Monoclonal IgM rheumatoid factors bind IgG at a discontinuous epitope comprised of amino acid loops from heavy-chain constant-region domains 2 and 3.

Artandi, Steven E.; Calame, Kathryn; Morrison, Sherie L.; Bonagura, Vincent R.

doi:10.1073/pnas.89.1.94

Cited by 59 publications

(54 citation statements)

References 32 publications

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“…Later it was shown that many RA-derived RFs bind IgG at a discontinuous epitope comprising residues from both the CH2 and CH3 regions [35]. Studies in Waldenström's macroglobulinemia patients revealed that at least three regions, two from CH2 and one from CH3, contribute to the binding epitope [36]. Amongst a panel of monoclonal RFs, Mageed et al [37] observed four specificity profiles, namely reactivity with an epitope expressed on (a) all IgG subclasses, (b) IgG1, IgG2, IgG4 and certain IgG3 molecules, (c) IgG1, IgG2 and IgG4, but not IgG3, (d) some but not all IgG within the subclasses.…”

Section: Specificity Of Anti-ig Absmentioning

confidence: 99%

Natural Anti-Immunoglobulin Autoantibodies: Irrelevant By-Products or Immunoregulatory Molecules?

Terness

Opelz²

1998

Int Arch Allergy Immunol

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Anti-immunoglobulin autoantibodies (anti-Ig auto-Abs), particularly IgM-anti-IgG (classical rheumatoid factor), have been studied mainly in the context of rheumatoid arthritis. In this article we focus on other members of the anti-Ig family, including the natural IgG-anti-F(ab′)₂ auto-Ab, and look for clinical and experimental findings supporting a role of these antibodies in the regulation of the immune response. We discuss the evidence for suppression of auto- and alloreactive B cells by IgG-anti-F(ab′)₂ auto-Ab and the role of this Ab in the pathogenesis of certain diseases, such as autoimmune hemolytic anemia. The structure of the antibody’s antigen-binding site was clarified by isolating the VL and VH gene segments from the cDNA of B cells. Sequence analyses revealed germline gene identity of VL chains and 88% homology with the closest germline gene of VH chains. Finally, we discuss hypothetical models concerning the immunoregulatory role of natural anti-Ig auto-Abs.

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Section: Specificity Of Anti-ig Absmentioning

confidence: 99%

Natural Anti-Immunoglobulin Autoantibodies: Irrelevant By-Products or Immunoregulatory Molecules?

Terness

Opelz²

1998

Int Arch Allergy Immunol

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“…We studied monoclonal RFs derived both from synovial and peripheral B cell lines from RA patients and found that they have diverse antigenic specificities not found among malignancy-associated RFs (22,23). The basis for these differences might relate to usage ofdiverse genes and gene combinations to encode RFs or, alternatively, to the presence of somatic mutations in the RFs from RA patients.…”

Section: Introductionmentioning

confidence: 99%

Rheumatoid factors from the peripheral blood of two patients with rheumatoid arthritis are genetically heterogeneous and somatically mutated.

Youngblood

Fruchter²,

Ding³

et al. 1994

J. Clin. Invest.

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We report the DNA sequences of the heavy and light chain immunoglobulin genes of 11 monoclonal rheumatoid factor (RF)-secreting lines derived from the peripheral blood of two patients with rheumatoid arthritis (RA). It is evident from immunogenetic analysis of these lines that RA-associated RF activity can arise from a wide variety of heavy and light chain genes and gene combinations. Although the RF response from our two patients shows a bias in gene usage toward those genes used to encode monoclonal RF, particularly VkIII, relatively few of these RFs are reactive with the monoclonal antiidiotypes 6B6.6 and 17.109 that define VkIII germline-encoded light chains and the loss of this idiotypic reactivity is clearly related to somatic mutation. Finally, RFs derived from peripheral blood of RA patients show a similar heterogeneity of epitope binding to Fc as that seen for synovium-derived RF and some are clearly different in binding specificity from the restricted RF population found in patients with B cell malignancies. Somatic mutations as well as different VH /VL combinations contribute to the heterogeneity in the binding patterns of these RA-derived RF. (J. Clin. Invest. 1994. 93:852-861.)

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“…Yet, healthy individuals have circulating B cells with specificity for autoantigens (20,21). Autoantibodies exist that recognize different domains of Igs, such as the Fc domain-binding rheumatoid factor (22). There is also evidence for autoantibodies that recognize proteolytically cleaved Igs in the form of Fab and F(abЈ) 2 (23)(24)(25).…”

mentioning

confidence: 99%

Human Anti-IgG1 Hinge Autoantibodies Reconstitute the Effector Functions of Proteolytically Inactivated IgGs

Brezski¹,

Luongo²,

Petrone³

et al. 2008

The Journal of Immunology

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A number of proteases of potential importance to human physiology possess the ability to selectively degrade and inactivate Igs. Proteolytic cleavage within and near the hinge domain of human IgG1 yielded products including Fab and F(ab′)2 possessing full Ag binding capability but absent several functions needed for immune destruction of cellular pathogens. In parallel experiments, we showed that the same proteolytically generated Fabs and F(ab′)2s become self-Ags that were widely recognized by autoantibodies in the human population. Binding analyses using various Fab and F(ab′)2, as well as single-chain peptide analogues, indicated that the autoantibodies targeted the newly exposed sequences where proteases cleave the hinge. The point of cleavage may be less of a determinant for autoantibody binding than the exposure of an otherwise cryptic stretch of hinge sequence. It was noted that the autoantibodies possessed an unusually high proportion of the IgG3 isotype in contrast to Abs induced against foreign immunogens in the same human subjects. In light of the recognized potency of IgG3 effector mechanisms, we adopted a functional approach to determine whether human anti-hinge (HAH) autoantibodies could reconstitute the (missing) Fc region effector functions to Fab and F(ab′)2. Indeed, in in vitro cellular assays, purified HAH autoantibodies restored effector functions to F(ab′)2 in both Ab-dependent cellular cytotoxicity and complement-dependent cytotoxicity assays. The results indicate that HAH autoantibodies selectively bind to proteolytically cleaved IgGs and can thereby provide a surrogate Fc domain to reconstitute cell lytic functions.

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Monoclonal IgM rheumatoid factors bind IgG at a discontinuous epitope comprised of amino acid loops from heavy-chain constant-region domains 2 and 3.

Abstract: A combination of site-directed mutagenesis and exon exchange has been used to further define the structure

Cited by 59 publications

References 32 publications

Natural Anti-Immunoglobulin Autoantibodies: Irrelevant By-Products or Immunoregulatory Molecules?

Natural Anti-Immunoglobulin Autoantibodies: Irrelevant By-Products or Immunoregulatory Molecules?

Rheumatoid factors from the peripheral blood of two patients with rheumatoid arthritis are genetically heterogeneous and somatically mutated.

Human Anti-IgG1 Hinge Autoantibodies Reconstitute the Effector Functions of Proteolytically Inactivated IgGs

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