Preferential utilization of a novel vλ3 gene in monoclonal rheumatoid factors derived from the synovial cells of rheumatoid arthritis patients

Ermel, Richard W.; Kenny, Thomas P.; Wong, Alice; Solomon, Alan; Chen, Pojen P.; Robbins, Dick L.

doi:10.1002/art.1780370614

Cited by 26 publications

(12 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recently, it has been confirmed that the corresponding germline gene 1 -69 [19] or DP10 [18] is indeed the main heavy chain gene encoding RF from healthy human immunized donors, from peripheral blood lymphocytes (PBL) from RA patients and from paraproteins [27]. Some of the RF-encoding germline genes reported by other authors, mainly from studies of RF-secreting hybridomas [24,28,29], occurred recurrently in our investigation, namely the 3.23/DP-47/VH26, the 3.53/DP-42, the 4.59/DP-71/4.11 and the 4.18 germline gene.…”

Section: Discussionmentioning

confidence: 93%

Analysis of VH gene rearrangements from synovial B cells of patients with rheumatoid arthritis reveals infiltration of the synovial membrane by memory B cells

Gause

Gundlach

Carbon

et al. 1997

Rheumatology International

View full text Add to dashboard Cite

The VH gene (Variable gene segments of the heavy chain locus) repertoire can be investigated by DNA analysis of rearranged immunoglobulin VH genes, which also allows for an indirect estimation of antibody selection by analysis of somatic mutations. Using a polymerase chain reaction (PCR) it is also possible to analyse these genes in small numbers of cells or even single cells. This approach was chosen to investigate germinal centre like lymphocyte follicles in the synovial membranes of two patients with rheumatoid arthritis (RA) in order to analyse the local humoral immune response in RA. Individual B-cell aggregates of synovial membrane of two patients with RA were isolated by micromanipulation from microscopic slides. VH-DH-JH (variable, diversity, and joining segments of the heavy chain locus) rearrangements in all possible VH-JH combinations were amplified from these B cell foci, cloned and subjected to sequence analysis. Sequence analysis revealed that most of the rearranged VH genes were somatically mutated with at least 1% (range 1.3-14.9%) somatic mutations and therefore were derived from antigen-selected memory B cells. Intraclonal diversity in one-third of the clones indicated the generation of memory B cells in the synovial membrane and characterized the synovial membrane as lymphatic tissue where secondary immune responses to an as yet unknown antigen take place.

show abstract

Section: Discussionmentioning

confidence: 93%

Analysis of VH gene rearrangements from synovial B cells of patients with rheumatoid arthritis reveals infiltration of the synovial membrane by memory B cells

Gause

Gundlach

Carbon

et al. 1997

Rheumatology International

View full text Add to dashboard Cite

show abstract

“…V λ genes have been shown to be critical parts of a number of human autoantibodies, including antibodies to double‐stranded DNA (29–32), antibodies to La/SSB and Ro/SSA (9, 33), RF (5, 34–37), and antibodies to lamin B (38) and phospholipids (39). Notably, however, these particular V λ gene segments have not previously been shown to encode autoantibodies.…”

Section: Discussionmentioning

confidence: 99%

Immunoglobulin V? light chain gene usage in patients with Sj�gren's syndrome

Kaschner

Hansen

Jacobi

et al. 2001

Arthritis & Rheumatism

View full text Add to dashboard Cite

Objective To determine whether patients with Sjögren's syndrome (SS) have abnormalities in Ig Vλ and Jλ gene usage, differences in somatic hypermutation, defects in selection, or indications for perturbations of B cell maturation. Methods Individual peripheral B cells from SS patients were analyzed for their Vλ gene usage by single‐cell polymerase chain reaction amplification of genomic DNA and compared with those from normal controls. Results Molecular differences from controls in Vλ–Jλ recombination were identified that were reflected by findings in the nonproductive Vλ repertoire of the patients, including enhanced rearrangement of Vλ10A and Jλ2/3 gene segments. In addition, a number of abnormalities in the productive repertoire were identified, indicating disordered selection. A greater usage of 4 Vλ genes (2A2, 2B2, 2C, and 7A), representing 56% of all productive Vλ rearrangements, was observed, suggesting positive selection of these genes. Overutilization of Jλ2/3 and underutilization of Jλ7 in both nonproductive and productive Vλ rearrangements of SS patients compared with controls suggested decreased receptor editing in SS. The mutational frequency did not differ from that in controls, and positive selection of mutations into the productive V gene repertoire was found, similar to that in controls, although mutational targeting toward RGYW/WRCY motifs, typically found in controls, was not found in SS patients. Conclusion Disturbed regulation of B cell maturation with abnormal selection, defects in editing Ig receptors, and abnormal mutational targeting may contribute to the emergence of autoimmunity in SS.

