Anti-Fab antibodies in humans. Predominance of minor immunoglobulin G subclasses in rheumatoid arthritis.

Persselin, Jay E.; Stevens, Ronald H.

doi:10.1172/jci112027

Cited by 50 publications

(32 citation statements)

References 27 publications

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“…Without question, the most antigenic sites were those exposed in or adjacent to the lower hinge by proteases that generated F(abЈ) 2 s. It also became apparent that IgG3 was highly represented among the human anti-F(abЈ) 2 autoantibodies, similar to reports of IgG3 anti-Fab autoantibodies in two diseases (27,40). It is not clear what factors might bias anti-hinge autoantibodies toward IgG3.…”

Section: Discussionmentioning

confidence: 90%

“…A functional role for anti-hinge autoantibodies remains uncertain although several investigations showed correlations between serum titers of the Abs and pathogical conditions such as systemic lupus erythematosus (38), cold agglutination (39), HIV (40), and rheumatoid arthritis (25). One group also suggested a potential immunoregulatory role for anti-hinge autoantibodies via induction of B cell apoptosis (28).…”

Section: Discussionmentioning

confidence: 99%

“…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). However, most earlier anti-fragment autoantibody studies used Fab and F(abЈ) 2 generated with papain and pepsin (26,27), proteases of questionable relevance for most human tissue and disease.…”

mentioning

confidence: 99%

“…There is also evidence for autoantibodies that recognize proteolytically cleaved Igs in the form of Fab and F(abЈ) 2 (23)(24)(25). However, most earlier anti-fragment autoantibody studies used Fab and F(abЈ) 2 generated with papain and pepsin (26,27), proteases of questionable relevance for most human tissue and disease. Many of these studies did not indicate whether the anti-Fab and anti-F(abЈ) 2 autoantibodies were specific for variable, hinge, or Fab constant regions.…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…66 Studies have correlated the titer of anti-hinge autoantibodies with pathological conditions such as cold agglutination, HIV, rheumatoid arthritis, and systemic lupus erythmatosus. [68][69][70][71] Others have suggested that natural anti-hinge autoantibodies bound to antigen-engaged F(ab') 2 fragments serve to augment complement activity. 72 One group speculated that anti-hinge autoantibodies can serve in an immunoregulatory role by inducing B cell apoptosis in antigen-engaged B cells by binding to the inhibitory receptor FcγRIIb.…”

Section: Autoantibodies Directed Against Cleaved Igg1 Hingementioning

confidence: 99%