The Journal of Allergy and Clinical Immunology
Volume 127, Issue 2 , Pages 315-323, February 2011

The IgG molecule as a biological immune response modifier: Mechanisms of action of intravenous immune serum globulin in autoimmune and inflammatory disorders

  • Mark Ballow, MD

      Affiliations

    • Corresponding Author InformationReprint requests: Mark Ballow, MD, Allergy/Clinical Immunology Division, Women & Children's Hospital, 219 Bryant St, Buffalo, NY 14222.

Allergy/Clinical Immunology Division, Department of Pediatrics, Women & Children's Hospital of Buffalo, and the School of Medicine and Biomedical Sciences, SUNY Buffalo, Buffalo, NY

Received 15 September 2010; received in revised form 21 October 2010; accepted 22 October 2010. published online 27 December 2010.

Article Outline

Intravenous immune globulin (IVIG) is an important treatment modality in patients with humoral or B-cell immune deficiency as replacement therapy. Soon after its introduction in the early 1980s for the treatment of patients with immune deficiency, IVIG was used in the treatment of children with idiopathic thrombocytopenia purpura. Presently, more commercial IVIG is used for the treatment of autoimmune and inflammatory disorders than as replacement therapy in patients with immune deficiency. Understanding the mechanisms of action of IVIG in these autoimmune and inflammatory disorders has occupied investigators over the past 3 decades. A number of mechanisms for the immune modulation and anti-inflammatory actions of IVIG have been described, including Fc receptor blockade, inhibition of complement deposition, enhancement of regulatory T cells, inhibition or neutralization of cytokines and growth factors, accelerated clearance of autoantibodies, modulation of adhesion molecules and cell receptors, and activation of regulatory macrophages through the FcγRIIb receptor. It can now be appreciated that IVIG affects many different pathways to modulate the immune and inflammatory response. Further delineation of these pathways might lead to new treatment strategies.

Key words: Intravenous immune globulin, immune response modifier, complement, Fcγ receptors, apoptosis

Abbreviations used: CIDP, Chronic inflammatory demyelinating polyradiculoneuropathy, DC-SIGN, Dendritic cell–specific ICAM grabbing nonintegrin, FcRn, Neonatal Fc receptor, FOXP3, Forkhead box protein 3, GBS, Guillain-Barré syndrome, ICAM, Intercellular adhesion molecule, ITP, Idiopathic thrombocytopenia purpura, IVIG, Intravenous immune globulin, MAC, Membrane attack complex, SIGN-R1, Specific ICAM-3 grabbing nonintegrin-related 1, Treg, Regulatory T

 

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Information for Category 1 CME Credit 

Credit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions.

Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted.

Date of Original Release: February 2011. Credit may be obtained for these courses until January 31, 2013.

Copyright Statement: Copyright © 2011-2013. All rights reserved.

Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease.

Target Audience: Physicians and researchers within the field of allergic disease.

Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates these educational activities for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

List of Design Committee Members: Mark Ballow, MD

Activity Objectives

1.To recognize that, in addition to acting as immunoglobulin replacement therapy for patients with primary immunodeficiency disorders, intravenous immunoglobulin (IVIG) functions as an immunomodulatory treatment for autoimmune and inflammatory disorders through a variety of mechanisms.

2.To understand the mechanisms by which IVIG can alter several effector functions of the immune system.

Recognition of Commercial Support: This CME activity has not received external commercial support.

Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: M. Ballow is on advisory boards for Talecris Biotherapeutics, CSL-Behring, and Baxter; has received research support from Grifols; and has provided legal consultation or expert witness testimony related to a patient with immune deficiency.

Discuss this article on the JACI Journal Club blog: www.jaci-online.blogspot.com.

Glossary

 

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BULLOUS PEMPHIGOID 

Bullous pemphigoid is a chronic blistering autoimmune skin disease caused by autoantibodies to the hemidesmosomal proteins BP230 and BP180.

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C3 

All 3 complement pathways, classical, mannose binding, and alternate, converge on the conversion of C3 to C3b, which functions for both opsonization and formation of C5 convertase, which allows subsequent formation of the MAC.

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CD95 (FAS) 

CD95 and CD95 ligand are also known as Fas and Fas ligand, respectively. CD95 is expressed mainly on activated T cells, B cells, and eosinophils and is a member of the TNF receptor superfamily. Apoptosis is induced through the “death domain,” which is important for recruiting caspase-8 and caspase-10, which function as proapoptotic signaling molecules.

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CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY (CIDP) 

CIDP is an autoinflammatory disease of the myelin sheath that results in peripheral weakness and impaired sensory function. CIDP is more common in young adult males and is considered the chronic counterpart to Guillain-Barré syndrome.

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DENDRITIC CELL–SPECIFIC ICAM-3 GRABBING NONINTEGRIN (DC-SIGN) 

DC-SIGN is a C-type lectin receptor present on macrophages and dendritic cells that is important for endothelial interactions and binds to ICAM-3. Human DC-SIGN is of special interest because it is involved in the interaction of certain dendritic cells with several viruses (HIV-1, hepatitis C virus, dengue virus, cytomegalovirus, and Ebola virus) and other microbes, as well as Leishmania and Candida species.

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FcγRIIa, FcγRIIb 

Although they share 96% sequence homology in the extracellular domain, FcγRIIa and FcγRIIb have opposing functions. FcγRIIa is expressed on neutrophils and carries an immunoreceptor tyrosine-based activation motif to send proinflammatory signals. In contrast, FcγRIIb is expressed on B cells, mast cells, and some T cells and sends inhibitory signals through an immunoreceptor tyrosine-based inhibition motif.

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GUILLAIN-BARRÉ SYNDROME (GBS) 

GBS is an acute peripheral demyelinating disease that can follow a viral respiratory tract or gastrointestinal illness and from which most patients recover. Plasmapheresis, high-dose IVIG, and supportive care are the mainstays of therapy.

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INTERCELLULAR ADHESION MOLECULE (ICAM), VASCULAR CELL ADHESION MOLECULE (VCAM) 

ICAM-1, also known as CD54, is expressed on vascular endothelial molecule cells after activation by IL-1– and TNF-α–activated endothelial cells, which allows the binding and trafficking of leukocytes through lymphocyte function–associated antigen 1 and Mac-1. ICAM-1 is also important for cell-cell adhesion and activation. VCAM-1 allows cell adhesion through very late antigen 4 and is also induced by TNF-α and IL-4.

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IFN-γ 

Interferons were originally named for their ability to “interfere” with viral function. IFN-γ is made by T cells and stimulated by IL-12 and increases the production of IL-1 and TNF-α. IFN-γ is an important part of the therapeutic regimen for chronic granulomatous disease.

