New roles for rheumatoid factor.

Abstract

In the 1940s, anti-IgG autoantibodies were discovered in the sera of patients with rheumatoid arthritis and given the term rheumatoid factors (RF).' The measurement of agglutinating IgM-RF is still the most useful serological test for the diagnosis of rheumatoid arthritis. High titers of IgM-RF are also present in primary Sjogren's syndrome, mixed cryoglobulinemia, and in several different chronic infections (1).Recent advances in molecular and cellular immunology are gradually revealing the genetic and environmental factors that control RF production. Two sets of results were largely unexpected. First, genes encoding RF are present in most normal people, and their expression is carefully regulated during the development of the immune system. Second, lymphocytes with RF receptors on their plasma membranes are remarkably abundant in normal people, who have only low levels ofcirculating autoantibody. These data have suggested a new role for RF in the capture, processing, and presentation to T cells of antigens trapped in immune complexes. They may explain why RF production is vestained in patients with both rheumatoid arthritis and lymphoproliferative diseases. Genetics ofRFThe antibody molecule is composed of heavy and light chains that are encoded by genes on separate chromosomes. Aside from the diversity allowed by the pairing oftwo separate chains to form a heterodimer, each chain has a variable region capable of achieving tremendous diversity through the process of immunoglobulin gene arrangement.The haploid human genome contains -100-200 heavy chain variable (V) region genes, -100 kappa light chain V genes, and an unknown number oflambda light chain V genes (2, 3). A functional light chain immunoglobulin gene is generated by the rearrangement in early B lymphocytes of one V gene to a separate joining (J) gene segment. In the case of the heavy chain gene, an additional gene segment, termed D for diversity, rearranges with the J segment before V gene rearrangement. This process, together with inaccuracies produced during VDJ and VJ recombination, and sequential somatic mutations in antibody V genes, produces a virtually unlimited array of different antibody molecules. Because immunoglobuReceivedfor publication 12 September 1990 and in revisedform 9 October 1990.1. Abbreviations used in this paper: CLL, chronic lymphocytic leukemia; D, diversity gene segment; HLA, histocompatibility molecule; J, joining gene segment; RF, rheumatoid factor; V, variable gene segment.lin gene rearrangements and somatic mutations occur throughout life, self tolerance is never permanent at the B cell level. Autoantibodies can arise at any time. The important issues are (a) how the inherited repertoire of antibody genes influences the probability of specific autoantibody production, and (b) how the immune system prevents the expansion ofself-reactive B lymphocytes.Before Unequivocal proof that RF paraproteins are structurally related and are the products ofa limited set ofimmunoglobulin V genes required (a) the generation of multiple...

T Cell Activation in Rheumatoid Synovium Is B Cell Dependent

“…B cells, however, are highly efficient in Ag presentation because they accumulate and incorporate Ag by specifically capturing them with their Ig receptors. This mechanism is particularly important for B cells with RF reactivity because RF-positive B cells bind immune complexes and process them for Ag presentation (18,25). They could, therefore, function as APCs in a cognate interaction.…”

“…B cells may be superior to dendritic cells in capturing Ag, in particular, if Ag concentrations are limiting. B cells expressing Ig with RF activity could take up immune complexes presented by the follicular dendritic cells and thereby enrich for an infrequent Ag included in these complexes (18,25).…”

“…Several possible mechanisms could underlie the critical role of B cells in regulating the activation of tissue-invading CD4 T cells. Given the ability of B cells to specifically capture Ag with their Ig receptors and present it to T cells (17,18), B cells may be uniquely situated to stimulate proinflammatory T cells in rheumatoid synovitis.…”

Persistence of a rheumatoid factor (RF)-producing B cell clone with a somatically mutated Igκ chain in a patient with rheumatoid arthritis

“…They have a low-affinity binding for multiple apparently unrelated antigens (reviewed in [6]), Several investigators propose a physiological role for these RF, They are thought to promote the clearance of circulating immune complexes (reviewed in [7]). RF-expressing B cells are considered to act as highly efficient antigen-presenting cells for low concentrations of immune-complexed antigen [8].…”

Thienotriazolopyrimidine Derivatives Inhibit STAT3 Activation Induced by IL-6

“…2,3 Many studies have reported that excess Il-6 were produced in inflammatory tissues related human disease such as rheumatoid arthritis, psoriasis, inflammatory bowel disease, osteoarthritis, and multiple myeloma. 4,5 It is also found in human atherosclerotic plaques, and is related to the impairment of endothelium-dependent dilatation in human veins.…”