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Autoantibodies in Therapeutic Preparations of Human Intravenous Immunoglobulin (IVIg)
CHAPTER
Autoantibodies in Therapeutic Preparations of Human Intravenous Immunoglobulin (IVIg)
36
Veerupaxagouda Patil,1,2,3 Jagadeesh Bayry,1,2,3,4 Sébastien Lacroix-Desmazes,1,2,3,4 Michel D Kazatchkine,5 and Srini V Kaveri,1,2,3,4 1Institut
National de la Santé et de la Recherche Médicale Unité 872, Paris, France, de Recherche des Cordeliers, Unité Mixte de Recherche-Santé 872, Université Pierre et Marie Curie-Paris 6, Paris, France, 3Unité Mixte de Recherche-Santé 872, Université Paris Descartes, Paris, France, 4International Associated Laboratory IMPACT (Institut National de la Santé et de la Recherche Médicale, France – Indian Council of Medical Research, India), National Institute of Immunohaematology, Mumbai, India, 5UNAIDS 20, Geneva, Switzerland 2Centre
Historical notes The term intravenous immunoglobulin (IVIg) refers to the polyclonal antibody (IgG) prepared from the plasma pools from several thousand healthy human donors. Initially, IVIg was used for the treatment of primary and secondary antibody deficiencies. However, the beneficial thrombocytotic effect of IVIg in Wiskott-Aldrich syndrome led to its therapeutic use in idiopathic thrombopenic purpura (ITP). The successful result in ITP further paved the way for widespread application of IVIg in a variety of autoimmune and inflammatory disorders. The beneficial effects of IVIg are attributed to the complex mechanisms of action, in a mutually nonexclusive way. These mechanisms include Fc receptor-mediated effects, attenuation of complement-mediated damage, modulation of cytokine production, neutralization of pathogenic autoantibodies, and the regulation of autoreactive B-cell clones by anti-idiotype antibodies, modulation of cellular compartment including monocytes, dendritic cells, natural killer (NK) cells, neutrophils, and B and T lymphocytes [1,2]. IVIg comprises intact IgG molecules and also contains trace amounts of soluble CD4, CD8, HLA molecules, and certain cytokines. The major fraction of IVIg is the monomeric IgG. However, dimeric IgG molecules containing idiotype (Id)/anti-Id complexes may also participate in mediating the beneficial therapeutic effects. It is now well established that IVIg also contains naturally occurring autoantibodies (NAbs) that recognize molecules relevant in immune regulation. In this chapter, we summarize the findings on the role of NAbs that exist in IVIg pools (Table 36.1). NAbs with germline or close to germline configurations exhibit specificities to self- and altered selfcomponents, in the absence of deliberate immunization with a target antigen. Furthermore, NAbs are believed to be polyreactive, low-titer, low-affinity but high-avidity antibodies that mediate tissue homeostatic roles and modulate cellular and enzyme properties (Fig. 36.1) [1,2]. Autoantibodies. http://dx.doi.org/10.1016/B978-0-444-56378-1.00036-8 Copyright © 2014 Elsevier B.V. All rights reserved.
305
306
CHAPTER 36 Autoantibodies in Therapeutic Preparations of Human IVIg
Table 36.1 The List of Some of the Examples of Naturally Occurring Antibodies in Intravenous Immunoglobulins S.l. no. 1.
2. 3.
4.
Name of Naturally Occurring Antibodies NAbs to Ids of a. Anti-DNA antibody, b. antithyroglobulin, c. anti-intrinsic factor, d. antimicrosomal IgG and anti-GM IgG antibodies Anti-CD5 antibody Anti-CCR5 antibody
5.
Anti-GM-CSF and Anti-B-cell activating factor (BAFF) Anti-HLA I antibody
6. 7. 8. 9.
Anti-Fas antibody Anti-RGD antibody Anti-HSP90 antibody Anti-Aβ antibody
10.
Anti-TCR antibody
11.
