Résumé
Bien que les immunoglobulines intraveineuses (IgIV) soient utilisées depuis une vingtaine d’années dans les maladies auto-immunes et inflammatoires, les mécanismes moléculaires à la base de leur effet bénéfique ne sont pas complètement élucidés. Ces mécanismes dépendent des fragments constants (Fc) et/ou variables (Fab’)2. Les IgIV intéragissent avec de nombreux composants du système immunitaire comme les récepteurs Fc, le complément, les cytokines, les lymphocytes T et B, les cellules dendritiques, les granulocytes et les cellules NK, ce qui explique en partie leurs effets anti-inflammatoires.
Summary
Despite the fact that IVIG is used for more than two decades in the treatment of a number of autoimmune and inflammatory conditions, the underlying molecular mechanisms that account for its beneficial effect have not been completely elucidated. These mechanisms implicate both the constant (Fc) and the variable region (Fab’) of the immunoglobulins. 2 The interaction of IVIG with a large number of components of the immune system including Fc receptors, complement molecules, cytokines, B and T lymphocytes, neutrophils and NK cells, may explain at least in part their anti-inflammatory effects. Intravenous immunoglobulin (IVIG) is a therapeutic preparation of polyspecific antibodies isolated from pools of plasma obtained from several thousand healthy blood donors [1]. Conceived initially for antibody replacement therapy in patients with primary and secondary immunodeficiencies, IVIG is now used in several autoimmune and inflammatory diseases. IVIG contains at least 96 % IgG with traces of IgA and IgM. The size of the plasma pool ensures the vast diversity of IgG repertoire in IVIG that interacts with a large number of self-antigens, in addition to pathogens and external antigens [2]. The self-reactive immunoglobulins referred to as natural autoantibodies (NAbs) have been shown to exert homeostatic roles [1]. Thus, IVIG has high content of selfreactive NAbs, which also includes those interacting with idiotypes of other Ab molecules. IVIG is used in (i) low dose or ‘‘substitution’’ therapy in immunodeficient patients up to 300-500 mg/kg body weight every 3-4 weeks and [3] (ii) in high dose ‘‘ immunomodulatory ’’ therapy of autoimmune and inflammatory diseases employing 1-2 g/kg body weight in single injection or five daily doses of 400 mg/kg with additional maintenance dose at 4-6 week intervals [4, 5]. IVIG is injected preferably through intravenous route, but more recently subcutaneous route (SCIg) is also employed in replacement therapy of immunodeficient patients and also in longterm therapy of autoimmune diseases [6]. The half-life of infused IVIG is approximately 3 weeks [7, 8]. Augmentation of the platelet counts in the immune thrombocytopenic purpura (ITP) as first demonstrated by Imbach and co-workers, opened the way for the application of IVIG in other autoimmune and inflammatory diseases [1, 9]. In addition to its use in diseases wherein the clinical effectiveness is clearly demonstrated by randomized, double-blind, placebo-controlled trials, IVIG is also used in over 100 other diseases in an off-label manner. The off-label use of IVIG amounts to an estimated 50-70 % of the global consumption of IVIG [10]. Recent studies have also provided a support for the use of IVIG as a steroid-sparing agent [11]. IVIG acts at various levels of autoimmune response such as initiation, amplification and effector phase by targeting various soluble and cellular compartments of the immune system. Thus, several mutually non-exclusive mechanisms have been proposed to account for the beneficial effects of IVIg, that may indeed reflect the homeostatic effects of natural antibodies in physiology. In autoantibody-mediated diseases, Fc-mediated mechanisms have been highlighted. Thus, blockade of activating FcγR inhibits binding of opsonized antigens, induction of effector functions and secretion of pro-inflammatory cytokines by macrophages, and degranulation of granulocytes. In conditions such as like ITP that is autoantibody-mediated, IVIG Fc fragmentmediated competitive blockade of activating FcγR might inhibit: binding of opsonized antigens, induction of effector functions and secretion of pro-inflammatory cytokines by macrophages, and degranulation of granulocytes [1, 12]. FcRn expressed in endosomal compartment of intestinal epithelium, vascular endothelium and macrophages regulates the serum IgG levels by binding to the pinocytosed antibodies and recirculating them to cell surface without intracellular degradation. As shown in the experimental models of ITP and autoimmune blistering diseases, saturation of FcRn obtained by high dose IVIG results in an enhanced clearance of pathogenic autoantibodies and their decreased serum levels with significant beneficial effects [13, 14]. The role of cell surface FcRn expressed in human monocytes and macrophages in the therapeutic effect of IVIG remains to be explored. IVIG-mediated modulation of the expression of FcγR leading to sustained unresponsiveness of phagocytes to