Anti-Fibrillin-1 Autoantibodies in Systemic Sclerosis Are GM and KM Allotype-Restricted

Abstract

GM and KM allotypes – genetic markers of immunoglobulin (Ig) γ and ĸ chains, respectively – have been shown to play an important role in genetic predisposition to some autoimmune diseases. To determine their role in susceptibility to systemic sclerosis (SSc; scleroderma) and in the generation of anti-fibrillin-1 antibodies, 148 SSc patients and 191 controls were typed for several GM and KM allotypes by a standard hemagglutination inhibition method. IgG and IgM antibodies to fibrillin-1 were measured by radioimmunoassay. GM and KM phenotypes were not significantly associated with SSc. However, these determinants significantly influenced the production of anti-fibrillin-1 antibodies in SSc patients. In Caucasians, GM1,3,17 23 5,13,21 and GM3 23 5,13 phenotypes were associated with the presence and absence of IgG autoantibodies, respectively. The production of these autoantibodies was also associated with KM allotypes, KM1,3 heterozygosity being associated with response and homozygosity for the KM3 allele with nonresponse to fibrillin-1. In African-Americans, the KM1 homozygotes were associated with the absence of anti-fibrillin-1 antibodies and the KM3 homozygotes with the presence of autoantibodies. In this ethnic group, the GM1,17 5,13 phenotype was associated with the absence of IgM autoantibodies. This represents the first description of genetic control of autoimmunity to fibrillin-1 in scleroderma.

Epistatic effects of genes encoding immunoglobulin GM allotypes and interleukin-6 on the production of autoantibodies to 60- and 65-kDa heat-shock proteins

“…GM f,z loci, too, have been implicated in autoimmune responses. 13,14 Thus, B cells carrying particular f,z allotypes on their Ig receptors may be more efficient in the uptake, processing, and subsequent presentation of hsp60-derived peptides to the collaborating T cells, resulting in anti-hsp60 autoantibody production. Although GM markers are constant-region determinants, they can influence immune responsiveness, normally associated with the variable-region, in several ways: direct contribution to the formation of idiotypic determinants, modulation of antibody binding affinity, linkage disequilibrium with alleles coding for the variable-region epitopes.…”

Immunoglobulin Allotypes Influence Antibody Responses to Mucin 1 in Patients with Gastric Cancer

“…More recent studies in humans have shown that immune responsiveness to a variety of antigens-infectious agents, vaccines, autoantigens, including some tumor-associated antigens-are associated with particular GM and KM allotypes, hereditary antigenic determinants of g and n chains, respectively (7)(8)(9)(10)(11)(12). The aim of the present investigation was to determine whether the variation in naturally occurring antibody levels to MUC1 in patients with gastric cancer is associated with these genetic markers.…”

Development of Two Murine Monoclonal Antibodies Recognizing Human nG1m(a)-Like Isoallotypic Markers

“…Genetic variation is a further basis for study of IgG molecules in a variety of childhood diseases. (3) The role of Gm allotypes in genetic predisposition to filariasis, (2) typhoid fever, (4) SLE, (5) childhood allergy, (6) and systemic sclerosis (sclerodema) (7) has already been reported. In scleroderma, anti-fibrillin-1 autoantibodies are Gm and Km (allotypic markers of kappa light chains) allotype restricted.…”