Shared idiotypes and restricted immunoglobulin variable region heavy chain genes characterize murine autoantibodies of various specificities.

Monestier, Marc; Manheimer-Lory, A; Bellon, B; Painter, Catherine J.; Dang, Howard; Talal, N; Zanetti, Maurizio; Rs, Schwartz; Pisetsky, D S; Kuppers, Rudolf C.

doi:10.1172/jci112637

Cited by 101 publications

(44 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It has been previously demonstrated that the VH gene families most proximal to the D region locus rearrange frequently in B lymphocytes from fetal or neonatal mice as well as in pre-B lymphocyte lines [24,25], in contrast to adult mature B cells which utilize VH gene families at frequencies that correlate with family size [26]. In natural autoantibodies a similar biased utilization of VH gene families proximal to the D region locus has been reported by several investigators [27][28][29], but has not been confirmed by others [2,7,30]. Our observation that all five anti-mouse erythrocyte MoAbs are encoded by members of the 5' most proximal VH gene families further argues against the preferential rearrangement of VH families proximal to the D regions for the generation of autoantibodies, and is in agreement with previous studies of anti-mouse erythrocyte autoantibodies [9,10].…”

Section: Dtscusstonsupporting

confidence: 71%

Molecular mechanisms resulting in pathogenic anti-mouse erythrocyte antibodies in New Zealand black mice

Scott

Sadigh

Stow

et al. 1993

Clinical and Experimental Immunology

View full text Add to dashboard Cite

SUMMARYThe New Zealand black (NZB) mouse strain is genetically predisposed to develop, at approximately 6 months of age, a spontaneous and severe autoimmune anaemia caused by production of pathogenic anti-mouse erythrocyte autoantibodies. In order to investigate the molecular mechanisms which lead to anti-mouse erythrocyte autoantibody production we have generated eight anti-mouse erythrocyte MoAbs producing hybridomas from splenocytes of 9-and 12-month-old NZB with spontaneous autoimmune anaemia. IgG2a was the predominant isotype, while IgM, IgGl and IgG2b were each produced by one hybridoma cell line. All anti-mouse erythrocyte MoAbs were characterized for their antigen specificities. None of the MoAbs cross-reacted with ss-or dsDNA or with other species' erythrocytes, with the exception of one MoAb which cross-reacted with rat erythrocytes. None ofthe eight hybridomas was demonstrated to express surface or cytoplasmic CD5, suggesting that they derived from CD5" B lymphocytes. All hybridomas when implanted intraperitoneally into BALB/c mice caused anaemia. In order to define the genetic basis and investigate the molecular mechanisms resulting in pathogenic anti-mouse erythrocyte autoantibody production, the pattern of immunoglobulin variable region gene use has been studied. Five ofthe eight MoAbs whose IgVH genes were sequenced all have functionally rearranged genes from the VH J558 gene family. There is evidence for somatic point mutations in the complementarity-determining regions (CDR) ofthe IgVH genes in all of these five MoAbs when compared with the closest known germline gene. We suggest that these nucleotide sequence changes are likely to reflect selection by an antigen-driven mechanism. Furthermore, the data indicate that pathogenic anti-mouse erythrocytes are not derived from 'natural' autoantibodies. Keywords autoantibodies complementarity-determining region monoclonal antibody H genes B lymphocytes tNTRODUCTtONAntibodies have diverse antigen specificities resulting from the structure ofthe assembled V, D and J heavy chain and V and J light chain gene products. Antibodies generated during the rearrangement of germline V(D)J gene segments without the presence of foreign antigen represent the pre-immune repertoire. Due to the almost unlimited potential for V region diversity caused by the combinatorial events during VH-D-JH and VL-JL gene rearrangements and subsequent somatic mutations, antibodies with specificity for autoantigen can occur [1]. The immunoglobulin coding region is organized into largely non-overlapping Vn-gene family clusters, the most proximal to the D and J region loci being the 7183 and Q52 VH-gene families, and J558 and 3609 VH-gene families being most distal.

show abstract

Section: Dtscusstonsupporting

confidence: 71%

Molecular mechanisms resulting in pathogenic anti-mouse erythrocyte antibodies in New Zealand black mice

