Faculty Bibliography

An interpretive summary of recent immunologic and molecular biologic data concerning the molecular basis of susceptibility of rheumatoid arthritis will be presented. The central point of view is taken that the MHC class II molecules encoding disease susceptibility function in a specific immune recognition event. This could involve an antigen 'X' that currently eludes characterization or be directed to polymorphic determinants on the MHC molecule itself. The problem of understanding the meaning of the association of susceptibility to rheumatoid arthritis with diverse MHC alleles such as DR4 (Dw4 and Dw14) and DR1 is approached by detailed biochemical analysis that led to the identification of common stretches of amino acid sequence, presumably encoding conformationally equivalent structures. The sequence shared by the otherwise unrelated DR1 and DR4 haplotypes from residue 67 in the DR a chain that appears to confer susceptibility is Leu-X-X-Gln-Arg/Lys. Non-classic MHC polymorphisms related to disease susceptibility but not associated with particular alleles such as identified by Ab109d6 prove especially valuable in suggesting new directions for attempting to understand the significance of these associations. Consideration is given to the possibility that a family of either slightly different or identical conformations encoded in either cis or trans cumulatively confer the liability to develop rheumatoid arthritis. This implies a highly non-classic mode of inheritance. It seems reasonable to consider the pathogenesis of rheumatoid arthritis as evolving from a typical immune response based on a simple immune recognition event directed to a single antigen

Since the first description of human leukocyte agglutination antibodies, knowledge of the MHC, particularly the Ia region, has grown immensely and it is now recognized as a major polymorphic multigene family involved in the regulation of immune response and disease susceptibility. This review examined the hypothesis that there is another level of complexity within the Ia system, beyond multiple loci and allelic series, that involves specific epitopes as the functionally important components of the Ia molecule. Certain of these epitopes are likely to be responsible for the regulation of immune responses and susceptibility to certain autoimmune diseases such as rheumatoid arthritis (RA). Evidence was presented that certain monoclonal antibodies recognize epitopes found in a significantly more positive association with susceptibility to RA than available markers such as DR4. Biochemical characterization of the Ia molecules bearing this epitope revealed that the same epitope was present on two different molecules. The possibility was considered that such epitopes are closely related but not identical to Ia determinants that are primarily involved in producing the abnormal immune state characterizing those with RA.

The monoclonal antibodies 109d6 and IVD12 reacted with separate polymorphic Ia epitopes in immunofluorescent studies. Using a panel of lymphoblastoid B cell lines, antibody 109d6 reacted with all HLA-DR4 or DR7 positive lines in a pattern resembling the MT3 specificity recognized by human alloantisera. The antibody IVD12 reacted with all HLA-DR4 and two of three DR5 positive B cell lines suggesting that it recognized a specificity similar to MB3. The intensity of fluorescence was greater on DR5(+) cell lines than on DR4(+) cell lines relative to the amount of a nonpolymorphic Ia determinant. Among 45 unrelated control individuals reactivity with antibody 109d6 was correlated most closely with (r = 0.724) but not identical in occurrence to the MT3 specificity. Cocapping experiments demonstrated that the 109d6 epitope and the IVD12 epitope were present on independently redistributed cell surface molecules of DR4 homozygous lymphoblastoid cell lines. Furthermore, the DR4 alloantigens detected by an absorbed polyclonal human alloserum were similarly identified on molecules that were independent from those bearing either the 109d6 epitope or the IVD12 epitope. Taken together, these data indicate the existence of at least four distinct, serologically defined Ia molecular species.

Among individuals with rheumatoid arthritis the presence of the polymorphic Ia antigen epitope detected by the monoclonal antibody 109d6 is more strongly correlated with disease susceptibility than are other specificities, such as HLA DR4, DRw53 (MT3) or the antigenic determinant, defined by the monoclonal antibody 17-3-3S. The cells of 93% of Caucasian and Hispanic patients react with the 109d6 reagent. As was the case in normal individuals, all DR4-positive patients express the 109d6 determinant; however, 26% of those with rheumatoid arthritis have the epitope recognized by antibody 109d6, but lack the specificity DR4. Of these, one-third expresses only HLA DR1 and DQw1 (MT1, MB1) determinants. Studies of family members reveal that here the determinants 109d6, DR1, and DQw1 are encoded by the same unusual haplotype. In certain other individuals with rheumatoid arthritis who express DR4, DRw53, and the 109d6 determinants, family studies show that the 109d6 epitope is encoded not only by the haplotype specifying DR4 but also by the opposite haplotype that does not bear the genes for DR4. This suggests that homozygosity for certain Ia epitopes is relevant to determining the disease-susceptibility state. These studies emphasize the utility of monoclonal antibodies as reagents for the recognition of Ia epitopes that are more closely involved in the determination of disease susceptibility than are allomorphic molecules detected by conventional typing alloantisera