autoantibodies is being recognised as an important mechanism of action of IVIG in autoimmune diseases [15]. IVIG blocks the expression of activating FcγR s on monocytes and antigen presenting cells in man and in mouse models [16-18]. The group of Ravetch reported that induction of inhibitory FcγRIIB on macrophages by Fc fragments of IgG as the main mechanism of anti-inflammatory effects of IVIG [18, 19]. This finding also corroborated in a clinical set-up, wherein up-regulated FcγRIIB expression was observed on monocytes and B lymphocytes following IVIG therapy in CIDP patients [20]. Later, the same team identified α2,6-linkage of sialic acid to galactose on the glycan at Asn297 in the Fc fragment of IgG as the active moiety of anti-inflammatory IVIG [21]. The α2,6-sialylated IgG constituted 1-2 % of IVIG and could reproduce the benefits of IVIG when used at much lower dose and as a recombinant human IgG1 Fc protein [15]. Recently sialylated Fc region of IgG has been demonstrated to interact with the C-type lectin receptor, SIGN-R1 on ‘regulatory macrophages’ residing in the marginal zone of the spleen. These in turn up-regulate the expression of FcγRIIB on CSF-1- independent ‘effector macrophages’ to mediate the anti-inflammatory effects of IVIG [22]. However, we observed that DC-SIGN and α2,6-sialylated IgG Fc interaction are not indispensable for the effect of IVIG on human monocyte-derived dendritic cells [23]. IVIG contains anti-idiotypic antibodies that inhibit the activity of a large spectrum of disease-associated or pathogenic autoantibodies and thus believed to contribute to therapeutic effect observed in autoimmune hemophilia, anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis, antibody-mediated neuropathies, systemic lupus erythematosus (SLE), myasthenia gravis and Lambert-Eaton syndrome [1]. IVIG also prevents complement-mediated tissue damage by preventing the generation of C5b-9 membrane attack complex, scavenging active complement components (C3b and C4b) and deviating complement from attaining cellular targets [24, 25]. These effects are relevant in the treatment of patients with severe dermatomyositis, Guillain Barré syndrome (GBS) and myasthenia gravis [26]. IVIG modulates the expression of Th1 and Th2 cytokines with an increase in the anti-inûammatory cytokine IL-10 in ITP patients [27]. Following IVIG infusion, decreased levels of the proinflammatory cytokine IL-1 and increased levels of IL-1R antagonist (IL-RA) are observed in patients with Kawasaki disease and decreased circulating IL-1β levels in GBS [1]. A reduced production of TGF-β1, IL-2, IL-3, IL-12, IL-22 and GM-CSF is also observed in the muscles of patients with dermatomyositis who responded to IVIG therapy [28, 29]. In endothelial cells, IVIG inhibits the expression of chemokines and adhesion molecules [1]. IVIG preparations contain antibodies against cytokines including GM-CSF, IFN-α, TNF-α, B cell activating TNF family factor (BAFF)/APRIL that can neutralize the target cytokines [1, 30]. Dendritic cells play a major role as professional antigen presenting cells, in immune tolerance and autoimmunity. We have shown that high-dose IVIG inhibits the differentiation, maturation and function of human DC [31, 32]. IVIG abrogates the IL-12 secretion upon activation of mature DC, while enhancing the production of IL-10 [31, 32]. Further, Siragam et al. [33] demonstrated that adoptive transfer of ex vivo IVIG-treated DC can ameliorate autoimmune disease in vivo . Thus, IVIG is believed to induce tolerogenic activity in DC to exert immunomodulation in autoimmune diseases [12]. In vitro , replacement-dose IVIG was found to restore the defective expression of markers on DC from patients with primary immunodeficiency (PID) such as XLA and CVID [34, 35]. These substitution doses of IgG stimulate the maturation of impaired DC in patients with PID [9, 34, 35]. More recently, we have observed that IVIG at doses equivalent of replacement therapy also activate the neutrophils. IVIG inhbits the expansion of autoreacitve B-lymphocytes and production of pathogenic autoantibodies and cytokine, which is mediated by signaling via FcγRIIB, idiotype-mediated inhibition of B-cell receptors and neutralization of cytokines such as the BAFF/APRIL [1, 12, 36-38]. Further, B lymphocytes are resistant to immunomodulation by ‘IVIg-educated’ dendritic cells [39]. Contrary to inhibitory effects, IVIG may also induce proliferation and immunoglobulin synthesis from B cells of patients with CVID without induction of B cell effector cytokine IFN-γ and of transcription factor T-bet, which is in part mediated by by selfreactive anti-CD40 [3]. IVIG has prominent effects on T cells, which play a central role in the process of immune response. IVIG inhibits human T cell activation, proliferation and cytokine production after mitogenic and allogeneic stimulation in vitro [40-44]. Recent studies have revealed the critical role of impact of IVIG on Treg population in mediating the anti-inflammatory and immune regulatory activities of IVIG [45, 46]. In a mouse model