Srini Kaveri - Academia.edu (original) (raw)

Papers by Srini Kaveri

Research paper thumbnail of Generation and specificity of monoclonal anti-idiotypic antibodies against human HIV-specific antibodies. I. Cross-reacting idiotopes are expressed in subpopulations of HIV-infected individuals

The Journal of Immunology

In this study we have generated monoclonal anti-idiotypic antibodies against human monoclonal and... more In this study we have generated monoclonal anti-idiotypic antibodies against human monoclonal and polyclonal anti-HIV antibodies in seropositive sera. A human anti-gp41 mAb (H2, IgM kappa) was used to immunize BALB/c mice and to prepare hybridoma anti-antibodies that react with H2 and not with normal human IgM. Similar monoclonal anti-antibodies were made in BALB/c mice immunized with Ig fraction prepared from a pool of HIV-seropositive sera. Both kinds of anti-idiotypic antibodies reacted with antibodies in pools of seropositive sera and with individual seropositive sera but not with normal human Ig or seronegative sera. The Id-positive Ig from single donors were isolated on two different anti-Id immunoabsorbents and shown to bind to p24 and gp120, respectively. The detection and isolation of idiotypically cross-reactive human anti-HIV antibodies from seropositive donors demonstrated, for the first time, the existence of shared Id expressed by antibodies against HIV Ag. The utility...

Research paper thumbnail of Therapeutic normal IgG intravenous immunoglobulin activates Wnt-β-catenin pathway in dendritic cells

Communications Biology, 2020

Therapeutic normal IgG intravenous immunoglobulin (IVIG) is a well-established first-line immunot... more Therapeutic normal IgG intravenous immunoglobulin (IVIG) is a well-established first-line immunotherapy for many autoimmune and inflammatory diseases. Though several mechanisms have been proposed for the anti-inflammatory actions of IVIG, associated signaling pathways are not well studied. As β-catenin, the central component of the canonical Wnt pathway, plays an important role in imparting tolerogenic properties to dendritic cells (DCs) and in reducing inflammation, we explored whether IVIG induces the β-catenin pathway to exert anti-inflammatory effects. We show that IVIG in an IgG-sialylation independent manner activates β-catenin in human DCs along with upregulation of Wnt5a secretion. Mechanistically, β-catenin activation by IVIG requires intact IgG and LRP5/6 co-receptors, but FcγRIIA and Syk are not implicated. Despite induction of β-catenin, this pathway is dispensable for anti-inflammatory actions of IVIG in vitro and for mediating the protection against experimental autoim...

Research paper thumbnail of Antibodies to the FVIII light chain that neutralize FVIII procoagulant activity are present in plasma of nonresponder patients with severe hemophilia A and in normal polyclonal human IgG

Blood, 2000

We have analyzed the properties of anti-factor VIII (FVIII) immunoglobulin (Ig) G recovered by af... more We have analyzed the properties of anti-factor VIII (FVIII) immunoglobulin (Ig) G recovered by affinity chromatography on FVIII-Sepharose from the IgG fraction of the plasma of healthy individuals and nonresponder patients with hemophilia A. Affinity-purified anti-FVIII antibodies were found to neutralize FVIII activity and to bind to FVIII with an affinity similar to that of anti-FVIII IgG that had been affinity-purified from the plasma of inhibitor-positive hemophilia patients and of patients with anti-FVIII autoimmune disease. The antibodies also exhibited patterns of reactivity with thrombin-digested FVIII similar to those of FVIII inhibitors and preferentially recognized epitopes located in the light chain of FVIII. These observations suggest that FVIII inhibitors occurring in hemophilia A and in patients with anti-FVIII autoimmune disease originate from the expansion of preexisting natural anti-FVIII clones that exhibit FVIII-neutralizing properties.

Research paper thumbnail of Circulating Normal IgG as Stimulator of Regulatory T Cells: Lessons from Intravenous Immunoglobulin

Trends in Immunology, 2017

Research paper thumbnail of Monomeric Immunoglobulin A from Plasma Inhibits Human Th17 Responses In Vitro Independent of FcαRI and DC-SIGN

Frontiers in Immunology, 2017

Research paper thumbnail of Predisposing factors, pathogenesis and therapeutic intervention of Kawasaki disease

