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Intravenous immunoglobulin: Exploiting the potential of natural antibodies
Autoimmunity Reviews 11 (2012) 792–794
Contents lists available at SciVerse ScienceDirect
Autoimmunity Reviews journal homepage: www.elsevier.com/locate/autrev
Review
Intravenous immunoglobulin: Exploiting the potential of natural antibodies Srini V. Kaveri ⁎ INSERM, U872, 15 rue de l'Ecole de Médicine, Paris, F-75006, France Centre de Recherche des Cordeliers, Equipe 16—Immunopathology and therapeutic immunointervention, Université Pierre et Marie Curie—Paris 6, UMR S 872, Paris, F-75006, France Université Paris Descartes, UMR S 872 Paris, F-75006, France International Associated Laboratory IMPACT (Institut National de la Santé et de la Recherche Médicale, France—Indian council of Medical Research, India), National Institute of Immunohaemotology, Mumbai, India
a r t i c l e
i n f o
a b s t r a c t Antibodies present in healthy conditions in the absence of deliberate immunization or infections are called natural antibodies. A significant proportion of natural antibody pool is believed to interact with self-antigens, and thus is called natural autoantibodies. Natural autoantibodies belong to IgG, IgM and IgA subclasses, and are encoded by V(D)J genes in germline configuration and bind to self molecules with varying affinities. In addition to serving in first line defense mechanism, natural antibodies participate in the homeostasis of the immune system. Intravenous immunoglobulin (IVIg) is a therapeutic preparation that contains substantial amount of natural antibodies exclusively of IgG subclass. In addition to its role in protection against pathogens in primary and secondary immunodeficiency patients, IVIg exerts a number of immunoregulatory functions through its interaction with innate and adaptive immune system and thereby imposing immune homeostasis. © 2012 Elsevier B.V. All rights reserved.
Available online 12 February 2012 Keywords: Natural antibodies Intravenous immunoglobulin Homeostasis
Contents 1. Introduction . . . . . . . . . 2. Origin of natural autoantibodies 3. Role of natural autoantibodies . 4. Effect of IVIg . . . . . . . . . Take-home messages . . . . . . . References. . . . . . . . . . . . .
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1. Introduction Initially conceived for the antibody replacement therapy of patients with primary immunodeficiency, intravenous immunoglobulin (IVIg) is now increasingly being used in the treatment of a large number of autoimmune and inflammatory diseases [1–5]. IVIg contains a broad spectrum of antibody specificities against bacterial, viral, parasitic, and mycoplasma antigens, that are capable of both opsonization and neutralization of microbes and toxins. The anti-microbial activity of IVIg is believed to be critical for the replacement therapy of patients with primary humoral immune deficiencies. However, natural antibodies also constitute integral components of IVIg. A significant fraction of natural antibody repertoire is suggested to be specific for a number of self-antigens, and is believed to be
⁎ INSERM U 872, Equipe 16-Centre de Recherche des Cordeliers, 15 rue de l'Ecole de Médicine, Paris, F-75006, France. Tel.: + 33 1 44 27 82 03; fax: + 33 1 44 27 81 94. E-mail address: [email protected]. 1568-9972/$ – see front matter © 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.autrev.2012.02.006
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essential for the immunoregulatory effects of IVIg in immunemediated disorders through establishing normal immune homeostasis [6]. In this brief essay as a tribute to the achievements of Pierre Youinou and his colleagues over the last few decades on the origin, nature and the function of natural antibodies, an overview on the importance of natural antibodies with a particular emphasis on the mechanisms of action of IVIg is provided.
