lec 28 - autoimmunity and tolerance

what is self tolerance

a state in which an individuals immune system does not attack the normal tissues of the body

what is autoimmunity

a breakdown or failure of the mechanisms of self-tolerance

how we get self tolerance

during lymphocyte development potentially self-reactive T and B cells are identified and deleted - central tolerance

some self-reactive cells escape elimination

tolerance induced in mature lymphocytes that have left the central lymphoid organs is peripheral tolerance

central tolerance - B cells development 

initial testing of the BCR on immature B cells 

no self reactivity - migrates to the periphery and matures 

self reactivity - negative selection 

self reactive B cells what happens

anergy (unresponsiveness or paralysis of function)

elimination/deletion (apoptosis)

rescue by receptor editing (continued expression of RAG which can allow cells to continue light chain rearrangement leading to alteration of specificity 

central tolerance - T cell development 

dangerously autoreactive DP thymocytes (i.e. strongly reactive with self MHC or MHC with self peptide) are removed by negative selection 

cells strongly reactive with MHC presenting self antigen are also removed 

AIRE creates a peripheral shadow i the thymus - expresses small amounts of tissue specfic proteins to test against T cell receptors 

AIRE

a transcription factor that causes a small amount of lots of different proteins in the thymus so that T cells can

peripheral tolerance - what

occurs after central tolerance when mature B and T cells have migrated into the periphery 

mechanisms of peripheral tolerance

anergy (unresponsiveness)

Tregs 

functional deviation (autoreactive T cells → induced Tregs)

activation induced cell death - hyperactivity of cells can lead to them dying or anergy 

layers of self tolerance diagram

how to induce peripheral tolerance

very large doses of antigen 

regulatory T cells 

oral antigen - because GIT designed to not react to oral antigen 

types of autoimmunity

breakdown of central tolerance - APECED

breakdown of peripheral tolerance - Treg function - IPEX

breakdown of peripheral tolerance (self antigen) - multiple sclerosis

APECED - what symptoms

highly variable disease phenotype

failure of multiple endocrine glands

chronic mucocutaneous candadiasis

ectodermal symptoms (e.g. pitted nail dystrophy, dental enamel hypoplasia, alopecia, vitiligo)

APECED - disease mechanism

individual organs of the body express tissue-specific antigens

in the thymus T cells arise capable of recognising tissue-specific antigens

under control of the AIRE protein thymic meduallary cells express tissue-sepcific proteins, deleting tissue-reactive T cells

but in the absence of AIRE, T cells reactive to tissue-specific antigens mature and leave the thymus - not exposed

how does APECED lead to symptoms

autoimmune reactions to endocrine glands leads to type I diabetes, addison’s disease, hypopituitarism etc

to self antigens leads to ectodermal symptoms eg enamel hypoplasia, alopecia

why are people with APECED susceptible to candadiasis

associated with autoantibodies against IL-17

Th17 cells are important for protection against fungi at the epithelium

IPEX

breakdown of peripheral tolerance 

characterised by systemic autoimmunity, typically in 1st year of life 

caused by mutation in FoxP3 

multiple sclerosis

impaired peripheral

T cell mediated neurological disorder

destructive immune response against brain antigens eg myelin basic protein

symptoms include muscle weakness, blindness, paralysis

multiple sclerosis pathogenesis

unknown trigger sets up initial focus of inflammation in brain and blood-brain barrier becomes locally permeable to leukocytes and blood proteins

T cells specific for CNS antigen and activated in peripheral lymphoid tissues reencounter antigen presented on microglia or dendritic cells in brain

inflammatory reaction in brain due to mast-cell activation, complement activation, antibodies and cytokines

demyelation of neurons

MS treatment 

type I interferon 

act on APCs to produce Tregs which can produce cytokines to reduce inflammation 

caused by Th17

not curative

betaferon 

fingolimod

derived from myriocin isolated from the fungus isaria sinclairii 

prevents egress of T and B cells from secondary lymphoid organs, preventing cells from entering the blood and tissues (including the CNS) 

types of risk factors for autoimmune disease

genetic factors

environmental factors

host factors

genetic risk factors for autoimmune disease

gene loci associated with susceptibility (often genes encoding molecules of the immune system)

epigeneitc changes (DNA methylation, histone modification) which alter gene accessibility

environmental risk factors for autoimmune disease 

infection (bacterial or viral - e.g. epstein barr virus) 

geographical - sunlight exposure?

also host factors - age, sex (F»M), ethnicity