Drug Discovery Today, 2016

Kawasaki disease (KD) is an acute febrile childhood inflammatory disease, associated with coronar... more Kawasaki disease (KD) is an acute febrile childhood inflammatory disease, associated with coronary artery abnormalities. The disease is believed to result from an aberrant inflammatory response to an infectious trigger in a genetically predisposed individual. KD is associated with an endothelial cell injury as a consequence of T cell activation and cytotoxic effects of various proinflammatory cytokines. Intravenous immunoglobulin (IVIG) infusion and aspirin are the standard treatment of acute KD. However, 10-20% of patients show resistance to IVIG therapy and present higher risk of coronary vasculitis. The relative roles of second IVIG infusion, corticosteroids, calcineurin inhibitors, interleukin-1 antagonists and anti-tumor necrosis factor agents remain uncertain. In this review, we highlight the predisposing factors, pathogenesis and therapeutic intervention of KD, particularly new therapeutics for IVIG-resistant patients. Reviews POST SCREEN

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

Molecular medicine (Cambridge, Mass.), Apr 14, 2015

Sepsis is a major cause for death worldwide. Numerous interventional trials with agents neutraliz... more Sepsis is a major cause for death worldwide. Numerous interventional trials with agents neutralizing single pro-inflammatory mediators have failed to improve survival in sepsis and aseptic systemic inflammatory response syndromes. This failure could well 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 ...

Research paper thumbnail of Heme oxygenase-1 is dispensable for the anti-inflammatory activity of intravenous immunoglobulin

Scientific reports, Jan 22, 2016

Intravenous immunoglobulin G (IVIG) is used in the therapy of various autoimmune and inflammatory... more Intravenous immunoglobulin G (IVIG) is used in the therapy of various autoimmune and inflammatory conditions. The mechanisms by which IVIG exerts anti-inflammatory effects are not completely understood. IVIG interacts with numerous components of the immune system including dendritic cells, macrophages, T and B cells and modulate their functions. Recent studies have reported that heme oxygenase-1 (HO-1) pathway plays an important role in the regulation of inflammatory response in several pathologies. Several therapeutic agents exert anti-inflammatory effects via induction of HO-1. Therefore, we aimed at exploring if anti-inflammatory effects of IVIG are mediated via HO-1 pathway. Confirming the previous reports, we report that IVIG exerts anti-inflammatory effects on innate cells as shown by the inhibitory effects on IL-6 and nitric oxide production and confers protection in experimental autoimmune encephalomyelitis (EAE) model. However, these effects were not associated with an indu...

Research paper thumbnail of The protective role of immunoglobulins in fungal infections and inflammation

Seminars in Immunopathology, 2014

Increased incidence of fungal infections in the immunocompromised individuals and fungi-mediated ... more Increased incidence of fungal infections in the immunocompromised individuals and fungi-mediated allergy and inflammatory conditions in immunocompetent individuals is a cause of concern. Consequently, there is a need for efficient therapeutic alternatives to treat fungal infections and inflammation. Several studies have demonstrated that antibodies or immunoglobulins have a role in restricting the fungal burden and their clearance. However, based on the data from monoclonal antibodies it is now evident that the efficacy of antibodies in fungal infections is dependent on epitope specificity, abundance of protective antibodies and their isotype. Antibodies confer protection against fungal infections by multiple mechanisms that include direct neutralization of fungi and their antigens, inhibition of growth of fungi, modification of gene expression, signaling and lipid metabolism, causing iron starvation, inhibition of polysaccharide release and biofilm formation. Antibodies promote opsonization of fungi and their phagocytosis, complement activation and antibody-dependent cell toxicity. Passive administration of specific protective monoclonal antibodies could prove to be beneficial in drug-resistance cases, to reduce the dosage and associated toxic symptoms of anti-fungal drugs. The longer half-life of the antibodies and flexibilities to modify their structure/forms are additional advantages. The clinical data obtained with two monoclonal antibodies should incite interests in translating pre-clinical success into the clinics. The anti-inflammatory and immunomodulatory role of antibodies in fungal inflammation could be exploited by intravenous immunoglobulin or IVIg.

Research paper thumbnail of Natural recognition repertoire and the evolutionary emergence of the combinatorial immune system

The FASEB Journal, 2002

The primordial combinatorial immune recognition repertoire arose in the evolution of jawed verteb... more The primordial combinatorial immune recognition repertoire arose in the evolution of jawed vertebrates ϳ450 million years ago as a rapid genetic process independent of antigenic selection. We propose that it encompassed the entire repertoire of innate immunity involving molecules that had evolved over billions of years. The 'antigen-driven' compartment involving invasive pathogens operates in 'real time' showing inducibility and increases in affinity. Individuals within a species differ in their repertoires because of distinct antigenic challenges, genetics, or local environmental effects. The 'homeostatic' compartment that recognizes invariant cell and serum components should be conserved in all individuals of a species. The potential to recapitulate the entire recognition spectrum must be regenerated during the formation of new species. Evidence for the capacity of the combinatorial response to encompass the entire preexisting repertoire was obtained in studies of natural human IgG antibodies present in intravenous immunoglobulin. Since essential cellular recognition and regulatory elements are conserved throughout evolution, we propose that the natural antibodies of sharks, the most anciently emerged vertebrates to possess the combinatorial immune response, will resemble those of mammals in showing specificity for the conserved recognition/regulatory molecules. If verified, this hypothesis will establish the fundamental importance of natural antibodies not only in defense, but in regulation and functional homeostasis of the individual.

