Autoimmunity Flashcards
Autoimmune response?
Response to one or more self antigens in absence of self tolerance, triggering normal immune responses
Because self antigens can’t be cleared, the response is chronic
AD stats?
Affect 5-8% of pop
More than 80 types, varied symptoms, targeting many different tissues
Chronic
Rheumatoid arthritis is one of the most common
Classifying ADs?
Organ specific e.g. myelin sheath in CNS axons in MS
OR
Systemic - affects multiple tissues where antigens are widespread
Autoimmune haemolytic anaemia can be organ specific, or systemic if combined with SLE
Immunological features of ADs
Autoreactive CD4+ Th cells
Auto-antibodies
Cellular infiltrate where T and B cells congregate
Pathologies of AD?
Primary - direct immune action e.g. Hashimoto’s - destruction of thyroid organ
Secondary - consequences of primary i.e. Hashimoto’s is hypothyroidism
Experimental autoimmune encephalomyelitis?
EAE studied in mice to give model for MS, via T cell disease mechanisms
Mediated by Th17 and Th1 specific for MBP, as transferral of these to a healthy animal induces the disease - therefore cell driven
T cell mediated disease mechanisms?
Th17/1/2 Proinflammatory cytokines Damage epithelial barrier CD8 cytotoxic action Macrophages Inflammatory response Antibody responses
Complement mediated lysis?
e.g. autoimmune haemolytic anaemia
Anti-rbc auto-antibodies binds rbs, fix complement, and generate lysis
Opsonisation and phagocytic removal?
e.g. autoimmune thrombocytopenia
Anti-platelet auto antibodies bind platelets
Acts as opsonin -phagocytosis (macrophages bind with FcR)
Alteration of function diseases?
Graves Disease - stimulate receptors with agonists
TSH receptor auto antibodies = thyroid hormone overproduction
Myasthenia Gravis - inhibition of function
Auto antibodies block Ach binding/internalise sodium channels so no muscle contraction
Pernicious anaemia - blocking function
Intrinsic factor auto-antibodies block B12 absorption
Deposition of immune complexes?
Systemic lupus erythematosus
Deposit in small blood vessel walls throughout body - inflammatory response giving varied symptoms
Examples of tolerance failures?
AIRE and FOXP3 mutations
Concordance/genetic basis to AD
Twin studies - greater in identical, less than 50%, so both
Most ADs are multigenic, which several contributors
Many of those genes are polymorphic
NOT due to mutations - due to polymorphisms, expressing different alleles
Several genes add up
Relative risk?
Extent to which an allele increases susceptibility
What do genetic factors affect?
Autoantigen availability and clearance e.g. MHCII (about 50% of risk) Apoptosis Signalling thresholds Cytokine expression/signalling Tregs Sex - often X linked
Role of environment in ADs?
Microbial agents i.e. pathogens may resemble self-antigens
Vitamin D (suppress Th17)
Drugs - bind self to make it seem foreign
Toxins
Microbiota/hygiene e.g. microbiome, lack of exposure
Infections - Epstein Barr virus interacts with gene loci associated with AD
Loss of self-tolerance mechanisms?
Bypassing T helpers
Tolerance loss
Bypassing Ths?
B cells mitogens stimulate auto-antibody production
e.g. bacterial products like LPS can stimulate plasma differentiation
Not antigen specific - any B cell
Transient - lost when mitogen leaves
Tolerance loss?
Where pathogens and self antigens are similar: With microbe, B cells that can act on self are stimulated with T help, as the shared novel epitope recruits them
e.g. rheumatic fever
OR
Drug induced/chemical induced changes:
Drug/chemical binds self-antigen and modifies it to give a foreign T cell epitope
Should be transient with presence of drug, but may become chronic in susceptible individuals: positive feedback loop with non-clearance of self-antigens, epitope spreading = broader response