Anti-CD40 antibody
Possible Function/Mode of Action Prevent the interaction of pathogenic autoantibodies with its cognate antigen
Immunomodulation of T and B cells Prevent the infection of macrophages/ monocytes and lymphocytes by R5 tropic HIV-1 strains Modulate the half-life and transport cytokines Immunomodulation of class I restricted cellular interactions Induction of T- and B-cell apoptosis Immunomodulation and anti-inflammatory effect Shape the natural self-reactive B-cell repertoires Inhibit fibrillation, toxicity of β-amyloid and improve cognition in a transgenic mouse model Regulators of T cells, possibly through expansion of the regulatory T cells Sustain differentiation and maturation of human dendritic cells
FIGURE 36.1 Naturally occurring autoantibodies (NAbs) maintain immune/tissue homeostasis. The figure shows a diverse repertoire of functions mediated by NAbs under a variety of settings.
Maintenance of immune/tissue homeostasis
307
Maintenance of immune/tissue homeostasis Idiotype (Id)/anti-Id functional network The expansion and expression of autoreactive clones are regulated by anti-Id antibodies. Commercially available preparations of IVIg have been found to be the source of a variety of anti-idiotype antibodies against other disease-associated autoantibodies. Notable ones are those against the Id of anti-deoxyribonucleic acid (DNA), anti thyroglobulin IgG, anti-acetylcholine receptor, anti-intrinsic factor autoantibodies, antimicrosomal IgG, and anti-Ganglioside M1 (GM1) IgG [2]. These antibodies block the interaction of pathogenic autoantibodies with their antigens and may downregulate autoantibody-producing B cells.
Immunomodulation The beneficial effects of IVIg could be attributed to several NAbs that exert functional immunomodulation of cells of the immune system. This is dependent on the ability of variable regions of therapeutic IgG to interact with both membrane and soluble molecules of the immune system. Thymocytes, mature T lymphocytes, and a subpopulation of autoantibody generating B cells (CD20+, B-1) express CD5 on the cell surface. Furthermore, CD5+ B-cell number is substantially higher in rheumatoid arthritis, systemic lupus erythematosus, Sjögren syndrome, and chronic lymphocytic leukemia. Anti-CD5 NAbs that might functionally modulate T and CD5+ B cells have been characterized in IVIg [2]. Major histocompatibility complex (MHC) molecules are involved with the presentation of antigenic peptides to T cells. MHC class I molecules are made up of polymorphic α heavy chain and an invariant β2 microglobulin chain. The antigen peptide binding site consists of two homologous α1 and α2 segments of ∼90 amino acids at the amino terminus of the α chain. Synthetic peptides originating from the conserved regions of α1 helix have been reported to block the differentiation of human cytotoxic lymphocyte (CTL) precursors in a nonallele-restricted fashion in vitro. IVIg contains antibodies that recognize a 10-amino acid peptide derived from a highly conserved region of the α1 helix of human class I molecules [3]. These antibodies were shown to block the class-I restricted T-cell-mediated cytotoxicity, and they might be important for the immunomodulatory effects of IVIg in autoimmunity and transplantation. Impaired homeostasis of cellular turnover (cell proliferation or apoptosis) is associated with several experimental and human autoimmune diseases and inflammatory and lymphoproliferative disorders. The therapeutic effect of IVIg in the above-mentioned settings could be at least in part attributed to the presence of agonistic antibodies to Fas [4]. IVIg-mediated apoptosis involves the initiation of the pathway by activation of caspases and the consequent Bcl2 phosphorylation. IVIg, however, also contains antagonistic anti-Fas antibodies that block the Fas-mediated apoptosis. Divalent cation-dependent cell–cell and cell–matrix interactions are mediated by a class of conserved cell-surface glycoproteins known as integrins. They carry out both signaling and adhesive functions. Most of the integrins display affinity towards the Arg-Gly-Asp (RGD) recognition sequence in their extracellular matrix ligand and could discriminate different proteins with RGD sequence. AntiRGD NAbs have been identified [5], and they block the integrin-dependent platelet aggregation and the adhesion of B cells to fibronectin. These antibodies might be of relevance for anti-inflammatory and immunomodulatory effects of IVIg. Human heat shock proteins (HSP) represent conserved self-antigens and share significant structural homology with their bacterial counterparts. HSP90 is an immune-dominant antigen that is recognized
308
CHAPTER 36 Autoantibodies in Therapeutic Preparations of Human IVIg
by autoantibodies from both healthy individuals and patients with autoimmune diseases. The presence of anti-HSP90 NAbs in IVIg [6] supports the hypothesis that conserved epitopes of HSP90 might shape the natural self-reactive B-cell repertoires. Understanding the mechanisms of recognition of other highly conserved self-antigens by NAbs may lead to novel immunomodulation strategies to a variety of autoimmune disorders.