2. Origin of natural autoantibodies Human serum in physiological situations contains antibodies of the IgG, IgM and IgA isotype. These antibodies are referred to as “natural” as they are produced in the absence of intentional immunization and independently of introduction of foreign antigens [7]. A major proportion of natural antibodies in the serum of healthy blood donors and, as a result in IVIg, are natural autoantibodies (nAAbs). Several independent studies support the claim that nAAbs are the products of positively selected autoreactive B cells [8]. nAAbs are
S.V. Kaveri / Autoimmunity Reviews 11 (2012) 792–794
encoded by germline, unmutated or minimal mutated, variable region genes, as opposed to antibodies that result from active immunization, the immune antibodies or antibodies that are associated with autoimmune pathologies, that are encoded by genes having undergone somatic hypermutation [9]. The evidence that nAAbs originate from a distinct subset of human B cells remains controversial. Although it was believed that nAABs are generated by CD5+ B cells, studies by the groups of Youinou and Lydyard indicate that expression of surface CD5 on cord blood B cells is not a definitive marker of an auto/polyreactive population [10]. While in mice, CD5+ B-1 cells are considered as a source of natural IgM antibodies, their role in humans is debated, partly because CD5 may be an activation marker on human B cells. Further, recently CD20+CD27+CD43+ memory B cells have been identified as the human B1 cell equivalent [11]. It was generally believed that nAAbs display lower affinity and elevated avidity for autoantigens [12]. However, subsequent studies reported a wide range of affinity values with dissociating constants between 10 − 5 and 10 − 8 M [13–15]. Interestingly, nAAbs are more polyreactive than immune antibodies, in that they often recognize several antigens including a wide range of self-antigens. This has been clearly shown for anti-thyroglobulin autoantibodies [16]. Immune and disease-associated autoantibodies express idiotypes different from those borne by nAAbs of the same specificity. Thus, a majority of the patients with Hashimoto's thyroiditis express T44 idiotype on their anti-thyroglobulin autoantibodies while a negligible number of healthy individuals' anti-thyroglobulin autoantibodies displayed T44 idiotype [17]. In a series of interesting studies, it has been demonstrated that certain disease-associated autoantibodies exhibit an ability to hydrolyze target antigens as in the case of anti-DNA autoantibodies in lupus, anti-MBP antibodies in multiple sclerosis, anti-thyroglobulin autoantibodies in autoimmune thyroiditis, anti-Factor VIII autoantibodies in autoimmune hemophilia and others, whereas natural autoantibodies with the same specificities exhibit reduced or no catalytic activity [18,19]. 3. Role of natural autoantibodies Several functions have been proposed for nAAbs [20]. nAAbs neutralize microbes and microbial toxins as a consequence of their polyreactivity or cross-reactivity, strongly suggesting a role for nAAbs in natural host defense against infection. nAAbs contribute to the removal of senescent/altered self molecules, cells, and tumors, possibly by virtue of their ability to hydrolyze some of their target antigens. Indeed, it has been shown that antibodies from healthy individuals display a promiscuous hydrolytic activity, as opposed to more specific enzymatic activity of antigen-specific autoantibodies in patients with autoimmune diseases [21]. The binding of nAAbs to antigens contributes to their internalization by antigen-presenting cells and thus modulates the processing of antigens and their subsequent presentation to T cells. Of particular interest for the dissection of the effects of IVIg in antibody-mediated autoimmune diseases, is the role of nAAbs in the maintenance of cellular homeostasis, in preventing the expansion of specific autoreactive clones, and in the ability of nAAbs to regulate self-reactivity. There is little information on direct demonstration of the functions of natural antibodies. However, most of the functions that have been attributed to the natural antibodies are deduced from the wide range of observed effects of IVIg when administered to patients with autoimmune and inflammatory situations. 4. Effect of IVIg Several mutually non-exclusive mechanisms have been proposed to account for the beneficial effects of IVIg, that may indeed reflect
793
