Publisher Summary This chapter discusses conceptual and technical developments in the field of human Ia antigens by describing the chemical structure and immunologic relationship to their murine counterparts. The distribution of human Ia antigens is limited primarily to the B lymphocyte series, stimulated T cells, and stem and precursor hematopoietic cells, suggestive of both cell type and differentiation specificity. The association of certain Ia antigens with susceptibility or resistance to a variety of diseases, including rheumatoid arthritis, systemic lupus erythematosus, idiopathic thrombocytopenic purpura, rheumatic fever, multiple sclerosis, and diabetes, provides both a valuable clinical predictive measure and a lead for the future study of pathogenetic factors possibly related to the particular Ia genes involved. The chapter examines the Ia antigens from two principal perspectives: (1) as membrane components related to differentiation, and (2) as part of a genetically intricate system of molecules bearing alloantigens that have relevance to susceptibility to certain diseases. Three types of antisera are used to detect Ia antigens: alloantisera, heteroantisera raised in rabbits or similar species, and monoclonal hybridoma reagents. It is apparent that the relationship of diseases to the Ia alloantigens is an intricate one and is likely to involve several distinct factors.

The human Ia system.

The hutnan major histocompatibility complex, called the HLA region, is located on the short arm of chromosome 6. To date this region is known to code for about six proteins expressed on the cell surface and several serum complement factors. The HLA region could accomodate the structural genes for many more proteins. The HLA-controlled cell surface antigens are highly polymorphic both serologically and structurally. This polymorphism is essential for the function of these molecules which, evidence indicates, is to allow ceils of the immune system to discriminate self from non-self.

HLA-DR antigens: structure, separation of subpopulations, gene cloning and function.

HLA class I glycoproteins contain the functional sites that bind peptide antigens and engage lymphocyte receptors. Recently, clinical application of sequence-based HLA typing has uncovered an unprecedented number of novel HLA class I alleles. Here we define the nature and extent of the variation in 3,489 HLA-A, 4,356 HLA-B and 3,111 HLA-C alleles. This analysis required development of suites of methods, having general applicability, for comparing and analyzing large numbers of homologous sequences. At least three amino-acid substitutions are present at every position in the polymorphic α1 and α2 domains of HLA-A, -B and -C. A minority of positions have an incidence >1% for the 'second' most frequent nucleotide, comprising 70 positions in HLA-A, 85 in HLA-B and 54 in HLA-C. The majority of these positions have three or four alternative nucleotides. These positions were subject to positive selection and correspond to binding sites for peptides and receptors. Most alleles of HLA class I (>80%) are very rare, often identified in one person or family, and they differ by point mutation from older, more common alleles. These alleles with single nucleotide polymorphisms reflect the germ-line mutation rate. Their frequency predicts the human population harbors 8-9 million HLA class I variants. The common alleles of human populations comprise 42 core alleles, which represent all selected polymorphism, and recombinants that have assorted this polymorphism.

/pdf/distinguishing-functional-polymorphism-from-random-variation-1rki8bmpmi.pdf

Distinguishing functional polymorphism from random variation in the sequences of >10,000 HLA-A, -B and -C alleles

The relationships of HLA—DR and the newer DS (second D locus) B cell alloantigens (MB and MT) to the clinical and serologic expression of primary and secondary forms of Sjogren's syndrome (SS) were examined in 102 patients (86 whites and 16 blacks). Although HLA-DR3 was significantly increased in whites (25 of 50, 50%) and blacks (4 of 5, 80%) with primary SS compared with race-matched normal controls, it was not appreciably elevated in those with systemic lupus erythematosus (SLE)-SS, rheumatoid arthritis (RA)-SS, or connective tissue disease-SS. The MT2 specificity, however, was more strongly associated with primary SS (86% of whites and 100% of blacks) and also with SLE-SS and RA-SS compared with race-matched normal controls. Furthermore, MT2 was significantly increased in SLE-SS and RA-SS when compared with non-sicca SLE and RA controls. Although primary and secondary SS were most strongly associated with this DS specificity (MT2), the anti-Ro (SS-A) and anti-La (SS-B) antibody responses were more closely allied to DR antigens. HLA-DR3 was increased in anti-Ro positive patients, both whites and blacks, with primary SS (74%) and in total anti-Ro positive subjects (54%) compared with their anti-Ro negative counterparts (38% and 31%, respectively). Among DR3 negative patients, HLA-DR2 correlated with anti-Ro in both primary SS (83%) and in the total SS group (58%). Thus, 96% of Ro antibody positive patients with primary SS had DR3 and/or DR2, as did 80% of anti-Ro positive subjects in all categories. Antibodies to La (SS-B) correlated only with DR3 in primary SS and in the total group. These data suggest that MT2 is the strongest major histocompatibility complex determinant for primary and secondary SS. However, HLA-DR3 and DR2 may mediate the Ro/La antibody responses that are characteristic of more severe disease. The clinical expression of Sjogren's syndrome appears to result from the complex genetic interplay of multiple HLA-D region factors.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/art.1780271106

Sjöugren's syndrome influence of multiple hla-d region alloantigens on clinical and serologic expression

Monoclonal antibody IVD12 was used to isolate and characterize a human Ia molecule present on B cells that generally display DR4 or DR5 phenotypes. The specificity of binding of IVD12 to human peripheral blood B cells from 75 normal individuals and 19 homozygous human lymphoblastoid B cell lines was identical to the supertypic specificity MB3 previously defined. Furthermore, IVD12-reactivity was shown to segregate with HLA in three informative families. In each family, individuals positive for IVD12 binding were also positive for DR4 or DR5. Using IVD12, a molecule has been isolated from the homozygous cell line PRIESS (DR4/4) and has been shown by amino acid sequence analysis to be homologous to the murine I-A and human HLA-DS molecules. These findings suggest that the MB3 specificity is found on a molecule encoded by loci distinct from those loci which encode HLA-DR molecules. This molecule represents the third family of HLA-D region molecules isolated from the cell line PRIESS. Both HLA-DR and HLA-SB molecules from this cell line were previously shown by amino acid sequence analysis to be I-E-like but distinct from one another. Collectively, these data provide evidence that the HLA-D region contains at least six loci encoding distinct alpha and beta chains for the HLA-SB, HLA-DR, and HLA-DS molecules.

/pdf/structural-analysis-of-a-human-i-a-homologue-using-a-3wefmpili6.pdf

Structural analysis of a human I-A homologue using a monoclonal antibody that recognizes an MB3-like specificity.

Evidence for a second B-cell locus separate from the DR locus.

Serology of HLA.

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Evidence for a second B-cell locus separate from the DR locus.

Serology of HLA.