Naturally occurring antibodies that prevent infection NAbs are predominant players in the first line of defense against microbial infections. Most of the reports have attributed this role to NAbs of the IgM isotype. However, studies performed using IVIg have provided strong evidence for the anti-infectious capacity of NAbs of the IgG isotype. IVIg contains NAbs against several cell surface molecules, including CD4, the beta-chemokine (CC) receptor CCR5 (CD195), and the dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin molecule (DC-SIGN, CD209). CD209 is implicated in the attachment and transmission of HIV from dendritic cells to T lymphocytes. The chemokine receptors CXCR4 and CCR5 are the major coreceptors for T lymphocyte and macrophage tropic HIV-1 isolates referred to as X4 and R5 isolates, respectively. The majority of the sexually transmitted human immunodeficiency virus (HIV) infections are caused by R5 isolates. These chemokine receptors serve as attractive targets to block the entry of the virus and the infection of lymphocytes and macrophages. NAbs to CCR5 coreceptor for HIV-1 have been characterized [2], and they inhibited the infection lymphocytes and macrophages with primary R5 and laboratory-adapted strains of HIV-1.
Naturally occurring antibodies that prevent inflammation Cytokines play a crucial role in the maintenance of homeostasis, and they function in a complex network of agonists and antagonists. NAbs to a variety of cytokines have been identified and characterized in IVIg and they have been found to possess effective and specific regulatory roles. Notable examples include NAbs to granulocyte-macrophage colony stimulating factor and the BAFF (B-cell-activating factor of the TNF family) [2]. Anticytokine NAbs regulate the half-life of the cytokines and some of the NAbs might also be involved with the transport of cytokines. The physiologic role of these anticytokine antibodies is not fully appreciated at present. They might provide a novel layer of regulation and mediate the anti-inflammatory effect of IVIg. Neurodegenerative diseases are characterized by inflammation and dysfunction due to the aggregation and deposition of misfolded proteins or peptides. NAbs to patterns generated by the abovedescribed misfolded fibrillar or aggregated proteins have been identified. These NAbs specifically recognize fibrils formed from light chains, amyloidogenic precursor proteins, including serum amyloid A, transthyretin, and amyloid beta 1-40 peptide (Abeta40) in fibrillar forms but not their native nonfibrillar forms. The current hypothesis suggests that these anti-Abeta NAbs can inhibit fibrillation and toxicity of β-amyloid and improve cognition in a transgenic mouse model. These findings have led to a phase III clinical study using IVIg [7]. IgG from IVIg also binds to the T cell receptor (TCR) in the complementary determining region 1 of the TCR β chain. It has been proposed that NAbs against the TCR serve as regulators of T cells, possibly through expanding the regulatory T cells [8].
