Autoimmunity Flashcards
Autoimmunity
Physiological autorecognition with secondary epiphenomena. It is the failure of an organism in recognising its own constituent parts as non-self.
Autoimmune disease
Immune response contributing directly to tissue / organ damage
PATHOLOGICAL PROCESS
Prevalence of autoimmune disease
20%
Causes of autoimmunity (genetic factors)
Human Leukocyte Antigen can correlate with certain diseases
Very seldom is there an individual, pin-pointable gene
Though in some instances the presence of single gene defects such as FAS/FasL, AIRE, FOXP3, Complement Genes (Lupus) can cause autoimmune disease
Hormonal factors contributing to autoimmunity
Women more likely to be affected than men (as high as 10/1)
SLE 10x more common in women than men in reproductive years, but only 2x more common in early/later life
Environmental factors contributing to autoimmune disease
UV sun exposure
Klebsiella pneumonia and Coxsackie B have been strongly correltated with ankylosing spondylitis and diabetes.
Cell mediated autoimmunity (T and NK cells)
T cellsdestroy intracellular pathogens by killing infected cells and by activating macrophages but they also have a central role in the destruction of extracellular pathogens by activating B cells.
Interact with cells bearing the antigen they don’t recognize
Stop cells that could potentially lyse and release viruses
Type 1 Diabetes
Auto-reactive T cells against Pancreatic Islet cell Antigens, leading to destruction and non-production of insulin
Crohn’s Disease
Triggered by a foreign pathogen leading to APC presentation to TH
Autoreactive T cells against intestinal Flora antigens leading to lymphocyte infiltration of exocrine glands
Can be familial (NOD2 gene)
For reasons not clearly understood, pathogens make it past the mucosa in the gut, and are engulfed by APCs. The cytokine reaction from T-Helper cells is dysfunctional and exaggerated, leading to lots of Macrophages creating proteases and platelet activating factors, which causes inflammation
Psoriasis
Autoreactive T-cells against Skin associated antigens
Coeliac Disease
In coeliac disease B cells for transglutamine are helped by T cells recognising gliadin (an amino acid sequence in Gluten).
Secretory IgA in mucosal membrane (normally a marker of immune cell destruction, crosses to lamina proprieta.
Macrophages uptake these TTG antibodies, express MHCII antibodies (HLA-DQ2)
CD4+ TH Cells release IFNγ and TNF – destroying villi, CD8+ TC destroy damaged endomysial cells
Antibody mediated autoimmunity
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.
Type II Hypersensitivity Reaction
Goodpasture Syndrome
Genetic risk - HLA-DR15
Environmental risk – Infection/Smoking/Solvents (dry cleaning). Places likely to be damaged are lung and kidneys
IgG reactions to alpha 3 collagen (after some damage). C1 attaches to collagen and activates and cleaves other elements. This attracts granular cells which release their enzymes resulting in inflammation and tissue damage.
Immune Complex Autoimmunity
Antigen-antibody/Immune complex formation and deposition, activating phagocytes and causing damage
Type III Hypersensitivity reaction
A fully differentiated B cell called a plasma cell secretes antibodies into serum, and has antibodies bound to it’s cell surface to act as receptors
When an antigen cross links 2 surface antibodies on the plasma cell, it absorbs it, and offers a piece of it to T Helper cells.
They join via stimulatory CD4 and CD40 Ligands and the B-cell releases cytokine which switch it’s Immunoglobulin class
Antibody binds to targets leading to damage by FC receptor macrophage and or complement lysis (AIHA, ITP, Anti-GBM)
SLE
A failure of self-tolerance allows a B-cell to react to leaked DNA auto-antigen from a damaged cell
If a T-cell that is also specific to this, it begins to secrete anti-dsDNA antibodies to be produced
Myasthenia Gravis
Myasthenia gravis is anautoimmune diseasewhich results fromantibodiesthat block or destroynicotinic acetylcholine receptorsat thejunction between the nerve and muscle.[1]This preventsnerve impulsesfrom triggeringmuscle contractions. Complement activation also causes local inflammation
ACH Receptor antibodies in 85%. Thymomas are cancers of the Thymus, and can cause autoantibody release
Treatment
Cholinesterase Inhibitors
Immunosupression
Thymoma
Graves Disease
Autoantibodies against the Thyroid stimulating hormone receptor. Activates the TSH and over-produces Thyroid hormones
Rheumatic Fever
infection with Group A beta-haemolyticstreptococci. Although rheumatic fever has been attributed to molecular mimicry for half a century no antigen has been formally identified (if anything too many have been proposed). Moreover, the complex tissue distribution of the disease (heart, joint, skin, basal ganglia) argues against a cardiac specific antigen. It remains entirely possible that the disease is due to e.g. an unusual interaction between immune complexes, complement components and endothelium.
Multiple Sclerosis
T-cells specific to Myelin, cross the BBB and release cytokines
BBB damage, macrophage and Tc cell migration attacks Oligodendrocyte
Despite Treg cells allowing healing, eventually the damage become worse
Associated to HLA-DR2, and Vit D Deficiency
Treatment of Autoimmune Disease
Immunosuppressive therapy
Anti-inflammatory therapy
Plasmapheresis
Stem Cell/Bone Marrow Transplant (?)
Replacement of lost physiological factor
Organ / tissue / mechanical graft
Tolerance
A state of unresponsiveness of the immune system to self
Central control of Tolerance
Thymus.
Inactivation of cells required for initiation of an immune response.
Enhancement of central control of tolerance
IL-10 and TGF beta
Inhibition of central tolerance
Leuktriene, IFN-Ɓ and TNF-Ɓ
Peripheral control of tolerance
Peripheral tolerance is key to preventing over-reactivity of the immune system to various environmental entities (allergens,gut microbes, etc.) Clonal deletion (apoptotic cell death); clonal anergy (functional inactivation without cell death); clonal ignorance (failure to recognize or recognition of antigens without costimulation); suppression of lymphocyte activation and effector functions by regulatory lymphocytes
Regulated by Treg cells
HLA
Chromosome 6
Two alleles, 6 loci
Co-dominantly expressed
Themajor histocompatibility complex(MHC) is a set ofcellsurface proteins essential for theacquired immune systemto recognize foreign molecules invertebrates, which in turn determineshistocompatibility.
Histocompatibility
Histocompatibility, or tissue compatibility, is the property of having the same, or sufficiently similar,allelesof a set ofgenescalledhuman leukocyte antigens(HLA).
HLA molecules that increase chance of autoimmune disease
HLA-B27 - ankylosing spondylitis
HLA DR3 - addisons disease, graves disease, myasthenia gravis
A working immune system has
Recognition (including past infections and self) Interaction with foreign antigens Response Elimination Control & Regulation
