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

Baccalà, Roberto; Quang, Tuyen Vo; Gilbert, Michele; Ternynck, Thérèse; Avraméas, Stratis

doi:10.1073/pnas.86.12.4624

Cited by 135 publications

(61 citation statements)

References 59 publications

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“…Early studies indicate that the general biochemical and immunologic features of NAA are comparable to those of conventional, monospecific Abs. NAAs are usually encoded by germline Ig V region genes with little or no somatic mutation (2,9,14,15), but they use the same spectrum of V H and V L genes as those used by conventional Abs (9,16). Previously, we have shown that NAAs differ from Ag-induced Abs in the third hypervariable region of the H chain (9), a finding subsequently confirmed by others in human polyreactive Abs (17)(18)(19).…”

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confidence: 61%

B Cells Expressing a Natural Polyreactive Autoantibody Have a Distinct Phenotype and Are Overrepresented in Immunoglobulin Heavy Chain Transgenic Mice

Tian¹,

Beardall²,

Xu³

et al. 2006

The Journal of Immunology

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Despite stringent regulation of disease-associated autoantibodies, a substantial proportion of circulating Abs in sera of healthy individuals exhibit self-reactivity. These Abs are referred to as naturally occurring or natural autoantibodies (NAAs). To understand the origin and function of NAAs, we have generated a new site-directed transgenic mouse model in which a prerearranged VDJ gene coding for the H chain of a typical polyreactive NAA, ppc1-5, is inserted into the IgH locus. This H chain, when combined with its original L chain, the λ1 L chain, yields a NAA that characteristically binds a variety of self and non-self Ags including ssDNA, actin, ubiquitin, and nitrophenyl phosphocholine. Despite their autoreactivity, B cells expressing ppc1-5H/λ1 NAA are not negatively selected, but rather are overrepresented in the transgenic mice. The shift toward λ1 expression mainly occurs during the transition of immature to mature B cells in the spleen, suggesting a BCR selection process. The ppc1-5H/λ1 B cells exhibit a phenotype that is different from those of the known mature B cell populations, and they are located predominantly in the lymphoid follicles of the spleen and the lymph nodes. These B cells are functionally active, producing high levels of Abs in vivo and responding well to BCR stimulation in vitro. The findings indicate that the ppc1-5/λ1 natural autoantibodies originate from a distinct B cell subset that may be positively selected by virtue of its poly/autoreactivity.

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confidence: 61%

B Cells Expressing a Natural Polyreactive Autoantibody Have a Distinct Phenotype and Are Overrepresented in Immunoglobulin Heavy Chain Transgenic Mice

Tian¹,

Beardall²,

Xu³

et al. 2006

The Journal of Immunology

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“…Modifications of self-proteins may affect their recognition by the immune system in a number of ways. For example, the immunogenic nitrophenyl moiety may enhance binding to natural antibodies or increase uptake, processing, and presentation of antigen (31)(32)(33)(34). Alternatively, a single modified residue may induce changes in endosomal/lysosomal processing and allow epitopes that usually are not presented to be exposed on the surface to the MHC molecules (35)(36)(37)(38).…”