References
309
Another study has documented the presence of anti-BAFF and anti-APRIL (a proliferation-inducing ligand) NAbs in IVIg. These can neutralize the functional role of BAFF in B-cell survival. These antiBAFF NAbs may rectify the damaging effects of BAFF in B-cell-mediated autoimmune diseases [9]. Monocytes act as precursors for dendritic cells or macrophages. Dendritic cells are the professional antigen-presenting cells that are important for both T-cell activation and tolerance. The factors that mediate the differentiation and maturation of dendritic cells are not fully understood. Monocytes and dendritic cells circulate in the peripheral blood that is rich in NAbs. Anti-CD40 NAbs have been shown to sustain the differentiation and maturation of human dendritic cells. It is noteworthy that the signaling by NAbs does not trigger interleukin (IL)-12 production and, thus, does not lead to Th1 differentiation by default. Therefore, under steady-state conditions, NAbs might induce the maturation of dendritic cells without increasing their immunostimulatory capacity [10]. The above-described developments in the field of IVIg therapy indicate that NAbs operate by different mechanisms under different settings. Furthermore, at any given time, not all the NAbs of IVIg are equally active functionally. It is also possible that many of the above-described mechanisms might operate simultaneously in vivo. How do these NAbs operate functionally under different conditions and how are they regulated? What are the functionally active NAbs in different settings? Answers to these questions would unlock the immense therapeutic potential of IVIg and rationalize its usage.
Clinical utilities 1. I VIg is an important therapeutic option for autoimmune and inflammatory diseases. 2. Dissecting the mechanisms of action of NAbs is of importance for IVIg therapy. 3. Understanding which Nab(s) of IVIg bring about the therapeutic effect under different settings would help clinicians and researchers to design focused therapies by antibody engineering.
Take-home messages 1. 2. 3. 4. 5.
I VIg comprises pooled IgG from healthy donors. The polyreactive, low-titer, low-affinity but high-avidity NAbs are part of the composition of IVIg. NAbs that recognize molecules of relevance for immune regulation have been identified in IVIg. NAbs play a significant role in maintaining tissue and immune homeostasis. Understanding the mechanisms by which NAbs operate under different settings will help in improving IVIg therapy.
References [1] Kazatchkine MD, Kaveri SV. Immunomodulation of autoimmune and inflammatory diseases with intravenous immune globulin. N Engl J Med 2001;345:747–55. [2] Seite JF, Shoenfeld Y, Youinou P, Hillion S. What is the contents of the magic draft IVIg? Autoimmun Rev 2008;7:435–9.
310
CHAPTER 36 Autoantibodies in Therapeutic Preparations of Human IVIg
[3] Kaveri S, Vassilev T, Hurez V, Lengagne R, Lefranc C, Cot S, et al. 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. J Clin Invest 1996;97:865–9. [4] Prasad NK, Papoff G, Zeuner A, Bonnin E, Kazatchkine MD, Ruberti G, et al. Therapeutic preparations of normal polyspecific IgG (IVIg) induce apoptosis in human lymphocytes and monocytes: a novel mechanism of action of IVIg involving the Fas apoptotic pathway. J Immunol 1998;161:3781–90. [5] Vassilev TL, Kazatchkine MD, Duong Van Huyen JP, Mekrache M, Bonnin E, Mani JC, et al. Inhibition of cell adhesion by antibodies to Arg-Gly-Asp (RGD) in normal immunoglobulin for therapeutic use (intravenous immunoglobulin, IVIg). Blood 1999;93:3624–31. [6] Pashov A, Kenderov A, Kyurkchiev S, Kehayov I, Hristova S, Lacroix-Desmazes S, et al. Autoantibodies to heat shock protein 90 in the human natural antibody repertoire. Int Immunol 2002;14:453–61. [7] Bach JP, Dodel R. Naturally occurring autoantibodies against β-amyloid. Adv Exp Med Biol 2012;750:91–9. [8] Marchalonis JJ, Kaymaz H, Dedeoglu F, Schluter SF, Yocum DE, Edmundson AB. Human autoantibodies reactive with synthetic autoantigens from T-cell receptor beta chain. Proc Natl Acad Sci U S A 1992;89: 3325–9. [9] Le Pottier L, Bendaoud B, Dueymes M, Daridon C, Youinou P, Shoenfeld Y, et al. BAFF, a new target for IVIg in autoimmunity and cancer. J Clin Immunol 2007;27:257–65. [10] Bayry J, Lacroix-Desmazes S, Donkova-Petrini V, Carbonneil C, Misra N, Lepelletier Y, et al. Natural antibodies sustain differentiation and maturation of human dendritic cells. Proc Natl Acad Sci U S A 2004;101:14210–5.