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. High dose IVIg may also implicate saturation of FcRn leading to an increased clearance of pathogenic autoantibodies resulting in decreased serum levels [22]. Initial observations of the dramatic drop in the titer of pathogenic autoantibodies suggested that IVIg contains anti-idiotypic antibodies that can neutralize the activity of pathogenic autoantibodies and hence believed to contribute to therapeutic effect observed in several antibody-dependent pathologies. Among other mechanisms proposed were inhibition of complement-mediated cellular damage by blocking the generation of C5b-9 membrane attack complex, scavenging active complement components (C3b and C4b) and diverting complement attack from cellular targets [23]. Subsequent studies have highlighted the importance of the interaction of IVIg with the cellular compartment to exert antiinflammatory 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. IVIg suppresses the activation of monocytes and macrophages by modulating transcription of various inflammatory genes and lowers circulating levels of monocyte or macrophage inflammatory cytokines, TNF-α and IL-1β, while selectively up-regulating the antiinflammatory cytokine, IL-1Ra. IVIg preparations contain antibodies against cytokines including GM-CSF, IFN-γ, TNF-α and BAFF/APRIL that can potentially exert inhibitory effect on their effector functions [24]. At the B cell level, IVIg suppresses the expansion of autoreactive B-lymphocytes and production of pathogenic autoantibodies and cytokines, causes cell cycle arrest at G(1) phase and induces B cell apoptosis [25–29]. High-dose IVIg inhibits the differentiation and maturation of human DC [30] while imposing on them a tolerogenic phenotype. Further, IVIg can expand CD4+CD25+Foxp3+ regulatory T cells (Tregs). Following the in vitro observations that IVIg increases the TGFβ + IL-10+ Foxp3+ Tregs by the group of Shoenfeld [31], we showed that IVIg expands Tregs in vivo. Thus, IVIg-mediated protection of C57BL/6J mice from experimental autoimmune encephalomyelitis is associated with early expansion of CD4+CD25+Foxp3+ regulatory T cells [32] and is also confirmed in patients with autoimmune diseases [33]. We further showed that IVIg inhibits the differentiation and amplification of human Th17 cells, as well as the production of their effector cytokines IL-17A, IL-17F, IL-21 and CCL20. The inhibitory effects of IVIg on Th17 cells involve interference with the expression of transcription factor RORC and activation of STAT3 [34,35]. Since the year 2001, the group of Ravetch has underlined the role of FcγRIIB on macrophages as a major pathway of anti-inflammatory effect of IVIg [36]. Thus, human IgG with α2,6-linkage of sialic acid to galactose on the glycan at Asn297 in the CH2 region of Fc fragment appears to be the active component of IVIg. By using humanized DCSIGN mouse model, they have further shown that sialylated Fc interacts with DC-SIGN on marginal zone “regulatory macrophages” of the spleen, which secrete IL-33. IL-33 then stimulates basophils to produce IL-4, which then signals the effector macrophages to up-regulate the expression of FcγRIIB resulting in anti-inflammatory effects [37]. Although a significant progress has been made in the exploration of the mechanisms of action of IVIg in autoimmune and inflammatory conditions, this therapeutic preparation remains a mystery. Incidentally, the exciting area of investigation of the mechanisms of IVIg has also allowed unraveling the role of natural antibodies not merely in the first line of defense against microbes and microbial toxins, but also as a potent and incessant biological response modifier.
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S.V. Kaveri / Autoimmunity Reviews 11 (2012) 792–794
Take-home messages • Antibodies present in healthy conditions in the absence of deliberate immunization or infections are called natural antibodies. • Human serum contains natural IgG, IgM and IgA antibodies. • Natural antibodies are produced by the B-1 subset of B cells. • Although the precise functions of natural antibodies are not fully elucidated, they are believed to play an important role in maintaining immune homeostasis. • IVIg is a therapeutic preparation used in the treatment of autoimmune and inflammatory conditions consisting essentially natural antibodies of IgG subclass. • The beneficial effects of IVIg may be related to its ability to interact with both innate and adaptive compartment of the immune system.