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IL-1 

The primary sources of IL-1 are monocytes/macrophages. IL-1 has multiple proinflammatory effects, including increasing vascular endothelial activation and promoting the production of cytokines IL-6 and TNF-α. IL-1 blockers include anakinra, which is used for rheumatoid arthritis and familial cold autoinflammatory syndrome.

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INTEGRINS 

Integrins are receptors that mediate cell-cell or cell–extracellular matrix adhesion, including through binding to fibronectin, collagen, and laminin. Integrins, such as α4β1 (very late antigen 4) and αLβ2 (lymphocyte function–associated antigen 1) are important for the adhesion of inflammatory cells to activated vascular endothelium.

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KAWASAKI DISEASE 

The most common cause of acquired heart disease in children, Kawasaki disease is defined by fevers for more than 5 days, rash, conjunctivitis with perilimbic sparing, swollen hands and feet, and lymphadenopathy. Kawasaki disease is treated first line with IVIG, and refractory disease can be treated with TNF-α blockade

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TNF-α 

There are multiple cellular sources of TNF-α, including monocytes/macrophages, T cells (including TH17 cells), and epithelial cells. TNF-α's effects are similar to those of IL-1. TNF-α blockers include etanercept (Enbrel), infliximab (Remicade), and adalimumab (Humira), which are used to treat rheumatoid arthritis, psoriasis/psoriatic arthritis, Crohn disease, and refractory Kawasaki disease.

The Editors wish to acknowledge Seema Aceves, MD, PhD, for preparing this glossary.

Immune serum globulin was originally used as an intramuscular injection for replacement therapy in patients with hypogammaglobulinemia in the early 1950s, particularly those with X-linked agammaglobulinemia or Bruton disease and common variable immunodeficiency. It was recognized that this preparation had many immune-enhancing properties related to the function of the IgG molecule, including precipitation, agglutination, and neutralization of viral and bacterial pathogens, and was recognized as an important opsonin in the process of phagocytosis by neutrophils and phagocytes. The initial gammaglobulin preparations could only be used through the intramuscular route because of the risk of anaphylactoid reactions. Over a 20-year period, manufacturers of blood products examined a number of approaches, such as reduction and alkylation, low pH, and low concentrations of pepsin, to make the gammaglobulin preparation suitable for use through the intravenous route. However, it was not until the early 1980s that the first commercial gammaglobulin product became available for use by the intravenous route. Clearly, this product had a significant advantage over the intramuscular preparation in that it allowed the rapid administration of larger amounts of purified IgG that could achieve nearly normal serum IgG levels in patients with primary immune deficiency disorders. In 1981, Imbach was treating patients with immune deficiency with these newer preparations of intravenous immune globulin (IVIG). Several of these patients concomitantly had idiopathic thrombocytopenia purpura (ITP), and after treatment with IVIG, the platelet counts increased dramatically immediately after the IVIG infusion. These observations led to a subsequent study1 in children with ITP, which demonstrated that the administration of high-dose IVIG in children with ITP led to a dramatic increase in platelet counts and often resolution of the disease process. Subsequent to these observations by Imbach in the early 1980s, there has been an explosion in the use of IVIG in patients with a variety of autoimmune and inflammatory disorders. Today, approximately 70% of the IVIG used in the United States is for immune modulation in patients with autoimmune and inflammatory disorders. This review will examine the mechanisms of action of IVIG in modulation of the immune system in patients with autoimmune and inflammatory disorders (Table I).

Table I. Mechanisms of action of IVIG
Blockade of Fc receptors on macrophages of the reticuloendothelial system of liver and spleen
Restoration of the idiotypic–anti-idiotypic network
Suppression or neutralization of cytokines by specific antibodies in the IVIG
Blockage of binding of adhesion molecules on leukocytes to vascular endothelium
Inhibition of complement uptake on target tissues
Neutralization of microbial toxins
Blockage of Fas ligand–mediated apoptosis by anti-Fas antibodies in the IVIG
Induction of apoptosis with anti-Fas antibodies at high concentrations of IVIG
Neutrophil apoptosis by anti–Siglec-9 antibodies in IVIG
Saturation of the FcRn receptors to enhance the clearance of autoantibodies
Induction of inhibitory FcγRIIb receptors on effector macrophages
Neutralization of growth factors for B cells, such as B-cell activating factor
Inhibition of T cell–proliferative responses
Expansion, activation, or both of a population of Treg cells
Inhibition of the differentiation and maturation of dendritic cells
Enhancement of the differentiation and maturation of “primed” dendritic cells

Siglec, Sialic acid–binding immunoglobulin-like lectin.

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Fc receptor blockade 

After administration of 1 to 2 g/kg IVIG, platelet counts increase rapidly in patients with ITP.2 Fc receptor blockade of the reticuloendothelial system was suggested as the mechanism by which platelet counts rapidly increase after the administration of IVIG.3, 4 Autoantibody-opsonized platelets are destroyed in the spleen and liver by means of FcγR-mediated phagocytic clearance.3, 5 Fehr et al4 showed that the administration of IVIG in patients with ITP prolonged the in vivo clearance of radiolabeled antibody-sensitized red blood cells. Further supporting evidence for Fc receptor blockade on macrophages in the spleen and in other parts of the reticuloendothelial system was reported by Clarkson et al,6 who demonstrated a marked increase in platelet counts in patients with ITP using an mAb directed against the FcγRIIIa receptor. Intravenous administration of Fcγ fragments prepared from IVIG in children with acute ITP resulted in a rapid increase in platelet counts.7 The efficacy of using Fcγ fragment therapy in patients with ITP strengthens the hypothesis that Fcγ receptor blockade is the main mechanism of action of IVIG for the rapid increase in platelet counts seen in these patients. Other studies have suggested that Fcγ receptor downregulation or a change in receptor affinity might also be involved.8

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Restoration of the idiotypic–anti-idiotypic network 

Kazatchkine and Kaveri9 and others10 postulated that a number of autoimmune disorders might have a deficiency in their idiotypic network that contributes to the autoimmune process; these disorders might be responsive to IVIG therapy by restoring this idiotypic network.9, 11, 12 A number of diseases can serve as models for this mechanism of IVIG, including patients with circulating autoantibody inhibitors to Factor VIII coagulant activity, systemic lupus erythematosus, and anti-neutrophil cytoplasmic antibody–associated vasculitis. Whereas anti-idiotypic antibodies are rarely found in IgG preparations prepared from a single healthy subject, IVIG prepared from large pools of plasma donors contain such anti-idiotypic antibodies. This hypothesis stems from the work of Jerne, who originally postulated the idiotypic network theory of immune regulation as a mechanism by which the host regulates antibody production (Fig 1).9, 11 Anti-idiotypic antibodies targeting B lymphocytes that express these idiotopes could potentially downregulate or even eliminate potentially autoreactive clones.9, 13

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  • Fig 1. 