Autoantibodies in Therapeutic Preparations of Human Intravenous Immunoglobulin (IVIg)
36
Veerupaxagouda Patil,1,2,3 Jagadeesh Bayry,1,2,3,4 Sébastien Lacroix-Desmazes,1,2,3,4 Michel D Kazatchkine,5 and Srini V Kaveri,1,2,3,4 1Institut
National de la Santé et de la Recherche Médicale Unité 872, Paris, France, de Recherche des Cordeliers, Unité Mixte de Recherche-Santé 872, Université Pierre et Marie Curie-Paris 6, Paris, France, 3Unité Mixte de Recherche-Santé 872, Université Paris Descartes, Paris, France, 4International Associated Laboratory IMPACT (Institut National de la Santé et de la Recherche Médicale, France – Indian Council of Medical Research, India), National Institute of Immunohaematology, Mumbai, India, 5UNAIDS 20, Geneva, Switzerland 2Centre
Historical notes The term intravenous immunoglobulin (IVIg) refers to the polyclonal antibody (IgG) prepared from the plasma pools from several thousand healthy human donors. Initially, IVIg was used for the treatment of primary and secondary antibody deficiencies. However, the beneficial thrombocytotic effect of IVIg in Wiskott-Aldrich syndrome led to its therapeutic use in idiopathic thrombopenic purpura (ITP). The successful result in ITP further paved the way for widespread application of IVIg in a variety of autoimmune and inflammatory disorders. The beneficial effects of IVIg are attributed to the complex mechanisms of action, in a mutually nonexclusive way. These mechanisms include Fc receptor-mediated effects, attenuation of complement-mediated damage, modulation of cytokine production, neutralization of pathogenic autoantibodies, and the regulation of autoreactive B-cell clones by anti-idiotype antibodies, modulation of cellular compartment including monocytes, dendritic cells, natural killer (NK) cells, neutrophils, and B and T lymphocytes [1,2]. IVIg comprises intact IgG molecules and also contains trace amounts of soluble CD4, CD8, HLA molecules, and certain cytokines. The major fraction of IVIg is the monomeric IgG. However, dimeric IgG molecules containing idiotype (Id)/anti-Id complexes may also participate in mediating the beneficial therapeutic effects. It is now well established that IVIg also contains naturally occurring autoantibodies (NAbs) that recognize molecules relevant in immune regulation. In this chapter, we summarize the findings on the role of NAbs that exist in IVIg pools (Table 36.1). NAbs with germline or close to germline configurations exhibit specificities to self- and altered selfcomponents, in the absence of deliberate immunization with a target antigen. Furthermore, NAbs are believed to be polyreactive, low-titer, low-affinity but high-avidity antibodies that mediate tissue homeostatic roles and modulate cellular and enzyme properties (Fig. 36.1) [1,2]. Autoantibodies. http://dx.doi.org/10.1016/B978-0-444-56378-1.00036-8 Copyright © 2014 Elsevier B.V. All rights reserved.
305
306
CHAPTER 36 Autoantibodies in Therapeutic Preparations of Human IVIg
Table 36.1 The List of Some of the Examples of Naturally Occurring Antibodies in Intravenous Immunoglobulins S.l. no. 1.
2. 3.
4.
Name of Naturally Occurring Antibodies NAbs to Ids of a. Anti-DNA antibody, b. antithyroglobulin, c. anti-intrinsic factor, d. antimicrosomal IgG and anti-GM IgG antibodies Anti-CD5 antibody Anti-CCR5 antibody
5.
Anti-GM-CSF and Anti-B-cell activating factor (BAFF) Anti-HLA I antibody
6. 7. 8. 9.
Anti-Fas antibody Anti-RGD antibody Anti-HSP90 antibody Anti-Aβ antibody
10.
Anti-TCR antibody
11.