Section: Resultsmentioning

confidence: 99%

Loss of CD4 T-cell–dependent tolerance to proteins with modified amino acids

Gauba

Grünewald

Gorney

et al. 2011

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

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The site-specific incorporation of the unnatural amino acid p-nitrophenylalanine (pNO 2 Phe) into autologous proteins overcomes self-tolerance and induces a long-lasting polyclonal IgG antibody response. To determine the molecular mechanism by which such simple modifications to amino acids are able to induce autoantibodies, we incorporated pNO 2 Phe, sulfotyrosine (SO 3 Tyr), and 3-nitrotyrosine (3NO 2 Tyr) at specific sites in murine TNF-α and EGF. A subset of TNF-α and EGF mutants with these nitrated or sulfated residues is highly immunogenic and induces antibodies against the unaltered native protein. Analysis of the immune response to the TNF-α mutants in different strains of mice that are congenic for the H-2 locus indicates that CD4 T-cell recognition is necessary for autoantibody production. IFN-γ ELISPOT analysis of CD4 T cells isolated from vaccinated mice demonstrates that peptides with mutated residues, but not the wild-type residues, are recognized. Immunization of these peptides revealed that a CD4 repertoire exists for the mutated peptides but is lacking for the wild-type peptides and that the mutated residues are processed, loaded, and presented on the I-A b molecule. Overall, our results illustrate that, although autoantibodies are generated against the endogenous protein, CD4 cells are activated through a neo-epitope recognition mechanism. Therefore, tolerance is maintained at a CD4 level but is broken at the level of antibody production. Finally, these results suggest that naturally occurring posttranslational modifications such as nitration may play a role in antibody-mediated autoimmune disorders.loss of tolerance | autologous antibody response | protein nitration P reviously we showed that the site-specific incorporation of the unnatural amino acid p-nitrophenylalanine (pNO 2 Phe) into a protein can induce autoantibodies against the endogenous, unmodified protein (1, 2). The murine proteins TNF-α and retinolbinding protein (RBP4) were modified genetically to incorporate pNO 2 Phe at several surface-exposed positions and were used as immunogens. Vaccination of mice with these altered proteins resulted in an IgG polyclonal antibody response against the endogenous proteins that lasted for at least 40 wk. Experiments involving hybridomas generated from the TNF-α-immunized mice revealed that the IgG antibody response was directed against different regions of the protein and not exclusively against the region containing the pNO 2 Phe residue. The autoantibodies generated by the mutated proteins were tested in an endotoxemia model for their ability to neutralize wild-type TNF-α. Protection from endotoxemia indicated that vaccination with pNO 2 Phemodified self-protein is able to elicit physiologically relevant autoantibody responses. Although these initial studies implicated a role for CD4 T cells in autoantibody production, the exact mechanism by which the site-specific incorporation of pNO 2 Phe breaks immunological self-tolerance remained to be elucidated.Recent studies have indicated that postt...

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“…Independent clones of CD5 B cells may express identical V genes without evidence for somatic mutation (51,52). The antibodies encoded by such V genes frequently are reactive with a variety of self antigens, i.e., proteolytically processed erythrocyte membranes, denatured DNA, and/or the Fc portion of self IgG (53)(54)(55)(56)(57). Stable expression of such V genes with little or no somatic mutation may account for the finding that CD5 B cells are enriched for cells that spontaneously produce IgM autoantibodies (19,20).…”

Section: Resultsmentioning

confidence: 99%

Relationship of the CD5 B cell to human tonsillar lymphocytes that express autoantibody-associated cross-reactive idiotypes.

Kipps

Duffy²

1991

J. Clin. Invest.

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We examined human tonsillar B cells for expression of autoantibody heavy-chain or kappa light-chain cross-reactive idiotypes (CRIs), respectively defined by murine MAbs G6 or 17.109. We find 17.109 or G6 each specifically binds a subpopulation of B cells, respectively reacting with 3.8±3% (mean±SD) or 2.0±1.2% of all tonsillar lymphocytes. Cells reactive with both 17.109 and G6 comprise only 0.4±0.3% of tonsillar lymphocytes. Although each tested specimen had 17.109-positive cells, 2 of 19 tonsils (11%) did not have any G6-reactive cells. We find that CRI-positive cells and CD5 B cells both co-express slgD but fail to bind peanut agglutinin or MAbs specific for CD10, indicating that both cell types reside in the mantle zones of secondary B cell follicles. However, less than half of the B cells bearing one or both of these CRIs express detectable levels of CD5. Nevertheless, we find that G6-reactive lymphocytes constitute a multiclonal population of cells that express homologous heavy chain variable region genes, each rearranged to one of several distinct and apparently nonmutated D and JH gene segments. Collectively, these studies indicate that expression of nondiversified autoantibody-encoding variable region genes may not be an exclusive property of B cells that bear detectable levels ofthe CD5 surface antigen. (J. Clin.

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

Cited by 135 publications

References 59 publications

B Cells Expressing a Natural Polyreactive Autoantibody Have a Distinct Phenotype and Are Overrepresented in Immunoglobulin Heavy Chain Transgenic Mice

B Cells Expressing a Natural Polyreactive Autoantibody Have a Distinct Phenotype and Are Overrepresented in Immunoglobulin Heavy Chain Transgenic Mice

Loss of CD4 T-cell–dependent tolerance to proteins with modified amino acids

Relationship of the CD5 B cell to human tonsillar lymphocytes that express autoantibody-associated cross-reactive idiotypes.

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