    The red portion of the immunoglobulin cartoon shows the antigen-binding site variable regions of the heavy and light chains. Anti-idiotypic antibodies are directed against either idiotope sequences of the antigen-binding site or idiotope determinants that are not part of the antigen binding site. These anti-idiotypic antibodies can bind to the surface immunoglobulin on B cells or circulating antibody in the plasma. Niels Jerne, in 1974, postulated that these anti-idiotypic antibodies could regulate the immune response or even negate or neutralize autoantibodies. Several investigators9, 11 have documented that intravenous immune globulin (IGIV) contains anti-idiotypic antibodies of various specificity to known autoantibodies.

The presence of anti-idiotypic antibodies in IVIG was first suggested by the clinical observation of the response to IVIG therapy in a patient with acquired hemophilia and inhibitory autoantibodies to Factor VIII.14, 15 Sultan et al15 showed that IVIG reduced Factor VIII inhibitor activity in vitro and that this immunomodulatory effect resided within the F(ab′)2 fragment. Dietrich and Kazatchkine11 prepared F(ab′)2 fragments from commercial IVIG preparations that could neutralize or bind to known autoantibodies, such as anti-Factor VIII, anti-thyroglobulin, anti-DNA, anti-intrinsic factor, and anti-neutrophil cytoplasmic antibody. Others have shown that pathogenic autoantibodies, such as antibodies to GM1 ganglioside (anti-GM1) in patients with Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and anti-acetylcholine receptor antibodies in patients with myasthenia gravis,16, 17, 18, 19, 20 can be “neutralized” by antibodies with idiotypic specificities in IVIG preparations. Malik et al21 suggested that an idiotype/anti-idiotype interaction is a possible mechanism by which IVIG modifies the immune-mediated disease process and could contribute to remyelination in patients with GBS and CIDP.

Because of the small amounts of anti-idiotypic antibody in IVIG, it is not clear whether this potential mechanism of action of IVIG is a significant immune-modulating mechanism for autoimmune and inflammatory disorders. Idiotype–anti-idiotype interactions between anti-platelet GPIIb/IIIa autoantibodies, one of the major targets of pathogenic autoantibody in ITP, and IVIG could affect autoantibody production in patients with ITP.22 However, more recent research has shown that anti-idiotypic antibodies present in IVIG are not required for increasing platelet counts in a murine model of ITP.23 Further studies are necessary to determine the significance of these anti-idiotypic antibodies in IVIG as immune modulators in the pathogenesis of human autoimmune diseases. Most experimental systems have shown that the active component of IVIG lies within the Fc fragments rather than the F(ab′)2 component, implicating Fc receptor effects rather than F(ab′)2 neutralization mechanisms. Nevertheless, these anti-idiotypic antibodies might also act in concert with the effects of IVIG on the FcγRIIb receptor on B cells to produce a negative “off signal” to the B cells synthesizing these autoimmune antibodies.24

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Suppression of cytokine production 

Kawasaki disease is an inflammatory disease that is a US Food and Drug Administration–approved indication for treatment with IVIG.25 Kawasaki disease is an acute multisystem disease of unknown cause that primarily affects young children. Although the acute illness is generally self-limited, coronary artery abnormalities related to inflammation and immune activation of small- and medium-sized blood vessels develop in up to 25% of untreated patients. Geographic clustering, epidemics and even pandemics in Japan, and seasonal variations, such as late winter and spring, suggest an infectious cause. Leung and colleagues26, 27 proposed that Staphylococcus enterotoxins acting as superantigens are responsible for the inflammatory and immunologic process in patients with Kawasaki disease. Takei et al28 showed that IVIG preparations contain neutralizing antibodies to staphylococcal-derived enterotoxins and that the antibodies in IVIG can inhibit T-cell activation by these staphylococcal and streptococcal superantigens. The immune-suppressing effects of IVIG in patients with Kawasaki disease and, more importantly, its ability to prevent the development of coronary artery aneurysms might relate to the neutralizing antibody activity in IVIG against these bacterial enterotoxins26 and proinflammatory cytokines.29

It was also shown in patients with Kawasaki disease that IVIG therapy could modify the production of cytokines by mononuclear cells. IVIG inhibits the production of IL-1, TNF-α, TNF-β, and IFN-γ by PBMCs stimulated with bacterial superantigens or LPS while increasing the production of IL-1 receptor antagonist, an anti-inflammatory cytokine that counteracts the effects of IL-1.30 Furthermore, Xu et al,31 using human umbilical vein endothelial cells, demonstrated that IVIG inhibits endothelial cell proliferation and downregulates the mRNA expression of adhesion molecules (intercellular adhesion molecule [ICAM] 1 and vascular cell adhesion molecule 1), chemokines (monocyte chemoattractant protein 1), growth factors (monocyte colony-stimulating factor and GM-CSF), and proinflammatory cytokines (TNF-α, IL-1α, and IL-6). A number of in vitro studies have shown that IVIG can inhibit the production of or bind to and neutralize a number of cytokines and growth factors from various cell types.32, 33, 34, 35, 36 Thus IVIG can exert its anti-inflammatory effects in patients with Kawasaki disease by interrupting or modifying a number of different steps in the inflammatory cascade from the inhibition of effector cell function to a reduction in cytokine-induced endothelial cell activation. Leung37 postulated that cytokines in patients with Kawasaki disease stimulate local inflammatory responses of blood vessels by modifying leukocyte adhesion after increasing the expression of cell-surface determinants on vascular endothelial cells. IVIG could modulate this cytokine-mediated endothelial cell activation by neutralizing the effects of the cytokines, inhibiting endothelial cell responses to the cytokines, or inhibiting the production of cytokines and growth factors. None of these mechanisms are mutually exclusive.

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Modulation of adherence molecules 

IVIG contains antibodies reactive to cell-surface determinants and matrix proteins. Vassilev et al38 showed that IVIG contained specific antibodies to a 10-peptide sequence containing the RGD (Arg-Gly-Asp) motif that are expressed as adhesion molecules on a variety of cell surfaces. Most integrins bind to this RGD sequence. These authors showed that the IVIG inhibits the adhesion of B cells to fibronectin and modifies platelet aggregation by the specific antibodies in IVIG, which inhibit binding to this RGD motif. In patients with sickle cell disease, abnormal sickle red blood cells adhere to each other, other blood elements, and the vascular endothelium, resulting in vascular occlusion and sickle cell crisis. Chang et al39 and Turhan et al40 investigated the effects of IVIG in a murine model of sickle cell acute vaso-occlusive crisis. The administration of high-dose IVIG given after the onset of a crisis induced by TNF-α resulted in improved blood flow and prolonged survival. The mechanism of action of IVIG in this model was a rapid reduction in neutrophil adhesion to the vascular endothelium and decreased interaction between red blood cells and leukocytes.