Research paper thumbnail of Autoimmunity as a Predisposition for Infectious Diseases

Research paper thumbnail of Auditing Protein Therapeutics Management by Professional APCs: Toward Prevention of Immune Responses against Therapeutic Proteins

The Journal of Immunology, 2008

Alloimmunization is a crippling concern in the management of patients undergoing administration o... more Alloimmunization is a crippling concern in the management of patients undergoing administration of protein therapeutics as evidenced in replacement therapy and other treatment procedures. Several issues in the genesis and modulation of such deleterious immune responses have been studied. While authors have focused on the downstream events of the specific immune response and suggested modification of protein therapeutics to eliminate epitopes that interact with B cell receptors, T cell receptors, or MHCII molecules, the mechanisms underlying Ag interaction with APCs, a step upstream of immune effectors, have been grossly neglected. We wish to emphasize that the recent knowledge in understanding the capacities of an APC to handle an Ag and the importance of the surrounding microenvironment in this process are crucial for designing novel protein therapeutics with reduced immunogenicity.

Research paper thumbnail of Analysis of human self-reactive antibody repertoires by quantitative immunoblotting

Journal of Immunological Methods, 2000

We review the use of a quantitative immunoblotting technique to characterize human self-reactive ... more We review the use of a quantitative immunoblotting technique to characterize human self-reactive antibody repertoires in health and disease. The interactions of plasma IgM and IgG with tissue extracts as sources of self-antigens were analyzed by quantitative immunoblotting. Data were compared by means of multiparametric statistical analysis. The data summarized here demonstrate that natural self-reactive antibody repertoires of healthy individuals are restricted to a limited subset of immunodominant autoantigens that is selected early in development, and remains conserved between individuals through ageing. The selection of human natural self-reactive IgG antibody repertoires requires normal T-/ B-cell interactions. The immunoblotting assay has the potential to distinguish between autoimmune diseases with organ-related oligoclonal expansion of self-reactive clones and those characterized by broad alterations of immunoregulation. However, organ-specific autoimmune diseases may be characterized by altered patterns of antibody repertoires unrelated to the target organ. The assay also revealed an unexpected defect in the regulatory function of self-reactive IgM on the expression of self-reactive IgG repertoires in several systemic and organ-specific autoimmune diseases. The results are discussed in the light of our current understanding of the processes of selection of self-reactive B-cells and the pathophysiology of autoimmunity.

Research paper thumbnail of Antibodies to a conserved region of HLA class I molecules, capable of modulating CD8 T cell-mediated function, are present in pooled normal immunoglobulin for therapeutic use

Journal of Clinical Investigation, 1996

Intravenous immunoglobulin (IVIg) is increasingly used for the treatment of autoimmune diseases a... more Intravenous immunoglobulin (IVIg) is increasingly used for the treatment of autoimmune diseases and the prevention of infections and of graft versus host reactions in recipients of allogeneic bone marrow transplants. The immunomodulatory effects of IVIg are largely dependent on their ability to interact with membrane molecules of lymphocytes. We report here that IVIg recognizes the B07.75-84 peptide, corresponding to a conserved region of the ␣ 1 helix of the first domain of HLA-B7 01, which represents a nonpolymorphic determinant of HLA class I molecules. Intact IVIg and its F(ab Ј) 2 fragments bound to the peptide as well as to purified soluble HLA and to HLA on a human T cell line. Binding of IVIg to HLA was assessed by ELISA, immunofluorescence, and real-time analysis of the interaction using the BIAlite system. The binding of antipeptide antibodies to HLA was inhibited by free peptide. Antipeptide antibodies isolated from IVIg by affinity chromatography inhibited CD8 cellmediated cytotoxicity of an influenza virus-specific human T cell line. The presence in IVIg of antibodies to critical regions of HLA class I molecules suggests a possible role for IVIg in modulation of class I-restricted cellular interactions in the immune response.

Research paper thumbnail of Intravenous Immunoglobulin: An Update on the Clinical Use and Mechanisms of Action

Journal of Clinical Immunology, 2007

Initially used as a replacement therapy for immunodeficiency diseases, intravenous immunoglobulin... more Initially used as a replacement therapy for immunodeficiency diseases, intravenous immunoglobulin (IVIg) is now widely used for a number of autoimmune and inflammatory diseases. Considerable progress has been made in understanding the mechanisms by which IVIg exerts immunomodulatory effects in autoimmune and inflammatory disorders. The mechanisms of action of IVIg are complex, involving modulation of expression and function of Fc receptors, interference with activation of complement and the cytokine network and of idiotype network, regulation of cell growth, and effects on the activation, differentiation, and effector functions of dendritic cells, and T and B cells.

