Autoimmune and Autoinflammatory diseases Flashcards
Define immunopathology
Define autoimmune and autoinflammatory diseases
Damage to the host cause by the immune response
Immunopathology in the absence of infection
What is the difference?
Autoinflammatory = abnormal response of innate system (macrophages, neutrophils). Often localised site
Autoimmune = breaking of tolerance in adaptive immune system (B and T cells. May get organ-specific Abs in preclinical period
Monogenic autoinflammatory diseases:
MOA
Examples
Single gene mutation -> abnormal cytokine TNF/IL-1 signalling
Familial mediterranean fever, TRAPS
Pyrin-Marenostrin -ve regulator and cryopyrin +ve on ASC protein.
ASC -> procaspase 1-> IL-1, NFkappaB, Apoptosis
inflammasome complex
(which is activated by toxins, microbial antigens and urate)
Monogenic autoinflammatory diseases there is loss function pyrin and gain function cryoparin
MEFV gene mutation
loss function pyrin-marenostrin on neutrophils
Familial mediterranean fever
Monogenic auto-inflammatory disease
Presentation of Familial mediterranean fever
Periodic fevers lasting 48-96 hours
+ ‘-itis’
Abdominal pain due to peritonitis
Chest pain due to pleurisy and pericarditis
Arthritis
Rash (often red)
Tx Familial mediterranean fever
Colchicine 500ug bd (binds to tubulin in neutrophils and disrupts neutrophil functions)
2nd line: Anakinra or Etanercept
Complications Familial mediterranean fever
AA Amyloidosis (Inflammation stimulates liver to produce lots of acute phase proteins amyloid A which deposits in kidneys, liver, spleen)
Monogenic Autoimmune diseases 3 kinds:
Abnormality in tolerance
Abnormality of regulatory T cells
Abnormality of lymphocyte apoptosis
Abnormality in tolerance = APS1/APECED, due to defect in AIRE
Abnormality of regulatory T cells = IPEX due to Foxp3 mutation
Abnormality of lymphocyte apoptosis
= ALPS due to defect in death pathway of lymphocytes
APS1/APECED
Defect in AIRE transcription factor leads to failure of central tolerance and -> Autoreactive T and B cells
Monogenic autoimmune disease
Leads to abnormality in tolerance
Clinical presentation of APS1/APECED
auto-immune diseases
- Hypoparathyroidism
- Addisons
- Hypothyroidism,
- Diabetes, Vitiligo,
- Enteropathy
- Candidiasis infections due to anti-cytokine antibodies (IL-17 and IL-22)
Monogenic AI disease
Abnormalities of regulatory T cells
IPEX
Mutations in Foxp3 ->
Failure to negatively regulate T cell responses + Autoantibody formation
Clinical presentation of IPEX
Autoimmune diseases - 3 D's (diarrhoea, diabetes, dermatitis) Enteropathy Diabetes Mellitus Hypothyroidism Dermatitis (eczema)
Monogenic AI disease
Mutations within FAS pathway - >Abnormality of lymphocyte apoptosis
ALPS
Clinical presentation of ALPS
High WCC large spleen and lymph nodes double negative (CD4-CD8-) T cells Auto-immune disease commonly auto-immune cytopenias Lymphoma
Single gene mutation involving FOXp3 resulting in abnormality of T reg cells
IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X linked)
Single gene mutation involving MEFV and affecting the inflammasome complex, resulting in recurrent episodes of serositis
Familial Mediterranean Fever
Mutation within the Fas pathway associated with lymphocytosis, lymphomas and auto-immune cytopenias
Auto-immune lymphoproliferative syndrome (ALPS)
Polygenic Autoinflammatory diseases
Examples
Crohns, UC, osteoarthritis, giant cell arteritis, Takayasu’s arteritis
Local factors at sites predisposed to disease
Weak HLA associations
No auto-antibodies
Polygenic Autoinflammatory diseases
RF: NOD2 gene mutations are present in 30% patients/CARD15 mutation
Also Other genetic influences/Environmental factors
-> crypt inflammation, granulomatas, tissue damage, mucosal ulceration
Crohns disease
Abdominal pain and tenderness
Diarrhoea (blood, pus, mucous)
Fevers, malaise
Crohns disease
Tx of Crohns disease
- Corticosteroid
- Azathioprine
- Anti-TNF alpha antibody
- Anti-IL12/23 antibody
Mutations in genes encoding proteins involved innate and adaptive immune cell