Anti-CD40 antibody
Possible Function/Mode of Action Prevent the interaction of pathogenic autoantibodies with its cognate antigen
Immunomodulation of T and B cells Prevent the infection of macrophages/ monocytes and lymphocytes by R5 tropic HIV-1 strains Modulate the half-life and transport cytokines Immunomodulation of class I restricted cellular interactions Induction of T- and B-cell apoptosis Immunomodulation and anti-inflammatory effect Shape the natural self-reactive B-cell repertoires Inhibit fibrillation, toxicity of β-amyloid and improve cognition in a transgenic mouse model Regulators of T cells, possibly through expansion of the regulatory T cells Sustain differentiation and maturation of human dendritic cells
FIGURE 36.1 Naturally occurring autoantibodies (NAbs) maintain immune/tissue homeostasis. The figure shows a diverse repertoire of functions mediated by NAbs under a variety of settings.
Maintenance of immune/tissue homeostasis
307
Maintenance of immune/tissue homeostasis Idiotype (Id)/anti-Id functional network The expansion and expression of autoreactive clones are regulated by anti-Id antibodies. Commercially available preparations of IVIg have been found to be the source of a variety of anti-idiotype antibodies against other disease-associated autoantibodies. Notable ones are those against the Id of anti-deoxyribonucleic acid (DNA), anti thyroglobulin IgG, anti-acetylcholine receptor, anti-intrinsic factor autoantibodies, antimicrosomal IgG, and anti-Ganglioside M1 (GM1) IgG [2]. These antibodies block the interaction of pathogenic autoantibodies with their antigens and may downregulate autoantibody-producing B cells.
Immunomodulation The beneficial effects of IVIg could be attributed to several NAbs that exert functional immunomodulation of cells of the immune system. This is dependent on the ability of variable regions of therapeutic IgG to interact with both membrane and soluble molecules of the immune system. Thymocytes, mature T lymphocytes, and a subpopulation of autoantibody generating B cells (CD20+, B-1) express CD5 on the cell surface. Furthermore, CD5+ B-cell number is substantially higher in rheumatoid arthritis, systemic lupus erythematosus, Sjögren syndrome, and chronic lymphocytic leukemia. Anti-CD5 NAbs that might functionally modulate T and CD5+ B cells have been characterized in IVIg [2]. Major histocompatibility complex (MHC) molecules are involved with the presentation of antigenic peptides to T cells. MHC class I molecules are made up of polymorphic α heavy chain and an invariant β2 microglobulin chain. The antigen peptide binding site consists of two homologous α1 and α2 segments of ∼90 amino acids at the amino terminus of the α chain. Synthetic peptides originating from the conserved regions of α1 helix have been reported to block the differentiation of human cytotoxic lymphocyte (CTL) precursors in a nonallele-restricted fashion in vitro. IVIg contains antibodies that recognize a 10-amino acid peptide derived from a highly conserved region of the α1 helix of human class I molecules [3]. These antibodies were shown to block the class-I restricted T-cell-mediated cytotoxicity, and they might be important for the immunomodulatory effects of IVIg in autoimmunity and transplantation. Impaired homeostasis of cellular turnover (cell proliferation or apoptosis) is associated with several experimental and human autoimmune diseases and inflammatory and lymphoproliferative disorders. The therapeutic effect of IVIg in the above-mentioned settings could be at least in part attributed to the presence of agonistic antibodies to Fas [4]. IVIg-mediated apoptosis involves the initiation of the pathway by activation of caspases and the consequent Bcl2 phosphorylation. IVIg, however, also contains antagonistic anti-Fas antibodies that block the Fas-mediated apoptosis. Divalent cation-dependent cell–cell and cell–matrix interactions are mediated by a class of conserved cell-surface glycoproteins known as integrins. They carry out both signaling and adhesive functions. Most of the integrins display affinity towards the Arg-Gly-Asp (RGD) recognition sequence in their extracellular matrix ligand and could discriminate different proteins with RGD sequence. AntiRGD NAbs have been identified [5], and they block the integrin-dependent platelet aggregation and the adhesion of B cells to fibronectin. These antibodies might be of relevance for anti-inflammatory and immunomodulatory effects of IVIg. Human heat shock proteins (HSP) represent conserved self-antigens and share significant structural homology with their bacterial counterparts. HSP90 is an immune-dominant antigen that is recognized
308
CHAPTER 36 Autoantibodies in Therapeutic Preparations of Human IVIg
by autoantibodies from both healthy individuals and patients with autoimmune diseases. The presence of anti-HSP90 NAbs in IVIg [6] supports the hypothesis that conserved epitopes of HSP90 might shape the natural self-reactive B-cell repertoires. Understanding the mechanisms of recognition of other highly conserved self-antigens by NAbs may lead to novel immunomodulation strategies to a variety of autoimmune disorders.
