Rheumatoid arthritis is significantly associated with the HLA determinant HLA-DRw4 and cell-mediated reactivity to collagen. To determine ifgenes linked to those coding for HLA-DRw4 constituted immune response genes for collagen reactivity, peripheral blood mononuclear cells from 20 individuals with rheumatoid arthritis, 13 individuals with other arthropathies, and 41 normal individuals were compared for their ability to synthesize the lymphokine leukocyte inhibition factor in response to denatured bovine collagen. All individuals were responsive to the control antigen Candida albicans. While 90% of the patients with rheumatoid arthritis responded to collagen, so did 30% of the individuals without rheumatoid arthritis. This included 15 normal individuals without any evidence of arthritis. Collagen responsiveness was dependent on interactions between T cells and macrophages and was directed against determinants expressed by primary amino acid sequences in the synthetic polypeptide (GlyPro).. HLA-DRw typing of 59 individuals revealed a highly significant relationship (P < 0.0001, x2 = 33.7) between and collagen responsiveness, irrespective of whether or not rheumatoid arthritis was present. All normal individuals who were HLA-DRw4-positive were collagen responders. These studies demonstrate that the cellular, molecular, and genetic characteristics of collagen reactivity in man parallel those documented for the T cell-dependent response to antigens under immune response gene control in rodents.Immune response (Ir) gene control ofT cell reactivity to soluble antigens in rodents demonstrates the following characteristics. First, the depicted reactivity requires presentation of antigen by macrophages (MO) to reactive T cells and is thus both MO and T cell dependent (1-3). Second, the reactivity is specific for determinants inherent in linear amino acid sequences of synthetic polypeptides or limited regions ofglobular proteins (4-7). That is to say, it is not dependent on conformational determinants dictated by tertiary structure. Third, the reactivity is controlled by genes closely linked to those in the Ir region of the major histocompatability complex (MHC) (2,4).Previous studies from this laboratory demonstrated that murine T cell reactivity to denatured beef collagen, as measured by proliferation in vitro, was linked to Ir genes (8). This finding, coupled with the observations of others that (i) T cell reactivity to collagen in man is seen in a high proportion of patients with rheumatoid arthritis (9-12) and (ii) rheumatoid arthritis is significantly associated with cell surface determinants (HLA-Dw4 and HLA-DRw4) that are products of genes in the proposed human Ir locus, suggested that collagen reactivity in man might also be under Ir gene control (13,14). The results ofthe studies presented here indicate that the cellular and antigenic requirements for collagen-induced production of leukocyte inhibition factor (LIF) in man parallel those established for Ir gene control ofT cell reactivity in rodents. M...