References [1] Kazatchkine MD, Kaveri SV. Immunomodulation of autoimmune and inflammatory diseases with normal polyspecific human IgG (Intravenous Immunoglobulin, IVIg). N Engl J Med 2001;345:747–55. [2] Bayry J, Negi VS, Kaveri SV. Intravenous immunoglobulin therapy in rheumatic diseases. Nat Rev Rheumatol 2011;7:349–59. [3] Katz U, Achiron A, Sherer Y, Shoenfeld Y. Safety of intravenous immunoglobulin (IVIG) therapy. Autoimmun Rev 2007;6:257–9. [4] Galeotti C, Bayry J, Kone-Paut I, Kaveri SV. Kawasaki disease: aetiopathogenesis and therapeutic utility of intravenous immunoglobulin. Autoimmun Rev 2010;9:441–8. [5] Danieli MG, Pettinari L, Moretti R, Logullo F, Gabrielli A. Subcutaneous immunoglobulin in polymyositis and dermatomyositis: a novel application. Autoimmun Rev 2011;10: 144–9. [6] Seite JF, Shoenfeld Y, Youinou P, Hillion S. What is the contents of the magic draft IVIg? Autoimmun Rev 2008;7:435–9. [7] Avrameas S. Natural autoantibodies: from ‘horror autotoxicus’ to ‘gnothi seauton’. Immunol Today 1991;12:154–9. [8] Hayakawa K, Asano M, Shinton SA, Gui M, Allman D, Stewart CL, et al. Positive selection of natural autoreactive B cells. Science 1999;285:113–6. [9] Conrad K, Bachmann MP, Matsuura E, Shoenfeld Y. From animal models to human genetics: research on the induction and pathogenicity of autoantibodies. Autoimmun Rev 2005;4:178–87. [10] Mackenzie LE, Youinou PY, Hicks R, Yuksel B, Mageed RA, Lydyard PM. Auto- and polyreactivity of IgM from CD5+ and CD5− cord blood B cells. Scand J Immunol 1991;33:329–35. [11] Griffin DO, Holodick NE, Rothstein TL. Human B1 cells in umbilical cord and adult peripheral blood express the novel phenotype CD20+ CD27+ CD43+ CD70. J Exp Med 2011;208:67–80. [12] Coutinho A, Kazatchkine MD, Avrameas S. Natural autoantibodies. Curr Opin Immunol 1995;7:812–8. [13] Bendtzen K, Hansen MB, Ross C, Svenson M. High-avidity autoantibodies to cytokines. Immunol Today 1998;19:209–11. [14] Adib-Conquy M, Gilbert M, Avrameas S. Effect of amino acid substitutions in the heavy chain CDR3 of an autoantibody on its reactivity. Int Immunol 1998;20:341–6. [15] Casali P, Prabhakar BS, Notkins AL. Characterization of multireactive autoantibodies and identification of Leu-1+ B lymphocytes as cells making antibodies binding multiple self and exogenous molecules. Int Rev Immunol 1988;3:17–45. [16] Hurez V. Polyreactivity is a property of natural and disease associated human antibodies. Scand J Immunol 1993;38:190–6.
[17] Dietrich G, Kazatchkine MD. Normal immunoglobulin G (IgG) for therapeutic use (intravenous Ig) contain antiidiotypic specificities against an immunodominant, disease-associated, cross-reactive idiotype of human anti-thyroglobulin autoantibodies. J Clin Invest 1990;85:620–5. [18] Lacroix-Desmazes S, Moreau A, Sooryanarayana, Bonnemain C, Stieltjes N, Pashov A. Catalytic activity of antibodies against factor VIII in patients with hemophilia A. Nat Med 1999;5:1044–7. [19] Li L, Paul S, Tyutyulkova S, Kazatchkine M, Kaveri S. Catalytic activity of anti-thyroglobulin antibodies. J Immunol 1995;154:3328–32. [20] Lacroix-Desmazes S, Kaveri SV, Mouthon L, Ayouba A, Malanchère E, Coutinho A, et al. Self-reactive antibodies (Natural Autoantibodies) in healthy individuals. J Immunol Methods 1998;216:117–37. [21] Kalaga R, Li L, O'Dell JR, Paul S. Unexpected presence of polyreactive catalytic antibodies in IgG from unimmunized donors and decreased levels in rheumatoid arthritis. J Immunol 1995;155:2695–702. [22] Roopenian DC, Akilesh S. FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol 2007;7:715–25. [23] Durandy A, Kaveri SV, Kuijpers TW, Basta M, Miescher S, Ravetch JV, et al. Intravenous immunoglobulins—understanding properties and mechanisms. Clin Exp Immunol 2009;158(Suppl 1):2–13. [24] Le Pottier L, Bendaoud B, Dueymes M, Daridon C, Youinou P, Shoenfeld Y, et al. BAFF, a new target for intravenous immunoglobulin in autoimmunity and cancer. J Clin Immunol 2007;27:257–65. [25] Tha-In