Antibody affinity: immunogenetic aspects and relationship to immune complex disease.

Itisnowwidely accepted that theimmuneresponse isundera variety ofgenetic controls which, in several instances, arelinked tothemajorhistocompatibility locus (McDevitt andBenacerraf, 1969; Benacerraf andMcDevitt, 1972;Benacerraf and Katz,1975). Thefunctional expression ofsuch autosomal-dominant genetic control ismediated through theco-operative interactions ofB andT lymphocytes andmacrophages. Inaddition, afurther aspect ofthegenetic control oftheimmuneresponse hasbeendescribed byBiozzi andhiscoworkers (Biozzi etal., 1968) inwhichthecharacteristic of 'general immuneresponsiveness' ispolygenically controlled byagroupofabout 10independent loci. Thecontrol ofthischaracteristic appears tobe antigen non-specific andtobeexpressed primarily at thelevel ofthemacrophage. Morerecently, however, evidence hasbeenaccumulating whichindicates that there isanadditional genetically-controlled parameteroftheimmuneresponse, that ofthequality or affinity ofantibody. Inthis paper theevidence forthe genetic control ofantibody affinity anditspossible relationship tothedevelopment ofimmunecomplex disease will bediscussed. Evidence forgenetic control ofantibody affinity Although strain-related variations in thefine specificity ofantibodies toavariety ofantigens in mice, guinea-pigs, andrats havebeenrecognised by workers inseveral laboratories forsometime(for example, Yoshida etal., 1970; Pauletal., 1970), direct evidence forthegenetic control ofantibody affinity hasonlyrecently becomeavailable. The demonstration ofconsistent strain-related variations inmiceoftheaffinity ofantibody produced to humanserumalbumin (HSA), transferrin (HST), the DNP hapten, and streptococcal carbohydrate injected insaline (Soothill andSteward, 1971; Petty etal., 1972; andunpublished observations) wasthe first indication that affinity wasgenetically determined. However, suchstrain-related differences werenot observed whentheantigen wasadministered in complete Freund's adjuvant (Soothill andSteward, 1971). Subsequently breeding studies wereperformed withinbred strains ofmiceproducing either highor lowaffinity antibody toHSA orHST injected in saline. Analysis oftheaffinity ofantibody produced in theparents, Fl hybrids, andbackcrosses hasdemonstrated thatantibody affinity isunder polygenic control. Themeanaffinity value intheFl hybrids ofahigh-affinity strain andalow-affinity strain wasintermediate between themeanvalues of thetwoparental strains. Inthebackcrosses segregation ofaffinity values wasobserved, whichwas consistent withsomeformofgenetic control. Thus thedistribution ofaffinity values inthe(F1x high affinity parent) backcrosses wasnotsignificantly different fromthatofthehighaffinity parents and thedistribution ofaffinity values inthe(F1x low affinity parent) backcrosses wasnotsignificantly different fromthatofthelowaffinity parents.