Immunoglobulin Allotypes, Immune Response, and Diseases

IMMUNOGLOBULIN ALLOTYPES, IMMUNE RESPONSE, AND DISEASES

Numerous studies have shown that immune responsiveness to certain antigens and suscep-tibility/resistance to particular diseases are influenced by GM and KM allotypes. How can C-region allotypes influence immune responsiveness thought to be exclusively associated with the V-region genes? The most likely mechanism involves the possible influence of C-region allotypes on antibody affinity. Contrary to the previously held views that the C do-mains do not play any role in antibody-binding affinity, the contribution of CH2 and CH3 domains—where the majority of the GM markers are located—on IgG binding strength is now firmly established. The CH1 domain—where allelic determinants G1M3 and 17 are located—has also been shown to modulate the kinetic competence of antigen-binding sites. Whether the structural differences in the CH domains caused by GM alleles also play a role in antibody affinity needs to be investigated.

Occasionally, particular alleles of the HLA, GM, and KM loci interact to influence immune responsiveness and disease susceptibility. The mechanisms underlying the inter-action of these unlinked genetic systems are not understood.

The biological role and reasons for the extensive polymorphism of Ig allotypes re-main unknown. The marked differences in the frequencies of Ig allotypes among races, strong linkage disequilibrium within a race, and racially restricted occurrence of GM hap-lotypes all suggest that differential selection over many generations may have played an important role in the maintenance of polymorphism at these loci. One mechanism could be the possible association of these markers with immunity to certain lethal infectious pathogens implicated in major epidemics, and different races may have been subjected to different epidemics throughout our evolutionary history. After a major epidemic, only in-dividuals with allotypic combinations conferring immunity to the pathogen would survive. In this context, it is interesting to note that GM and HLA genes have been shown to influ-ence the chance for survival in typhoid and yellow fever epidemics in Surinam.