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YR5 Immunology > Autoimmune and Autoinflammatory Disease 2 > Flashcards

Autoimmune and Autoinflammatory Disease 2 Flashcards

1
Q

What is the pathophysiology of polygenic auto-immune diseases?

A

Mutations in genes encoding proteins involved in pathways a/w adaptive immune cell function.

HLA associations are common.

Aberrant B + T cell responses in primary + secondary lymphoid organs lead to breaking of tolerance with development of immune reactivity towards self-antigens.

Auto-antibodies are found.

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2
Q

What are the 2 genetic requirements for polygenic autoimmune disease to develop?

A
  1. SENSITISATION to antigens: certain HLA alleles increase disease risk, thus HLA associations are more common. Immune system ready to attack self antigen
  2. OVERCOMING PERIPHERAL TOLERANCE (mutations in mechanisms that inhibit peripheral immune system)
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3
Q

What are the genetic polymorphisms of polygenic auto-immune disease?

A

PTPN 22

  • Protein tyrosine phosphatase non-receptor 22.
  • Suppresses T cell activation.
  • SLE, T1DM, RA.

CTLA4

  • Cytotoxic T lymphocyte associated protein 4. Expressed by T cells + transmits inhibitory signal to control T cell activation.
  • SLE, T1DM, RA, AI thyroid disease.
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4
Q

What is the association between polygenic auto-immune diseases and HLA presentations?

A

HLA presentation of antigen is required for development of T cell + T cell-dependent B cell responses.

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5
Q

What is the susceptibility allelle and relative risk (fold) increase of Goodpasture Disease?

A

HLA -DR15

10

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6
Q

What is the susceptibility allelle and relative risk (fold) increase of Grave’s Disease?

A

HLA-DR3

4

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7
Q

What is the susceptibility allelle and relative risk (fold) increase of SLE?

A

HLA-DR3

6

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8
Q

What is the susceptibility allelle and relative risk (fold) increase of T1DM?

A

HLA -DR3/DR4

25

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9
Q

What is the susceptibility allelle and relative risk (fold) increase of RhA?

A

HLA-DR4

4

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10
Q

What is the Gel and Coobs classification for hypersensitivities?

A

TI: Anaphylactic
Immediate hypersensitivity, allergy, IgE mediated. Mast cells + Eosinophils. (Rarely self antigen)

TII: Cytotoxic
Antibody reacts with CELLULAR antigen.

TIII: Immune complex.
Antibody reacts with SOLUBLE antigen to form an immune complex.

TIV: Delayed type.
T-cell mediated response.

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11
Q

Describe the immunopathogenic mechanisms of receptor activation or blockade in Type II hypersensitivity reaction (aka Type V)

A

Antibody activates receptor on binding e.g. Graves

Antibodies to TSHr - stimulates action of thyroid stimulating hormone- production of T3 + T4

(reaction with Cellular antigen, but not cytotoxic)

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12
Q

Which immunopathogenic mechanisms of antibody dependent destruction occur in Type II hypersensitivity reactions?

A

Fc Complement activation + cell lysis

Bind Fc receptors on NK cells- release of cytotoxic granules + membrane attack

Bind Fc receptors on macrophages- phagocytosis

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13
Q

What generally results from immune complex formation in type III hypersensitivity reactions?

A

Complexes deposit in vessels

Activate complement + innate cells

Cytokine release, increased vascular permeability

Can cause small amount of bleeding + purpuric rash

Cutaneous vasculitis: complexes in vessels irritating skin

Glomerulonephritis: complexes in kidney

Arthritis: complexes in joints

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14
Q

What are 4 Type II antibody driven auto-immune diseases?

A

Goodpasture Disease

Pemphigus vulgaris

Graves Disease

Myaesthenia Gravis

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15
Q

Which auto-antigen and clinical manifestation is associated with Goodpasture Disease?

