Autoimmunity Flashcards
Tolerance
- A state of unresponsiveness of the immune system to self
- Central and peripheral
What is autoimmunity?
Failure of organism in recognising its own constituent parts as self
What causes autoimmunity?
- Immune regulation
- Genetic factors
- Environment
- Unknown
Autoimmunity
Physiological autorecognition with secondary epiphenomena
Autoimmune disease
Immune response contributing directly to tissue/organ damage
What is the epidemiology of autoimmune disease?
- F:M 4:1
- 10-50% of identical twins develop disease so cannot be purely genetic
- Some HLA alleles occur in certain populations and people more often
What are the 2 types of autoimmune disease?
- Organ specific
- Non-organ specific
Give examples of HLA associated risk factors for autoimmune disease
- Ankylosing spondylitis (B27)
- Coeliac disease (DQ2, DQ8)
- Multiple sclerosis (DQ6)
- Rheumatoid arthritis (DR4)
- Juvenile rheumatoid arthrtitis (DR8)
Give examples of cell mediated autoimmune reactions
- T1DM
- Crohn’s disease
- Psoriasis
- Coeliac disease
What is the pathogenesis of T1DM?
- Autoreactive T cells against pancreatic islet cell antigens, leading to destruction and non-production of insulin
- Anti-glutamic acid decarboxylase
What is the pathophysiology of Crohn’s disease?
- Triggered by a foreign pathogen that makes it past the mucosa of the gut leading to APC presentation
- Autoreactive T cells against intestinal flora antigens leading to lymphocyte infiltration of exocrine glands
- The cytokine reaction is dysfunctional and exaggerated leading to lots of macrophages creating proteases and platelet activating factors which causes inflammation
What familial gene is associated with IBD?
NOD2
What is the pathophysiology of psoriasis?
Autoreactive T cells against skin associated antigens
What is the pathophysiology of coeliac disease?
- B cells for transglutamine are helped by T cells to -Secretory IgA in mucosal membrane crosses to lamina proprieta
- Macrophages uptake these TTG antibodies and express MCHII antibodies (HLA-DQ2)
- CD4 Th cells release IFNy and TNF which destroy the villi, CD8 Tc destroy damaged endomysial cells
What is thought to be the cause of coeliac disease?
Thought to be caused by breakdown in immune tolerance in which a lack of T regulatory cells or the participation of Th17 cells plays a critical role in the pathogenesis of these disorders
What type of hypersensitivity reaction is antibody mediated autoimmunity?
Type II
What happens in antibody mediated autoimmunty?
Antibody binds to targets leading to damage by Fc receptor macrophage with or without complement lysis
- Can also lead to immune complex formation and deposition, activating phagocytes and causing damage (SLE)
- Direct effect of the autoantibodies on the autoantigen affecting its function (pemphigus, myasthenia gravis)
Give examples of antibody mediated autoimmune disease.
- Goodpasture’s syndrome
- Myasthenia gravis
What is the pathogenesis of Goodpasture’s syndrome?
- IgG antibodies react to alpha 3 collagen in the lungs and kidneys (after damage/event)
- C1 attaches to collagen and activates it by cleaving other elements.
- This attracts other cells including neutrophils that cause enzyme release and damage
What sites are likely to be affected in Goodpasture’s syndrome?
Lungs and kidneys
What are the risk factors for Goodpasture’s syndrome?
Genetic
-HLA-DR15
Environmental
-Infection, smoking, solvents
What is the distribution of age or myasthenia gravis?
Bimodal distribution of age
- Young women 20-30
- Older men 60-70
What is the pathogenesis of myasthenia gravis?
- Autoreactive T cells and B cell ACH receptor antibodies block or destroy nicotinic acetylcholine receptors at the NMJ
- Prevents nerve impulses from triggering muscle contractions
- Complement activation also causes local inflammation
- Results in weakness and fatiguability
What tumour is myasthenia gravis associated with?
Thymoma in 15%
What type of hypersensitivity reaction is immune complex autoimmunity?
Type III
Give an example of an immune complex autoimmune disease?
SLE
What is immune complex autoimmunity?
Antigen-antibody/immune complex formation and deposition, activating phagocytes and causing damage
What is the pathogenesis of immune complex autoimmunity?
- A fully differentiated B cell (plasma cell) secretes Abs into serum and has Abs bound to its cell surface to act as receptors
- Antigen cross links to surface antibodies on plasma cell and gets absorbed. B cell offers a piece of it to Th cells
- They join via CD4 and CD40 ligands and the B cell releases cytokine which switch its Ig class.
- This soluble antibody binds to targets leading to damage by FC receptor macrophage and or complement lysis
What is the pathogenesis of SLE?
- Failure of tolerance allowing self-reactive B/T cells to circulate
- Leaked auto-antigen is presented to B cell, passed to Th cells and antibodies to DNA made
- Secrets anti dsDNA antibodies
- Complexes form from DNA fragments but are too small for macrophages to sweep up
- They deposit in tissues (basement membrane), wherein complement is activated and neutrophils are recruited via chemokines who de-granulate and cause inflammation and necrosis
- More DNA is released making it worse
Why are the kidneys and joints affected in SLE?
Blood is filtered through the kidneys and synovium hence where the damage occurs
Give an example of mixed autoimmunity?
Grave’s disease
What is the pathophysiology of Grave’s disease?
- Autoantibodies against the TSH receptor.
- Leads to activation of TSH and over-production of T3 and T4
What is molecular mimicry?
- Describes a situation in which a foreign antigen can initiate an immune response in which a T or B cell component cross-recognises self.
- The cross reactive immune response is responsible for the autoimmune disease state
How does molecular mimicry occur?
An exogenousantigenmay share structural similarities with certain host antigens; thus, any antibody produced against this antigen (which mimics the self-antigens) can also, in theory, bind to the host antigens, and amplify the immune response
What is the pathophysiology of MS?
- T cells specific to myelin cross the BBB and release cytokines
- BBB damage, macrophage and Tc cell migration attacks oligodendrocyte
- Despite Tr cells allowing healing, eventually the damage becomes worse
What can contribute to MS?
Association with HLA-DR2 and vitamin D deficiency
What is responsible for T cell mediated autoimmune attack in coeliac disease?
Gliadin
What is component is damaged in Goodpasture’s?
Type 4 collagen
