Immunology - Autoinflammatory + Autoimmune Flashcards
How are autoinflammatory and autoimmune diseases characterised?
Immunopathology in the absence of infection
Autoinflammatory = innate immune response
- Not characterised by auto-antibodies
- Weaker HLA associations
Autoimmune = Adaptive immune response
- Autoantibodies present
- HLA associations common
Mixed Disease = Mixed Innate/Adaptive
- Autoantibodies absent
- HLA associations possible
What are some rare monogenic autoinflammatory diseases?
- Familial mediterranean fever
- TRAPS
What are some polygenic autoinflammatory diseases?
- Crohn’s disease
- Ulcerative colitis
- Osteoarthritis
- Giant cell arteritis
- Takayasu’s arteritis
What are some mixed pattern diseases?
- Ankylosing spondylitis
- Psoriatic arthritis
- Behcet’s syndrome
What are some polygenic autoimmune diseases?
- Rheumatoid arthritis
- Myaesthenia Gravis
- Pernicious anaemia
- Graves disease
- SLE
- Primary biliary cirrhosis
- ANCA associated vasculitis
- Goodpasture disease
What are some rare monogenic autoimmune diseases?
- APS-1, APECED
- ALPS
- IPEX
What is the cause and characteristics of monogenic autoinflammatory diseases?
Cause:
- Mutations in gene encoding protein involved in pathway associated with innate immune cell function
Characteristics:
- Abnormal signalling via key cytokine pathways involving TNF +/- IL-1 is common
What is the pathogenesis of Familial Mediterranean Fever?
- Autosomal Recessive
- Mutation in MEFV gene
- Gene encodes pyrin-marenostrin
- Pyrin-marenostrin expressed mainly in neutrophils
- Failure to regulate cryopyrin driven activation of neutrophils
What is the clinical presentation of Familial Mediterranean Fever?
- Periodic fevers lasting 48-96hrs
- Abdo pain (peritonitis)
- Chest pain (Pleurisy + Pericarditis)
- Arthritis
- Rash
How is Familial Mediterranean Fever a long term risk of AA Amyloidosis?
- Liver produces serum amyloid A as acute phase protein
- Serum amyloid A deposits in kidneys, liver spleen
- Kidney deposition most clinically important
- Proteinuria = nephrotic syndrome
- Renal failure
What is the treatment for Familial Mediterranean Fever?
- Colchicine 500ug BD
- Anakinra (IL-1 receptor antagonist)
- Etanercept (TNF α inhibitor)
What is the MoA of Colchicine?
Binds ot tubulin in neutrophils + disrupts neutrophil functions (inc. migration + chemokine secretion)
What is a monogenic autoimmune disease?
Mutation of a protein involved in a pathway associated with adaptive immune cell function
What is APS1/APECED?
- Autoimmune Polyendocrine Syndrome Type 1
- Autoimmune PolyEndocrinopathy Candidiasis Ectodermal Dystrophy Syndrome
What is the abnormality in APS1/APECED?
Abnormality in central tolerance
What is the inheritance pattern of APS1/APECED?
Autosomal recessive
What is pathogenesis of APS1/APECED?
- Defect in autoimmune regulator AIRE
- AIRE = transcription factor involved in development of T cell tolerance in thymus
- Defect causes upregulation of expression of self-antigens by thymic cells + promotes T cell apoptosis
- Defect leads to failure of central tolerance causing auto-reactive T + B cells
What are the clinical features of APS1/APECED?
Multiple Auto-immune diseases:
- Hypoparathyroidism
- Addison’s
- Hypothyroidism
- Diabetes
- Vitiligo
- Enteropathy
Abs VS IL17 + IL22 leads to candidiasis
What is IPEX?
Immune dysregulation, polyendocrinopathy, enteropathy
What is the abnormality in IPEX?
Abnormality of regulatory T cells (failure of peripheral tolerance)
What is the inheritance of IPEX?
X-linked
What is the pathogenesis of IPEX?
- Mutations in Foxp3 causes failure to negatively regulate T cell responses
- Results in autoreactive B cells
- Foxp3 is required for development of Treg cells
What are some clinical features of IPEX?
Autoimmune diseases:
- Diabetes
- Hypothyroidism
- Enteropathy
- Diarrhoea
- Diabetes
- Dermatitis
What is ALPS?
Autoimmune lymphoproliferative syndrome
What is the abnormality in ALPS?
Abnormality of lymphocyte apoptosis
What is the inheritance pattern of ALPS?
Autosomal Dominant (incomplete penetrance)
What is the pathogenesis of ALPS?
Mutations within FAS pathway
- e.g. TNFRSF6 - encodes FAS
- Disease is heterogenous depending on mutation
Defect in apoptosis of lymphocytes resilts in failure of tolerance + lymphocyte homeostasis
What are some clinical features of ALPS?
- High lymphocyte numbers (CD4 + CD8 T cells)
- Splenomegaly
- Lymphadenopathy
- Autoimmune diseases (commonly autoimmune cytopenias)
- High risk: Lymphoma
What are polygenic auto-inflammatory diseases?
- Mutations in genes encoding proetins involved in innate immune cell function
- Local factors at sites predisposed to disease lead to activate of innate immune cells (e.g. macrophages + neutrophils) resulting in tissue damage
- HLA associations less strong
- Not characteristed by presence of auto-antibodies
What is peripheral tolerance?
- T cells can’t be activated without co-stimulation
- Action of regulatory T cells
- Sites of immune privilege (e.g. eyes, testes, CNS)
What is central tolerance?
The deletion of auto-reactive lymphocytes in sites of maturation
What mutations are associated with Crohn’s disease in polygenic autoinflammatory disease?
IBD1 gene (Chr 16) identified as NOD2 (CARD-15)
- NOD2 expressed in cytoplasm of myeloid cells
- NOD2 is an intracellular receptor for bacterial products (it recognises muramyl dipeptide) + stimulates NFKb
- Activation of NFKb results in autophagy in dendritic cells
What are mixed pattern diseases?
- Mutations in genes encoding proteins involved in pathways associated with innate immune cell function + adaptive immune cell function
- HLA associations may be present
- Auto-antibodies not usually a feature
What are polygenic autoimmune diseases?
- Mutations in genes encoding proteins invoveld in adaptive immune cell function
- HLA associations
- Aberrant B cell + T cell responses in primary + secondary lymphoid organs lead to breaking of tolerance with developemnt of immune reactivity towards self antigens
- Auto-antibodies found
What are the genetic polymorphisms involved in polygenic autoimmune diseases and how do they operate?
PTPN22:
- Lymphocyte specific tyrosine phosphatase with suppresses T cell activation
- Associated with development of RA, SLE, T1DM
CTLA4:
- Receptor for CD80/CD86 expressed by T cells which transmits inhibitory signal to control T cell activation
- Associated with SLE, T1DM, autoimmune thyroid disease
What HLA allele is associated with Ankylosing Spondylitis?
HLA B27
What HLA allele is associated with Goodpasture’s syndrome?
HLA DR15/DR2
What HLA allele is associated with Graves’ Disease?
HLA-DR3
What HLA allele is associated with SLE?
HLA-DR3
What HLA allele is associated with T1DM?
HLA DR3/DR4
What HLA allele is associated with Rheumatoid arthritis?
HLA DR4
(There are 4 walls in a Rheum)
What HLA alleles are associated with coeliacs disease?
DQ2/DQ8
( I 8 2 much gluten at Dairy Queen)
