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Myasthenia gravis (MG1) is an autoimmune neuromuscular disease characterized by muscle weakness. Antibody mediated destruction of muscle membrane acetylcholine receptors (AChR) is the primary pathology in MG. Because of the association of HLA-DR3 gene in MG, we studied the role of class II genes and their product in the murine model of MG, experimental autoimmune MG (EAMG), which mimics human MG in all respects. Initial studies on B10 congenic and recombinants suggested the involvement of IA subregion gene on EAMG pathogenesis. Later, evaluation of IA beta chain mutant bm12 revealed that IA molecule is one of the determinants which mediates EAMG. Recent studies pointed out that L3T4+ helper T cells, which participate in T cell response to class II antigens is required for EAMG pathogenesis. Therefore, specific therapy of MG is possible by modulating the functions of DQ/CD4 determinants, which are analogous to IA/L3T4 determinants in the mouse.

Adherent or accessory cells, previously indicated as “A”-cells are of paramount importance in the immune response in vitro as well as in vivo. The nonlymphoid adherent population of peritoneal exudate cells, which have phagocytic properties, comprise the accessory cells which have to be present in lymphoproliferative responses in vitro. Most of these cells were obviously macrophages. However, they constitute a heterogeneous population of cells. It appeared that only a minority (8–15%) of these cells bear the Ia determinants of the immune response gene complex (1) which determines their antigen presenting function. Moreover, macrophages may change their properties in this respect during adhesion in vitro (2).

T dependent reactivity controlled by immune response (Ir) genes in rodents exhibits the following three characteristics. (1–3) First, it is dependent on interactions between T cells and antigen presenting accessory cells (conveniently referred to here as MO). Second, the reactivity is directed against determinants inherent in either synthetic polypeptides or limited regions of globular proteins. Third, the reactivity is controlled by genes present in the immune response (Ir) locus of the major histocompatibility complex.

In earlier studies it was shown that synthetic and chemically well-defined Dnp-oligolysines did induce both cellular and humoral immunity in guinea pigs, and that this response was under immune response gene control (1, 2). Sera of guinea pigs of genetic responder strain immunized with synthetic Dnp-oligolysine peptides have been shown to contain highly specific antibodies of restricted heterogeneity which could discriminate Dnp-oligolysines with minimal changes in hapten position, chain length, D-lysine-alanine sub-stituents (3–7). Like specificity has been shown in T-cell responses of responder guinea pigs to these simple antigens since they could also discriminate equally well the homologous immunizing antigen from closely related ones in assays measuring antigen-induced delayed hypersensitivity, tritiated thymidine incorporation, and mediator production (8–9). Non-responder animals, in contrast, lack a T-cell response to these antigens and the antibody produced in the absence of T-cells, while Dnp-specific, could not discriminate one Dnp-oligopeptide from another (6). Exquisite specificity of antibody in animals with highly specific T-cell responses and the lack of it in non-responder guinea pigs immunized to the same antigen suggested that T-cells could select specific B-cell clones to proliferate (10). To test this possibility, studies were undertaken to explore antigen-induced B-cell responses in both strain 2 and 13 guinea pigs in the presence and absence of Dnp-oligolysine-specific T-cells. These experiments will emphasize the role of specific T-cells in the selection and amplification of unique B-cell clones.

The observation that inheritance can influence immune reactions was made more than half a century ago. Cooke and van der Veer (1916) found that inheritance plays a significant role in the development of hay fever, bronchial asthma, gastro-enteritis, and other forms of human sensitization. They concluded that this phenomenon is genetically transmitted from parent to offspring as a dominant characteristic, and that it does not involve the transmission of sensitization itself. It was not until several decades later that the genetic controls of antibody responses to diphtheria toxoid (Scheibel, 1943), to pneumococcal polysaccharide (Fink and Quinn, 1953), and to insulin (Arquilla and Finn, 1963, 1965) were discovered. This has been followed in recent years by a deluge of isolated and interrelated reports of genetic control of immune response for many immunogens in at least four species. Nevertheless, the most significant recent progress made in elucidation of this very complex and intriguing genetically-determined phenomenon can be attributed to advance made in three independent scientific areas.