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Inhibition of complement deposition on target tissues 

Berger et al41 showed in in vitro studies that high levels of IgG could inhibit the uptake of C3 on erythrocytes and postulated that inhibition of binding of C3b to antibodies on platelets could reduce C3b-dependent opsonization of antibody-coated platelets by macrophages of the reticuloendothelial system. This mechanism could work in concert with the Fc receptor blockade. Basta and coworkers42 showed that high-dose IVIG could prevent the death of guinea pigs induced to undergo Forssman shock, a disease process mediated by complement uptake and activation of endothelial cells that results in tissue damage. IVIG prevented active C3 and C4 fragments from binding to target cells, resulting in modulation of acute complement-dependent tissue injury.

Dermatomyositis is an autoimmune disease characterized by the subacute onset of muscle weakness affecting predominantly the proximal muscle groups and is often accompanied or preceded by a characteristic skin rash and associated with circulating autoantibodies to endothelial cells and histidyl-tRNA synthetase (Jo-1).43, 44 A humoral immune process directed against the intramuscular capillaries leads to a complement-mediated endomysial microangiopathy with deposition of the membrane attack complex (MAC) consisting of activated complement components C5b-9.44 The endomysial capillary damage as a result of MAC deposition leads to microinfarcts within the muscle fascicles, muscle ischemia, inflammation, and eventually perifascicular atrophy.45 Dalakas and coworkers44, 46 have shown decreased C3 and MAC deposition on the endomysial capillaries and decreased ICAM-1 expression in the muscle tissues in muscle biopsy specimens of patients with dermatomyositis treated with IVIG.44, 46 This mechanism of action of IVIG on complement deposition might also be working in patients with GBS, CIDP, and myasthenia gravis.47, 48 In another model of ischemic injury mediated by complement activation, Arumugam et al49 reported that IVIG protects the brain against experimental stroke in a murine model by preventing complement-mediated neuronal cell death.

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Modulation of apoptosis 

Toxic epidermal necrolysis is a severe drug-induced bullous skin reaction in which the death of the keratinocytes leads to large sections of the epidermis sloughing off. Keratinocytes express Fas, and the sera of these patients contain high circulating levels of Fas ligand. Patients with toxic epidermal necrolysis treated with high-dose IVIG showed rapidly reversed disease progression.50 Viard et al50 showed that IVIG contains anti-Fas antibodies that could prevent keratinocyte cell death by blocking the effects of Fas ligand on the Fas receptor on keratinocytes. After depletion of these anti-Fas antibodies, the IVIG could no longer prevent keratinocyte apoptosis. Others have shown that the anti-Fas antibodies in IVIG can enhance the apoptosis of human lymphocytes and monocytes.51 Altznauer et al52 showed that low concentrations of IVIG (1-10 mg/mL) blocked anti-CD95–mediated neutrophil apoptosis, whereas high concentrations of IVIG (20-50 mg/mL) induced neutrophil death. Thus the immune-modulating effects of these anti-Fas antibodies might depend on the dose of IVIG and the clinical disease state.

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Modulation of B cells 

A number of investigators have commented that the long-term effects in patients with ITP could be due to effects on B-cell antibody production. Several in vitro studies have reported that IVIG inhibits immunoglobulin secretion.53, 54 More recently, using purified murine B cells, Proulx et al55 reported that IVIG inhibited both B-cell receptor–dependent and independent antigen presentation. This inhibitory effect was not mediated through the FcγRIIb receptor but was mediated by intracellular events. This is similar to the observations of Zhuang and Mazer.54 However, other studies with human B cells indicate that under specific conditions of B-cell activation, such as CD40 activation, IVIG can promote differentiation into IgG-secreting B cells and enhance immunoglobulin secretion.56 Thus, as with other immune-modulating activities of IVIG, the effects might depend on the in vitro systems used and the state of activation of the “test” cells.

IVIG contains other specific antibodies that react with a number of cell-surface determinants that could potentially modulate the immune response, such as the αβ T-cell receptor, cytokine receptors, HLA determinants, CD5, CCR5, CD40, and sialic acid–binding immunoglobulin-like lectins 8 and 9.57, 58, 59, 60, 61, 62, 63, 64

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Saturation of the neonatal Fc receptor 

The neonatal Fc receptor (FcRn) is a specialized receptor that binds serum IgG, protects the IgG from degradation inside the lysosomes, and returns the IgG intact to the plasma circulation. These specialized receptors account for the long half-life of serum IgG of 21 to 25 days.65 Yu and Lennon66 postulated that IVIG saturates this FcRn receptor found in the endocytoxic vesicles of endothelial cells, resulting in the enhanced catabolism of the autoantibodies in antibody-mediated autoimmune diseases. In murine models of bullous pemphigoid and arthritis, IVIG treatment resulted in a reduction in pathogenic antibodies to levels less than the disease-causing threshold, and this effect is attenuated in FcRn-deficient mice.67 In fact, the long-term effects of IVIG in patients with ITP cannot be attributed to Fcγ receptor blockade alone.68 Hansen and Balthasar69 reported that high-dose IVIG in a rat model of immune thrombocytopenia enhanced the clearance of antiplatelet antibodies through the saturation of the FcRn receptor for IgG that might account for 50% of the total protective effects of IVIG in this rat model. These studies were supported by additional observations by Hansen and Balthasar70 that IVIG failed to increase the clearance of anti-platelet antibodies in an FcRn knockout mouse.

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Modulation of immunoregulatory function through the Fc receptor 

