ABSTRACT
Linkage with HLA Genes? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185 13.4 Possibilities for the Future . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186
There is a growing interest in the likelihood that cytokine gene polymorphisms, identified by SNP and haplotype analysis, are associated with disease, particularly for those cytokines (e.g. TNF-a) implicated in both non-specific inflammatory reactions, as well as in acquired immune-mediated reactivity. The discussion below briefly overviews the biology of TNF:TNFR interactions in order to consider biological mechanism(s) which underly the association of TNF:TNFR with disease. Subsequently the evidence for a role for TNF-a polymorphisms in the regulation of disorders as broad as autoimmune diseases, infection, malignancy, and transplantation is discussed, along with more recent data suggesting a linkage with susceptibility to cardiovascular disease, schizophrenia, and even longevity per se.
TNF-a has been known for some time to be a major mediator of inflammatory diseases and of organ-specific autoimmune diseases.1 One mechanism whereby inflammatory processes are induced by TNF-a, at least in the brain, resides in the crucial role played in regulating lymphocyte trafficking following control of chemokine expression.2 A wealth of literature suggests a role for anti-TNF-a or the decoy receptor (TNFR linked to an immunoglobulin Fc region) in suppression of autoimmunity.3 Given the evolutionary importance of this inflammatory pathway, perturbation of TNF-a-induced inflammation, as expected, produces undesired side-effects.4 Although TNF-a and TNF-b (lymphotoxin) share sequence homology (30%), and can compete for binding to TNFRs, the discussion that follows is restricted, with few exceptions, to a review of TNF-a alone.5