Research paper thumbnail of Immunomodulation by Intravenous Immunoglobulin: Role of Regulatory T Cells

Journal of Clinical Immunology, 2010

An altered immune homeostasis as a result of deficiency or defective function of CD4 + CD25 + Fox... more An altered immune homeostasis as a result of deficiency or defective function of CD4 + CD25 + FoxP3 + regulatory T cells (Tregs) is common in several autoimmune diseases. Hence, therapeutic strategies to render Tregs functionally competent are being investigated. Intravenous immunoglobulin (IVIG) is being increasingly used for the treatment of a wide range of autoimmune and inflammatory diseases. Recent studies have demonstrated that IVIG induces the expansion of Tregs and enhances their suppressive functions. These effects of IVIG on Tregs correlate with the beneficial effects of IVIG in patients with autoimmune diseases. Thus, modulation of Tregs by IVIG represents a novel mode of action that explains the therapeutic effects of IVIG in T cell-mediated autoimmune diseases. However, the molecular mechanisms involved in IVIG-mediated modulation of Tregs are unclear and need further investigation.

Research paper thumbnail of Autoantibodies with enzymatic properties in human autoimmune diseases

Journal of Autoimmunity, 2011

Immunoglobulins (Ig) or antibodies are heavy plasma proteins, with sugar chains added to amino ac... more Immunoglobulins (Ig) or antibodies are heavy plasma proteins, with sugar chains added to amino acid residues by N-linked glycosylation and occasionally by O-linked glycosylation. The versatility of antibodies is demonstrated by the various functions that they mediate such as neutralization, agglutination, fixation with activation of complement and activation of effector cells. In addition to this plethora of functions, some antibodies express enzymatic activity. Antibodies endowed with enzymatic properties have been described in human autoimmune manifestations for more than a decade in a variety of disorders such as autoimmune thyroiditis, systemic erythematosus (SLE), scleroderma, rheumatoid arthritis (RA), multiple sclerosis (MS) and acquired hemophilia (AH). Antibodies isolated from these conditions were able to specifically hydrolyze thyroglobulin, DNA, RNA, myelin basic protein (MBP), and factor VIII (FVIII) or factor IX (FIX), respectively. The therapeutic relevance of these findings is discussed.

Research paper thumbnail of Autoantibodies to heat shock protein 90 in the human natural antibody repertoire

International Immunology, 2002

The present study demonstrates the presence of natural autoantibodies of the IgG isotype directed... more The present study demonstrates the presence of natural autoantibodies of the IgG isotype directed against heat shock protein 90 (HSP90). The binding properties of af®nity-puri®ed anti-HSP antibodies were compared with those of natural antibodies speci®c for other self antigens, including anti-thyroglobulin and anti-myoglobin autoantibodies, by using semiquantitative immunoblotting, with solubilized proteins from normal liver tissue as antigens, and cross-blot analysis using puri®ed self proteins. Af®nity-puri®ed anti-HSP90 antibodies were polyreactive and the non-HSP90-speci®c fraction of normal IgG was depleted in its natural autoantibody content. We further observed that self antigens including HSP, myosin, tubulin and aldolase with highly conserved structures show similar patterns of binding with natural antibodies, and form a well-de®ned cluster as demonstrated by cluster analysis of immunoreactivity data, whereas the lessconserved self and non-self antigens remained unclustered. The results favor the hypothesis that HSP90 belongs to a subset of highly conserved and immunodominant self antigens that are the primary target for natural autoantibodies in normal human IgG.

Research paper thumbnail of Intravenous immunoglobulins (IVIg) in the treatment of autoimmune diseases

Clinical and Experimental Immunology, 2008

SUMMARY Intravenous immunoglobulin (IVIg) therapy is increasingly used in autoimmune diseases. Al... more SUMMARY Intravenous immunoglobulin (IVIg) therapy is increasingly used in autoimmune diseases. Although its efficacy has only been established in a few specific antibody-mediated autoimmune conditions, accumulating evidence on the regulatory role of circulating immunoglobulins in the selection of peripheral B cell repertoires makes it an attractive potential therapeutic option to clinical immunologists. This overview briefly discusses the current use of IVIg in human autoimmune diseases with a particular emphasis on the possible mechanisms by which IVIg could suppress pathological autoimmune responses.