T, Bayry J, Metselaar HJ, Kaveri SV, Kwekkeboom J. Modulation of the cellular immune system by intravenous immunoglobulin. Trends Immunol 2008;29: 608–15. [26] Seite JF, Cornec D, Renaudineau Y, Youinou P, Mageed RA, Hillion S. IVIg modulates BCR signaling through CD22 and promotes apoptosis in mature human B lymphocytes. Blood 2010;116:1698–704. [27] Bayry J, Fournier EM, Maddur MS, Vani J, Wootla B, Siberil S, et al. Intravenous immunoglobulin induces proliferation and immunoglobulin synthesis from B cells of patients with common variable immunodeficiency: a mechanism underlying the beneficial effect of IVIg in primary immunodeficiencies. J Autoimmun 2011;36: 9–15. [28] Seite JF, Guerrier T, Cornec D, Jamin C, Youinou P, Hillion S. TLR9 responses of B cells are repressed by intravenous immunoglobulin through the recruitment of phosphatase. J Autoimmun 2011;37:190–7. [29] Maddur MS, Hegde P, Sharma M, Kaveri SV, Bayry J. B cells are resistant to immunomodulation by ‘IVIg-educated’ dendritic cells. Autoimmun Rev 2011;11:154–6. [30] Bayry J, Lacroix-Desmazes S, Carbonneil C, Misra N, Donkova V, Pashov A, et al. Inhibition of maturation and function of dendritic cells by intravenous immunoglobulin. Blood 2003;101:758–65. [31] Kessel A, Ammuri H, Peri R, Pavlotzky ER, Blank M, Shoenfeld Y, et al. Intravenous immunoglobulin therapy affects T regulatory cells by increasing their suppressive function. J Immunol 2007;179:5571–5. [32] Ephrem A, Chamat S, Miquel C, Fisson S, Mouthon L, Caligiuri G, et al. Expansion of CD4+CD25+ regulatory T cells by intravenous immunoglobulin: a critical factor in controlling experimental autoimmune encephalomyelitis. Blood 2008;111: 715–22. [33] Bayry J, Mouthon L, Kaveri SV. Intravenous immunoglobulin expands regulatory T cells in autoimmune rheumatic patients. J Rheumatol 2012;39:450–1. [34] Maddur MS, Vani J, Hegde P, Lacroix-Desmazes S, Kaveri SV, Bayry J. Inhibition of differentiation, amplification, and function of human TH17 cells by intravenous immunoglobulin. J Allergy Clin Immunol 2011;127:823–30 e1-7. [35] Maddur MS, Kaveri SV, Bayry J. Comparison of different IVIg preparations on IL-17 production by human Th17 cells. Autoimmun Rev 2011;10:809–10. [36] Nimmerjahn F, Ravetch JV. Anti-inflammatory actions of intravenous immunoglobulin. Annu Rev Immunol 2008;26:513–33. [37] Anthony RM, Kobayashi T, Wermeling F, Ravetch JV. Intravenous gammaglobulin suppresses inflammation through a novel T(H)2 pathway. Nature 2011;475: 110–3.
Vitamin D deficiency, atherosclerosis and systemic lupus erythematosus Biologic effects of Vitamin D extend far beyond the control of calcium metabolism. Data from observational, cross-sectional and longitudinal studies suggest that vitamin D insufficiency is associated with coronary heart disease, hypertension, diabetes, heart failure and peripheral atherosclerosis. Vitamin D deficiency is more common in patients affected with systemic lupus erythematosus (SLE) compared with age and gender matched controls. Furthermore, Vitamin D deficiency is associated with increased lupus disease activity in some studies. Reynolds et al (Rheumatology 2012;51:544-51) in a cross-sectional study carried out in 75 SLE patients found that Vitamin D deficiency was associated with higher BMI and insulin resistance compared with those with normal Vitamin D serum levels (defined as 25(OH)D >20 ng/ml). Lower serum levels of 25(OH)D was also associated with increased aortic stiffness measured by aortic pulse wave velocity, independently from other CV risk factors, including insulin resistance. However, in the regression model the association was no longer significant when adjusted for SLE disease activity index (SLEDAI)-2000. Although Vitamin D deficiency is associated with vascular damage independently of traditional CV risk factors, it has to be taken into account that also SLE activity might play a relevant role in developing vascular stiffness in these patients. Further prospective interventional studies focused on the effect of vitamin D supplementation on disease activity and vascular damage in SLE patients are needed. Luca Iaccarino