of EAE, IVIG-induced protection was associated with an early and sustained peripheral expansion of CD4+CD25+Foxp3+ Tregs in spleen and lymph nodes [47]. However, IVIG was not able to protect the mice depleted of CD25+ Treg population. In agreement with the experimental evidence and animal models, IVIG therapy expands the number of peripheral Tregs in patients with acute-stage Guillain Barré syndrome, Kawasaki disease and SLE, which also correlated with an improvement of clinical parameters and symptoms [48-52]. In fact, it has been known for long time that IVIG induces suppression of T cell proliferation and cytokine secretion Further, IVIG also reduces the production of Th1 cytokines IFN-γ and IL-2 in T cells activated by CD3 stimulation as well as mitogens such as phytohemagglutinin [41, 42, 53]. In agreement with the in vitro
evidence, IVIG-mediated protection from clinical symptoms of experimental myasthenia gravis involved suppression of Th1 cell responses without implicating Tregs [54]. Further, IVIG modulated the expression pattern of Th1/Th2 cytokine genes in children with ITP, where stable remission following IVIG treatment was associated with change of Th1 phenotype to Th0 or Th2 phenotype and increase in the plasma TGF-β levels [27]. Similarly, a reduced Th1/Th2 ratio in peripheral blood was observed after IVIG therapy in women with recurrent spontaneous abortions associated with anti-phospholipid antibodies (APS) [55, 56]. IVIG has also been shown to inhibit Th2 cell response-mediated airway hyperresponsiveness and goblet cell hyperplasia in murine model [57, 58]. We have also documented the inhibition of invariant NKT cell-mediated allergic airway inflammation through FcγRIIIAdependent mechanisms. Recent results from our group further extend the inhibitory effect of IVIG on T cells ; we demonstrated that IVIG suppresses differentiation and amplification of Th17 cells, which play a critical pathogenic role in several immunemediated diseases [59-61].
Several studies have thus highlighted the importance of the interaction of IVIg with the cellular compartment to exert anti-inflammatory or tolerogenic effect on immune system. IVIg interacts with cells of the innate and adaptive immune compartments. IVIg exerts its effect on polymorphonuclear cells, NK cells and NKT cells [62, 63]. We therefore, believe that by interacting with several cellular and molecular components of both innate and adaptive compartments of the immune system, IVIG restores immune homeostasis in patients with autoimmune and inflammatory conditions.
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DISCUSSION
M. Pierre GODEAU
A côté des mécanismes complexes physio-pathologiques n’y a-t-il pas un mécanisme plus simple commun à diverses maladies ? Celui de la diversion de la phagocytose a pu être suspecté dans le PTT traité par les antiD ?
IVIg is effective in a large number of extremely diverse diseases. The underlying immunopathologic process in these diseases is complex and heterogeneous. Although in most diseases, the common factor is inflammation, the factors that lead to the inflammation are varied and therefore at present time, it is hard to imagine one single, simple and common mechanism in these multiple conditions.
M. François-Bernard MICHEL
J’aimerais que vous nous disiez si l’on connaît, après une seule injection, le délai d’apparition de l’efficacité et la durée de celle-ci ?
In Kawasaki disease and acute immune thrombocytopenia, a relatively long-lasting clinical improvement has been reported within 24 hours after a single injection of IVIg.
In animal studies of experimental autoimmune encephalomyelitis, a similar effect has been reported.
M. Jacques-Louis BINET
Quel est finalement le mécanisme de la thrombopénie ?
There is not one single mechanism is responsible for thrombopenia. It is rather well established that the decrease in the number of platelets implicates different processes including those factors that are responsible for a decreased production of platelets including hereditary syndromes ; those that cause increased destruction ; medicationinduced conditions and also immunological destruction of platelets. IVIg is extremely benefical in the treatment of ITP. Although the recent studies reported by Dr Jeff Ravetch of Rockefeller University, New York, seem to emphasize on the role of increased expression of inhibitory IgG Fc receptor IIB (FcγRIIB) as a single mechanism, there is no consensus on this question.
M. Bernard LAUNOIS
On n’a pas parlé des immunoglobulines spécifiques anti-HBS qui permettent aux immunoglobulines de guérir les cirrhoses post-hépatites B sur risque de récidive ?
Yes, indeed. Antibodies specific for several viral antigens including hepatitis, West-Nile virus, Parvovirus B19 and cytomegalovirus, respiratory syncitial virus have shown clinical benefit. In fact, in the face of emerging crisis due to antibiotic resistance, such antibodies might prove valuable either alone or in combination with other drugs.
Bull. Acad. Natle Méd., 2012, 196, no 1, 39-48, séance du 17 janvier 2012