Although Fc receptor blockade with the administration of IVIG might result in the rapid increase in platelet counts seen in patients with ITP, studies have shown that the levels of anti-platelet antibodies decrease over time.3, 68 Recent studies now suggest that IVIG stimulates inhibitory FcγRIIb receptors found on a variety of cell types, including macrophages, B cells, and a subpopulation of T cells.71, 72 This receptor provides an inhibitory signal to cells through a pathway mediated by an immunoregulatory tyrosine-based inhibition motif (ITIM). In a murine model of immune thrombocytopenia, Samuelsson et al73 reported that the protective effects of IVIG required an inhibitory Fcγ receptor, ie FcγRIIb, in which either disruption of this receptor or blocking with an mAb reversed the therapeutic effects of IVIG. The protective effects of IVIG were associated with the increased expression of FcγRIIb on splenic macrophages.73 Subsequently, Kaneko et al74 showed that that the inhibitory properties of IVIG were linked to the sialylation of the glycan component of the Fc fragment. A fully processed form of the carbohydrate component with a terminal sialic acid moiety is present in only 5% of the total serum IgG. More than 30 different covalently attached carbohydrate glycans in the IgG molecule have been identified. The important glycan moiety in the IgG molecule is located at the asparagine (Asn297) site in the second domain of the constant region. Using a K/BxN serum-induced arthritis model in mice, Kaneko et al72 showed that IVIG at 1 g/kg inhibited the inflammatory arthritic process. Deglycosylated or neuraminidase-treated IVIGs were unable to inhibit this inflammation. IVIG enriched for the sialylated glycan moiety had comparable inhibitory effects on the inflammatory process at only one tenth of the dosage used with intact IVIG. This inhibitory activity was dependent on FcγRIIb expression on effector macrophages. Recently, Anthony et al75 have engineered a recombinant/sialylated human IgG1 Fc protein that had a 35-fold enhanced immune-modulating activity compared with native IVIG. However, antibodies enriched for the sialic acid moiety have reduced binding to the FcγRs,76 which suggests that other receptors are involved with the inhibitory or anti-inflammatory properties of IVIG. Anthony et al77 performed studies to examine the mechanism by which the sialylated Fc fragment could mediate its anti-inflammatory activity and identify the target cell that initiates this anti-inflammatory pathway. A splenic marginal zone macrophage expressing the C-type lectin receptor, such as specific ICAM-3 grabbing nonintegrin-related 1 (SIGN-R1), was required for the anti-inflammatory activity of IVIG in concert with its ability to bind to sialylated Fc domains. The authors proposed that the interaction between sialylated IgG Fc and SIGN-R1 leads to the upregulation of the inhibitory FcγRIIb receptor on effector cells (Fig 2).75, 77 They suggest that dendritic cell–specific ICAM-grabbing nonintegrin (DC-SIGN), the human orthologue of SIGN-R1, has a comparable role for the anti-inflammatory effects of IgG Fc fragment on human macrophages and dendritic cells. These exciting studies define an important mechanism by which IVIG modulates immune processes mediated through sialylated Fc on the IgG molecule and the receptors, such as FcγRIIb and SIGN-R1, involved in this anti-inflammatory process. Activation of the inhibitory FcγRIIb receptor on effector macrophages and the saturation of the FcRn receptor might act together to reduce the levels of autoantibodies.

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  • Fig 2. 

    Intravenous immune globulin (IGIV) contains both sialylated IgG (approximately 1% to 3% of the total IgG in intravenous immune globulin) and nonsialylated IgG. Sialylated IgG molecules in the intravenous immune globulin bind through the Fc domain to a C-type lectin receptor (DC-SIGN) on a dendritic regulatory cell. Engagement of the DC-SIGN receptor leads to the secretion of a mediator that acts on effector macrophages to increase the cell-surface expression of the inhibitory FcγRIIb receptor. Upregulation of the inhibitory FcγRIIb receptor on macrophages inhibits the activating Fcγ receptors engaged by autoantibody immune complexes, such as antiplatelet and glomerular basement membrane autoantibodies, thus preventing the release of inflammatory mediators and tissue damage.75, 77

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Modulation of T-cell immunoregulatory function 

Although there is strong evidence for the role of FcγR-mediated mechanisms of action for IVIG, the effects of IVIG on T cell–mediated autoimmune diseases can be explained by other immune-modulating effects of IVIG. There are many older studies that have demonstrated that IVIG suppresses T-cell proliferative responses to mitogens and inhibits cytokine production, although the mechanisms were not delineated.78, 79 In a recent study MacMillan et al80 reported that both IVIG and F(ab′)2 fragments could inhibit the proliferation of T cells to CD3 and CD28 stimulation; the mechanism was not delineated. Another mechanism by which IVIG could modulate the immune system is by expanding and enhancing the function of forkhead box protein 3 (FOXP3)–positive regulatory T (Treg) cells. In a murine model of multiple sclerosis, such as experimental autoimmune encephalomyelitis, animals treated with IVIG had less severe disease and expanded their population of CD4+CD25+FOXP3+ Treg cells.81 This protective effect was lost in mice depleted of Treg cells. Kessel et al82 reported that IVIG added in vitro to human CD4+CD25hi Treg cells increased the intracellular expression of TGF-β, IL-10, and FOXP3 and enhanced the suppressive function of these Treg cells. In patients with Kawasaki disease and GBS, clinical improvement with IVIG therapy correlated with an increase in the number and function of Treg cells.83 De Groot et al84 showed that the IgG molecule contains regions or epitopes, called “Tregitopes,” in the Fc region that are capable of activating CD4+CD25hiFOXP3+ Treg cells. The mechanism or mechanisms responsible for the expansion and function of Treg cells could be direct or indirect through increased production of cytokines, such as IL-10 or TGF-β, or effects on dendritic cells. Bayry et al85 reported that IVIG inhibited the maturation of peripheral blood monocytes into immature dendritic cells. Interestingly, these same investigators57 showed that dendritic cells from patients with X-linked agammaglobulinemia had impaired differentiation, but in the presence of IVIG, a source of natural antibodies, such as anti-CD40, led to a partial correction of the maturation defect. In a related observation Wasserbauer et al86 demonstrated that if peripheral blood monocytes were primed first with nonmitogenic doses of LPS or other Toll-like receptor agonists, on the addition of IVIG, the monocytes differentiated into a more mature dendritic cell phenotype and had enhanced antigen-presenting function. Thus priming monocytes through the Toll-like receptors followed by exposure to IVIG can enhance the differentiation and function of these cells into a more mature dendritic cell, which can be important in modulating the differentiation and function of T cells.87

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Summary 

IVIG has become an extremely important treatment modality for patients with a wide variety of autoimmune and inflammatory disorders.88 In fact, the IgG molecule is the single most important naturally occurring specific immune component capable of modulating the immune system (Fig 3).89 In the future, we can expect new processes to bioengineer the IgG molecule using the tools of molecular biology to incorporate the necessary factors into the IgG molecule that enhance its regulatory properties. The studies of Ravetch and colleagues suggest that this is possible for a sialylated Fc domain fragment.74, 75 Because IVIG is a human blood product, the prospects of bioengineering a molecule with similar immune-modulating properties as native IVIG will be an important achievement and save a precious human-derived life-supporting blood product. We have come a long way since the early 1980s, when Imbach and colleagues used IVIG to treat children with ITP in understanding the mechanisms by which IVIG modulates the immune system.90 Although many mechanisms for the effects of IVIG on immune modulation have been reported (Fig 3 and Table I), these mechanisms are not mutually exclusive and most likely work in concert, depending on the dose of IVIG and the inflammatory process occurring in the disease.

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  • Fig 3. 

