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PathY5 > Autoimmune and Autoinflammatory Diseases 2 > Flashcards

Autoimmune and Autoinflammatory Diseases 2 Flashcards

1
Q

What are the polygenic autoimmune diseases?

A

Rheumatoid arthritis
Systemic lupus erythematosus
Myaesthenia Gravis
Primary biliary cholangitis
Pernicious anaemia
Addison disease

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2
Q

What is a polygenic autoimmune disease?

A

Mutations in genes encoding proteins involved in pathways associated with adaptive immune cell function

HLA associations are common

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

Auto-antibodies are found

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3
Q

What is PTPN22?

A

Protein tyrosine phosphatase non-receptor 22
Lymphocyte specific tyrosine phosphatase which suppresses T cell activation
Allelic variants found in: SLE, RhA and T1DM

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4
Q

What is CTLA4?

A

Cytotoxic T lymphocyte associated protein 4
Expressed by T cells and transmits inhibitory signal to control T cell activation
Allelic variants found in: SLE, AI thyroid disease, T1DM and RhA (kind of)

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5
Q

What is the susceptibility allele for:

  1. Goodpasture disease
  2. Graves disease
  3. Systemic lupus erythematosus
  4. Type I diabetes
  5. Rheumatoid arthritis
A
  1. HLA DR15 (RR = 10)
  2. HLA DR3 (RR = 4)
  3. HLA DR3 (RR = 6)
  4. HLA DR3/4 (RR = 25)
  5. HLA DR4 (RR = 4)
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6
Q

What is the pathophysiology of a polygenic autoimmune disease?

A

Genetic polymorphisms
Loss of tolerance
Auto reactive T cells
Auto antibody formation
Immunopathology
Disease

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7
Q

What is the Gel and Coombs classification?

A

Type I: Anaphylactic hypersensitivity
- Immediate hypersensitivity which is IgE mediated – rarely self antigen

Type II: Cytotoxic hypersensitivity
- Antibody reacts with cellular antigen

Type III: Immune complex hypersensitivity
- Antibody reacts with soluble antigen to form an immune complex

Type IV: Delayed type hypersensitivity
- T-cell mediated response

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8
Q

What is the Immunopathogenic mechanisms in Type II disease?

A

Antibody dependent destruction (NK cells, phagocytes, complement)

Receptor activation or blockade (sometimes considered Type V response)

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9
Q

What are the Type II antibody driven auto-immune disease?

A
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10
Q

What is Type III hypersensitivity reactions in autoimmune disease: Immune complex driven autoimmune disease?

A

Antibody binds to soluble antigen to form circulating immune complex

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11
Q

What are the Immunopathogenic mechanisms in type III responses?

A

Immune complex formation and deposition in blood vessels

Complement activation

Infiltration of macrophages and neutrophils

Cytokine and chemokine expression

Granule release from neutrophils

Increased vascular permeability

Inflammation and damage to vessels

Cutaneous vasculitis

Glomerulonephritis

Arthritis

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12
Q

What are Type III immune complex driven autoimmune diseases?

A
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13
Q

What is Type IV hypersensitivity reactions in autoimmunity CD8 T-cells?

A

HLA class I molecules present antigen to CD8 T cells

HLA class II molecules present antigen to CD4 T cells

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14
Q

What are Type IV T-cell mediated diseases?

A
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15
Q

Which diseases have organ specific antibodies?

A

Graves disease

Hashimotos thyroiditis

Type I diabetes

Pernicious anaemia

Myaesthenia gravis

Goodpasture disease

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16
Q

Which diseases have RhF and anti CCP?

A

RhA

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17
Q

Which diseases have ANA?

A

SLE

Sjogren’s syndrome

Systemic sclerosis

Dermato/Polymyostis

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18
Q

Which diseases have ANCA?

A

ANCA-associated vasculitis

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19
Q

What is Graves’ Disease?

A

S/S- Nervous, Palpitations, Heat intolerant, Diarrhoea

  • Excessive production of thyroid hormones
  • Mediated by IgG antibodies which stimulate the TSH receptor

–Evidence

  • Antibodies stimulate thyrocytes in vitro
  • Passive transfer of IgG from patients to rats often produces similar symptoms (!)
  • Babies born to mothers with Graves’ may show transient hyperthyroidism
20
Q

What is the pathology of GRaves’?

A
  • Stimulating autoantibodies against TSH-receptor bind to receptor
  • Act as TSH agonists
  • Induce uncontrolled overproduction of thyroid hormones
  • Negative feedback cannot override antibody stimulation
21
Q

What is Hashimoto’s thyroiditis?

A

S/S

  • Lethargic
  • Dry skin and hair
  • Constipation
  • Cold intolerant
  • Commonest cause of hypothyroidism in iodine-replete areas
  • Goitre – enlarged thyroid infiltrated by T and B cells
  • Associated with anti-thyroid peroxidase antibodies

–Presence correlates with thyroid damage and lymphocyte inflammation

–Some shown to induce damage to thyrocytes

•Associated with presence of anti-thyroglobulin antibodies

22
Q

But is measuring anti-thyroglobulin and anti-thyroid peroxidase antibodies clinically useful?