Contents lists available at SciVerse ScienceDirect
Autoimmunity Reviews journal homepage: www.elsevier.com/locate/autrev
Review
Intravenous immunoglobulin: Exploiting the potential of natural antibodies Srini V. Kaveri ⁎ INSERM, U872, 15 rue de l'Ecole de Médicine, Paris, F-75006, France Centre de Recherche des Cordeliers, Equipe 16—Immunopathology and therapeutic immunointervention, Université Pierre et Marie Curie—Paris 6, UMR S 872, Paris, F-75006, France Université Paris Descartes, UMR S 872 Paris, F-75006, France International Associated Laboratory IMPACT (Institut National de la Santé et de la Recherche Médicale, France—Indian council of Medical Research, India), National Institute of Immunohaemotology, Mumbai, India
a r t i c l e
i n f o
a b s t r a c t Antibodies present in healthy conditions in the absence of deliberate immunization or infections are called natural antibodies. A significant proportion of natural antibody pool is believed to interact with self-antigens, and thus is called natural autoantibodies. Natural autoantibodies belong to IgG, IgM and IgA subclasses, and are encoded by V(D)J genes in germline configuration and bind to self molecules with varying affinities. In addition to serving in first line defense mechanism, natural antibodies participate in the homeostasis of the immune system. Intravenous immunoglobulin (IVIg) is a therapeutic preparation that contains substantial amount of natural antibodies exclusively of IgG subclass. In addition to its role in protection against pathogens in primary and secondary immunodeficiency patients, IVIg exerts a number of immunoregulatory functions through its interaction with innate and adaptive immune system and thereby imposing immune homeostasis. © 2012 Elsevier B.V. All rights reserved.
Available online 12 February 2012 Keywords: Natural antibodies Intravenous immunoglobulin Homeostasis
Contents 1. Introduction . . . . . . . . . 2. Origin of natural autoantibodies 3. Role of natural autoantibodies . 4. Effect of IVIg . . . . . . . . . Take-home messages . . . . . . . References. . . . . . . . . . . . .
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1. Introduction Initially conceived for the antibody replacement therapy of patients with primary immunodeficiency, intravenous immunoglobulin (IVIg) is now increasingly being used in the treatment of a large number of autoimmune and inflammatory diseases [1–5]. IVIg contains a broad spectrum of antibody specificities against bacterial, viral, parasitic, and mycoplasma antigens, that are capable of both opsonization and neutralization of microbes and toxins. The anti-microbial activity of IVIg is believed to be critical for the replacement therapy of patients with primary humoral immune deficiencies. However, natural antibodies also constitute integral components of IVIg. A significant fraction of natural antibody repertoire is suggested to be specific for a number of self-antigens, and is believed to be
⁎ INSERM U 872, Equipe 16-Centre de Recherche des Cordeliers, 15 rue de l'Ecole de Médicine, Paris, F-75006, France. Tel.: + 33 1 44 27 82 03; fax: + 33 1 44 27 81 94. E-mail address: [email protected]. 1568-9972/$ – see front matter © 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.autrev.2012.02.006
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792 792 793 793 794 794
essential for the immunoregulatory effects of IVIg in immunemediated disorders through establishing normal immune homeostasis [6]. In this brief essay as a tribute to the achievements of Pierre Youinou and his colleagues over the last few decades on the origin, nature and the function of natural antibodies, an overview on the importance of natural antibodies with a particular emphasis on the mechanisms of action of IVIg is provided.