    Mechanisms of action of intravenous immune globulin (IgIV) on the immune modulation of various components of the innate and adaptive immune systems. Adapted from Tha-In et al.89 DC, Dendritic cell; Mo, monocyte; NK, natural killer.

Key concepts


•The IgG molecule might be the single most universal “natural” immune-modulating molecule of the immune system.

•IVIG modulates a number of immune effector pathways, including Fc receptor blockade, neutralization, or enhanced clearance of antoantibodies; decreases production of cytokines; blocks adherence molecules; and inhibits the uptake of complement components on target tissues, modulation of apoptosis, and immune regulation of both B-cell and T-cell immune function.

•Immune regulation through the FcγRIIb receptor on effector macrophages is an important mechanism of action for IVIG modulation.

•The sialylated Fc domain of the IgG molecule is important in this mechanism of action and is mediated through the DC-SIGN receptor in activating the FcγRIIb receptor.

•The immunoregulatory properties of IVIG in T cell–mediated diseases might be mediated by enhancing Treg cells.

•A number of these immune-modulating mechanisms of action of IVIG act together to regulate the immune system.

Therapeutic implications

•IVIG is an important treatment modality for patients with autoimmune and inflammatory disorders.

•Delineating the mechanisms of action of IVIG will lead to a better understanding of the disease pathogenesis of autoimmune and inflammatory disorders.

•Understanding which component or components of the IgG molecule mediate the immune-modulating effects might help investigators design more specific immune-modulating molecules by using molecular engineering.