show abstract

“…Based on nucleotide sequence homology, the xlIIb L chains of the anti-rabbit IgG RF H4 (14) were most closely related to those of LBR150 and, thus, were also products of the germline hsigglll50 gene. Ermel et al (49) have recently reported that two other synovial cell-derived anti-rabbit IgG RF from another RF patient contained xlIIb L chains identical to those of RF H4 (14). The predominance of xlIIb L chains among RF with comparable specificity, especially those that are related to the hsiggl1150 VxlIIb germline gene, implies the functional importance of this gene in certain patients with RA and related diseases.…”

Section: Discussionmentioning

confidence: 99%

Human rheumatoid factors with restrictive specificity for rabbit immunoglobulin G: auto- and multi-reactivity, diverse VH gene segment usage and preferential usage of V lambda IIIb.

Fang

Kannapell

Gaskin

et al. 1994

The Journal of Experimental Medicine

View full text Add to dashboard Cite

SummaryTo determine the molecular and functional properties of human rheumatoid factors (RF), we established stable hybridomas and Epstein-Barr virus-transformed B cell lines from the synovial fluid or peripheral blood of three patients with rheumatoid arthritis and one patient with systemic lupus erythematosus. 17 cell lines were obtained that produced high-titer immunoglobulin M (IgM) RF that reacted exclusively with rabbit but not human IgG or IgG of other mammalian species. Certain anti-rabbit IgG RF also had specificity for other mammalian antigens (Ag), including cytoskeletal proteins and intracellular proteins found in HeLa cells, as well as for Ag present in an extract prepared from the cell wall of group A streptococci. 13 of the 17 RF contained h-type light (L) chains, of which 12 were classified serologically as members of the X-L chain variable region (Vx) subgroup, designated VxlII. The heavy chain V region (VH) and Vx sequences of nine of these IgMX tLF were determined at the cDNA level. Five VH genes in three V. families were used by these antibodies (Ab), including V.I (dp21/1-4b and dpl0 [51pl]/ hv1051), V.3 (dp38/3-15 and dp77/13-21), and V.4 (dp70/4-4b). The deduced V gene-encoded amino acid sequences of the X chains of these IgMX tLF confirmed their serological classification as xlII, and they were further classified as members of the relatively uncommon VxlII subgroup, designated VxlIIb. Based on cDNA analyses, nine were the product of three different VxlIIb germline genes. Two such genes, designated hsiggl1150 and hsiggl1295, were cloned and sequenced from genomic DNA. Unique combinations of these V. and VxlIIb genes could be related to distinctive patterns of reactivity among the IgMX RF. Although the V, and Vx regions of these Abs were expressed primarily as germline-encoded sequences, four of nine multireactive Abs had extensive V region mutation, indicative of an Ag-driven process. The finding that xlIIb L chains are preferentially found among anti-rabbit IgG RF, and that some of these Ab have specificity for other protein, cellular, and bacterial Ag, provides new insight into the pathogenesis of RA and related diseases.

show abstract

Preferential utilization of a novel vλ3 gene in monoclonal rheumatoid factors derived from the synovial cells of rheumatoid arthritis patients

Cited by 26 publications

References 39 publications

Analysis of VH gene rearrangements from synovial B cells of patients with rheumatoid arthritis reveals infiltration of the synovial membrane by memory B cells

Analysis of VH gene rearrangements from synovial B cells of patients with rheumatoid arthritis reveals infiltration of the synovial membrane by memory B cells

Immunoglobulin V? light chain gene usage in patients with Sj�gren's syndrome

Human rheumatoid factors with restrictive specificity for rabbit immunoglobulin G: auto- and multi-reactivity, diverse VH gene segment usage and preferential usage of V lambda IIIb.

Contact Info

Product

Resources

About