Origin and Diversification of Anti‐DNA Antibodies

129

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...

Section: Genetics Ofrfmentioning

confidence: 99%

New roles for rheumatoid factor.

Carson¹,

Chen²,

Kipps³

1991

129

“…Among the various human autoantibodies, anti-DNA antibodies have been a particular object of investigation, originally in the context of their strong association with systemic lupus erythematosus (SLE) and, more recently, with regard to their occurrence in apparently healthy individuals (5). To investigate the genetic origins of this autoimmune response, we undertook studies of V gene utilization in "natural" anti-DNA antibodies derived from nonautoimmune subjects.…”

Section: Introductionmentioning

confidence: 99%

“…Until recently, however, little information has been available with regard to the genetic basis of specific autoimmune responses, and in particular, the contribution of variable region (V)1 genes and somatic mutation to the generation of such responses. From studies in many laboratories it has been shown that there is frequent sharing of crossreactive idiotypes among human autoantibodies of given specificities, implying that they use the same or similar germline V genes with little somatic change (4)(5)(6). This interpretation is supported by the finding ofextensive similarity among the heavy and light chain V regions of idiotypically related monoclonal autoantibodies (7,8), and more recently by data showing complete identity between a germline VK gene (Humkv325) and four human rheumatoid factor light chains (9,10).…”

Section: Introductionmentioning

confidence: 99%

A natural autoantibody is encoded by germline heavy and lambda light chain variable region genes without somatic mutation.

Siminovitch¹,

Misener²,

Kwong³

et al. 1989

While nonmutated germline variable region (V) genes have been found to encode heavy or light chains of various human autoantibodies, the use of germline V genes by both chains of a given autoantibody has not been documented. Recently, we reported that the heavy chain V gene (designated Humha346) of the Kim4.6 anti-DNA antibody is identical to a germline VH gene, 1.9111. To investigate whether this autoantibody was entirely germline encoded, we searched for the germline counterpart to the Kim4.6 VX segment (designated Humlal46) and isolated a VXI gene designated Humlvll7, which was identical to Humlal46. Together with the sequence identity of the Kim4.6/Humha346 and 1.9111 VH genes, the current data provide the first direct proof that an autoantibody can be encoded entirely by germline V genes without any somatic change. In addition, Humlvll7 is the first VXI germline gene that has been isolated, and is highly homologous to the VX genes expressed in two lymphomas. Thus, this VXI gene should provide a useful tool for investigating the expression of the human VX gene repertoire, particularly with regard to autoimmune and/or lymphoproliferative diseases.

“…Receivedfor publication 2 April 1990 and in revisedform 16 January 1991. germline Ig variable region (V)1 genes with no somatic mutation (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). In addition, serological analyses of newborn mice showed a high frequency of autoreactive B cells, whose expressed autoantibodies often shared cross-reactive idiotypes (CRIs) (17)(18)(19).…”

Section: Introductionmentioning

confidence: 99%

Molecular basis of an autoantibody-associated restriction fragment length polymorphism that confers susceptibility to autoimmune diseases.

Olee¹,

Yang²,

Siminovitch³

et al. 1991

Recently, combined serological and molecular studies ofautoantibodies have revealed that these antibodies play an important role in the normal function of the immune system and in the development of the B cell repertoire. Accordingly, we hypothesized that a homozygous deletion of a critical autoantibody-associated Ig variable (V) gene may alter the immune system and thus predispose the host to autoimmune disorders. Initial experiments revealed several restriction fragment length polymorphisms (RFLP) of the Humhv3005 gene, that is likely to encode heavy chains of rheumatoid factors, and the closely related 1.9111 gene. By probing EcoRl-digested DNA with the Humhv3005/P1 probe, we found that one of the four major hybridizing bands was missing in -20% of patients with either rheumatoid arthritis or systemic lupus erythematosus, but only 2% of normal subjects. To delineate the genetic basis of this polymorphism, we have now employed the PCR to amplify and analyze hv3005, 1.9III, and homologous genes in individuals with characteristic RFLP genotypes. Our results indicate that the human Vh gene repertoire contains several hv3005-and 1.9II-like genes, and that a complete deletion of the hv3005-like genes is relatively restricted to a subset of autoimmune patients. These findings provide initial evidence for deletion of developmentally regulated autoreactive V genes in autoimmune diseases. (J. Clin. Invest. 1991.88:193-203.)