Induction of Natural Autoantibody Activity Following Treatment of Human Immunoglobulin with Dissociating Agents

Bouvet, Jean‐Pierre; Stahl, Dulcelina A.; Rose, Stéphanie; Quan, Canh P.; Kazatchkine, Michel D.; Kaveri, Srini V.

doi:10.1006/jaut.2000.0472

Cited by 68 publications

(62 citation statements)

References 43 publications

(30 reference statements)

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“…Our results showed that, despite the considerable increase in the number of recognized antigens (demonstrated by immunoblot analysis), the binding affinity of the Fe(II)-exposed antibody to its cognate antigen remained unaltered. This result is in agreement with previous studies where the increase of the antibody polyspecificity has been achieved by exposure to acidic pH or chaotropic agents (13,14). In these studies, however, the K D values were determined using competitive binding enzyme-linked immunosorbent assay.…”

Section: Discussionsupporting

confidence: 78%

“…However, it is unknown whether the oxidative modifications induced by the highly reactive forms of oxygen could influence the antigen-binding properties of the immunoglobulins present at inflammation sites. Of special interest would be the behavior of the IgG fraction, which was shown to be very sensitive to a transient exposure to different protein-destabilizing agents (14). Indeed, in the present study, we have shown that, under conditions where the antibody-catalyzed water oxidation pathway is functioning (UV light irradiation of a human polyclonal IgG preparation), IgG molecules significantly increase their antigen-binding activity.…”

Section: Discussionmentioning

confidence: 60%

“…They play a major role in preventing pathogen dissemination in pre-immune organisms through enhanced antigen trapping (11), a property attributed to their ability to bind multiple unrelated antigens (12). Interestingly, polyspecificity of a fraction of IgG antibodies, present in all healthy individuals, can be induced in vitro by transient exposure to protein-destabilizing agents (low or high pH, high salt concentration, or chaotropic agents) (13,14), without concomitant denaturation of the immunoglobulin molecules. Thus, in their native state, these IgGs recognize a limited panel of antigens, but exposure to the destabilizing agents leads to a dramatic expansion of the spectrum of recognized antigens.…”

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confidence: 99%

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Ferrous Ions and Reactive Oxygen Species Increase Antigen-binding and Anti-inflammatory Activities of Immunoglobulin G

Dimitrov

Ivanovska

Lacroix‐Desmazes

et al. 2006

Journal of Biological Chemistry

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Polyspecific antibodies represent a first line of defense against infection and regulate inflammation, properties hypothesized to rely on their ability to interact with multiple antigens. We demonstrated that IgG exposure to pro-oxidative ferrous ions or to reactive oxygen species enhances paratope flexibility and hydrophobicity, leading to expansion of the spectrum of recognized antigens, regulation of cell proliferation, and protection in experimental sepsis. We propose that ferrous ions, released from transferrin and ferritin at sites of inflammation, synergize with reactive oxygen species to modify the immunoglobulins present in the surrounding microenvironment, thus quenching pro-inflammatory signals, while facilitating neutralization of pathogens.The immune system is capable of producing a large and diverse repertoire of antibodies that can recognize a wide variety of different molecular structures and conformations. Three models for antibodyantigen interactions have been described, differing by the role of molecular flexibility. The "lock-and-key" model proposes binding between geometrically optimized partners without substantial structural alterations. In contrast, antibodies that recognize epitopes according to the "induced fit" model undergo significant structural reorganization upon binding, resulting in increased antibody-antigen complementarity (1-3). Although the first model is typical for antigen recognition by affinity-matured antibodies, the second one is intrinsic for germ line antibodies (2-5). The "conformational isomerism" model proposes that a single antibody molecule may adopt several different binding site conformations, independently of the presence of the antigen. These antibody isomers exist in equilibrium and each may recognize unrelated antigens (6 -8).An antibody molecule that relies on the use of active site flexibility for antigen binding (according to the last two models) is usually capable of accommodating a large number of structurally unrelated antigens (2, 8 -10); i.e. such an antibody is polyspecific. Polyspecific antibodies in healthy individuals represent Ͼ20% of all circulating antibodies. They play a major role in preventing pathogen dissemination in pre-immune organisms through enhanced antigen trapping (11), a property attributed to their ability to bind multiple unrelated antigens (12). Interestingly, polyspecificity of a fraction of IgG antibodies, present in all healthy individuals, can be induced in vitro by transient exposure to protein-destabilizing agents (low or high pH, high salt concentration, or chaotropic agents) (13, 14), without concomitant denaturation of the immunoglobulin molecules. Thus, in their native state, these IgGs recognize a limited panel of antigens, but exposure to the destabilizing agents leads to a dramatic expansion of the spectrum of recognized antigens. The molecular mechanism and the biological significance of this "hidden" polyspecificity remain unclear. It is also not known whether this phenomenon occurs in vivo and whether the highl...