Naturally occurring antibodies that prevent infection NAbs are predominant players in the first line of defense against microbial infections. Most of the reports have attributed this role to NAbs of the IgM isotype. However, studies performed using IVIg have provided strong evidence for the anti-infectious capacity of NAbs of the IgG isotype. IVIg contains NAbs against several cell surface molecules, including CD4, the beta-chemokine (CC) receptor CCR5 (CD195), and the dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin molecule (DC-SIGN, CD209). CD209 is implicated in the attachment and transmission of HIV from dendritic cells to T lymphocytes. The chemokine receptors CXCR4 and CCR5 are the major coreceptors for T lymphocyte and macrophage tropic HIV-1 isolates referred to as X4 and R5 isolates, respectively. The majority of the sexually transmitted human immunodeficiency virus (HIV) infections are caused by R5 isolates. These chemokine receptors serve as attractive targets to block the entry of the virus and the infection of lymphocytes and macrophages. NAbs to CCR5 coreceptor for HIV-1 have been characterized [2], and they inhibited the infection lymphocytes and macrophages with primary R5 and laboratory-adapted strains of HIV-1.
Naturally occurring antibodies that prevent inflammation Cytokines play a crucial role in the maintenance of homeostasis, and they function in a complex network of agonists and antagonists. NAbs to a variety of cytokines have been identified and characterized in IVIg and they have been found to possess effective and specific regulatory roles. Notable examples include NAbs to granulocyte-macrophage colony stimulating factor and the BAFF (B-cell-activating factor of the TNF family) [2]. Anticytokine NAbs regulate the half-life of the cytokines and some of the NAbs might also be involved with the transport of cytokines. The physiologic role of these anticytokine antibodies is not fully appreciated at present. They might provide a novel layer of regulation and mediate the anti-inflammatory effect of IVIg. Neurodegenerative diseases are characterized by inflammation and dysfunction due to the aggregation and deposition of misfolded proteins or peptides. NAbs to patterns generated by the abovedescribed misfolded fibrillar or aggregated proteins have been identified. These NAbs specifically recognize fibrils formed from light chains, amyloidogenic precursor proteins, including serum amyloid A, transthyretin, and amyloid beta 1-40 peptide (Abeta40) in fibrillar forms but not their native nonfibrillar forms. The current hypothesis suggests that these anti-Abeta NAbs can inhibit fibrillation and toxicity of β-amyloid and improve cognition in a transgenic mouse model. These findings have led to a phase III clinical study using IVIg [7]. IgG from IVIg also binds to the T cell receptor (TCR) in the complementary determining region 1 of the TCR β chain. It has been proposed that NAbs against the TCR serve as regulators of T cells, possibly through expanding the regulatory T cells [8].
