The MHC is a cluster of genes that encode HLA molecules in humans on chromosome 6. A major function of these molecules is to enable macrophages and dendritic cells to present antigens to T cells in the periphery: Presentation of antigen by HLA to T cells is ineffective unless costimulatory molecules are present on both antigen-presenting cells (for example, B7.1 and B7.2) and lymphocytes (for example, CD28 and CTLA-4). CD8⁺ T cells are governed by MHC class I molecules (HLA A, B, and C); in CD4⁺ T cells, antigen is presented by MHC class II molecules (HLA D).

The following summary compresses many investigations in rheumatoid arthritis done in the past 15 years:

1. In many patients, rheumatoid arthritis is associated with specific MHC class II molecules (for example, DR); in contrast, ankylosing spondylitis is associated with specific MHC class I antigens (for example, HLA-B27).

2. Crystallographic analyses of the HLA antigens have shown that the and ß chains that form these antigen-presenting molecules have a configuration not unlike a trough (or rain gutter). Antigens are bound by sequences of amino acids in a pocket along the bottom and sides of the trough or cavity, and this complex forms a heterotrimer with the T-cell receptor on CD4⁺ cells.

3. A common sequence of amino acids (residues 70 to 74) in the HLA-DRB1 chains is found in alleles that are associated with rheumatoid arthritis. The sequence, variably referred to as the "susceptibility cassette," "shared epitope," or "rheumatoid pocket," is one of two variations: glutamine(Q)-lysine(K)-arginine(R)-alanine(A)-alanine(A) or QRRAA.

These susceptibility cassettes are found in many different DRB1 alleles, and the sequencing of alleles has clarified much confusion about HLA and rheumatoid arthritis. For example, although alleles within the DR4 haplotype are most often associated with rheumatoid arthritis (see Table 2 in the paper by McDaniel and colleagues in this issue [4]), few Yakima Indians of the Pacific Northwest have DR4 haplotypes. However, rheumatoid arthritis is common in the tribe. The explanation? The DR6 (HLA-Dw16) allele DRB1*1402 that is found in 83% of Yakima Indians with rheumatoid arthritis contains the susceptibility cassette [5].

4. Assuming that the prevalence of rheumatoid arthritis in white persons in the United States is 1%, the upper limits of risk ratios for HLA haplotypes and alleles has been calculated as follows [6]:

HLA Class II Gene Risk Ratio of Developing Rheumatoid Arthritis

Dw4 (DRB1*O401)———————————1 in 35

Dw14 (DRB1*O404)——————————1 in 20

Dw1 (DRB1*O101)———————————1 in 80

Dw4 and Dw 141 in 7

5. The presence of two alleles containing the shared epitope puts a patient with rheumatoid arthritis at a greater risk for both severe arthritis and for development of extra-articular manifestations [7].

6. There are "protective" phenotypes of HLA-DR that appear to occur more frequently in healthy controls than in patients with rheumatoid arthritis in the same populations [8]. HLA-DR1/DR5, DR2, DR2/DR3, and DR3/DR7 are the protective haplotypes. One can only speculate on the mechanism for this "protection." One possibility is that the protective haplotypes may, in association with a particular arthritogenic peptide, encourage development of suppressor T cells that could down-regulate inflammatory immune responses. Another possibility is that antigen presentation by these molecules is, for some reason, not associated with the costimulatory molecules essential for T-cell activation and that clonal anergy of the matched T cell would occur.

Despite all of these exciting associations with the "susceptibility cassette," more and more data have evolved to indicate that the shared epitope is not the entire story and that susceptibility and severity of rheumatoid arthritis are governed by multiple genes. In 1993, 70 patients with rheumatoid arthritis were described in a Spanish population. All these patients were rheumatoid factor positive, and one third did not share the epitope in DRB1 chains that is characteristically associated with the disease [9]. In contrast to white persons in northern Europe and North America, DR4 in these Spanish patients gave a relative risk of only 2.4, and DR10 gave a relative risk of 4.27. A similarly low rate of HLA-DR4 was found in northern Italy [10].

The prevalence of rheumatoid arthritis in black persons of Caribbean descent is lower than that in white persons in the inner city of Manchester, United Kingdom [11]. Without associated immunogenetic studies, one would be tempted to blame an as-yet unknown infectious agent transmitted among crowded city dwellers. In the study by McDaniel and colleagues reported in this issue [4], allele-specific typing of exons that contain the hypervariable region was done in African-American patients with rheumatoid arthritis and in African-American controls. Although the authors observed an increased frequency of HLA-DRB1*0404 alleles containing the shared epitope in seropositive patients with rheumatoid arthritis (27.3%) compared with controls (13.1%), frequencies of other DRB1 alleles were similar in both groups. Approximately three quarters of both rheumatoid factor-positive and rheumatoid factor-negative African-American patients were HLA-DR4 negative. Few of these patients encoded the susceptibility cassette in other alleles, and no differences in the aggressiveness of the disease were found in patients who were homozygous, heterozygous, or null for the shared epitope.

When confronted with such data, do we need to consider discarding the paradigm of the susceptibility cassette in the DRB1 chains of HLA class II molecules? Probably not, although the data reinforce the concept that rheumatoid arthritis is indeed a polygenic process. In addition, close examination of the data presented in Table 4 of the article by McDaniel and colleagues [4] offers some interesting additional interpretations and insights. First, the DRB1*0101 and *0102 alleles, both containing the QRRAA cassette, are lumped together with DRB1*0103, which has aspartic acid(D) and glutamic acid(E) instead of glutamine(Q) and arginine(R) at residues 70 and 71. The *0103 allele has not been associated with rheumatoid arthritis. If the *0101 and *0102 alleles had been reported separately from the *0103 allele, would there have been a difference in the prevalence of these two alleles in patients with rheumatoid arthritis compared with controls?

Second, if, from data in McDaniel and colleagues' Table 4, one adds the prevalence of the reported "protective epitopes" (for example, DR5[DRB1*1101], DR2(DRB1*1501), DR3(DRB1*0301), and DR7^[0701]), it becomes apparent that each of the seropositive patients who did not have a double dose of the susceptibility cassette could have had one of these "protective" alleles; if so, however, that protection was not provided.

McDaniel and colleagues emphasize that a person who does not have the susceptibility cassette for rheumatoid arthritis can nevertheless develop full-blown rheumatoid arthritis. And because it has been known for years that only a small percentage of persons who express this susceptibility cassette develop rheumatoid arthritis, we must continue to search for other genes that are involved in the initiation of a chronic immune synovitis or, alternatively, in protection from such an illness. It is not unreasonable to postulate, at this stage of our knowledge, that rheumatoid arthritis arises from various forces that generate acute and chronic synovitis in almost every patient. Genes determining T-cell receptors, T-cell subtypes, B-cell responses, cytokine expression, cortisol production, vascular adhesion molecules, metalloprotease synthesis, and other components of the inflammatory response may link with the susceptibility cassette on DRB1 molecules. These factors, combined with one or more of the many stimuli presented by the environment, may then produce what we see as a case of chronic polyarticular synovitis, and name it rheumatoid arthritis.