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Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 60%

mentioning

confidence: 99%

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Ferrous Ions and Reactive Oxygen Species Increase Antigen-binding and Anti-inflammatory Activities of Immunoglobulin G

Dimitrov

Ivanovska

Lacroix‐Desmazes

et al. 2006

Journal of Biological Chemistry

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“…Thus, the administration of the acid pH-treated IVIg, but not of the same unmodified preparation, significantly decreased mortality in animals with endotoxemia (12,13). Previous studies by our group and others have proven that, in addition to low pH buffers, the exposure to a number of other substances (for example, ferrous ions, heme, reactive oxygen species, and so on) also increases the antigen-binding polyspecificity of some IgG molecules (5,(15)(16)(17). IVIg modified by Fe(II) exposure could bind to the human proinflammatory cytokine interferon (IFN)-γ and could improve survival in mice injected intravenously with 5 × 10 8 live Escherichia coli or intraperitoneally with bacterial LPS (15,18).…”

Section: Materials and Methods Micementioning

confidence: 93%

“…aimed to target individual mediators of inflammation were used, has been hard to explain so far (1,2,4,5).…”

mentioning

confidence: 99%

Intravenous Immunoglobulin with Enhanced Polyspecificity Improves Survival in Experimental Sepsis and Aseptic Systemic Inflammatory Response Syndromes

Djoumerska-Alexieva

Roumenina

Pashov

et al. 2015

Mol Med

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Sepsis is a major cause for death worldwide. Numerous interventional trials with agents neutralizing single proinflammatory mediators have failed to improve survival in sepsis and aseptic systemic inflammatory response syndromes. This failure could be explained by the widespread gene expression dysregulation known as "genomic storm" in these patients. A multifunctional polyspecific therapeutic agent might be needed to thwart the effects of this storm. Licensed pooled intravenous immunoglobulin preparations seemed to be a promising candidate, but they have also failed in their present form to prevent sepsis-related death. We report here the protective effect of a single dose of intravenous immunoglobulin preparations with additionally enhanced polyspecificity in three models of sepsis and aseptic systemic inflammation. The modification of the pooled immunoglobulin G molecules by exposure to ferrous ions resulted in their newly acquired ability to bind some proinflammatory molecules, complement components and endogenous "danger" signals. The improved survival in endotoxemia was associated with serum levels of proinflammatory cytokines, diminished complement consumption and normalization of the coagulation time. We suggest that intravenous immunoglobulin preparations with additionally enhanced polyspecificity have a clinical potential in sepsis and related systemic inflammatory syndromes. online address: http://www.molmed.org

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Association of the idiotype:antiidiotype antibody ratio with the efficacy of intravenous immunoglobulin treatment for the prevention of recurrent autoimmune‐associated congenital heart block

Routsias

Kyriakidis

Friedman

et al. 2011

Arthritis & Rheumatism

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Objective Congenital heart block (CHB), a manifestation of neonatal lupus, is associated with maternal anti-Ro/SSA and anti-La/SSB autoantibodies and recurs in ~18% of subsequent pregnancies. This study was undertaken to investigate the effect of the idiotype: antiidiotype (Id:anti-Id) antibody ratio in the ability of intravenous immunoglobulin (IVIG) administered during subsequent pregnancies to prevent CHB. Methods We studied 16 anti-Ro/SSA and anti-La/ SSB–positive pregnant women from the Preventive IVIG Therapy for Congenital Heart Block study who had previously given birth to a child with neonatal lupus. In 3 of the mothers, the study pregnancy resulted in the birth of a child with neonatal lupus (2 with CHB and 1 with rash). Sequential serum samples were obtained from all mothers immediately before the administration of IVIG during pregnancy and were evaluated for antibodies against the major B cell epitope 349–364aa of La/SSB (idiotype) and its antiidiotypic antibodies. Results Following IVIG treatment, serum titers of anti-La(349–364) (Id antibodies) decreased in 80% of the mothers, and in 60% an increase in anti-Id antibodies against anti-La(349–364) was observed. The Id: anti-Id ratio was significantly higher in mothers whose offspring developed neonatal lupus compared to mothers who gave birth to a healthy child (P < 0.0001). Removal of anti-Id antibodies substantially increased the reactivity against La(349–364) in sera from 5 of 7 mothers tested. All IVIG preparations were examined for Id and anti-Id antibody activity. IVIG from batches administered to mothers who gave birth to a healthy child had an Id:anti-Id activity ratio of <1, in contrast to that given to mothers who gave birth to a child with neonatal lupus. Addition of the IVIG preparations to the maternal sera further enhanced antiidiotypic activity (by up to 4.7-fold) in 11 of 13 patients studied. Conclusion This is the first study in humans to demonstrate that IVIG influences the Id–anti-Id network of a specific pathogenic autoantibody. Specifically, we showed that IVIG enhanced the anti-Id antibody response in pregnant women with anti-La/SSB antibodies. A high Id:anti-Id ratio in both the IVIG preparation and the maternal serum may explain the absence of an effect of IVIG in preventing recurrent neonatal lupus in some cases.

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Induction of Natural Autoantibody Activity Following Treatment of Human Immunoglobulin with Dissociating Agents

Cited by 68 publications

References 43 publications

Ferrous Ions and Reactive Oxygen Species Increase Antigen-binding and Anti-inflammatory Activities of Immunoglobulin G

Ferrous Ions and Reactive Oxygen Species Increase Antigen-binding and Anti-inflammatory Activities of Immunoglobulin G

Intravenous Immunoglobulin with Enhanced Polyspecificity Improves Survival in Experimental Sepsis and Aseptic Systemic Inflammatory Response Syndromes

Association of the idiotype:antiidiotype antibody ratio with the efficacy of intravenous immunoglobulin treatment for the prevention of recurrent autoimmune‐associated congenital heart block

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