Research paper thumbnail of Treatment of autoimmune diseases with normal immunoglobulin through manipulation of the idiotypic network

Clinical and Experimental Immunology, 2008

Research paper thumbnail of Generation and specificity of monoclonal anti-idiotypic antibodies against human HIV-specific antibodies. I. Cross-reacting idiotopes are expressed in subpopulations of HIV-infected individuals

The Journal of Immunology

In this study we have generated monoclonal anti-idiotypic antibodies against human monoclonal and... more In this study we have generated monoclonal anti-idiotypic antibodies against human monoclonal and polyclonal anti-HIV antibodies in seropositive sera. A human anti-gp41 mAb (H2, IgM kappa) was used to immunize BALB/c mice and to prepare hybridoma anti-antibodies that react with H2 and not with normal human IgM. Similar monoclonal anti-antibodies were made in BALB/c mice immunized with Ig fraction prepared from a pool of HIV-seropositive sera. Both kinds of anti-idiotypic antibodies reacted with antibodies in pools of seropositive sera and with individual seropositive sera but not with normal human Ig or seronegative sera. The Id-positive Ig from single donors were isolated on two different anti-Id immunoabsorbents and shown to bind to p24 and gp120, respectively. The detection and isolation of idiotypically cross-reactive human anti-HIV antibodies from seropositive donors demonstrated, for the first time, the existence of shared Id expressed by antibodies against HIV Ag. The utility...

Research paper thumbnail of Therapeutic normal IgG intravenous immunoglobulin activates Wnt-β-catenin pathway in dendritic cells

Communications Biology, 2020

Therapeutic normal IgG intravenous immunoglobulin (IVIG) is a well-established first-line immunot... more Therapeutic normal IgG intravenous immunoglobulin (IVIG) is a well-established first-line immunotherapy for many autoimmune and inflammatory diseases. Though several mechanisms have been proposed for the anti-inflammatory actions of IVIG, associated signaling pathways are not well studied. As β-catenin, the central component of the canonical Wnt pathway, plays an important role in imparting tolerogenic properties to dendritic cells (DCs) and in reducing inflammation, we explored whether IVIG induces the β-catenin pathway to exert anti-inflammatory effects. We show that IVIG in an IgG-sialylation independent manner activates β-catenin in human DCs along with upregulation of Wnt5a secretion. Mechanistically, β-catenin activation by IVIG requires intact IgG and LRP5/6 co-receptors, but FcγRIIA and Syk are not implicated. Despite induction of β-catenin, this pathway is dispensable for anti-inflammatory actions of IVIG in vitro and for mediating the protection against experimental autoim...

Research paper thumbnail of Antibodies to the FVIII light chain that neutralize FVIII procoagulant activity are present in plasma of nonresponder patients with severe hemophilia A and in normal polyclonal human IgG

Blood, 2000

We have analyzed the properties of anti-factor VIII (FVIII) immunoglobulin (Ig) G recovered by af... more We have analyzed the properties of anti-factor VIII (FVIII) immunoglobulin (Ig) G recovered by affinity chromatography on FVIII-Sepharose from the IgG fraction of the plasma of healthy individuals and nonresponder patients with hemophilia A. Affinity-purified anti-FVIII antibodies were found to neutralize FVIII activity and to bind to FVIII with an affinity similar to that of anti-FVIII IgG that had been affinity-purified from the plasma of inhibitor-positive hemophilia patients and of patients with anti-FVIII autoimmune disease. The antibodies also exhibited patterns of reactivity with thrombin-digested FVIII similar to those of FVIII inhibitors and preferentially recognized epitopes located in the light chain of FVIII. These observations suggest that FVIII inhibitors occurring in hemophilia A and in patients with anti-FVIII autoimmune disease originate from the expansion of preexisting natural anti-FVIII clones that exhibit FVIII-neutralizing properties.

Research paper thumbnail of Circulating Normal IgG as Stimulator of Regulatory T Cells: Lessons from Intravenous Immunoglobulin

Trends in Immunology, 2017

Research paper thumbnail of Monomeric Immunoglobulin A from Plasma Inhibits Human Th17 Responses In Vitro Independent of FcαRI and DC-SIGN

Frontiers in Immunology, 2017

Research paper thumbnail of Predisposing factors, pathogenesis and therapeutic intervention of Kawasaki disease

Drug Discovery Today, 2016

Kawasaki disease (KD) is an acute febrile childhood inflammatory disease, associated with coronar... more Kawasaki disease (KD) is an acute febrile childhood inflammatory disease, associated with coronary artery abnormalities. The disease is believed to result from an aberrant inflammatory response to an infectious trigger in a genetically predisposed individual. KD is associated with an endothelial cell injury as a consequence of T cell activation and cytotoxic effects of various proinflammatory cytokines. Intravenous immunoglobulin (IVIG) infusion and aspirin are the standard treatment of acute KD. However, 10-20% of patients show resistance to IVIG therapy and present higher risk of coronary vasculitis. The relative roles of second IVIG infusion, corticosteroids, calcineurin inhibitors, interleukin-1 antagonists and anti-tumor necrosis factor agents remain uncertain. In this review, we highlight the predisposing factors, pathogenesis and therapeutic intervention of KD, particularly new therapeutics for IVIG-resistant patients. Reviews POST SCREEN

