Tolerance and autoimmunity Flashcards
Tolerance to self
Tolerance to innocuous non self, e.g. food antigens, commensal bacteria
Autoimmunity = loss of tolerance to self. Response to antigen that is derived from a part of their body.
B cell development
Develop in bone marrow
Bone marrow stromal cells signal the development of lymphocyte progenitors from haematopoeitic stem cells and their differentiation to B cells
Express cell surface IgM = Mature B cells
Immature B cells are screened fr autoreactivity before they leave the bone marrow - central tolerance
Self reactive B cells that escape this and leave the bone marrow can stil. be removed from the repertoire - peripheral tolerance.
B cells
Central tolerance
IgM molecule is screened if they can react to antigen.
Immature B cells without strong reactivity to self antigens allowed to mature into naive B cells and leave the bone marrow.
Immature with stronger reactivity (to self):
-Underdoes receptor editing, replaces light chains can rescue the cells
-Clonal deletion - removal of cells with particular antigen specificity via apoptosis
-Anergy - state of permanent unresponsiveness, downregulate Ig so no longer can be activated by antigen.
Peripheral tolerance
Not all self antigens are expressed in bone marrow so some are made in peripheral tissues, additional mechanism is used.
No T cell help is available, so no cytokines so B cell doesnt become fully activated i.e Clonal deletion, anergy
Regulatory cells: generate these populations and regulate the immmune response (to self) and downregulate and self reactive T cells.
T cell development
T cell precursors migrate from bone marrow to thymus
Recently arrived cells undergo rapid expension under influence of key cytokines (VDJ re-arrangement)
Induced expression of transcription factors that commit cells to T cell lineage
CD4 CD8 cells
They both have a unique marker CD4 and CD8 markers
CD4 interacts with MHC class II CD8 interacts with MHC class I
Positive and Negative selection
Double positive cells have life span 3-4 days
Need to be rescued or they die
Rescued by engaging their T cells receptor and mature into CD4 or CD8
Range of self peptides in the thymus
Expression of mant other tissue specific proteins controlled in the thymus by a gene called AIRE (autoimmune regulator)
Peripheral tolerance
Abundant and persistent concentration of self antigen in the periphery can be tolerising
Absence of pro inflammatory or so stimulartory signal typically cia innate immune system
All are error prone- other mechanism also in operation
Annergy
Supression by regulatory T cells
Induction of death
Regulatory T cells (Treg cell)
Natural, risen in thymus during positive/negative selection, they escape and inhibit.
May downregulate cancer response.
Can regulate other T cell and other populations.
Autoimmunity
Each disease relatively rare - combined affect around 5% of populations in western countries
On the rise
Specific adaptive immune response to self antigens
Organ specific or systemic typically utilise multiple componenets of the immune system
antibody and effector T cells can contribute to tissue damage.
Psoriasis
Autoreactice T cells that react with skin associated antigens
Inflamation of skin - scaly patches/plaques
Systemic lupus
Autoantibodies to intracellular antigen (DNA, chromatin, proteins, and ubiquitus ribonucleoprotein antigens)
Glomerulonephritis, vasculitis, rash
1/200
Rheumatoid arthritis
Autoreactive T cells against joint synovium
Joint inflammation and destruction
1/200
Multiple schlerosis
Autoreactive antigen for brain antigens
Formation of sclerotic plaques in brain with destruction of myelin sheaths surrounding nerve cell axons
