Is Multiple Sclerosis an Autoimmune Disease?

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) with varied clinical presentations and heterogeneous histopathological features. The underlying immunological abnormalities in MS lead to various neurological and autoimmune manifestations. There is strong evidence that MS is, at least in part, an immune-mediated disease. There is less evidence that MS is a classical autoimmune disease, even though many authors state this in the description of the disease. We show the evidence that both supports and refutes the autoimmune hypothesis. In addition, we present an alternate hypothesis based on virus infection to explain the pathogenesis of MS

Evidence for the Role of B Cells and Immunoglobulins in the Pathogenesis of Multiple Sclerosis

The pathogenesis of multiple sclerosis (MS) remains elusive. Recent reports advocate greater involvement of B cells and immunoglobulins in the initiation and propagation of MS lesions at different stages of their ontogeny. The key role of B cells and immunoglobulins in pathogenesis was initially identified by studies in which patients whose fulminant attacks of demyelination did not respond to steroids experienced remarkable functional improvement following plasma exchange. The positive response to Rituximab in Phase II clinical trials of relapsing-remitting MS confirms the role of B cells. The critical question is how B cells contribute to MS. In this paper, we discuss both the deleterious and the beneficial roles of B cells and immunoglobulins in MS lesions. We provide alternative hypotheses to explain both damaging and protective antibody responses

Catalytic IgG from patients with hemophilia A inactivate therapeutic factor VIII

Factor VIII (FVIII) inhibitors are anti-FVIII IgG that arise in up to 50% of the patients with hemophilia A, upon therapeutic administration of exogenous FVIII. Factor VIII inhibitors neutralize the activity of the administered FVIII by sterically hindering its interaction with molecules of the coagulation cascade, or by forming immune complexes with FVIII and accelerating its clearance from the circulation. We have shown previously that a subset of anti-factor VIII IgG hydrolyzes FVIII. FVIII-hydrolyzing IgG are detected in over 50% of inhibitor-positive patients with severe hemophilia A, and are not found in inhibitornegative patients. Although human proficient catalytic Abs have been described in a number of inflammatory and autoimmune disorders, their pathological relevance remains elusive. We demonstrate here that the kinetics of FVIII degradation by FVIIIhydrolyzing IgG are compatible with a pathogenic role for IgG catalysts. We also report that FVIII-hydrolyzing IgG from each patient exhibit multiple cleavage sites on FVIII and that, while the specificity of cleavage varies from one patient to another, catalytic IgG preferentially hydrolyze peptide bonds containing basic amino acids

Catalytic antibodies directed against factor VIII in different human disorders

L'hémophilie A est une maladie qui touche un enfant mâle sur 5000 et se traduit par des niveaux plasmatiques insuffisants de facteur VIII fonctionnel. L'administration thérapeutique de facteur VIII exogène aux patients résulte dans environ 25-50% des cas dans le développement d'anticorps anti-facteur VIII. Ces anticorps inhibent l'activité pro-coagulante du facteur VIII par encombrement stérique. Nous avons décrit un nouveau mécanisme d'inhibition du facteur VIII par les anticorps: les anticorps de certains patients hydrolysent le facteur VIII. Dans ce travail, nous avons déterminé les mécanismes moléculaires de l'hydrolyse du facteur VIII par les anticorps des patients. Les sites de clivage ont été identifiés par séquençage des fragments de digestions. Les paramètres cinétiques qui caractérisent l'activité hydrolytique des IgG des patients ont été calculés à l'aide de substrats génériques. Des anticorps facteur VIII inhibiteurs surviennent en tant qu'auto-anticorps chez les patients atteints d'hémophilie acquise. Nous avons prouvé la présence d'IgG hydrolysant le facteur VIII chez 47% des patients atteints d'hémophilie acquise. Ainsi, décrivons nous pour la première fois la présence d'anticorps catalytiques, capables d'hydrolyser le facteur VIII et le facteur IX, chez certains patients transplants. Le contrôle des niveaux de facteur VIII circulant par anticorps catalytique apparaît comme le garant d'un équilibre délicat entre état hémogénique (hemophilie A) et état pro-thromobotique (transplantation) ou systémique (sepsis). Ce travail nous a permis de mieux connaître les propriétés enzymatiques des anticorps catalytiques anti-facteur VIII et leur importance physiopathologique.Hemophilia A is a disorder that affects one male out of 5000 and results in insufficient levels of functional factor VIII in plasma. Therapeutic administration of exogenous FVIII to patients with hemophilia A results in 25 to 50% of the cases in the development of anti-factor VIII antibodies. Anti-factor VIII antibodies inhibit the pro-coagulant activity of factor VIII by steric hindrance. We have demonstrated a novel inhibitory mechanism of anti-factor VIII antibodies: the antibodies from some patients hydrolyze factor Vlll.In the present work, we have determined the molecular mechanisms underiying the hydrolysis of factor VIII by the factor VIII-hydrolyzing antibodies (F8-HIgG) of the patients. The cleavage sites on the factor VIII molecule were identified by sequencing of the generated cleavage fragments. The kinetic parameters that characterized the hydrolytic activity of patients' polyclonal IgG were calculated using generic substrates. Factor VIII inhibitory IgG also develop as auto-antibodies in patients with acquired hemophilia. We have investigated the presence of F8-HIgG in patients with acquired hemophilia. We have identified the presence of F8-HIgG in the case of 47% of such patients. We also characterized the presence of F8-HIgG in other pathological situations defned by inflammation. For the first time, we describe the occurrence of catalytic antibodies that are capable of hydrolyzing FVIII and FIX, in some patients who have undergone transplantation. The control of factor VIII in circulation by the catalytic antibodies appears to rely on a delicate equilibrium between a hemogenic (hemophilia A) and prothrombotic state (transplantation) or systemic state (sepsis). The present work has allowed us a better understanding of the enzymatic properties of F8-HIgG and their physio-pathological relevance.COMPIEGNE-BU (601592101) / SudocSudocFranceF

