CTLA4 T1D,RAInhibitsT-cellresponsesbyterminatingactivationandpromotingactivityofregulatoryTcells;mayinterferewithself-tolerance
IL2RA MS,T1Dα chainofthereceptorforIL-2,whichisagrowthandsurvivalfactorforactivatedandregulatoryTcells;mayaffectdevelopmentofeffectorcellsand/orregulationofimmuneresponses
IRF5, IFIH1 SLERoleintypeIinterferonproduction;typeIIFNisinvolvedinthepathogenesisofSLE(seetext)
AS, Ankylosingspondylitis;IBD, inflammatoryboweldisease;IFN, interferon;MS, multiplesclerosis;PS, psoriasis;RA, rheumatoidarthritis;SLE, systemiclupuserythematosus;TID,typeIdiabetes.Theprobablelinkageofthesegeneswithvariousautoimmunediseaseshasbeendefinedbygenome-wideassociationstudies(GWAS)andothermethodsforstudyingdisease-associatedpolymorphisms.AdaptedfromZenewiczLA,AbrahamC,FlavellRA,etal:Unravelingthegeneticsofautoimmunity,Cell 140:791,2010.
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A Induction of costimulators on APCs
Activation of APC
Activation of T cells
Fig. 5.21 Postulated role of infections in autoimmunity. Infections may promote activation of self-reactive lymphocytes by inducing the expression of costimulators (A), or microbial antigens may mimic self antigens and activate self-reactive lymphocytes as a cross-reaction (B).
affect the relative proportions of effector and regulatory T cells, and shape the host response toward or away from aberrant activation. However, it is still not clear which microbes contribute to specific diseases in humans, or if the microbiome can be manipulated to prevent or treat these disorders.
Adding to the complexity of the link between microbes and autoimmunity are recent observations suggesting that infections paradoxically protect individuals from some autoimmune diseases, notably type 1 diabetes, multiple sclerosis, and Crohn disease. The possible mechanisms underlying this effect are not understood.
In addition to infections, the display of tissue antigens also may be altered by a variety of environmental insults. As discussed later, ultraviolet (UV) radiation causes cell death and may lead to the exposure of nuclear antigens, which elicit pathologic immune responses in lupus; this mechanism is the proposed explanation for the association of lupus flares with exposure to sunlight. Smoking is a risk factor for RA, perhaps because it leads to chemical modification of self antigens. Local tissue injury for any reason may lead to the release of self antigens and autoimmune responses.
Finally, there is a strong gender bias of autoimmunity, with many of these diseases being more common in women than in men. The underlying mechanisms are not well understood, but may involve the effects of hormones and other factors.
An autoimmune response may itself promote further autoimmune attack. Tissue injury caused by an autoimmune response or any other cause may lead to exposure of self antigen epitopes that were previously concealed but are now presented to T cells in an immunogenic form. The activation of such autoreactive T cells is called epitope spreading, because the immune response spreads to epitopes that were not recognized initially. This is one of the mechanisms that may contribute to the chronicity of autoimmune diseases.
Tolerance (unresponsiveness) to self antigens is a fundamentalproperty of the immune system, and breakdown of toleranceis the basis of autoimmune diseases.