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

Molecular medicine (Cambridge, Mass.), Apr 14, 2015

Sepsis is a major cause for death worldwide. Numerous interventional trials with agents neutraliz... more Sepsis is a major cause for death worldwide. Numerous interventional trials with agents neutralizing single pro-inflammatory mediators have failed to improve survival in sepsis and aseptic systemic inflammatory response syndromes. This failure could well 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 ...

Research paper thumbnail of Heme oxygenase-1 is dispensable for the anti-inflammatory activity of intravenous immunoglobulin

Scientific reports, Jan 22, 2016

Intravenous immunoglobulin G (IVIG) is used in the therapy of various autoimmune and inflammatory... more Intravenous immunoglobulin G (IVIG) is used in the therapy of various autoimmune and inflammatory conditions. The mechanisms by which IVIG exerts anti-inflammatory effects are not completely understood. IVIG interacts with numerous components of the immune system including dendritic cells, macrophages, T and B cells and modulate their functions. Recent studies have reported that heme oxygenase-1 (HO-1) pathway plays an important role in the regulation of inflammatory response in several pathologies. Several therapeutic agents exert anti-inflammatory effects via induction of HO-1. Therefore, we aimed at exploring if anti-inflammatory effects of IVIG are mediated via HO-1 pathway. Confirming the previous reports, we report that IVIG exerts anti-inflammatory effects on innate cells as shown by the inhibitory effects on IL-6 and nitric oxide production and confers protection in experimental autoimmune encephalomyelitis (EAE) model. However, these effects were not associated with an indu...

Research paper thumbnail of The protective role of immunoglobulins in fungal infections and inflammation

Seminars in Immunopathology, 2014

Increased incidence of fungal infections in the immunocompromised individuals and fungi-mediated ... more Increased incidence of fungal infections in the immunocompromised individuals and fungi-mediated allergy and inflammatory conditions in immunocompetent individuals is a cause of concern. Consequently, there is a need for efficient therapeutic alternatives to treat fungal infections and inflammation. Several studies have demonstrated that antibodies or immunoglobulins have a role in restricting the fungal burden and their clearance. However, based on the data from monoclonal antibodies it is now evident that the efficacy of antibodies in fungal infections is dependent on epitope specificity, abundance of protective antibodies and their isotype. Antibodies confer protection against fungal infections by multiple mechanisms that include direct neutralization of fungi and their antigens, inhibition of growth of fungi, modification of gene expression, signaling and lipid metabolism, causing iron starvation, inhibition of polysaccharide release and biofilm formation. Antibodies promote opsonization of fungi and their phagocytosis, complement activation and antibody-dependent cell toxicity. Passive administration of specific protective monoclonal antibodies could prove to be beneficial in drug-resistance cases, to reduce the dosage and associated toxic symptoms of anti-fungal drugs. The longer half-life of the antibodies and flexibilities to modify their structure/forms are additional advantages. The clinical data obtained with two monoclonal antibodies should incite interests in translating pre-clinical success into the clinics. The anti-inflammatory and immunomodulatory role of antibodies in fungal inflammation could be exploited by intravenous immunoglobulin or IVIg.

Research paper thumbnail of Natural recognition repertoire and the evolutionary emergence of the combinatorial immune system

The FASEB Journal, 2002

The primordial combinatorial immune recognition repertoire arose in the evolution of jawed verteb... more The primordial combinatorial immune recognition repertoire arose in the evolution of jawed vertebrates ϳ450 million years ago as a rapid genetic process independent of antigenic selection. We propose that it encompassed the entire repertoire of innate immunity involving molecules that had evolved over billions of years. The 'antigen-driven' compartment involving invasive pathogens operates in 'real time' showing inducibility and increases in affinity. Individuals within a species differ in their repertoires because of distinct antigenic challenges, genetics, or local environmental effects. The 'homeostatic' compartment that recognizes invariant cell and serum components should be conserved in all individuals of a species. The potential to recapitulate the entire recognition spectrum must be regenerated during the formation of new species. Evidence for the capacity of the combinatorial response to encompass the entire preexisting repertoire was obtained in studies of natural human IgG antibodies present in intravenous immunoglobulin. Since essential cellular recognition and regulatory elements are conserved throughout evolution, we propose that the natural antibodies of sharks, the most anciently emerged vertebrates to possess the combinatorial immune response, will resemble those of mammals in showing specificity for the conserved recognition/regulatory molecules. If verified, this hypothesis will establish the fundamental importance of natural antibodies not only in defense, but in regulation and functional homeostasis of the individual.