2. Origin of natural autoantibodies Human serum in physiological situations contains antibodies of the IgG, IgM and IgA isotype. These antibodies are referred to as “natural” as they are produced in the absence of intentional immunization and independently of introduction of foreign antigens [7]. A major proportion of natural antibodies in the serum of healthy blood donors and, as a result in IVIg, are natural autoantibodies (nAAbs). Several independent studies support the claim that nAAbs are the products of positively selected autoreactive B cells [8]. nAAbs are
S.V. Kaveri / Autoimmunity Reviews 11 (2012) 792–794
encoded by germline, unmutated or minimal mutated, variable region genes, as opposed to antibodies that result from active immunization, the immune antibodies or antibodies that are associated with autoimmune pathologies, that are encoded by genes having undergone somatic hypermutation [9]. The evidence that nAAbs originate from a distinct subset of human B cells remains controversial. Although it was believed that nAABs are generated by CD5+ B cells, studies by the groups of Youinou and Lydyard indicate that expression of surface CD5 on cord blood B cells is not a definitive marker of an auto/polyreactive population [10]. While in mice, CD5+ B-1 cells are considered as a source of natural IgM antibodies, their role in humans is debated, partly because CD5 may be an activation marker on human B cells. Further, recently CD20+CD27+CD43+ memory B cells have been identified as the human B1 cell equivalent [11]. It was generally believed that nAAbs display lower affinity and elevated avidity for autoantigens [12]. However, subsequent studies reported a wide range of affinity values with dissociating constants between 10 − 5 and 10 − 8 M [13–15]. Interestingly, nAAbs are more polyreactive than immune antibodies, in that they often recognize several antigens including a wide range of self-antigens. This has been clearly shown for anti-thyroglobulin autoantibodies [16]. Immune and disease-associated autoantibodies express idiotypes different from those borne by nAAbs of the same specificity. Thus, a majority of the patients with Hashimoto's thyroiditis express T44 idiotype on their anti-thyroglobulin autoantibodies while a negligible number of healthy individuals' anti-thyroglobulin autoantibodies displayed T44 idiotype [17]. In a series of interesting studies, it has been demonstrated that certain disease-associated autoantibodies exhibit an ability to hydrolyze target antigens as in the case of anti-DNA autoantibodies in lupus, anti-MBP antibodies in multiple sclerosis, anti-thyroglobulin autoantibodies in autoimmune thyroiditis, anti-Factor VIII autoantibodies in autoimmune hemophilia and others, whereas natural autoantibodies with the same specificities exhibit reduced or no catalytic activity [18,19]. 3. Role of natural autoantibodies Several functions have been proposed for nAAbs [20]. nAAbs neutralize microbes and microbial toxins as a consequence of their polyreactivity or cross-reactivity, strongly suggesting a role for nAAbs in natural host defense against infection. nAAbs contribute to the removal of senescent/altered self molecules, cells, and tumors, possibly by virtue of their ability to hydrolyze some of their target antigens. Indeed, it has been shown that antibodies from healthy individuals display a promiscuous hydrolytic activity, as opposed to more specific enzymatic activity of antigen-specific autoantibodies in patients with autoimmune diseases [21]. The binding of nAAbs to antigens contributes to their internalization by antigen-presenting cells and thus modulates the processing of antigens and their subsequent presentation to T cells. Of particular interest for the dissection of the effects of IVIg in antibody-mediated autoimmune diseases, is the role of nAAbs in the maintenance of cellular homeostasis, in preventing the expansion of specific autoreactive clones, and in the ability of nAAbs to regulate self-reactivity. There is little information on direct demonstration of the functions of natural antibodies. However, most of the functions that have been attributed to the natural antibodies are deduced from the wide range of observed effects of IVIg when administered to patients with autoimmune and inflammatory situations. 4. Effect of IVIg Several mutually non-exclusive mechanisms have been proposed to account for the beneficial effects of IVIg, that may indeed reflect
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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. High dose IVIg may also implicate saturation of FcRn leading to an increased clearance of pathogenic autoantibodies resulting in decreased serum levels [22]. Initial observations of the dramatic drop in the titer of pathogenic autoantibodies suggested that IVIg contains anti-idiotypic antibodies that can neutralize the activity of pathogenic autoantibodies and hence believed to contribute to therapeutic effect observed in several antibody-dependent pathologies. Among other mechanisms proposed were inhibition of complement-mediated cellular damage by blocking the generation of C5b-9 membrane attack complex, scavenging active complement components (C3b and C4b) and diverting complement attack from cellular targets [23]. Subsequent studies have highlighted the importance of