteroids, TNF blockers

-Type II and III disease mechanisms may be present as well

-Autoantibodies: Rheumatoid factor (anti-IgG IgM), anti-cyclic citrullinated peptide (anti-CCP)

55
Q

What is rheumatoid factor?

A

an anti-IgG molecule bound to self IgM = autoreactive antibody

-present in multiple autoimmune diseases

56
Q

What drives Rheumatoid arthritis pathology?

A

Th1-derived Tumor Necrosis Factor

TNF produced by macrophages & Th1

TNF signals to many immune and non-immune cells

Enhances inflammatory function of immune cells in the joint (T cells, macrophages)

Induces chronic inflammatory response by synovial fibroblasts ->tissue destruction

Induces vasodilation -> joint inflammation

57
Q

Tx of RA

A

TNF blockers

58
Q

Type IV hypersensitivities in the gut

A
  1. IBD - Crohn’s, UC
  2. Celiac
59
Q

Crohn’s Disease

A

IBD, not autoimmune
-due to loss of tolerance to gut antigens
-dysregulated Th1 & Th17
-Th1 ->IFNgamma, TNF, IL-2&6
-Th17 -> IL-17,22,6, TNF
-> transmural skip lesions in sm. & large bowel
-> obstruction
-linked to MHC I molecule HLA-B27

60
Q

Ulcerative Colitis

A

IBD, not autoimmune
-loss of tolerance to gut antigens (like Crohn’s)
-dysregulated Th2 -> IL-4, 5, 13
-> mucosal inflammation, large bowel only
-> bloody diarrhea
-linked to HLA-B27

61
Q

Celiac disease

A

=autoimmune disease
-rxn to gluten or self antigens (autoimmune), like anti-transglutaminase

-Type IV: gluten-specific Th1
-Type II: autoantibodies may participate
-> small bowel, villous atrophy
-> foul-smelling diarrhea
-linked to MHC Class II

62
Q

Multiple Sclerosis

A

Type IV HS rxn
-myelin-specific Th1 and Th17 formed
-activation of microglial cells and macrophages
-> local inflammation, neutrophils
-> oligodendrite death, myelin destruction
-> 2 forms: relapsing/remitting & chronic progressive disease
-persistent T cell activation vs waves of T cell activation

63
Q

Type I diabetes

A

Type IV HS rxn

=beta cell destruction by autoreactive Th1 and CTLs w/ insulin-specific CTLS that kill beta cells
-environmental triggers and genetic susceptibility (MHC Class II)
->incidence in males, more severe in females
-> diabetic ketoacidosis

-islet transplant

64
Q

2 types of undefined HS reactions

A
  1. Ankylosing spondylitis - maybe Type IV?
  2. Reactive arthritis - maybe Type IV?
  3. Sjogren’s Syndrome
65
Q

Ankylosing spondylitis

A

=inflammatory arthritic of sacro-iliac joint
-> systemic inflammation
-most common in young men
-linked to HLA-B27

Tx: TNF and IL-17 blockers

66
Q

Reactive arthritis

A

=inflammatory arthritis in large joints - sacroiliac, knees
-infectious triggers = Salmonella, Shigella, Campylobacter, and Chlamydia trachomatis
-linked to HLA-B27

tx: NSAIDs, TNF blockers

67
Q

Sjogren’s syndrome

A

-secretory gland disorder -> dry eyes, dry mouth, mucosal surfaces
-autoantibodies (anti-Ro/SSA, anti-La/SSB) target nuclear antigens
-> lymphocytic infiltration of secreotry glands

68
Q

Type IV HS Summary

A
69
Q

Type II HS Summary

A
70
Q

Tolerance and HS rxn Summary

A

H&D (23 decks)

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