Research paper thumbnail of Autoimmunity as a Predisposition for Infectious Diseases

Research paper thumbnail of Auditing Protein Therapeutics Management by Professional APCs: Toward Prevention of Immune Responses against Therapeutic Proteins

The Journal of Immunology, 2008

Alloimmunization is a crippling concern in the management of patients undergoing administration o... more Alloimmunization is a crippling concern in the management of patients undergoing administration of protein therapeutics as evidenced in replacement therapy and other treatment procedures. Several issues in the genesis and modulation of such deleterious immune responses have been studied. While authors have focused on the downstream events of the specific immune response and suggested modification of protein therapeutics to eliminate epitopes that interact with B cell receptors, T cell receptors, or MHCII molecules, the mechanisms underlying Ag interaction with APCs, a step upstream of immune effectors, have been grossly neglected. We wish to emphasize that the recent knowledge in understanding the capacities of an APC to handle an Ag and the importance of the surrounding microenvironment in this process are crucial for designing novel protein therapeutics with reduced immunogenicity.

Research paper thumbnail of Analysis of human self-reactive antibody repertoires by quantitative immunoblotting

Journal of Immunological Methods, 2000

We review the use of a quantitative immunoblotting technique to characterize human self-reactive ... more We review the use of a quantitative immunoblotting technique to characterize human self-reactive antibody repertoires in health and disease. The interactions of plasma IgM and IgG with tissue extracts as sources of self-antigens were analyzed by quantitative immunoblotting. Data were compared by means of multiparametric statistical analysis. The data summarized here demonstrate that natural self-reactive antibody repertoires of healthy individuals are restricted to a limited subset of immunodominant autoantigens that is selected early in development, and remains conserved between individuals through ageing. The selection of human natural self-reactive IgG antibody repertoires requires normal T-/ B-cell interactions. The immunoblotting assay has the potential to distinguish between autoimmune diseases with organ-related oligoclonal expansion of self-reactive clones and those characterized by broad alterations of immunoregulation. However, organ-specific autoimmune diseases may be characterized by altered patterns of antibody repertoires unrelated to the target organ. The assay also revealed an unexpected defect in the regulatory function of self-reactive IgM on the expression of self-reactive IgG repertoires in several systemic and organ-specific autoimmune diseases. The results are discussed in the light of our current understanding of the processes of selection of self-reactive B-cells and the pathophysiology of autoimmunity.

Research paper thumbnail of Antibodies to a conserved region of HLA class I molecules, capable of modulating CD8 T cell-mediated function, are present in pooled normal immunoglobulin for therapeutic use

Journal of Clinical Investigation, 1996

Intravenous immunoglobulin (IVIg) is increasingly used for the treatment of autoimmune diseases a... more Intravenous immunoglobulin (IVIg) is increasingly used for the treatment of autoimmune diseases and the prevention of infections and of graft versus host reactions in recipients of allogeneic bone marrow transplants. The immunomodulatory effects of IVIg are largely dependent on their ability to interact with membrane molecules of lymphocytes. We report here that IVIg recognizes the B07.75-84 peptide, corresponding to a conserved region of the ␣ 1 helix of the first domain of HLA-B7 01, which represents a nonpolymorphic determinant of HLA class I molecules. Intact IVIg and its F(ab Ј) 2 fragments bound to the peptide as well as to purified soluble HLA and to HLA on a human T cell line. Binding of IVIg to HLA was assessed by ELISA, immunofluorescence, and real-time analysis of the interaction using the BIAlite system. The binding of antipeptide antibodies to HLA was inhibited by free peptide. Antipeptide antibodies isolated from IVIg by affinity chromatography inhibited CD8 cellmediated cytotoxicity of an influenza virus-specific human T cell line. The presence in IVIg of antibodies to critical regions of HLA class I molecules suggests a possible role for IVIg in modulation of class I-restricted cellular interactions in the immune response.

Research paper thumbnail of Intravenous Immunoglobulin: An Update on the Clinical Use and Mechanisms of Action

Journal of Clinical Immunology, 2007

Initially used as a replacement therapy for immunodeficiency diseases, intravenous immunoglobulin... more Initially used as a replacement therapy for immunodeficiency diseases, intravenous immunoglobulin (IVIg) is now widely used for a number of autoimmune and inflammatory diseases. Considerable progress has been made in understanding the mechanisms by which IVIg exerts immunomodulatory effects in autoimmune and inflammatory disorders. The mechanisms of action of IVIg are complex, involving modulation of expression and function of Fc receptors, interference with activation of complement and the cytokine network and of idiotype network, regulation of cell growth, and effects on the activation, differentiation, and effector functions of dendritic cells, and T and B cells.