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References 

  1. Imbach P, Barandun S, d'Apuzzo V, Baumgartner C, Hirt A, Morell A, et al. High dose intravenous gammaglobulin for idiopathic thrombocytopenic purpura in childhood. Lancet. 1981;1:1228–1232
  2. Blanchette VS, Luke B, Andrew M, Sommerville-Nielsen S, Barnard D, de Veber B, et al. A prospective, randomized trial of high-dose intravenous immune globulin G therapy, oral prednisone therapy, and no therapy in childhood acute immune thrombocytopenic purpura. J Pediatr. 1993;123:989–995
  3. Bussel J. Modulation of Fc receptor clearance and antiplatelet antibodies as a consequence of intravenous immune globulin infusion in patient with immune thrombocytopenic purpura. J Allergy Clin Immunol. 1989;84:566–578
  4. Fehr J, Hofmann V, Kappeler U. Transient reversal of thrombocytopenia in idiopathic thrombocytopenic purpura by high- dose intravenous gammaglobulin. N Engl J Med. 1982;306:1254–1258
  5. Crow AR, Lazarus AH. Role of Fcγ receptors in the pathogenesis and treatment of idiopathic thrombocytopenic purpura. J Pediatr Hematol Oncol. 2003;25(suppl):S14–S18
  6. Clarkson SB, Bussel JB, Kimberly RP, Valinsky JE, Nachman RL, Unkeless JC. Treatment of refractory immune thrombocytopenic purpura with an anti-Fcg receptor antibody. N Engl J Med. 1986;314:1236–1239
  7. Debre M, Bonnet MC, Fridman WH, Carosella E, Philippe N, Reinert P, et al. Infusion of Fc gamma fragments for treatment of children with acute immune thrombocytopenic purpura. Lancet. 1993;342:945–949
  8. Kimberly K, Salmon J, Bussel J, Crow M, Hilgartner M. Modulation of mononuclear phagocyte functions by intravenous gamma globulin. J Immunol. 1984;132:745–750
  9. Kazatchkine M, Kaveri S. Immunomodulation of autoimmune and inflammatory diseases with intravenous immune globulin. N Engl J Med. 2001;345:747–755
  10. Shoenfeld Y. Idiotypic induction of autoimmunity: a new aspect of the idiotypic network. FASEB J. 1994;8:1296–1301
  11. 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;85:620–625
  12. Rossi F, Kazatchkine MD. Antiidiotypes against autoantibodies in pooled normal human polyspecific IgG. J Immunol. 1989;143:4104–4109
  13. Geha RS. Regulation of the immune response by idiotypic-anti-idiotypic interactions. N Engl J Med. 1981;305:25–28
  14. Sultan Y, Kazatchkine MD, Maisonneuve P, Nydegger UE. Anti-idiotypic suppression of autoantibodies to factor VIII (antihaemophilic factor) by high-dose intravenous gammaglobulin. Lancet. 1984;2:765–768
  15. Sultan Y, Rossi F, Kazatchkine MD. Recovery from anti-VIIIc (antihemophilic factor) autoimmune disease is dependent on generation of anti-idiotypes against anti VIIIc autoantibodies. Proc Natl Acad Sci U S A. 1987;84:828–831
  16. Dalakas MC. Molecular immunology and genetics of inflammatory muscle diseases. Arch Neurol. 1998;55:1509–1512
  17. Liblau R, Gajdos PH, Bustarret A, El Habib R, Bach JF, Morel E. Intravenous g-globulin in myasthenia gravis: interaction with anti-acetylcholine receptor autoantibodies. J Clin Immunol. 1991;11:128–131
  18. Van Der Meché FGA. The Guillain-Barré syndrome: pathogenesis and treatment. Rev Neurol (Paris). 1996;152:355–358
  19. van der Meché FGA, Visser LH, Jacobs BC, Endtz HP, Meuistee J, van Doorn PA. Guillain-Barré syndrome: multifactorial mechanisms versus defined subgroups. J Infect Dis. 1997;176(suppl):S99–S102
  20. Yuki N, Miyagi F. Possible mechanism of intravenous immunoglobulin treatment on anti-GM1 antibody-mediated neuropathies. J Neurol Sci. 1996;139:160–162
  21. Malik U, Oleksowicz L, Latov N, Cardo LJ. Intravenous γ-globulin inhibits binding of anti-GM1 to its target antigen. Ann Neurol. 1996;39:136–139
  22. Berchtold P, Dale GL, Tani P, McMillan R. Inhibition of autoantibody binding to platelet glycoprotein IIb/IIIa by antiidiotypic antibodies in intravenous gammaglobulin. Blood. 1989;74:2414–2417
  23. Crow AR, Song S, Semple JW, Freedman J, Lazarus AH. IVIg inhibits reticuloendothelial system function and ameliorates murine passive-immune thrombocytopenia independent of anti-idiotype reactivity. Br J Haematol. 2001;115:679–686
  24. Gergely J, Sarmay G. Fc gamma RII-mediated regulation of human B cells. Scand J Immunol. 1996;44:1–10
  25. Newburger JW, Takahashi M, Burns JC, Beiser AS, Chung KJ, Duffy CE, et al. The treatment of Kawasaki syndrome with intravenous gamma globulin. N Engl J Med. 1986;315:341–347
  26. Leung DY. Kawasaki syndrome: immunomodulatory benefit and potential toxin neutralization by intravenous immune globulin. Clin Exp Immunol. 1996;104:49–54
  27. Leung DY, Schlievert PM, Meissner HC. The immunopathogenesis and management of Kawasaki syndrome. Arthritis Rheum. 1998;41:1538–1547
  28. Takei S, Arora YK, Walker SM. Intravenous immunoglobulin contains specific antibodies inhibitory to activation of T cells by Staphylococcal toxin superantigens. J Clin Invest. 1993;91:602–607
  29. Hirono K, Kemmotsu Y, Wittkowski H, Foell D, Saito K, Ibuki K, et al. Infliximab reduces the cytokine-mediated inflammation but does not suppress infiltration of the vessel wall in refractory Kawasaki disease. Pediatr Res. 2009;65:696–701
  30. Gupta M, Noel GJ, Schaefer M, Friedman D, Bussel J, Johann-Liang R. Cytokine modulation with immune g-globulin in peripheral blood of normal children and its implications in Kawasaki disease treatment. J Clin Immunol. 2001;21:193–199
  31. Xu C, Poirier B, Van Huyen JPD, Lucchiari N, Michel O, Chevalier J, et al. Modulation of endothelial cell function by normal polyspecific human intravenous immunoglobulins. Am J Pathol. 1998;153:1257–1266
  32. Abe R, Horiuchi A, Miyake M, Kimura S. Anti-cytokine nature of natural human immunoglobulin: one possible mechanism of the clinical effect of intravenous immunoglobulin therapy. Immunol Rev. 1994;139:5–19
  33. Amemiya K, Dalakas MC. Cytokine mRNA expression in the muscle of patients with inclusion body myositis (IBM) before and after treatment with steroids and intravenous immunoglobulin. [abstract] Neurology. 1997;48:126
  34. Amemiya K, Semino-Mora C, Granger RP, Dalakas MC. Downregulation of TGF-β1 mRNA and protein in the muscles of patients with inflammatory myopathies after treatment with high-dose intravenous immunoglobulin. Clin Immunol. 2000;94:99–104
  35. Ankrust P, Muller F, Svenson M, Nordoy I, Bendtzen K, Froland SS. Administration of intravenous immunoglobulin (IVIg) in vivo downregulatory effects on the IL-1 system. Clin Exp Immunol. 1999;115:136–143
  36. 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;27:257–265
  37. Leung DY. Clinical and immunologic aspects of Kawasaki disease. Immunodeficiency Reviews. 1989;1:261–271
  38. Vassilev TL, Kazatchkine MD, Van Huyen JPD, 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. 2004;93:3624–3631
  39. Chang J, Shi P, Chiang E, Frenette P. Intravenous immunoglobulins reverse acute vaso-occlusive crises in sickle cell mice through rapid inhibition of neutrophil adhesion. Blood. 2008;111:915–923
  40. Turhan A, Jenab P, Bruhns P, Ravetch JV, Coller BS, Frenette PS. Intravenous immune globulin prevents venular vaso-occlusion in sickle cell mice by inhibiting leukocyte adhesion and the interactions between sickle erythrocytes and adherent leukocytes. Blood. 2004;103:2397–2400
  41. Berger M, Rosenkranz P, Brown CY. Intravenous and standard immune serum globulin preparations interfere with uptake of 125I-C3 onto sensitized erythrocytes and inhibit hemolytic complement activity. Clin Immun Immunopathol. 1985;34:227–236
  42. Basta M, Kirshbom P, Frank MM, Fries L. Mechanism of therapeutic effect of high-dose intravenous immunoglobulin: attenuation of acute, complement-dependent immune damage in a guinea pig model. J Clin Invest. 1989;84:1974–1981
  43. Dalakas MC. Polymyositis, dermatomyositis, and inclusion-body myositis. N Engl J Med. 1991;325:1487–1498
  44. Dalakas MC, Illa I, Dambrosia JM, Soueidan SA, Stein DP, Otero C, et al. A controlled trial of high-dose intravenous immunoglobulin infusions as treatment for dermatomyositis. N Engl J Med. 1993;329:1993–2000