Scott

Sadigh

Stow

et al. 1993

Clinical and Experimental Immunology

View full text Add to dashboard Cite

show abstract

“…Moreover, with few exceptions (37), autoantibodies seem to arise from the same genetic repertoire that encodes antibodies directed against exogenous antigens (34). The slight restriction for most 3' VH families (7183 and Q52) found for several autoantibodies (38,39) seems to correspond to a preferential rearrangement in normal pre-B cells (40) and to reflect the VH gene distribution in the total repertoire of normal mice (41). Our present results confirm the observation that autoantibodies and antibodies to exogenous antigens can be encoded by the same germ-line genes.…”

Section: E S G V P D R F T 0 S C S 0 T D F T L T I S S V Q a E D Lmentioning

confidence: 99%

Two murine natural polyreactive autoantibodies are encoded by nonmutated germ-line genes.

Baccalà

Quang

Gilbert

et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

135

View full text Add to dashboard Cite

show abstract

“…Indeed, it has beeen demonstrated that members of VH gene families localized most proximal to the D region locus (VH7183 and Q52) rearranged more frequently in B cells from fetal or neonatal mice or in pre-B cell lines [17], than in mature B cells which expressed VH gene families at a frequency related to the family size. The genetic origin of autoantibodies in the adult mouse has shown biased [18][19][20] and unbiased utilization of 3'-proximal VH gene families [21]. Analysis of the selection of autoantibody V genes during autoimmunity depends upon the assessment of the linkage of the autoantibodies to the pathogenic process.…”

Section: Discussionmentioning

confidence: 99%

Molecular heterogeneity of antigen- or idiotype-induced anti-thyroglobulin monoclonal autoantibodies

Bedin

Ropars

Mignon‐Godefroy

et al. 1995

Clinical and Experimental Immunology

View full text Add to dashboard Cite

SUMMARYTo define the molecular basis of the cognitive interaction in experimental autoimmune thyroiditis (EAT), we sequenced the variable regions of monoclonal autoantibodies to thyroglobulin (Tg), specific or not for the F40D peptide, a Tg peptide capable of inducing EAT in CBA/J mice. Three MoAbs were obtained by immunization with syngeneic Tg of CBA/J (3B8G9, 2F6F2) or C57B1/6 (4D1 1F4) mice. 3B8G9 was specific for F40D peptide, whereas 2F6F2 and 4D1 1F4 were not. Two others were raised in CBA/J mice by manipulation of idiotypic pathways: B12 resulted from the immunization with one Ab2,3, bearing the internal image of one F40D epitope, and TA2 from the immunization with F40D-specific cytotoxic HTC2 T cells. B12 and TA2 were both specific for F40D. All hybridomas expressed different members of the J558 VH family, except 3B8G9 which expressed a Q52 VH gene segment. These data led us to hypothesize that regulatory anti-id autoantibodies used members of one VH family located in the 5'-end of the VH locus, whereas EAT-associated autoantibodies used a member of one of the most D-proximal VH family. As expected, no homologies were found when anti-F40D monoclonal autoantibodies were compared with two other monoclonal autoantibodies displaying a different epitopic specificity. Among the anti-F40D monoclonal autoantibodies, one histidine residue located in position 35 of the CDR1 region was constantly found. Moreover, TA2 and B12 exhibited two common animo acids in their CDR3 regions, one glycine and one tyrosine, in positions 98 and 99, respectively. Striking homologies were found between TA2 and one anti-polyGAT MoAb, and between 3B8G9 and some anti-phenyloxazolone (phOx) monoclonal autoantibodies. Lastly, the VK sequence from 4DllF4 was identical at the amino acid level to the VK sequence from another monoclonal autoantibody, 81B1, which was previously raised towards syngeneic Tg in CBA/J mice. Our data imply that anti-idiotypic regulatory circuits in EAT might be generated by a heterogeneous population of B cells rather than obtained by a single dominant B cell population.

show abstract

Shared idiotypes and restricted immunoglobulin variable region heavy chain genes characterize murine autoantibodies of various specificities.

Cited by 101 publications

References 32 publications

Molecular mechanisms resulting in pathogenic anti-mouse erythrocyte antibodies in New Zealand black mice

Molecular mechanisms resulting in pathogenic anti-mouse erythrocyte antibodies in New Zealand black mice

Two murine natural polyreactive autoantibodies are encoded by nonmutated germ-line genes.

Molecular heterogeneity of antigen- or idiotype-induced anti-thyroglobulin monoclonal autoantibodies

Contact Info

Product

Resources

About