A

Noncollagenous domain of BM collagen type IV (in lungs + kidneys)

Glomerulonephritis

Pulmonary hemorrhage.

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16
Q

Which auto-antigen and clinical manifestation is associated with Grave’s Disease?

A

Thyroid stimulating hormone (TSH) receptor

Hyperthyroidism

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17
Q

Which auto-antigen and clinical manifestation is associated with pemphigus vulgaris?

A

Epidermal cadherin (skin)

Blistering of skin

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18
Q

Which auto-antigen and symptoms are associated with myaesthenia gravis?

A

Acetylcholine receptor

Muscle weakness

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19
Q

What is a Type III immune complex driven autoimmune disease?

A

SLE

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20
Q

Which auto-antigen and clinical manifestations are associated with SLE?

A

DNA, Histones, RNP

Rash, glomerulonephritis, arthritis

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21
Q

What are the 2 T cell mediated mechanisms in Type IV hypersensitivity reactions?

A

HLA I present antigen to CD8 T cells
Cytolytic granule release (Perforin/ Fas pathways)

HLA II present antigen to CD4 T cells

Produce IFN gamma- macrophages release TNF + inflammatory cytokines, upregulate HLA

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22
Q

What is a Type IV T-cell mediated disease?

A

T1DM

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23
Q

Which auto-antigen and symptoms are associated with T1DM?

A

Pancreatic b-cell antigen

b-cell destruction: CD8+ T-cells

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24
Q

What are 6 organ specific diseases mediated by organ specific antibodies?

A

Graves

Hashimotos thyroiditis

T1DM

Pernicious anaemia

Myaesthenia gravis

Goodpasture disease

25
Q

Which antibodies are specific for Rheumatoid Arthritis?

A

Rheumatoid factor

Anti-CCP antibody

26
Q

What are 4 multisystem diseases mediated by anti-nuclear antibodies?

A

SLE

Sjogren’s syndrome

Systemic sclerosis

Dermato/Polymyostis

27
Q

What antibodies are specific for ANCA-associated vasculitis?

A

Anti-neutrophil cytoplasmic antibody

(ANCA)

28
Q

What is the pathophysiology of Graves Disease?

A

Excessive production of thyroid hormones.

  • Stimulating IgG autoantibodies stimulate TSH-receptor
  • Induce uncontrolled overproduction of thyroid hormones.
  • -ve feedback (Thyroxine) CAN’T override antibody stimulation.
29
Q

What is the evidence that Graves Disease is mediated by IgG antibodies?

A
  • Antibodies stimulate thyrocytes in vitro.
  • Passive transfer of IgG from patients to rats often produces similar Sx.
  • Babies born to mothers with Graves’ may show transient hyperthyroidism.
30
Q

What is the commonest cause of hypothyroidism in iodine-replete areas?

A

Hashimoto’s Thyroiditis

31
Q

What is the pathophysiology of Hashimoto’s Disease?

A

T + B cell infiltration of Thyroid leads to Goitre.

A/w anti-thyroid peroxidase antibodies + anti-thyroglobulin antibodies:

  • Presence correlates with thyroid damage + lymphocyte inflammation.
  • Some shown to induce damage to thyrocytes.
32
Q

How is Hashimoto’s Thyroiditis considered to exhibit the bystander phenomenon?

A

TIV reaction damages Thyrocytes + expose cellular components (not usually exposed to immune system e.g. Thyroid peroxidase)

This can stimulate secondary antibody formation e.g. anti-thyroid peroxidase

33
Q

Describe the T cell involvement in pancreatic islet cell destruction in T1DM

A

CD8 T cells recognise auto-antigens presented by HLA I molecules on beta cells (GAD + IA2)
Kill beta cells

34
Q

How are antibodies related to the development of T1DM?

A

Antibodies pre-date development of disease.

Detection of antibodies not diagnostic as not all have them

35
Q

What is the pathophysiology of T1DM?

