Human F(ab′)2-containing immune complexes together with anti-hinge natural antibodies stimulate complement amplification in vitro and in vivo

Fumia, Sandra; Goede, Jeroen S.; Fischler, Manuel; Luginbühl, Alexander; Frick, Sonia; Fodor, Patricia; Lutz, Hans

doi:10.1016/j.molimm.2008.01.029

Cited by 30 publications

(32 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…27 Additionally, F(ab') 2 -containing immune complexes, together with naturally occurring antihinge antibodies, can induce complement activation. 28 These findings corroborate that removal of Fc from equine IgGs by pepsin digestion does not eliminate complement activation in vitro.…”

Section: Discussionsupporting

confidence: 70%

Anticomplementary Activity of Horse IgG and F(ab')2 Antivenoms

Squaiella-Baptistão¹,

Marcelino²,

Cunha³

et al. 2014

The American Society of Tropical Medicine and Hygiene

View full text Add to dashboard Cite

show abstract

Section: Discussionsupporting

confidence: 70%

Anticomplementary Activity of Horse IgG and F(ab')2 Antivenoms

Squaiella-Baptistão¹,

Marcelino²,

Cunha³

et al. 2014

The American Society of Tropical Medicine and Hygiene

View full text Add to dashboard Cite

show abstract

“…Namely, the HAH autoantibodies could be envisioned to bind to proteolytically derived fragments of endogenous IgGs that target pathogenic cells and thereby restore Fc effector functions. Additionally, a recent study hypothesized that anti-hinge natural Abs amplify complement activity to Ag-bound F(abЈ) 2 by enabling C3b complex binding to the conformationally stabilized hinge of the fragment (59). Although that pathway may be less applicable to ADCC, it serves to further highlight the potential complexity and contribution of anti-hinge Abs to humoral autoimmunity.…”

Section: Discussionmentioning

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

View full text Add to dashboard Cite

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.

show abstract

“…Others have demonstrated that IdeS cleaves IgGcoated S. pyogenes with resulting inhibition of killing by phagocytic cells (26). Moreover, the existence of human autoantibodies directed against the cleaved hinge of IgGs alludes to the presence of cleaved IgGs as autoantigens (27)(28)(29). These findings led to the present examination into the presence of proteolytic intermediates from in vivo samples and the functional attributes of single-cleaved IgG.…”

mentioning

confidence: 86%

Tumor-associated and microbial proteases compromise host IgG effector functions by a single cleavage proximal to the hinge

Brezski¹,

Vafa²,

Petrone³

et al. 2009

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

134

View full text Add to dashboard Cite

The successful elimination of pathogenic cells and microorganisms by the humoral immune system relies on effective interactions between host immunoglobulins and Fc␥ receptors on effector cells, in addition to the complement system. Essential Ig motifs that direct those interactions reside within the conserved IgG lower hinge/CH2 interface. We noted that a group of tumor-related and microbial proteases cleaved human IgG1s in that region, and the ''nick'' of just one of the heavy chains profoundly inhibited IgG1 effector functions. We focused on IgG1 monoclonal antibodies (mAbs) since IgG1 is the most abundant human subclass and demonstrates robust Fc-mediated effector functions. The loss of Fc-mediated cell killing activities was correlated with diminished binding to the Fc␥ family of receptors, but a similar decrease in affinity was not observed toward the FcRn receptor that maintains IgG in circulation. Endogenous human IgG cleavage products of comparable size to mAbs with the single cleavage were detected by Western blot analysis in synovial fluid from patients with rheumatoid arthritis and in breast carcinoma extracts. Their detection is problematic under physiological conditions, since there is no loss of structure, and antigen-binding capability is unaffected. These findings suggest that within the hostile proteolytic microenvironments associated with many diseases, key effector functions of host IgGs, or therapeutic Abs, may be compromised.antibody-dependent cellular cytotoxicity ͉ complement-dependent cytotoxicity ͉ Fc gamma Receptors ͉ matrix metalloproteinases ͉ monoclonal antibodies

show abstract

Human F(ab′)2-containing immune complexes together with anti-hinge natural antibodies stimulate complement amplification in vitro and in vivo

Cited by 30 publications

References 54 publications

Anticomplementary Activity of Horse IgG and F(ab')2 Antivenoms

Anticomplementary Activity of Horse IgG and F(ab')2 Antivenoms

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

Tumor-associated and microbial proteases compromise host IgG effector functions by a single cleavage proximal to the hinge

Contact Info

Product

Resources

About