Several autoimmune diseases are linked to the HLA locus, especially class II alleles (HLA-DR, HLA-DQ). The frequency of a disease in individuals with a particular HLA allele compared with those who do not inherit that allele, is called the odds ratio or relative risk (
Table 5.8 ). The relative risk ranges from 3 or 4 for
Table 5.8 Association of HLA Alleles and Inflammatory Diseases
SystemiclupusDRB1*03012erythematosusDRB1*15011.3 †TheoddsratioreflectsapproximatevaluesofincreasedriskforthediseaseassociatedwiththeinheritanceofparticularHLAalleles.ThedataarefromEuropean-derivedpopulations.
‡Anti-CCP Ab referstoantibodiesdirectedagainstcycliccitrullinatedpeptides.Dataarefrompatientswhotestpositivefortheseantibodiesintheserum.¶SE referstoshared epitope, socalledbecausethesusceptibilityallelesmaptooneregionoftheDRB1protein(positions70–74).TheDRB1proteinistheproductoftheβ chainoftheHLADRmolecule.CourtesyofDr.MichelleFernando,ImperialCollegeLondon.
rheumatoid arthritis (RA) and HLA-DR4 to 100 or more for ankylosing spondylitis and HLA-B27. However, how MHC genes influence the development of autoimmunity is still not clear. Notably, most individuals with a susceptibility-related MHC allele never develop disease, and, conversely, individuals without the relevant MHC gene may get it. Expression of a particular MHC gene is therefore but one variable that contributes to autoimmunity.
• Genome-wide association (GWAS) studies and linkage studies in families are revealing many genetic polymorphisms that are associated with different autoimmune diseases (
Table 5.9 ). Some of these genetic variants are disease-specific, but many of the associations are seen in multiple disorders, suggesting that they affect general mechanisms of immune regulation and self-tolerance. However, the mechanism by which most of these genetic variants contribute to particular autoimmune diseases is not established.
Role of Infections,Tissue Injury, and Other Environmental Factors
A variety of microbes, including bacteria, mycoplasmas, and viruses, have been implicated as triggers for autoimmunity. Microbes may induce autoimmune reactions by several mechanisms (
Fig. 5.21
Microbial infections with resultant tissue necrosis and inflammation can stimulate expression of costimulatory molecules on APCs in the tissue, thus favoring a breakdown of T cell tolerance and subsequent T cell activation.
Viruses and other microbes may share cross-reacting epitopes with self antigens, and as a result responses induced by the microbe may extend to self tissues, a phenomenon called molecular mimicry. The best example of a pathogenic immunologic cross-reaction is rheumatic heart disease, in which an antibody response against streptococci cross-targets cardiac antigens. It is not known if mimicry has a role in more common autoimmune diseases.
Recently, there has been great interest in the idea that the development of autoimmunity is influenced by the normal gut and skin microbiome (the diverse collection of commensal microbes that live with us in a symbiotic relationship). It is possible that different commensal microbes
Table 5.9 Selected Non–HLA Gene Variants Associated With Autoimmune Diseases
PTPN22 RA,T1D,IBDProteintyrosinephosphatase;mayaffectsignalinginlymphocytesandmayalternegativeselectionoractivationofself-reactiveTcells
IL23R IBD,PS,ASReceptorfortheTH17-inducingcytokineIL-23;mayalterdifferentiationofCD4+ TcellsintopathogenicTH17effectorcells