Type II collagen-induced murine arthritis. II. Genetic control of arthritis induction is expressed on L3T4+ T cells required for humoral as well as cell-mediated immune responses to type II collagen.

The present study investigates the cellular and molecular mechanisms responsible for expressing genetic control of type II collagen-induced murine chronic arthritis. Analyses were made for both humoral and cellular immune responses, since the induction of arthritis required synergy between both types of immunities. Immunization of high (DBA/1) and low (C57BL/6, C3H/He, BALB/c) responder mice with native bovine type II collagen resulted in the production of the respective high and low levels of anti-collagen antibody. However, polyclonal in vitro stimulation of normal spleen cells from high or low responder mice with lipopolysaccharide (LPS) induced a comparable magnitude of anti-collagen antibody responses, indicating the localization of the genetic defect at cellular levels other than B cells themselves. In contrast to immunization with native collagen, sensitization of DBA/1 mice with heat-denatured collagen failed to stimulate B cells, but resulted in selective generation of L3T4+ T cell-mediated immunity. These included anti-collagen delayed-type-hypersensitivity (DTH) responses and the generation of various interleukins (IL) responsible for antibody production as well as DTH responses. It was demonstrated that there was appreciable difference in the magnitudes of these responses between lymphoid cells from high and low responder mice. Differential effects of sensitization with heat-denatured collagen in high versus low responders were reflected on the genetic difference in the development of chronic arthritis. A typical arthritis was induced neither in denatured collagen-sensitized DBA/1 mice nor in unsensitized mice transferred with anti-collagen antiserum. However, the antiserum transfer into denatured collagen-sensitized DBA/1 mice induced chronic perpetuating arthritis. This sharply contrasted with the failure of the same aliquot of the antiserum to induce a chronic arthritis when inoculated into denatured collagen-sensitized low responder mice. These results indicate that the genetic control of the induction of arthritis is expressed on L3T4+ T cells which are required for generating anti-collagen humoral as well as cell-mediated immunities as assessed by DTH responses in vivo or lymphokine productions in vitro.