Autoimmune and Autoinflammatory Diseases 2 Flashcards
What are the polygenic autoimmune diseases?
Rheumatoid arthritis
Systemic lupus erythematosus
Myaesthenia Gravis
Primary biliary cholangitis
Pernicious anaemia
Addison disease
What is a polygenic autoimmune disease?
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
What is PTPN22?
Protein tyrosine phosphatase non-receptor 22
Lymphocyte specific tyrosine phosphatase which suppresses T cell activation
Allelic variants found in: SLE, RhA and T1DM
What is CTLA4?
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)
What is the susceptibility allele for:
- Goodpasture disease
- Graves disease
- Systemic lupus erythematosus
- Type I diabetes
- Rheumatoid arthritis
- HLA DR15 (RR = 10)
- HLA DR3 (RR = 4)
- HLA DR3 (RR = 6)
- HLA DR3/4 (RR = 25)
- HLA DR4 (RR = 4)
What is the pathophysiology of a polygenic autoimmune disease?
Genetic polymorphisms
Loss of tolerance
Auto reactive T cells
Auto antibody formation
Immunopathology
Disease
What is the Gel and Coombs classification?
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
What is the Immunopathogenic mechanisms in Type II disease?
Antibody dependent destruction (NK cells, phagocytes, complement)
Receptor activation or blockade (sometimes considered Type V response)
What are the Type II antibody driven auto-immune disease?
What is Type III hypersensitivity reactions in autoimmune disease: Immune complex driven autoimmune disease?
Antibody binds to soluble antigen to form circulating immune complex
What are the Immunopathogenic mechanisms in type III responses?
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
What are Type III immune complex driven autoimmune diseases?
What is Type IV hypersensitivity reactions in autoimmunity CD8 T-cells?
HLA class I molecules present antigen to CD8 T cells
HLA class II molecules present antigen to CD4 T cells
What are Type IV T-cell mediated diseases?
Which diseases have organ specific antibodies?
Graves disease
Hashimotos thyroiditis
Type I diabetes
Pernicious anaemia
Myaesthenia gravis
Goodpasture disease
Which diseases have RhF and anti CCP?
RhA
Which diseases have ANA?
SLE
Sjogren’s syndrome
Systemic sclerosis
Dermato/Polymyostis
Which diseases have ANCA?
ANCA-associated vasculitis
What is Graves’ Disease?
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
What is the pathology of GRaves’?
- Stimulating autoantibodies against TSH-receptor bind to receptor
- Act as TSH agonists
- Induce uncontrolled overproduction of thyroid hormones
- Negative feedback cannot override antibody stimulation
What is Hashimoto’s thyroiditis?
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
But is measuring anti-thyroglobulin and anti-thyroid peroxidase antibodies clinically useful?
Few indications for testing for these thyroid antibodies because high prevalence in normal individuals. Just do thyroid biochemistry
What is T1DM?
S/S:
- Thirsty
- Polyuria
- Malaise
- Urine dipstick confirms glycosuria
- Insulin dependent diabetes mellitus
Cells in T1DM?
CD8+ T-cell infiltration of pancreas
T cell clones have specificity for islet antigens
How are islet cells involved?
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
More of T1DM
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
What are important antibodies in endocrine disease?
What is pernicious anaemia?
- 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
What are the important autoantibodies in GI disease?
What are the important autoantibodies in Liver disease?
What is MG?
Anti-acetylcholine receptor antibodies present in
~75% patients and are useful in diagnosis
Offspring of affected mothers may experience
transient neonatal myaesthenia
What are the important autoantibodies in neurology disease?
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
Goodpastures
What would you get on Ix in goodpastures?
- 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)
How do we detect Autoantibodies in the kidney?
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
What are the autoantibodies in renal disease?
What is the genetics of RhA?
•HLA DR4 (DRB1 0401, 0404, 0405) and HLA DR1 (DRB1 0101) alleles
•
•Peptidyl arginine deiminase (PAD)2 and PAD4 polymorphisms
•
•PTPN22 polymorphism
Why is HLA DR4 and HLA DR1 important?
- 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
Why is Peptidylarginine deiminases PAD type 2 and 4 important in RhA?
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
What environmental factors increase citrullination?
•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
What are antibodies in RhA?
•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
How is RhF dysfunctional in RhA?
- 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
Which of the following is an example of Gel and Coombs type II hypersensitivity?
Goodpasture disease
Eczema
SLE
Multiple sclerosis
Graves disease
Goodpasture disease
Graves disease
Which of the following is an example of Gel and Coombs type III hypersensitivity
Goodpasture disease
Eczema
SLE
Multiple sclerosis
Graves disease
SLE
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
Anti-acetylcholine receptor antibody
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
Anti-intrinsic factor antibody