A

Cellular antigen-antibody (TII) + T cell element - both contribute

  • Anti-islet cell antibodies
  • Anti-insulin antibodies
  • Anti-GAD antibodies
  • Anti-IA-2 antibodies

3-4 of above: highly likely to develop T1DM

36
Q

Which diseases are the following autoantibodies associated with?

a) Anti-TSH R antibody (Anti-thyroid stimulating hormone receptor antibody)

b) Anti-thyroglobulin antibodies

c) Anti-thyroid peroxidase antibodies

A

a) Graves disease (hyperthyroidism)

b) Hashimoto disease

c) Hashimoto disease

37
Q

What is the pathophysiology of pernicious anaemia?

A

Failure of Vit B12 absorption: B12 deficiency.

Causes Macrocytic anaemia.

Antibodies to gastric parietal cells or intrinsic factor- useful in dx.

38
Q

What is a severe complication of pernicious anaemia?

A

Subacute combined degeneration of cord (posterior + lateral columns):

Peripheral neuropathy

Optic neuropathy.

39
Q

Why is it important to check for antibodies in vitamin B12 deficiency?

A

If immune mediated (anti-IF or anti-parietal cell) won’t absorb B12 oral supplements
Needs IM B12

40
Q

Which antibody is more sensitive for PA? Which is more specific?

A

Sensitive: Anti-gastric parietal cell

Specific: Anti-IF

41
Q

Which gastroenterological diseases are the following autoantibodies associated with?

a) Anti-intrinsic factor antibody

b) Anti-gastric parietal cell antibody

c) Anti-TTG (anti-tissue transglutaminase antibody)

d) Anti-endomyosial antibody

e) P-ANCA (anti-neutrophil cytoplasmic antibody, perinuclear staining)

A

Anti-IF: Pernicious anaemia

Anti-gastric parietal cell: Pernicious anaemia

Anti-TTG: Coeliac

Anti-endomyosial: Coeliac

P-ANCA: UC > Crohns

42
Q

Which liver diseases are the following auto-antibodies associated with?

a) ANA (anti-nuclear antibodies)

b) SMA (smooth muscle antibodies)

c) Anti-LKM (antibodies vs liver kidney microsomal proteins)

d) AMA (anti-mitochondrial antibody

e) P-ANCA (anti-neutrophil cytoplasmic antibody, perinuclear staining)

A

ANA: AI hepatitis, Primary biliary cholangitis

SMA: AI hepatitis

Anti-LKM: AI hepatitis

AMA: Primary biliary cholangitis

P-ANCA: AI hepatitis, Primary biliary cholangitis

43
Q

Describe what happens following arrival of an action potential in myasthenia gravis?

A

Antibodies bind to ACh receptors

ACh released, but can’t bind

Failure of depolarisation + absence of muscle action potential

Causes muscle weakness

44
Q

Characterise the weakness in Myasthenia Gravis

A

Weakness esp on repetitive activity

Sx worse at end of day

Becomes harder + harder to activate post synaptic neurone with each use- less available receptors due to antibody binding.

45
Q

What is the pathophysiology of myaesthenia gravis?

A

Anti-acetylcholine receptor antibodies present in ~75%: useful in dx.

Offspring of affected mothers may experience transient neonatal myaesthenia.

46
Q

What are the antibodies seen in Lambert Eaton syndrome? How does this weakness present?

A

VGCC

The more you use the muscle, the less fatigued it gets

47
Q

Small print

Which diseases are the following auto-antibodies associated with?

a) Anti-acetylcholine receptor antibody

b) Anti-striational antibody

c) Anti-AQP4 (aquaporin)

d) Anti-MOG (myelin oligodendrocyte glycoprotein)

e) Anti-NMDA receptor (Anti-N-methyl D-aspartate (NMDA) receptor)

f) Anti-GABA receptor (gamma aminobutyric acid receptor)

A

a) Myaesthenia Gravis

b) Myaesthenia Gravis with myositis

c) Neuromyelitis optica spectrum disorder (NMOS)

d) Optic neuritis, encephalomyelitis

e) Encephalitis (may be malignancy associated)

f) Seizures (may be malignancy associated)

48
Q

What antibodies underpin the pathology of Goodpasture’s disease? What is seen on renal biopsy?