Research paper thumbnail of Immunomodulation by Intravenous Immunoglobulin: Role of Regulatory T Cells

Journal of Clinical Immunology, 2010

An altered immune homeostasis as a result of deficiency or defective function of CD4 + CD25 + Fox... more An altered immune homeostasis as a result of deficiency or defective function of CD4 + CD25 + FoxP3 + regulatory T cells (Tregs) is common in several autoimmune diseases. Hence, therapeutic strategies to render Tregs functionally competent are being investigated. Intravenous immunoglobulin (IVIG) is being increasingly used for the treatment of a wide range of autoimmune and inflammatory diseases. Recent studies have demonstrated that IVIG induces the expansion of Tregs and enhances their suppressive functions. These effects of IVIG on Tregs correlate with the beneficial effects of IVIG in patients with autoimmune diseases. Thus, modulation of Tregs by IVIG represents a novel mode of action that explains the therapeutic effects of IVIG in T cell-mediated autoimmune diseases. However, the molecular mechanisms involved in IVIG-mediated modulation of Tregs are unclear and need further investigation.

Research paper thumbnail of Autoantibodies with enzymatic properties in human autoimmune diseases

Journal of Autoimmunity, 2011

Immunoglobulins (Ig) or antibodies are heavy plasma proteins, with sugar chains added to amino ac... more Immunoglobulins (Ig) or antibodies are heavy plasma proteins, with sugar chains added to amino acid residues by N-linked glycosylation and occasionally by O-linked glycosylation. The versatility of antibodies is demonstrated by the various functions that they mediate such as neutralization, agglutination, fixation with activation of complement and activation of effector cells. In addition to this plethora of functions, some antibodies express enzymatic activity. Antibodies endowed with enzymatic properties have been described in human autoimmune manifestations for more than a decade in a variety of disorders such as autoimmune thyroiditis, systemic erythematosus (SLE), scleroderma, rheumatoid arthritis (RA), multiple sclerosis (MS) and acquired hemophilia (AH). Antibodies isolated from these conditions were able to specifically hydrolyze thyroglobulin, DNA, RNA, myelin basic protein (MBP), and factor VIII (FVIII) or factor IX (FIX), respectively. The therapeutic relevance of these findings is discussed.

Research paper thumbnail of Autoantibodies to heat shock protein 90 in the human natural antibody repertoire

International Immunology, 2002

The present study demonstrates the presence of natural autoantibodies of the IgG isotype directed... more The present study demonstrates the presence of natural autoantibodies of the IgG isotype directed against heat shock protein 90 (HSP90). The binding properties of af®nity-puri®ed anti-HSP antibodies were compared with those of natural antibodies speci®c for other self antigens, including anti-thyroglobulin and anti-myoglobin autoantibodies, by using semiquantitative immunoblotting, with solubilized proteins from normal liver tissue as antigens, and cross-blot analysis using puri®ed self proteins. Af®nity-puri®ed anti-HSP90 antibodies were polyreactive and the non-HSP90-speci®c fraction of normal IgG was depleted in its natural autoantibody content. We further observed that self antigens including HSP, myosin, tubulin and aldolase with highly conserved structures show similar patterns of binding with natural antibodies, and form a well-de®ned cluster as demonstrated by cluster analysis of immunoreactivity data, whereas the lessconserved self and non-self antigens remained unclustered. The results favor the hypothesis that HSP90 belongs to a subset of highly conserved and immunodominant self antigens that are the primary target for natural autoantibodies in normal human IgG.

Research paper thumbnail of Intravenous immunoglobulins (IVIg) in the treatment of autoimmune diseases

Clinical and Experimental Immunology, 2008

SUMMARY Intravenous immunoglobulin (IVIg) therapy is increasingly used in autoimmune diseases. Al... more SUMMARY Intravenous immunoglobulin (IVIg) therapy is increasingly used in autoimmune diseases. Although its efficacy has only been established in a few specific antibody-mediated autoimmune conditions, accumulating evidence on the regulatory role of circulating immunoglobulins in the selection of peripheral B cell repertoires makes it an attractive potential therapeutic option to clinical immunologists. This overview briefly discusses the current use of IVIg in human autoimmune diseases with a particular emphasis on the possible mechanisms by which IVIg could suppress pathological autoimmune responses.

Research paper thumbnail of Treatment of autoimmune diseases with normal immunoglobulin through manipulation of the idiotypic network

Clinical and Experimental Immunology, 2008