Isotypes and IgG Subclasses of Anti-Fab Antibodies in Human Immunodeficiency Virus-Infected Hemophilia Patients

Süsal, Caner; Oberg, Hans‐Heinrich; Daniel, Volker; Dörr, Colette; Terness, Peter; Huth‐Kühne, Angela; Zimmermann, Rainer; Opelz, Gerhard

doi:10.1159/000462468

Cited by 3 publications

(3 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…HIV þ patients show a progressive decline of CD4 þ lymphocytes during the course of the disease. Beside the direct cytopathic effect of HIV on CD4 þ lymphocytes, apoptosis, metabolic abnormalities, syncytia formation, vb-deletion, autoreactive cytotoxic T cells, and anti-immunoglobulin autoantibodies as well as immune complexmediated autoimmune phenomena were reported to play a role in the pathogenesis of CD4 depletion [7,9,17,20,21,[25][26][27].…”

Section: Discussionmentioning

confidence: 99%

“…Firstsignal stimuli are provided by structural homologies of virus peptides with autoantigens as well as autoantigens unmasked during protein degradation after cell death. As a consequence, autoantibodies against several cellular and humoral autoantigens are formed [6,7,[14][15][16][17][18][19][20][21]. In addition, gp120 of HIV activates the complement system directly [22,23].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

CD4 depletion in HIV-infected haemophilia patients is associated with rapid clearance of immune complex-coated CD4+ lymphocytes

Daniel

Melk

Süsal

et al. 1999

Clinical and Experimental Immunology

View full text Add to dashboard Cite

The predominant immunological finding in HIV+ haemophilia patients is a decrease of CD4+ lymphocytes during progression of the disease. Depletion of CD4+ lymphocytes is paralleled by an increase in the proportion of immune complex-coated CD4+ cells. We examined the hypothesis that the formation of immune complexes on CD4+ lymphocytes is followed by rapid clearance of immune complex-coated CD4+ lymphocytes from the circulation. In this study, the relationship of relative to absolute numbers of immune complex-loaded CD4+ blood lymphocytes and their association with viral load were studied. Two measurements of relative and absolute numbers of gp120-, IgG- and/or IgM-loaded CD4+ lymphocytes were analysed in HIV+ and HIV- haemophilia patients, with a median interval of approx. 3 years. Immune complexes on CD4+ lymphocytes were determined using double-fluorescence flow cytometry and whole blood samples. Viral load was assessed using NASBA and Nuclisens kits. Whereas the proportion of immune complex-coated CD4+ lymphocytes increased with progression of the disease, absolute numbers of immune complex-coated CD4+ lymphocytes in the blood were consistently low. Relative increases of immune complex-coated CD4+ blood lymphocytes were significantly associated with decreases of absolute numbers of circulating CD4+ lymphocytes. The gp120 load on CD4+ blood lymphocytes increased in parallel with the viral load in the blood. These results indicate that immune complex-coated CD4+ lymphocytes are rapidly cleared from the circulation, suggesting that CD4+ reactive autoantibodies and immune complexes are relevant factors in the pathogenesis of AIDS. Relative increases of immune complex-positive cells seem to be a consequence of both an increasing retroviral activity as well as a stronger loading with immune complexes of the reduced number of CD4+ cells remaining during the process of CD4 depletion. The two mechanisms seem to enhance each other and contribute to the progressive CD4 decrease during the course of the disease.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

CD4 depletion in HIV-infected haemophilia patients is associated with rapid clearance of immune complex-coated CD4+ lymphocytes

Daniel

Melk

Süsal

et al. 1999

Clinical and Experimental Immunology

View full text Add to dashboard Cite

show abstract

“…Interestingly, these antibodies were found to bind not to intact IgG molecules, but only to IgG proteolytically cleaved into F(abЈ) 2 fragments. Antibodies to pepsin-digested IgG have been described in many reports (9)(10)(11)(12)(13)(14)(15)(16), and in recent years it was firmly established that these antibodies recognize epitopes in the hinge region (8,(17)(18)(19). These antibodies are currently referred to as antihinge antibodies (AHAs).…”

mentioning

confidence: 99%

Antibodies to IgG4 Hinge Can Be Found in Rheumatoid Arthritis Patients During All Stages of Disease and May Exacerbate Chronic Antibody‐Mediated Inflammation

Stadt

Vrieze

Derksen

et al. 2014

Arthritis & Rheumatology

View full text Add to dashboard Cite

Objective. In rheumatoid arthritis (RA), autoantibodies such as anti-citrullinated protein antibodies (ACPAs) develop in response to neoepitopes that are formed under conditions of chronic inflammation. These autoantibodies may subsequently be fragmented by inflammation-associated proteases, leading to the formation of F(ab) 2 fragments. The hinge of F(ab) 2 fragments can serve as a neoepitope, and so-called antihinge antibodies (AHAs) can be found in RA patients, which might modulate the function of (fragmented) autoantibodies. We undertook this study to investigate the presence and specificities of AHAs in different stages of RA and to study their function.Methods. The presence of AHAs was assessed by radioimmunoassay in healthy controls, blood donors who later developed RA, patients with arthralgia, patients with early RA, and patients with established RA. Specificity of the AHAs was analyzed with inhibition assays, and complement-activating ability was studied with a C4b deposition assay.Results. Antibodies to IgG1 hinge, IgG2 hinge, and IgG4 hinge were detected in patients with established RA, with anti-IgG4 hinge antibodies being most specific (appearing in 1% of healthy controls, 3.8% of blood donors who later developed RA, 13% of arthralgia patients, 19% of early RA patients, and 16% of established RA patients). Anti-IgG4 hinge antibodies were subclass specific and were able to restore C4b deposition by IgG4 F(ab) 2 fragments. In patients with arthralgia and patients with early RA, anti-IgG4 hinge antibodies were associated with rheumatoid factors and ACPAs.

show abstract

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

Isotypes and IgG Subclasses of Anti-Fab Antibodies in Human Immunodeficiency Virus-Infected Hemophilia Patients

Cited by 3 publications

References 15 publications

CD4 depletion in HIV-infected haemophilia patients is associated with rapid clearance of immune complex-coated CD4+ lymphocytes

CD4 depletion in HIV-infected haemophilia patients is associated with rapid clearance of immune complex-coated CD4+ lymphocytes

Antibodies to IgG4 Hinge Can Be Found in Rheumatoid Arthritis Patients During All Stages of Disease and May Exacerbate Chronic Antibody‐Mediated Inflammation

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

Contact Info

Product

Resources

About