RCMI International Symposium on Health Disparities
November 12-15, 2000
San Juan, Puerto Rico

Invited Speakers

GENETIC VARIATIONS OF RECEPTORS
FOR IMMUNOGLOBULIN (FcγR):
DETERMINANTS OF SEVERITY OF SLE

Jane E. Salmon, M.D.
Department of Medicine
Hospital for Special Surgery and
Weill Medical College of Cornell University
New York, NY

SLE is a heterogeneous disease with a relatively higher prevalence and worse outcome in non-Caucasian populations. Genetic factors are considered major determinants of disease and may, in part, account for variations in prevalence, clinical manifestations, course, and outcome of SLE among ethnic groups. Genetically determined alterations in receptors for the Fc region of IgG (FcγR) provide a possible basis for inherited susceptibility to SLE.

FcγR provide the link between the humoral and cellular aspects of the immune cascade. Allelic variants of human FcγR profoundly influence phagocyte biologic activity. Single amino acid substitutions within the extracellular domains of stimulatory FcγR alter the ability of the receptor to bind IgG and low binding alleles have been associated with risk for and phenotype of autoimmune and infectious disease.

FcγRIIa, expressed on mononuclear phagocytes, neutrophils, and platelets, has two codominantly expressed alleles, H131 and R131, which differ at amino acid position 131 in the extracellular domain (arginine or histidine, respectively) and differ substantially in their ability to bind human IgG2. H131 is the high binding allele, R131 low binding, and heterozygotes have intermediate function. Because IgG2 is a poor activator of the classical complement pathway, FcγRRIIa-H131 is essential for handling IgG2 immune complexes. FcγRIIIa, which is expressed on mononuclear phagocytes and natural killer cells, also has two codominantly expressed alleles, F176 and V176, which differ in one amino acid position 176 in the extracellular domain (phenylalanine or valine, respectively). FcγRIIIa alleles differ in IgG1 and IgG3 binding; V/V176 homozygotes bind IgG1 and IgG3 more efficiently than F/F176.

The interplay between the humoral immune response and FcγR genotypes is a key determinant of the handling of opsonized antigens. Such antigen-antibody immune complexes are removed from the circulation by the mononuclear phagocyte system, primarily the liver and spleen. Impaired removal of immune complexes in systemic lupus erythematosus (SLE) leads to tissue deposition of immune complexes, release of inflammatory mediators, influx of inflammatory cells, and target organ damage, events crucial to nephritis. We have shown that low binding alleles of FcγR (FcγRIIa-R131 and FcγRIIIa-F176) are enriched in African-American patients and Hispanic patients with SLE and nephritis. Recognition of specific inherited disease associated genotypes expands our understanding of disease pathogenesis and may provide prognostic markers for disease severity.