A

Few indications for testing for these thyroid antibodies because high prevalence in normal individuals. Just do thyroid biochemistry

23
Q

What is T1DM?

A

S/S:

  • Thirsty
  • Polyuria
  • Malaise
  • Urine dipstick confirms glycosuria
  • Insulin dependent diabetes mellitus
24
Q

Cells in T1DM?

A

CD8+ T-cell infiltration of pancreas

T cell clones have specificity for islet antigens

25
Q

How are islet cells involved?

A

Auto-antigens

Glutamic acid dehydrogenase (GAD 65)

Islet antigen 2 (IA2)

CD8+ cytotoxic T lymphocyte

Glucagon

Insulin

Somatostatin

CD8 T-cell mediated type IV pathology – recognise autoantigens presented by

MHC Class I molecules on beta cells

26
Q

More of T1DM

A

Antibodies pre-date development of disease

Anti-islet cell antibodies

Anti-insulin antibodies

Anti-GAD antibodies

Anti-IA-2 antibodies

Individuals with 3-4 of the above are highly likely

to develop type I diabetes

Detection of antibodies does not currently play a role in diagnosis

27
Q

What are important antibodies in endocrine disease?

A
28
Q

What is pernicious anaemia?

A
  • Failure of vitamin B12 absorption
  • Vitamin B12 deficiency
  • Macrocytic anaemia
  • Neurological features with subacute combined degeneration of cord (posterior and lateral columns), peripheral neuropathy, optic neuropathy

•

•Antibodies to gastric parietal cells or intrinsic factor - are useful in diagnosis

29
Q
A
30
Q

What are the important autoantibodies in GI disease?

A
31
Q

What are the important autoantibodies in Liver disease?

A
32
Q

What is MG?

A

Anti-acetylcholine receptor antibodies present in

~75% patients and are useful in diagnosis

Offspring of affected mothers may experience

transient neonatal myaesthenia

33
Q

What are the important autoantibodies in neurology disease?

A
34
Q

What is happening here:

  • 48 year old man
  • Haemoptysis with widespread crackles in lungs
  • Swelling of legs
  • Reduced urine output
  • Creatinine 472
  • Microscopic haematuria and proteinuria
  • CXR – widespread shadowing
  • Elevated TLCO suggesting pulmonary haemorrhage
A

Goodpastures

35
Q

What would you get on Ix in goodpastures?

A
  • Anti-basement membrane antibody positive
  • Crescentic nephritis on biopsy

•

•Antibodies specific for glomerular basement membrane disease underpin the pathology and are useful in diagnosis of anti-glomerular basement membrane disease (Goodpasture’s disease)

36
Q

How do we detect Autoantibodies in the kidney?

A

Antibodies may also be detected in tissue sections.

Antibodies have been deposited along the basement membrane to give ‘smooth linear staining’ visible when the secondary fluorescein conjugated anti-human immunoglobuline is added

Smooth linear deposition of antibody along

the glomerular basement membrane

Type II hypersensitivity

37
Q

What are the autoantibodies in renal disease?

A
38
Q

What is the genetics of RhA?

A

•HLA DR4 (DRB1 0401, 0404, 0405) and HLA DR1 (DRB1 0101) alleles

•

•Peptidyl arginine deiminase (PAD)2 and PAD4 polymorphisms

•

•PTPN22 polymorphism

39
Q

Why is HLA DR4 and HLA DR1 important?

A
  • Susceptible alleles share a sequence at positions 70-74 of the HLA DR beta chain
  • These alleles may bind ‘arthritogenic peptides’ and have been shown to bind to citrullinated peptides with high affinity
40
Q

Why is Peptidylarginine deiminases PAD type 2 and 4 important in RhA?

A

Peptidylarginine deiminases PAD type 2 and 4

Enzymes involved in deimination of arginine to create citrulline

Polymorphisms are associated with increased citrullination

This creates a high load of citrullinated proteins

41
Q

What environmental factors increase citrullination?

A

•Smoking associated with development of erosive disease

–Smoking associated with increased citrullination

•

•Gum infection with Porphyromonas gingivalis associated with rheumatoid arthritis

–P gingivalis is only bacterium known to express PAD enzyme and thus promote citrullination

42
Q

What are antibodies in RhA?

A

•Antibodies to cyclic citrullinated peptide

–Bind to peptides in which arginine has been converted to citrulline by peptidylarginine deiminase (PAD)

–Around 95% specificity for diagnosis of rheumatoid arthritis

–Around 60-70% sensitivity for diagnosis of rheumatoid arthritis

–Best blood test for diagnosis of Rheumatoid arthritis

43
Q

How is RhF dysfunctional in RhA?

A
  • A rheumatoid factor is an antibody directed against the common (Fc) region of human IgG
  • IgM anti-IgG antibody is most commonly tested although IgA and IgG rheumatoid factors may also be present in some individuals
  • Around 60-70% specificity and sensitivity for diagnosis of rheumatoid arthritis
44
Q

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

Goodpasture disease

Eczema

SLE

Multiple sclerosis

Graves disease

A

Goodpasture disease

Graves disease

45
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

46
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

47
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

PathY5 (98 decks)

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