A

Anti-(glomerular) basement membrane antibodies (Anti-GBM)

GBM expressed in lung + kidney

Biopsy: Crescentic nephritis

49
Q

Give 3 features of Goodpasture’s disease

A

Glomerulonephritis

Pulmonary haemorrhage

Haemoptysis

50
Q

What diseases are the following auto-antibodies associated with?

a) Anti-glomerular basement membrane (GBM) antibody

b) P-ANCA (anti neutrophil cytoplasmic antibody, perinuclear staining, anti-myeloperoxidase)

c) C-ANCA (anti-neutrophil cytoplasmic antibody, cytoplasmic staining, anti-proteinase 3)

A

a) Goodpasture disease.

b) ANCA associated vasculitis: Microscopic polyangiitis / Eosinophilic granulomatosis with polyangiitis.

c) ANCA associated vasculitis: Granulomatosis with polyangiitis

51
Q

What are the genetic components are associated with RA?

A

HLA DR4 (DRB1 0401, 0404, 0405) alleles

HLA DR1 (DRB1 0101) alleles

Peptidyl arginine deiminase (PAD)2 + PAD4 polymorphisms

PTPN22 polymorphism.

52
Q

What is the pathophysiology of rheumatoid arthritis?

A

PAD 2 + 4: Enzymes that deaminate arginine to citrulline.

Polymorphisms a/w increased citrullination.

HLA alleles bind arthitogenic citrullinated peptides, present to T cells

High load of citrullinated proteins increases risk of RA

53
Q

What environmental factors increase citrullination in rheumatoid arthritis?

A

Smoking a/w development of erosive disease + increased citrullination.

Porphyromonas gingivalis gum infection a/w RA. P. gingivalis is only bacterium known to express PAD enzyme + thus promote citrullination.

54
Q

Which antibodies are in RA?

A

Antibodies to cyclic citrullinated peptide (Anti-CCP):

  • Bind to peptides in which arginine has been converted to citrulline by PAD.
  • ~95% specificity
  • ~60-70% sensitivity
  • Best blood test for dx of RA
55
Q

What is rheumatoid factor?

A

IgM antibody directed against the common (Fc) region of human IgG.

IgM anti-IgG antibody is most commonly tested although IgA + IgG RFs can present in some individuals.

~60-70% specificity + sensitivity

56
Q

Is diagnosis of RA based on presence of anti-CCP or RF alone?

A

No

Significant no. patients are seronegative (have neither)

57
Q

Which of the following is an example of Gel and Coombs type III hypersensitivity?

  • Goodpasture disease
  • Eczema
  • SLE
  • Multiple sclerosis
  • Graves disease
A

SLE

58
Q

Which of the following antibodies are characteristically found in Myaesthenia Gravis?

  • Anti-GAD antibody
  • Anti-thyroglobulin antibody
  • Anti-basement membrane antibody
  • Anti-intrinsic factor antibody
  • Anti-acetylcholine receptor antibody
  • Anti-cyclic citrullinated peptide antibody
  • Anti-TSH receptor antibody
A

Anti-acetylcholine receptor antibody

59
Q

Which of the following antibodies are characteristically found in Pernicious Anaemia?

  • Anti-GAD antibody
  • Anti-thyroglobulin antibody
  • Anti-basement membrane antibody
  • Anti-intrinsic factor antibody
  • Anti-acetylcholine receptor antibody
  • Anti-cyclic citrullinated peptide antibody
  • Anti-TSH receptor antibody
A

Anti-intrinsic factor antibody

YR5 Immunology (14 decks)

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