Varied Immune Response to FVIII: Presence of Proteolytic Antibodies Directed to Factor VIII in Different Human Pathologies

The versatility of antibodies is demonstrated by the various functions that they mediate such as neutralization, agglutination, fixation of the complement and its activation, and activation of effector cells. In addition to this plethora of functions, antibodies are capable of expressing enzymatic activity. Antibodies with catalytic function are a result of the productive interplay between the highly evolved machinery of the immune system and the chemical framework used to induce them (antigens). Catalytic antibodies are immunoglobulins with an ability to catalyze the reactions involving the antigen for which they are specific. Catalytic immunoglobulins of the IgM and IgG isotypes have been detected in the serum of healthy donors. In addition, catalytic immunoglobulins of the IgA isotype have been detected in the milk of healthy mothers. Conversely, antigen-specific hydrolytic antibodies have been reported in a number of inflammatory, autoimmune, and neoplastic disorders. The pathophysiological occurrence and relevance of catalytic antibodies remains a debated issue. Through the description of the hydrolysis of coagulation factor VIII as model target antigen, we propose that catalytic antibodies directed to the coagulation factor VIII may play a beneficial or a deleterious role depending on the immuno-inflammatory condition under which they occur

Pathophysiology of catalytic antibodies

Immunoglobulins have initially been illustrated as proteins produced by the immune system for binding and neutralizing foreign molecules potentially harmful to the organism. The number of VH, DH, JH, VL and JL genes that encode the variable regions of immunoglobulins and the junctional diversity that occurs at the time of somatic rearrangement determine the extent of the repertoire of antibodies that may be potentially produced by an organism. This potential repertoire includes antibodies the antigen binding site of which may recognize external as well as autologous antigens, or may structurally resemble the active site of enzymes and be endowed with enzymatic activity. Under physiological conditions, B cell clones that produce antibodies naturally endowed with catalytic activity are negatively regulated and subjected to apoptosis. Catalytic antibodies are expressed only following active immunization, or if the physiological regulatory mechanisms that control the expression of catalytic antibody-producing B cell clones are perturbed, e.g. in the context of pregnancy or in the course of autoimmune diseases

Emergence of antibodies endowed with proteolytic activity against High-mobility group box 1 protein (HMGB1) in patients surviving septic shock

International audienceHigh-mobility group box 1 (HMGB1) concentration in serum or plasma has been proposed as an important biological marker in various inflammation-related pathologies. We previously showed that low titer autoantibodies against HMGB1 could emerge during the course of sepsis. Importantly their presence was positively related with patients' survival. In this study, we focused on plasma samples from 2 patients who survived sepsis and exhibited high titer antibodies to HMGB1. These antibodies were proved to be specific for HMGB1 since they did not bind to HMGB2 or to human serum albumin. Following IgG purification, it has shown that both patients secreted HMGB1-hydrolyzing autoantibodies in vitro. These findings suggested that proteolytic antibodies directed against HMGB1 can be produced in patients surviving septic shock

Physiopathology of catalytic antibodies: the case for factor VIII-hydrolyzing immunoglobulin G

Antibodies that are able to catalyze the antigen for which they are specific are produced spontaneously by the immune system. Catalytic immunoglobulins (Igs) both of the IgM and IgG isotypes have been detected in the serum of healthy donors, where they have been proposed to participate in the removal of metabolic waste and in the defense of the organism against invading pathogens. Conversely, antigen-specific hydrolytic IgG have been reported in a number of inflammatory, autoimmune and neoplastic disorders: their pathogenic effects have been demonstrated occasionally. The pathophysiological relevance of catalytic antibodies thus remains an elusive issue. Through the description of the pro-coagulation factor VIII as a model target antigen for catalytic antibodies, we propose that catalytic antibodies have either a beneficial or a deleterious role depending on the physiopathological context. Physiology thus relies on a delicate equilibrium between the levels of soluble target antigen and that of antigen-specific hydrolyzing immunoglobulins. Indeed, in patients with hemophilia A, in whom endogenous factor VIII is deficient or missing and exogenous factor VIII needs to be administered to treat hemorrhagic events, the development of factor VIII-hydrolyzing IgG that inactivate the therapeutically administered factor VIII, may reveal deleterious. In contrast, in a situation in which excess factor VIII may be detrimental and lead to excessive coagulation, disseminated thrombosis and organ ischemia, as seen in severe sepsis, our recent data suggest that the presence of factor VIII-hydrolyzing IgG may be beneficial to the patient