The HLA complex spans about 4Mb on the short arm of chromosome 6. It harbors dozens of genes, many of which encode proteins involved in the immune response, including the highly polymorphic polypeptide chains of the HLA class I and class II molecules. The chains encoded by the HLA-A, -B, and -C genes, located in the telomeric class I region, are expressed on the cell surface of virtually all nucleated cells; complexed with p2-microglobulin, they present peptides derived from cytosolic antigens, e.g., self antigens and the products of intracellular pathogens, to cytotoxic CD8+ T cells. The HLA-DR, -DQ, and -DP genes of the centromeric class II region encode the a and p chains of the heterodimeric cell-surface molecules that present endocytosed antigens, e.g., extracellular pathogens, to CD4+ "helper" T cells. The HLA class III region, located between the class I and class II regions, also contains a number of polymorphic genes encoding components of the immune system—such as complement factors and TNF-a and -p—but none encoding "classical" peptide-presenting HLA molecules.

In the early 1970s, Jersild et al. (26) first reported an association between MS and the HLA class I alleles, A3 and B7, and a year later, a stronger association to the class II specificity Dw2 (27). It became apparent that the former association was secondary to the latter, a result of the high degree of linkage disequilibrium (LD) in the HLA complex, whereby strings of alleles at adjacent loci escape separation by meiotic recombination and are inherited together as conserved haplotypes. The MS-associated HLA haplotype, whose boundaries have now been determined by genomic techniques, consists of alleles of four adjacent class II genes—DRB1*1501 DRB5*0101, DQA1*0102, and DQB1*0602. Although the haplotype is most common in Scandinavia, it appears to be increased, compared to frequencies in controls, in MS patients from all ethnic groups (28).

The extensive conservedness of this haplotype—the infrequency with which its component alleles occur unaccompanied by the others—makes it difficult to determine which part of haplotype is responsible for the susceptibility-conferring biological phenomena underlying the genetic association to MS. Recently, however, Oksenberg et al. (29) investigated a dataset of African American MS patients and controls—a population exhibiting greater haplotypic diversity than northern Europeans—and uncovered an association with HLA-DRB1*15, in the absence of DQB1*0602. This finding suggests that it is the DRB1 gene—or rather the DRp chain it encodes—that plays a functional role in etiopathogenesis of MS. In an earlier study, however, Caballero et al. (30), comparing a group of Brazilian MS patients of African origin with a group of ethnically matched controls, observed in patients an increase in the frequencies of DQA1*0102 and DQB1*0602, in the absence of DRB1*1501, implicating the DQ molecule as the functional culprit.

Meanwhile, Ligers et al. (31) found evidence of linkage to the HLA-DRB1 locus in 58 DRB1*1501-negative Canadian MS families, suggesting the existence either of a hierarchy of predispositional and protective DRB1 alleles; or of a primary, non-DRB1 susceptibility locus in strong LD with the DRB1*1501 allele (25). Indeed, in a study of the Sardinian population, Marrosu et al. (32) demonstrated not only the presence of four independent MS susceptibility loci within the HLA complex—at the DRB1, DQB1, and DPB1 loci, as well as at a locus telomeric to the classical class I genes—but also the positive association of five DRB1-DQB1 haplotypes with MS. To complicate matters even further, carriage of the HLA class I allele A*0201 appears to decrease the risk of MS (33), while studies by Barcellos et al. (34) and our own group (35) have demonstrated a dose effect of the serologically defined risk specificity HLA-DR15 (Table 2).

Although the mechanism by which alleles of classical or nonclassical HLA genes might predispose carriers to MS is still unknown, the following models have been proposed (36):

1. Determinant model. Carriage of the MS-associated HLA genotype facilitates presentation of encephalitogenic peptides to CD4+ T cells.

2. Thymic-selection model. Deletion of encephalitogenic T cells in the thymus is compromised by the presence of the MS-associated HLA genotype.

3. Molecular-mimicry model. The MS-associated HLA genotype is associated with presentation of bacterial or viral peptides with structural homology to autoantigens of the central nervous system (CNS).

4. Cytokine-regulation model. Carriage of the MS-associated HLA genotype entails high-level production of pro-inflammatory Thl-type cytokines.

5. Aberrant-expression model. Polymorphisms in promoter regions of classical HLA genes directly induce the local over-expression of the molecules encoded by the genes in the context of MS-related inflammation.

6. LD model. Non-HLA genes linked to the HLA complex confer susceptibility to MS, through the actions, or inaction, of their protein products.

Given the great number of HLA associations reported in MS—and the allelic and locus heterogeneity it implies—it is not unlikely that more than one of these mechanisms contributes to the pathogenesis of the disease. Indeed, in our own study cited above (35), the dominant mode of action of DR15, on the one hand, and the recessive mode of action of the more weakly associated specificity DR17, on the other, suggest the workings of a complex, two-mechanism model. To explain the multiple HLA class II associations in rheumatoid arthritis, Zanelli et al. (37) have in fact proposed such a model, involving both recessive loss of immune protection and dominant exacerbation of ongoing inflammation. In addition, the association, in

Table 2 HLA-DR Genotypes in Multiple Sclerosis

Risk genotype

Reference genotype

Barcellos et al. (34)a

Modin et al. (35)b

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