  45. Dalakas MC. Controlled studies with high-dose intravenous immunoglobulin in the treatment of dermatomyositis, inclusion body myositis, and polymyositis. Neurology. 1998;51(suppl):S37–S45
  46. Basta M, Dalakas MC. High-dose intravenous immunoglobulin exerts its beneficial effect in patients with dermatomyositis by blocking endomysial deposition of activated complement fragments. J Clin Invest. 1994;94:1729–1735
  47. Basta M, Illa I, Dalakas M. Increased in vitro uptake of the complement C3b in the serum of patients with Guillian-Barre syndrome, myasthenia gravis and dermatomyositis. J Neuroimmunol. 1996;71:227–229
  48. Dalakas M. Intravenous immunoglobulin in the treatment of autoimmune neuromuscular diseases: present status and practical therapeutic guidelines. Muscle Nerve. 1999;22:1479–1497
  49. Arumugam TV, Tang S-C, Lathia JD, Cheng A, Mughal MR, Chigurupati S, et al. Intravenous immunoglobulin (IVIG) protects the brain against experimental stroke by preventing complement-mediated neuronal cell death. Proc Natl Acad Sci U S A. 2007;104:14104–14109
  50. Viard I, Wehrli P, Bullanim R, Schneider P, Holler N, Salomon D, et al. Inhibition of toxic epidermal necrolysis by blockade of CD95 with human intravenous immunoglobulin. Science. 1998;282:490–493
  51. Prasad NKA, 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;161:3781–3790
  52. Altznauer F, von Gunten S, Spath P, Simon H-U. Concurrent presence of agnostic and antagonistic anti-CD95 autoantibodies in intravenous Ig preparations. J Allergy Clin Immunol. 2003;112:1185–1190
  53. Sigman K, Ghibu F, Sommerville W, Toledano B, Bastein Y, Cameron L, et al. Intravenous immunoglobulin inhibits IgE production in human B lymphocytes. J Allergy Clin Immunol. 1998;102:421–427
  54. Zhuang Q, Mazer B. Inhibition of IgE production in vitro by intact and fragmented intravenous immunoglobulin. J Allergy Clin Immunol. 2001;108:229–234
  55. Proulx D, Aubin E, Lemieux R, Bazin R. Inhibition of B cell-mediated antigen presentation by intravenous immunoglobulins (IVIg). Clin Immunol. 2010;135:422–429
  56. de Grandmont M, Racine C, Roy A, Lemieux R, Neron S. Intravenous immunoglobulins induce the in vitro differentiation of human B lymphocytes and the secretion of IgG. Blood. 2003;101:3065–3073
  57. 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;101:14210–14215
  58. Bouhlal H, Hocini H, Quillent-Gregoire C, Donkova V, Rose S, Amara A, et al. Antibodies to C-C chemokine receptor 5 in normal human IgG block infection of macrophages and lymphocytes with primary R5-tropic strains of HIV-1. J Immunol. 2001;166:7606–7611
  59. Kaveri S, Vassilev T, Hurex 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;97:865–869
  60. Marchalonis JJ, Kaymaz H, Dedcoglu F, Schlutter SF, Yocum DE, Edmundson AB. Human autoantibodies reactive with synthetic autoantigens from T-cell receptor b chain. Proc Natl Acad Sci U S A. 1992;89:3325–3329
  61. Svenson M, Hansen MB, Bendtzen K. Binding of cytokines to pharmaceutically prepared human immunoglobulin. J Clin Invest. 1993;92:2533–2539
  62. Vassilev T, Gelin C, Kaveri S, Zalber MT, Bournsell L, Kazatchkine MD. Antibodies to the CD5 molecule in normal human immunoglobuins for therapeutic use (intravenous immunogloublins, IVIg). Clin Exp Immunol. 1993;92:369–372
  63. von Gunten S, Schaub A, Vogel M, Stadler BM, Miescher S, Simon H-U. Immunologic and functional evidence for anti-Siglec-9 autoantibodies in intravenous immunoglobulin preparations. Blood. 2006;108:4255–4259
  64. von Gunten S, Vogel M, Schaub A, Stadler BM, Miescher S, Crocker PR, et al. Intravenous immunoglobulin preparations contain anti-Sieglec-8 autoantibodies. J Allergy Clin Immunol. 2007;119:1005–1011
  65. Junghans RP, Anderson CL. The protection receptor for IgG catabolism is the β2-microglobulin-containing neonatal intestinal transport receptor. Proc Natl Acad Sci U S A. 1996;93:5512–5516
  66. Yu Z, Lennon VA. Mechanism of intravenous immune globulin therapy in antibody-mediated autoimmune diseases. N Engl J Med. 1999;340:227–228
  67. Li N, Zhao M, Hilario-Vargas J, Prisayanh P, Warren S, Diaz LA, et al. Complete FcRn dependence for intravenous Ig therapy in autoimmune skin blistering diseases. J Clin Invest. 2005;115:3440–3450
  68. Bussel J, Pahwa S, Porges A. Changes in the vitro antibody synthesis in ITP treated with intravenous gamma globulin are closely linked to long-term outcome. J Clin Immunol. 1986;6:50–56
  69. Hansen RJ, Balthasar JP. Effects of intravenous immunoglobulin on platelet count and antiplatelet antibody disposition in a rat model of immune thrombycytopenia. Blood. 2002;100:2087–2093
  70. Hansen R, Balthasar J. Intravenous immunoglobulin mediates an increase in anti-platelet clearance via the FcRn receptor. Thromb Haemost. 2002;88:898–899
  71. Daeron M. Fc receptor biology. Annu Rev Immunol. 1997;15:203–234
  72. Kimberly RP, Salmon JE, Edberg JC. Receptors for immunoglobulin G. Arthritis Rheum. 1995;38:306–314
  73. Samuelsson A, Towers TL, Ravetch JV. Anti-inflammatory activity of IVIG mediated through the inhibitory Fc receptor. Science. 2001;291:484–486
  74. Kaneko Y, Nimmerjahn F, Ravetch J. Anti-inflammatory activity of immunoglobulin G resulting from Fc sialylation. Science. 2006;313:670–673
  75. Anthony R, Nimmerjahn F, Ashline D, Reinhold V, Paulson J, Ravetch J. Recapitulation of IVIG anti-inflammatory activity with a recombinant IgG Fc. Science. 2008;320:373–376
  76. Vaccaro C, Zhou J, Ober RJ, Ward ES. Engineering the Fc region of immunoglobulin G to modulate in vivo antibody levels. Nat Biotechnol. 2005;23:1283–1288
  77. Anthony RM, Wermeling F, Karlsson MC, Ravetch JV. Identification of a receptor required for the anti-inflammatory activity of IVIG. Proc Natl Acad Sci U S A. 2008;105:19571–19578
  78. Amran D, Renz H, Lack G, Bradley K, Gelfand EW. Suppression of cytokine-dependent human T-cell proliferation by intravenous immunoglobulin. Clin Immunol Immunopathol. 1994;73:180–186
  79. Aukrust P, Muller F, Nordoy I, Haug CJ, Froland SS. Modulation of lymphocyte and monocyte activity after intravenous immunoglobulin administration in vivo. Clin Exp Immunol. 1997;107:50–56
  80. MacMillan HF, Lee T, Issekutz AC. Intravenous immunoglobulin G-mediated inhibition of T-cell proliferation reflects an endogenous mechanism by which IgG modulates T-cell activation. Clin Immunol. 2009;132:222–233
  81. 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;111:715–722
  82. 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. 2010;179:5571–5575
  83. Furuno K, Yuge T, Kusuhara K, Takada H, Nishio H, Khajoee V, et al. CD25+CD4+ regulatory T cells in patients with Kawasaki disease. J Pediatr. 2004;145:385–390
  84. De Groot AS, Moise L, McMurry JA, Wambre E, Van Overtvelt L, Moingeon P, et al. Activation of natural regulatory T cells by IgG Fc-derived peptide “Tregitopes.”. Blood. 2008;112:3303–3311
  85. 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;101:758–765
  86. Wasserbauer N, Allen C, Ballow M. Effects of IVIG on dendritic cell (CD) maturation and function. J Allergy Clin Immunol. 2009;123(suppl):S162
  87. Steinman RM, Banchereau J. Taking dendritic cells into medicine. Nature. 2007;449:419–426
  88. Orange JS, Hossny EM, Weiler CR, Ballow M, Berger M, Bonilla FA, et al. Use of intravenous immunoglobulin in human disease: a review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology. J Allergy Clin Immunol. 2006;117(suppl):S525–S553
  89. Tha-In T, Bayry J, Metselaar H, Kaveri SV, Kwekkeboom J. Modulation of the cellular immune system by intravenous immunoglobulin. Trends Immunol. 2008;29:608–614
  90. Ballow M. Mechanisms of action of intravenous immune serum globulin in autoimmune and inflammatory diseases. J Allergy Clin Immunol. 1997;100:151–157

 Series editors: Joshua A Boyce, MD, Fred Finkelman, MD, William T. Shearer, MD, PhD, and Donata Vercelli, MD

 Terms in boldface and italics are defined in the glossary on page 316.

PII: S0091-6749(10)01645-3

doi:10.1016/j.jaci.2010.10.030

The Journal of Allergy and Clinical Immunology
Volume 127, Issue 2 , Pages 315-323, February 2011

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