Imm - Autoinflammatory and Autoimmune Disease 1 Flashcards
Define immunopathology
damage to the host caused by the immune response
What are the similarities and differences between auto-inflammatory and auto-immunity
Both are immunopathology in the absence of infection
Auto-inflammatory = abnormality in the innate immune system (macrophages, neutrophils)
Auto-immune = abnormality in the adaptive immune system (aberrant T and B cell response) where they may be a breaking of tolerance → immune reactivity toward self-antigens
How does genetics contribute to auto-inflammatory or auto-immune diseases
Most are polygenic, but may also be monogenic
Genetics: mutation in DNA (germline or somatic)
Epigenetics: heritable changes in gene expression e.g. via methylation
MicroRNA: small, non-coding, ssRNA that targets mRNA and regulates protein production
Give examples of monogenic immunological disease and state whether they are auto-inflammatory or auto-immune
Familial mediterranean fever (auto-inflammatory)
APECED/APS-1 (auto-immune)
IPEX (auto-immune)
ALPS (auto-immune)
Describe the pathogenesis of familial Mediterranean fever
Autosomal recessive
Mutation in the MEFV gene → pyrin-marenostrin inactivated (normally expressed in neutrophils) → increased pro-caspase 1 → increased inflammation → lots of neutrophils
Characterised by IL-1, (NF-kappa-B) TNFa, apoptosis
What are the clinical features of familial Mediterranean fever
Periodic fevers lasting 48-96 hours
Abdominal pain (peritonitis)
Chest pain (pleurisy and pericarditis)
Arthritis
Rash
What investigations should be done for familial Mediterranean fever and what would they show
CRP: high
Serum amyloid A (SAA): high
Blood sample testing for MEVF mutations
What condition does familial Mediterranean fever increase the risk of
AA amyloidosis
Liver produces serum amyloid A as an acute phase protein → deposits in kidneys, liver, spleen
Kidney deposition → proteinuria (nephrotic syndrome), renal failure
What conditions are associated with AA amyloidosis
Autoimmune diseases – rheumatoid arthritis, ankylosing spondylitis, IBD (CD & UC)
Autoinflammatory diseases – familial Mediterranean fever(FMF), Muckle–Wells syndrome(MWS)
Chronic infections – TB, bronchiectasis, chronic osteomyelitis
Cancer – Hodgkin’s lymphoma, Renal cell carcinoma
Chronic foreign body reaction
HIV/AIDS
What is the management for familial Mediterranean fever
Colchicine (binds to tubulin in neutrophils → disrupts function + secretion)
IL-1 and TNFa inhibitors (Anakinra, Etanercept respectively)
What is IPEX
Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX)
Mutation in FOXP3 (required for T-reg cell development) → abnormality in T-reg cells
Failure to negatively regulate T cell reponse → auto-reactive B cells → autoantibody formation
How does IPEX present
With other autoimmune diseases
Enteropathy
Diabetes mellitus
Dermatitis
Hypothyroidism
What is ALPS
Autoimmune lymphoproliferative syndrome (ALPS)
Mutation in FAS pathway (e.g. TNFRSF6 mutation) → Abnormality of lymphocyte apoptosis (failure of tolerance + lymphocyte homeostasis)
What are the clinical features of ALPS
Lymphocytosis + large spleen + lymph nodes
Autoimmune diseases (i.e. autoimmune cytopenias)
Lymphoma
What is APECED/APS-1
Autoimmune-polyendocrine syndrome type 1 (APS1) or Autoimmune-polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED)
Autosomal recessive
Defect in autoimmune regulator AIRE (transcription factor involved in thymus T-cell tolerance) → failure of central tolerance → autoreactive T and B cells
Which conditions does APECED predispose toward
Hypoparathyroidism
Addison’s
Candidiasis
Hypothyroidism
Diabetes
Vitiligo
Enteropathy
Give examples of polygenic autoinflammatory disease
Crohn’s disease
ulcerative colitis
Osteoarthritis
Giant cell arteritis
Takyasu’s arthritis
Which group of immune diseases are not characterised with autoantibodies
Polygenic auto-inflammatory (innate immune system) and mixed pattern disease
What have familial association studies shown about Crohn’s disease
> 200 polymorphisms
Monozygotic twins: 50%
Dizygotic twins: 10%
What is the most significant gene mutation associated with Crohn’s disease
IBD1 gene on Chr16 (NOD16/CARD-15)
3 different mutations of this gene are associated
NOD2 mutations are present in 30% of patients (but is not necessary)
Increased risk if 2 copies instead of 1
Also found in Blau syndrome and sarcoidosis
