IgM rheumatoid factor autoantibody and immunoglobulin-producing precursor cells in the bone marrow of humans

Fong, Sherman; Gilbertson, Timothy A.; Hueniken, Robert J.; Singhal, Sharwan K.; Vaughan, John H.; Carson, Dennis A.

doi:10.1016/0008-8749(85)90304-1

Cited by 20 publications

(11 citation statements)

References 34 publications

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“…Similarities, strongly indicative for this linkage, include a biased IgV gene use, expression of common Ig idiotypes, a similar pattern of binding specificities [27,[37][38][39][40][41][42][43]51] as well as a rather low affinity for the recognized antigens [40]. Moreover, autoreactive B cell precursors in the human bone marrow were frequently found to be in a proliferative state [52], presumably reflecting the nonspecific nature of their activation signals. Whether pathogenic highaffinity autoantibodies could arise by somatic hypermutation from the polyreactive cell pool [24,25], e.g., following a breakdown of T cell tolerance, or whether polyreactive B cells may be involved in normal and/or abnormal antigen processing is still unclear.…”

Section: Igv Gene Use By Normal Individuals and Naturally Occurring (mentioning

confidence: 99%

Use of Immunoglobulin Variable-Region Genes by Normal Subjects and Patients with Systemic Lupus Erythematosus

Hansen¹,

Dörner

Lipsky

2000

Int Arch Allergy Immunol

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Antibodies to specific autoantigens are serological hallmarks of systemic autoimmune diseases. These autoantibodies are thought to represent a consequence of immune dysregulation in these conditions, and, in part, have been shown to be involved in their pathologic consequences. However, the mechanisms that lead to the production of autoantibodies are still unknown. The observation that certain autoantibodies are frequently encoded by a limited number of immunoglobulin (Ig) variable-region gene segments suggested that a bias in the development of the Ig repertoire might play a role in the tendency to develop autoimmunity. Whether the use of these individual gene segments is random or different in normal subjects and patients with systemic autoimmune disorders remains a matter of controversy. New approaches for the analysis of variable-region genes from unstimulated individual human B cells employing the single-cell polymerase chain reaction have provided new insights in the B cell repertoire of both normal subjects and patients with systemic autoimmune diseases. Using this approach, the analysis of nonproductive and productive Ig variable-region gene rearrangements made it possible to distinguish molecular processes, as manifested in the nonproductive repertoire, from subsequent selection influences. An initial study in a patient with systemic lupus erythematosus has led to the hypothesis that the molecular generation of the B cell repertoire is similar in patients and normal subjects but subsequent influences and, most notably, extensive mutations and receptor editing differ significantly in shaping the peripheral IgV gene use by persons with autoimmune diseases.

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Section: Igv Gene Use By Normal Individuals and Naturally Occurring (mentioning

confidence: 99%

Use of Immunoglobulin Variable-Region Genes by Normal Subjects and Patients with Systemic Lupus Erythematosus

Hansen¹,

Dörner

Lipsky

2000

Int Arch Allergy Immunol

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“…RF precursor B cells must be exposed to immune complexes intermittently through life, and may be stimulated to divide and undergo somatic mutation whether or not the autoantibody is actually secreted. synthesis, selectively eliminates RF precursors without destroying the ability to generate nonspecific IgM or IgG after a polyclonal stimulus (43). This implies that RF cells often traverse the cell cycle.…”

Section: Rf Gene Polymorphisms and Autoimmunitymentioning

confidence: 99%

New roles for rheumatoid factor.

Carson¹,

Chen²,

Kipps³

1991

J. Clin. Invest.

129

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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...

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“…The use of immunohistological methods for detection of viral proteins [14] and in situ hybridization for viral DNA [27] indicated that EBV is predominantly in the epithelial cells rather than the lymphocytes; (c) in some SS patients, seroconversion for EBV has been observed in association with development of SS [19,41]; (d) EBV RNA can be associated with the autoantigens SS-A and SS-B [24]; (e) EBV stimulation of B-cells can give rise to rheumatoid factor [8] with the same crossreactive idiotype that is present in SS patients [13]; and (f) there are increased antibody titers against specific synthetic peptides encoded by the glycine-alanine repeat region of EBNA-1 [33] and against early antigen EA-D [14].…”

Section: Potential Role Of Ebv In Ssmentioning

confidence: 99%

Reactivation of Epstein-Barr virus in Sjögren's syndrome

Fox

Luppi

Kang

et al. 1991

Springer Semin Immunopathol

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Sjögren's syndrome (SS) is a chronic autoimmune disease characterized by severe dryness of the eyes and mouth, resulting from lymphocytic infiltration of the lacrimal and salivary glands. SS may exist as a primary condition (primary SS, 1.SS) or as a secondary condition (2.SS) in association with rheumatoid arthritis, systemic lupus erythematosus, or progressive systemic sclerosis. In some 1.SS patients, there may be involvement of the extraglandular organs, including skin, kidney, liver, lung and nervous system. Furthermore, these patients may develop a lymphoproliferative syndrome that includes lymphadenopathy and increased risk of lymphoma. In the pathogenesis of SS, a role for Epstein-Barr virus (EBV) has been suggested because: (a) EBV is present in salivary gland epithelial cells of normal individuals and exaggerated immune responses against EBV could play a role in the destruction of salivary glands in SS; (b) SS salivary gland biopsies contain increased levels of EBV DNA in comparison to normal salivary glands, indicating viral reactivation and inability of lymphoid infiltrates to control EBV replication in SS patients; and (c) salivary gland epithelial cells in SS patients express high levels of HLA-DR antigens and may present EBV-associated antigens to immune T cells in SS patients. Therefore, SS may represent a situation in which genetically predisposed individuals (i.e., HLA-DR3-DQA4-DQB2) have a persistent but ineffectual T cell immune response against EBV at its site of latency. Among 14 non-Hodgkin's lymphomas that developed in SS patients, EBV DNA was detected in increased amounts in the tumor tissue of one patient. Characterization of this tumor DNA revealed: (a) polyclonal immunoglobulin gene rearrangements; (b) EBV DNA with an unusual restriction fragment length polymorphism pattern involving the Bam M fragment; and (c) EBV terminal repeat sequences suggestive of viral replication, similar to those reported in EBV lymphomas occurring in other immunocompromised individuals. Early recognition of this clinical problem may allow beneficial use of antiviral agents.

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IgM rheumatoid factor autoantibody and immunoglobulin-producing precursor cells in the bone marrow of humans

Cited by 20 publications

References 34 publications

Use of Immunoglobulin Variable-Region Genes by Normal Subjects and Patients with Systemic Lupus Erythematosus

Use of Immunoglobulin Variable-Region Genes by Normal Subjects and Patients with Systemic Lupus Erythematosus

New roles for rheumatoid factor.

Reactivation of Epstein-Barr virus in Sjögren's syndrome

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