Immunogenetic Aspects of Rheumatic Diseases
Allan Gibofsky
The efforts of numerous investigators during the last three decades have resulted in the recognition of a major histocompatibility complex (MHC) in humans, consisting of the alleles of at least seven closely linked loci on the short arm of autosomal chromosome 6. The antigens that the genes of this region code for were first detected on white blood cells and were, therefore, originally referred to as human leukocyte antigens (HLA). Initially, these antigens were of interest primarily to transplantation physicians because similarity between donor and recipient antigens seemed to influence allograft survival; soon, however, it was recognized that certain clinical conditions might be associated with one or more antigens of this system. A large number of diseases have been studied, and individual antigens or combinations of antigens have appeared with greater frequency than would be expected in the normal population. This increase in the frequency of occurrence of antigens is particularly true for rheumatic diseases and related syndromes with features of altered immunoreactivity, where, as will be discussed in subsequent text, the strongest and most significant associations have been demonstrated. Although it is recognized that many of the rheumatic diseases may occur as a result of multiple genetic factors, the strongest influences have been with the HLA genes of the MHC. This chapter reviews the basic concepts of immunogenetics, emphasizing the potential significance of the HLA system antigens in clinical rheumatology.
IMMUNOGENETIC NOMENCLATURE
Gene. Segment of DNA that directs the synthesis of a polypeptide chain or protein.
Allele. Alternative form of the same gene, resulting from mutation or duplication.
Locus. The position of a gene on any given chromosome.
Genotype. The genetic composition of an individual.
Phenotype. The observed expression of the genotype.
Haplotype. Closely linked loci, transmitted as a unit from each parent; two haplotypes constitute the genotype.
Product of the A, B, C, or DR, DP, or DQ loci.
I. LOCI DEFINITION
Multiple closely linked loci have been defined by gene mapping techniques, and their products have been recognized by a combination of serologic and DNA typing methods. (A complete listing of the several hundred recognized alleles defined for the six loci can be found at http://www.ash1-hla.org.) These genes have been functionally assigned to several classes:
Class I includes the products of the HLA- A, B, and C series.
Class II includes the products of the HLA-DR, DP, and DQ series.
Class III has recently been described and consists of the genes for various peptide transporters [e.g., Transporter Associated With Antigen Processing (TAP)], proteosome subunits (e.g., LMP), and other proteins involved in autoimmunity (e.g., DM, DO).
Initial studies directed toward the development of serologic methods for the detection of HLA-D antigens resulted in the recognition of several additional gene products, preferentially expressed on the surface of B lymphocytes. These B-cell antigens have extensive biologic and chemical homologies with the I-region antigens of the murine histocompatibility system and are therefore also referred to as Ia antigens. These Ia alloantigens were primarily recognized with alloantibodies that developed as a result of immunization of the mother with paternal antigens during pregnancy or in the sera of renal transplant recipients who became immunized against nonmatching antigens present on the homograft. These human Ia antigens are highly polymorphic and have certain alloantigenic specificities related closely to HLA alleles. The gene products of the HLA-D region appear to be highly complex and polymorphic and have not yet been fully defined. Each product consists of a noncovalently associated combination of an α- and a β-chain. The α- and β-chains are substantially different from each other, and there is evidence for at least six α-chain genes and seven β-chain genes, all in the HLA region. These genes appear to be arranged in subsets corresponding to three distinct products, all of which are class II molecules: (a) DR molecules, (b) DQ molecules, and (c) DP molecules, which do not appear to be serologically defined. The α- and β-chain genes of each series’ products are substantially more similar to each other than to genes of one of the other allelic series.Related posts:
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