References
309
Another study has documented the presence of anti-BAFF and anti-APRIL (a proliferation-inducing ligand) NAbs in IVIg. These can neutralize the functional role of BAFF in B-cell survival. These antiBAFF NAbs may rectify the damaging effects of BAFF in B-cell-mediated autoimmune diseases [9]. Monocytes act as precursors for dendritic cells or macrophages. Dendritic cells are the professional antigen-presenting cells that are important for both T-cell activation and tolerance. The factors that mediate the differentiation and maturation of dendritic cells are not fully understood. Monocytes and dendritic cells circulate in the peripheral blood that is rich in NAbs. Anti-CD40 NAbs have been shown to sustain the differentiation and maturation of human dendritic cells. It is noteworthy that the signaling by NAbs does not trigger interleukin (IL)-12 production and, thus, does not lead to Th1 differentiation by default. Therefore, under steady-state conditions, NAbs might induce the maturation of dendritic cells without increasing their immunostimulatory capacity [10]. The above-described developments in the field of IVIg therapy indicate that NAbs operate by different mechanisms under different settings. Furthermore, at any given time, not all the NAbs of IVIg are equally active functionally. It is also possible that many of the above-described mechanisms might operate simultaneously in vivo. How do these NAbs operate functionally under different conditions and how are they regulated? What are the functionally active NAbs in different settings? Answers to these questions would unlock the immense therapeutic potential of IVIg and rationalize its usage.
Clinical utilities 1. I VIg is an important therapeutic option for autoimmune and inflammatory diseases. 2. Dissecting the mechanisms of action of NAbs is of importance for IVIg therapy. 3. Understanding which Nab(s) of IVIg bring about the therapeutic effect under different settings would help clinicians and researchers to design focused therapies by antibody engineering.
Take-home messages 1. 2. 3. 4. 5.
I VIg comprises pooled IgG from healthy donors. The polyreactive, low-titer, low-affinity but high-avidity NAbs are part of the composition of IVIg. NAbs that recognize molecules of relevance for immune regulation have been identified in IVIg. NAbs play a significant role in maintaining tissue and immune homeostasis. Understanding the mechanisms by which NAbs operate under different settings will help in improving IVIg therapy.
References [1] Kazatchkine MD, Kaveri SV. Immunomodulation of autoimmune and inflammatory diseases with intravenous immune globulin. N Engl J Med 2001;345:747–55. [2] Seite JF, Shoenfeld Y, Youinou P, Hillion S. What is the contents of the magic draft IVIg? Autoimmun Rev 2008;7:435–9.
310
CHAPTER 36 Autoantibodies in Therapeutic Preparations of Human IVIg
[3] Kaveri S, Vassilev T, Hurez V, Lengagne R, Lefranc C, Cot S, et al. 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. J Clin Invest 1996;97:865–9. [4] Prasad NK, Papoff G, Zeuner A, Bonnin E, Kazatchkine MD, Ruberti G, et al. Therapeutic preparations of normal polyspecific IgG (IVIg) induce apoptosis in human lymphocytes and monocytes: a novel mechanism of action of IVIg involving the Fas apoptotic pathway. J Immunol 1998;161:3781–90. [5] Vassilev TL, Kazatchkine MD, Duong Van Huyen JP, Mekrache M, Bonnin E, Mani JC, et al. Inhibition of cell adhesion by antibodies to Arg-Gly-Asp (RGD) in normal immunoglobulin for therapeutic use (intravenous immunoglobulin, IVIg). Blood 1999;93:3624–31. [6] Pashov A, Kenderov A, Kyurkchiev S, Kehayov I, Hristova S, Lacroix-Desmazes S, et al. Autoantibodies to heat shock protein 90 in the human natural antibody repertoire. Int Immunol 2002;14:453–61. [7] Bach JP, Dodel R. Naturally occurring autoantibodies against β-amyloid. Adv Exp Med Biol 2012;750:91–9. [8] Marchalonis JJ, Kaymaz H, Dedeoglu F, Schluter SF, Yocum DE, Edmundson AB. Human autoantibodies reactive with synthetic autoantigens from T-cell receptor beta chain. Proc Natl Acad Sci U S A 1992;89: 3325–9. [9] Le Pottier L, Bendaoud B, Dueymes M, Daridon C, Youinou P, Shoenfeld Y, et al. BAFF, a new target for IVIg in autoimmunity and cancer. J Clin Immunol 2007;27:257–65. [10] Bayry J, Lacroix-Desmazes S, Donkova-Petrini V, Carbonneil C, Misra N, Lepelletier Y, et al. Natural antibodies sustain differentiation and maturation of human dendritic cells. Proc Natl Acad Sci U S A 2004;101:14210–5.