The full-length gene that encodes the light chain variable regions of an idiotypically related group of human IgM kappa rheumatoid factors (RFs) has been cloned and sequenced. The deduced amino acid sequence is identical to four separate RF proteins. These results prove that genes capable of encoding human anti-IgG autoantibody light chains without any somatic mutation are present in the kappa gene repertoire of normal people.

Rheumatoid factors represent a normal component of the immune network. The autoantibodies promote complement fixation and clearance of immune complexes. They amplify the avidity of polyclonally induced IgG. Genes related to the primary structure of rheumatoid-factor light chains are widely distributed in the human population and have been conserved during the evolution and dispersion of the species. Products of these genes may be detected with anti-idiotypic antibodies against synthetic peptides corresponding to individual hypervariable regions on rheumatoid-factor light chains. Such anti-peptide antibodies provide unique reagents for analyzing the genetics of immunoglobulins in outbred populations. Precursors of rheumatoid factor are abundant among immature B lymphocytes. Some of these cells may tend to localize to mucosal surfaces, where they are stimulated directly by pathogenic microorganisms with polyclonal B cell-activating properties. Synthesis of rheumatoid factor regularly accompanies all secondary immune responses but is usually transient. Production of the autoantibody is T-cell dependent. The T cells may recognize antigen in an IgG-antigen immune complex that is processed and presented by B-cell precursors of rheumatoid factor. Rheumatoid factor-associated light-chain idiotypes are rare in serum IgG and on IgG myeloma proteins. They are common among monoclonal IgM proteins and on the surface of the malignant B cells from patients with chronic lymphatic leukemia. The rheumatoid factors that are produced by patients with mixed cryoglobulinemia, or primary Sjogren's syndrome can share idiotypic antigens with monoclonal rheumatoid factors. Rheumatoid factor synthesis in the diseases may reflect an abnormal proliferation of B-cells that is not antigen-driven and that can degenerate into malignancy. The rheumatoid factors in patients with rheumatoid arthritis are diverse and almost certainly represent the outcome of antigen-induced, T cell-dependent mechanisms. The antigens that drive the T cells have not been identified but could represent exogenous microorganisms, self components, or idiotypic antigens that fortuitously interact with rheumatoid factors.

The role of immunoglobulin structural genes in the generation of autoantibodies in humans has not been elucidated. Human monoclonal IgM anti-IgG autoantibodies (rheumatoid factors, RFs) from unrelated people often share idiotypic antigens. Antibodies against synthetic peptides have localized two of the shared idiotypic determinants to the second and third complementarity-determining regions of the K light chain. The reported sequences of several human RF light chains are remarkably homologous in these regions. Animal studies have shown that some shared idiotypic antigens represent serological markers for immunoglobulin variable (V)-region genes. Therefore, we hypothesized that human RF light chains derived from a single germ-line gene, designated V -(RF), or from a small family of very closely related genes. In the present experiments, we have isolated and sequenced two human VK germ-line genes that encode K light chains, which are identical or closely related to the light chains of human RF. The data indicate that the shared idiotypic antigens on RF are phenotypic markers for a K V-region gene that is highly conserved in the human population. The results also imply that the light chains of IgM anti-IgG autoantibodies can be encoded by germ-line genes without any somatic mutation.Immune responses are controlled by genes that encode histocompatibility antigens, T-cell receptors for antigens, and immunoglobulins. The inherited structural genes for immunoglobulin light and heavy chains dictate the potential antibody repertoire of any individual. However, immunoglobulin genes also undergo extensive rearrangements and somatic mutations during life (1, 2). Both polymorphisms in inherited immunoglobulin genes as well as somatic changes may therefore influence the ability to form autoantibodies. To dissect the importance of the two factors, one must first isolate potential autoantibody structural genes in their germline configuration. This goal has proved difficult to accomplish in outbred human populations.Idiotypes are antigens in the variable (V) portion of immunoglobulins (3,4). In many instances, idiotypic antigens have been localized at or near the antigen binding site. Immunoglobulins that share idiotypic determinants often are related structurally and may represent the protein products of identical or similar antibody V-region genes (5-8).Kunkel and co-workers first demonstrated that several human monoclonal IgM anti-IgG autoantibodies (rheumatoid factors, RFs) from unrelated subjects shared idiotypic antigens (9). A majority of these monoclonal RFs also had homologous sequences in the K light-chain V regions (10-13). Subsequent experiments with anti-peptide antibodies localized two of the shared idiotypic determinants, also termed cross-reactive idiotypes, to the second and third complementarity-determining regions of the K light chain. After an analysis of multiple RF light chains with a diverse series of anti-idiotypic reagents, we postulated that the cross-reactive idiotypes were markers for a single...

Airflow limitation is a frequent finding in patients with rheumatic diseases. We have previously suggested that it is associated with autoimmune exocrinopathy in Sjögren's syndrome. To compare clinical features of patients with and without airways dysfunction and to further test the hypothesis of a link between airways disease and exocrinopathy, we prospectively studied 2 groups of 15 lifetime nonsmoker female patients with seropositive rheumatoid arthritis (RA). The 2 groups were similar in their clinical and immunologic features, but differed in terms of airways function. Salivary, lacrimal, and sweat gland dysfunction were significantly more prevalent or severe in the group with airways disease. Antinuclear antibodies were also more prominent in the patients with airways disease, but antibodies against RNP, SS‐A, SS‐B, and double‐stranded DNA were not present in these patients. HLA‐DR4 was found in 80% of the RA patients with airways disease and in 57% of those without airways disease. HLA–B8 and DR3 were equivalently distributed in both groups. This prospective study further documents the existence of small airways disease in RA and supports the view that autoimmune exocrinopathy predisposes to its expression.