the interaction of IVIg with the cellular compartment to exert antiinflammatory 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. IVIg suppresses the activation of monocytes and macrophages by modulating transcription of various inflammatory genes and lowers circulating levels of monocyte or macrophage inflammatory cytokines, TNF-α and IL-1β, while selectively up-regulating the antiinflammatory cytokine, IL-1Ra. IVIg preparations contain antibodies against cytokines including GM-CSF, IFN-γ, TNF-α and BAFF/APRIL that can potentially exert inhibitory effect on their effector functions [24]. At the B cell level, IVIg suppresses the expansion of autoreactive B-lymphocytes and production of pathogenic autoantibodies and cytokines, causes cell cycle arrest at G(1) phase and induces B cell apoptosis [25–29]. High-dose IVIg inhibits the differentiation and maturation of human DC [30] while imposing on them a tolerogenic phenotype. Further, IVIg can expand CD4+CD25+Foxp3+ regulatory T cells (Tregs). Following the in vitro observations that IVIg increases the TGFβ + IL-10+ Foxp3+ Tregs by the group of Shoenfeld [31], we showed that IVIg expands Tregs in vivo. Thus, IVIg-mediated protection of C57BL/6J mice from experimental autoimmune encephalomyelitis is associated with early expansion of CD4+CD25+Foxp3+ regulatory T cells [32] and is also confirmed in patients with autoimmune diseases [33]. We further showed that IVIg inhibits the differentiation and amplification of human Th17 cells, as well as the production of their effector cytokines IL-17A, IL-17F, IL-21 and CCL20. The inhibitory effects of IVIg on Th17 cells involve interference with the expression of transcription factor RORC and activation of STAT3 [34,35]. Since the year 2001, the group of Ravetch has underlined the role of FcγRIIB on macrophages as a major pathway of anti-inflammatory effect of IVIg [36]. Thus, human IgG with α2,6-linkage of sialic acid to galactose on the glycan at Asn297 in the CH2 region of Fc fragment appears to be the active component of IVIg. By using humanized DCSIGN mouse model, they have further shown that sialylated Fc interacts with DC-SIGN on marginal zone “regulatory macrophages” of the spleen, which secrete IL-33. IL-33 then stimulates basophils to produce IL-4, which then signals the effector macrophages to up-regulate the expression of FcγRIIB resulting in anti-inflammatory effects [37]. Although a significant progress has been made in the exploration of the mechanisms of action of IVIg in autoimmune and inflammatory conditions, this therapeutic preparation remains a mystery. Incidentally, the exciting area of investigation of the mechanisms of IVIg has also allowed unraveling the role of natural antibodies not merely in the first line of defense against microbes and microbial toxins, but also as a potent and incessant biological response modifier.
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Take-home messages • Antibodies present in healthy conditions in the absence of deliberate immunization or infections are called natural antibodies. • Human serum contains natural IgG, IgM and IgA antibodies. • Natural antibodies are produced by the B-1 subset of B cells. • Although the precise functions of natural antibodies are not fully elucidated, they are believed to play an important role in maintaining immune homeostasis. • IVIg is a therapeutic preparation used in the treatment of autoimmune and inflammatory conditions consisting essentially natural antibodies of IgG subclass. • The beneficial effects of IVIg may be related to its ability to interact with both innate and adaptive compartment of the immune system.
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Vitamin D deficiency, atherosclerosis and systemic lupus erythematosus Biologic effects of Vitamin D extend far beyond the control of calcium metabolism. Data from observational, cross-sectional and longitudinal studies suggest that vitamin D insufficiency is associated with coronary heart disease, hypertension, diabetes, heart failure and peripheral atherosclerosis. Vitamin D deficiency is more common in patients affected with systemic lupus erythematosus (SLE) compared with age and gender matched controls. Furthermore, Vitamin D deficiency is associated with increased lupus disease activity in some studies. Reynolds et al (Rheumatology 2012;51:544-51) in a cross-sectional study carried out in 75 SLE patients found that Vitamin D deficiency was associated with higher BMI and insulin resistance compared with those with normal Vitamin D serum levels (defined as 25(OH)D >20 ng/ml). Lower serum levels of 25(OH)D was also associated with increased aortic stiffness measured by aortic pulse wave velocity, independently from other CV risk factors, including insulin resistance. However, in the regression model the association was no longer significant when adjusted for SLE disease activity index (SLEDAI)-2000. Although Vitamin D deficiency is associated with vascular damage independently of traditional CV risk factors, it has to be taken into account that also SLE activity might play a relevant role in developing vascular stiffness in these patients. Further prospective interventional studies focused on the effect of vitamin D supplementation on disease activity and vascular damage in SLE patients are needed. Luca Iaccarino