What is NOD2
Cytoplasmic microbial sensor (expressed in the cytoplasm of myeloid cells - macrophages, neutrophils, dendritic cells)
Recognises muramyl dipeptide → stimulates NFK-beta
Activation induces autophagy in dendritic cells
What are the clinical features of Crohn’s disease
Abdominal pain, tenderness
Diarrhoea – blood, pus, mucus
Fevers and malaise
What are the treatments for Crohn’s disease
1) Diet-induced remission (80-100% works; whole protein modular diet)
- Corticosteroid
- Anti-TNF-a antibody
2) Maintain remission with aminosalicylates (i.e. mesalazine)
Give examples of mixed pattern immunological diseases
Ankylosing spondylitis
Psoriatic arthritis
Behcets syndrome
In what proportion of people with ankylosing spondylitis are genetic polymorphisms found
> 90% → very heritable
Which alleles/receptors are associated with ankylosing spondylitis
HLA B27 (presents antigen to CD8 T cells) - RR 87
IL23R (receptor for IL23 which promotes Th17 differentiation)
ILR2 (inhibits IL1 activity)
What are the clinical features of ankylosing spondylitis
Low back pain and stiffness
Enthesitis
Large joint arthritis
What is the treatment for ankylosing spondylitis
NSAIDs
Immunosuppression (anti-TNFa or antiIL17)
Give examples of polygenic autoimmune diseases
Rheumatoid arthritis
Myasthenia Gravis
Pernicious anaemia
Addison’s disease
What are the HLA associations for the following: Goodpasture’s disease, Grave’s disease, SLE, T1DM, Rheumatoid arthritis
Goodpasture’s: HLA-DR15 (RR 10)
Grave’s: HLA-DR3 (4)
SLE: HLA-DR3 (6)
T1DM: HLA-DR3/4 (25)
RA: HLA-DR4 (4)
What is PTPN22 and what is it associated with
Protein tyrosine phosphatase non-receptor 22
Suppresses T cell activation
SLE, rheumatoid arthritis, T1DM
What is CTLA4 and what is it associated with
Cytotoxic T lymphocyte associated protein 4
Transmits inhibitory signals to control T cell activation
Auto-immune thyroid disease
SLE
T1DM
What is Gel and Coombs classification
Classifies Hypersensitivity reactions according to type of immune response
Antibody or T cell mediated
What are Type 1 hypersensitivity reactions
Rapid allergic reaction e.g. anaphylaxis, atopic asthma
Involves pre-existing IgE → binds to Fc R on mast cells and basophils → cell degranulation
Increased vascular permeability, leukocyte chemotaxis and SM contraction
Usually pollens, drugs, food, insect, animal hair (or self-antigens with eczema)
Which inflammatory mediators are released in type I hypersensitivity reactions
Pre-formed → histamine, serotonin, proteases
Synthesised → leukotrienes, prostaglandins, bradykinin, cytokines
What are type 2 hypersensitivity reactions
Antibody reacts with cells with displayed complement (cellular antigen) → destruction OR activation/blockage
e.g. Goodpasture’s disease, Grave’s disease
What are the two mechanisms of type 2 hypersensitivity reaction
- Antibody-dependent destruction (NK cells, phagocytes, complement)
- Receptor activation or blockade (may be considered type V response)
Which auto-antibody is associated with the following: Goodpasture’s disease, Pemphigus vulgaris, Graves disease, Myasthenia Gravis, membranous glomerulonephritis
Goodpasture’s: non-collagenous domain of the basement membrane collagen type IV
Pemphigus vulgaris: epidermal cadherin
Grave’s: TSH
Myasthenia Gravis: acetylcholine receptor
Membranous glomerulonephritis: Phospholipase A2-receptor Type M
What are type 3 hypersensitivity reactions
Immune complex hypersensitivity, involving deposition of antigen/antibody complexes in tissue
e.g. SLE, serum sickness
Antibody binds to soluble antigen → immune complex → immune complex deposits in blood vessels:
What does damage to vessels in type 3 hypersensitivity reactions cause
Cutaneous vasculitis
Glomerulonephritis
Arthritis
Which auto-antigens are associated with SLE and rheumatoid arthrits
SLE: ds-DNA, histones, RNP
RA: Fc region of IgG
What are type 4 hypersensitivity reactions
Delayed type hypersensitivity involving T-cell responses
HLA-class 1: Self-antigens to CD8 T cells → cell lysis
HLA-class 2: self-antigens to CD4 T cells → cytokine production → inflammation and tissue damage (activated macrophages to produce TNF-alpha)
Which autoantigens are associated with the following: T1DM, rheumatoid arthritis, multiple sclerosis
T1DM: pancreatic B-cell antigen
Rheumatoid: unknown synovial joint antigen
Multiple sclerosis: myelin basic protein