HLA associations may be present
Auto-antibodies are not usually a featur
Mixed pattern diseases
E.g. ankylosing spondylitis, psoriatic arthritis, Behcet’s syndrome
Enhanced inflammation occurs where there are high tensile forces
(entheses - sites of insertions of ligaments or tendons) e.g. affects sacroiliac joints
Heritability >90%
HLA B27
(Accounts for <50%overall genetic risk)
Anklyosing Spondylitis
Clinical presentation of Anklyosing Spondylitis
Low back pain and stiffness
Large joint arthritis
Enthesitis
Uveitis
Tx of Anklyosing Spondylitis
Non-steroidal anti-inflammatory drugs Immunosuppression Anti-TNF alpha Anti-IL17 Anti-IL12/23
Rheumatoid arthritis, Myaesthenia Gravis, Pernicious anaemia, Addison disease, Systemic lupus erythematosus, Primary biliary cirrhosis
Examples of Polygenic AI diseases
Genetic polymorphisms of
Polygenic AI diseases
HLA
(HLA presentation of antigen is required for development of T cell and T cell-dependent B cell responses)
HLA -DR3/DR4 - Type I diabetes
HLA-DR4 - Rheumatoid arthritis
Mechanism of AI disease
Autoimmune disease involves a loss of self-tolerance of Bc and Tc -> autoreactivity
Auto-antibodies are found
Principles of Gel and Coombs
What is actually causing the polygenic autoimmune disease? (want to separate cause from genetic mechanism driving it e.g. HLA mutation)
Immediate hypersensitivity which is IgE mediated
Type 1
Antibody reacts with cellular antigen
Type II
Antibody reacts with soluble antigen to form an immune complex
Type III
Delayed type hypersensitivity…T-cell mediated response
Type IV
ALLERGIC REACTION Allergen binds to Pre-existing Ig E Ab ->
Ig E bound to Fc epsilon receptors on mast cells and basophils -> mast Cell degranulation
Release of inflammatory mediators: Histamine, serotonin, proteases
Leukotrienes, prostaglandins,
bradykinin, cytokines are Synthesised ->
Increased vascular permeability,Leukocyte chemotaxis, Smooth muscle contraction
Ig E mediated reactions (Type I)
Antibody binds to cell-associated antigen
-> antibody dependent destruction (through complement, NK cells and phagocytes) all leading to cell damage OR autoantibodies blocking/activating receptors
Antibody driven immune reactions (Type II)
Auto-antigen = Noncollagenous domain of basement membrane collagen type IV expressed in lung and kidneys
-> Glomerulonephritis, pulmonary hemorrhage
Goodpasture
disease
(Type II hypersensitivity AI disease)
Auto-antigen = Epidermal cadherin
-> Blistering of skin
Pemphigus vulgaris
Type II hypersensitivity AI disease
Auto-antigen = Thyroid stimulating
hormone (TSH) receptor
-> Hyperthyroidism
Graves disease
Type II hypersensitivity AI disease
Auto-antigen =Acetylcholine receptor
-> Muscle weakness
Myaesthenia gravis
Type II hypersensitivity AI disease
hypersensitivity reactions
where antibodies bind to soluble antigen and deposit in blood vessels in the kidneys, joints and skin
Fc region of antibodies can activate complement cascade, macrophages, neutrophils -> cell damage
Type III
Example of type III
Autoantigen = DNA, Histones, RNP
–> Rash, glomerulonephritis, arthritis
Systemic lupus erythematosus
Example of type III
Autoantigen = Fc region of IgG
–> arthritis
Rheumatoid arthritis
Hypersensitivity reaction
- autoimmunity with CD8 Tcells
(HLA I present self-peptides to CD8Tc and activate them
Type IV
Examples Type IV hypersensitivity reactions
Insulin dependent diabetes mellitus (autoaAg = Pancreatic b-cell antigen ->
b-cell destruction: CD8+ T-cells)
RA (Auto-Ag = unknown, but -> joint inflammation + destruction)
MS (Auto Ag = Myelin basic protein -> Brain infiltration by CD4 Yc)
Which Hypersensitivity type is SLE?
Type III
Which Hypersensitivity type is Eczema?
Type I
Which Hypersensitivity type is Goodpasture disease?
Type II
Which Hypersensitivity type is MS?
Type IV
Polygenic Autoimmune diseases divided into…
organ-specific (e.g. Graves, Hashimotos, PA, MG, Goodpastures, T1DM) or
Organ non-specific (SLE, Sjogrens, systemic sclerosis, Dermato/polymyositis, ANCA vasculitis)
