Transfusion Clinique et Biologique 10 (2003) 165–169

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État de l’art

Mechanisms of action of intravenous immunoglobulins in autoimmune

and inflammatory diseases
Mécanismes d’action des immunoglobulines intraveineuses
dans les maladies auto-immunes et inflammatoires
J. Bayry, N. Misra, V. Latry, F. Prost, S. Delignat, S. Lacroix-Desmazes,
M.D. Kazatchkine, S.V. Kaveri *
INSERM U430, Institut des Cordeliers, Université Pierre et Marie Curie, 15, rue de l’Ecole de Médecine, 75006 Paris, France

Abstract

Therapeutic polyclonal intravenous immunoglobulin (IVIg) consists of normal IgG obtained from the pools of plasma of several thousand
healthy blood donors. IVIg is used as substitutive treatment of primary and secondary immunodeficiences. Since the first study of Paul Imbach
who demonstrated the beneficial effect in idiopathic thrombocytopenic purpura, IVIg is also used in a number of autoimmune and
inflammatory diseases. The immunoregulatory effects of IVIg in autoimmune diseases depend on the interaction of Fc portion of immuno-
globulins with Fc receptors and on the selection of lymphocyte repertoires of patients through variable regions of infused immunoglobulins.
IVIg modulates the activation and effector functions of B and T lymphocytes, neutralizes pathogenic autoantibodies, interferes with antigen
presentation and has a strong anti-inflammatory effect which depends on its interaction with the complement system, cytokines and endothelial
cells. The immunomodulatory potential of IVIg in patients is thus a result of a variety of complex mechanisms that act in a synergy.
© 2003 Éditions scientifiques et médicales Elsevier SAS. All rights reserved.

Résumé

Les immunoglobulines intraveineuses (IgIV) polyclonales utilisées en thérapeutique sont constituées d’IgG normales obtenues à partir de
pools de plasma provenant de plusieurs milliers de donneurs sains. Les IVIg sont utilisées dans le traitement substitutif des déficits primitifs
et acquis en anticorps. Depuis les premiers travaux de Paul Imbach qui en a démontré l’effet dans le purpura thrombopénique idiopathique, les
IgIV sont également indiquées et utilisées dans un grand nombre de maladies autoimmunes et inflammatoires systémiques. L’effet
immunorégulateur des IgIV au cours des maladies autoimmunes dépend de l’interaction du fragment Fc des immunoglobulines (Ig) avec les
récepteurs Fc et de la sélection des répertoires lymphocytaires du patient par les régions variables des immunoglobulines perfusées. Les IgIV
modulent l’activation et les fonctions effectrices des lymphocytes T et B, neutralisent les autoanticorps pathogènes, interfèrent avec la
présentation de l’antigène et ont un puissant effet anti-inflammatoire qui dépend de leurs interactions avec le système du complément, les
cytokines et les cellules endothéliales. Le potentiel immunomodulateur des IgIV observé chez les patients traités résulte donc d’un ensemble
complexe de mécanismes agissant en synergie.
© 2003 Éditions scientifiques et médicales Elsevier SAS. All rights reserved.

Keywords: Autoimmunity; Immunomodulation; Immunotherapy; Idiopathic thrombocytopenic purpura; Intravenous immunoglobulin

Mots clés : Autoimmunité ; Immunomodulation ; Immunotherapie ; Purpura thrombopénique idiopathique ; Intravenous immunoglobulin

* Corresponding author.
E-mail address: srini.kaveri@u430.bhdc.jussieu.fr (S.V. Kaveri).

© 2003 Éditions scientifiques et médicales Elsevier SAS. All rights reserved.

DOI: 10.1016/S1246-7820(03)00035-1
166 J. Bayry et al. / Transfusion Clinique et Biologique 10 (2003) 165–169

1. Introduction Table 2
Immunoregulatory effects of IVIg
Intravenous immunoglobulin (IVIg) has been used in the Fc receptors
treatment of primary and secondary antibody deficiencies for Blockade of Fc receptors on macrophages and effector cells
over 25 years. IVIg was first demonstrated to be effective in Antibody-dependent cellular cytotoxicity
autoimmune disorders two decades ago in the treatment of Induction of inhibitory FcgRIIB receptors
acute immune thrombocytopenia. Since then, the therapeutic Inflammation
Attenuation of complement-mediated damage
efficacy of IVIg has been established in the Guillain Barré
Decrease in immune complex-mediated inflammation
syndrome, chronic inflammatory demyelinating polyneur- Induction of anti-inflammatory cytokines
opathy, myasthenia gravis, dermatomyositis, Kawasaki syn- Inhibition of activation of endothelial cells
drome and the prevention of Graft vs. Host disease in recipi- Neutralization of microbial toxins
ents of allogeneic bone marrow transplants, and reported in a Reduction in steroid requirements
large number of other autoimmune and systemic inflamma- B cells and antibodies
tory conditions (Table 1) [1]. Control of emergent bone marrow B cell repertoires
Negative signalling through Fcg receptor
Selective down-regulation/up-regulation of antibody production
2. Mechanisms of action of IVIg Neutralization of circulating autoantibodies by anti-idiotypes
T cells
The mode of action of IVIg is complex, involving modu- Regulation of T helper cell cytokine production
lation of expression and function of Fc receptors, interfer- Neutralization of T cell superantigens
ence with complement activation and the cytokine network, Antigen-presenting cells
Modulation of function of dendritic cells
provision of anti-idiotypic antibodies and modulation of T
Cell growth
and B cell activation, differentiation and effector functions Inhibition of lymphocyte proliferation
(Table 2). Such a broad range of activities reflects the func- Regulation of apoptosis
tions of circulating immunoglobulins in the maintenance of
Table 1 tolerance to self and immune homeostasis in healthy indi-
Immune-mediated diseases in which a beneficial effect of IVIg has been viduals. In this presentation, emphasis is laid on the mecha-
reported nisms of action of IVIg that imply interaction of IVIg with
Idiopathic thrombocytopenic purpura (ITP)a the idiotypic network and with membrane molecules of lym-
Acquired immune thrombocytopenias phocytes that play an important role in immune regulation.
Autoimmune neutropenia
Autoimmune hemolytic anemia
Autoimmune erythroblastopenia 3. Fc receptor-mediated effects
Parvovirus B19-associated red cell aplasia
Anti-factor VIII autoimmune disease The blockade of Fcc receptors on macrophages by IVIg is
Acquired von Willebrand’s disease considered as the underlying mechanism for the effect of
Guillain-Barré Syndromea IVIg in idiopathic thrombocytopenic purpura (ITP) and other
Chronic inflamatory demyelinating polyneuropathy (CIDP)a peripheral autoimmune cytopenias. Evidence for this mecha-
Myasthenia gravisa nism of action of IVIg comes from the following observa-
Multifocal neuropathy
tions (i) anti-D IgG induces an increase in platelet counts in
Polymyositis
Rh(D)-positive ITP patients [2]; (ii) peripheral blood mono-
Dermatomyositisa
Kawasaki Diseasea
cytes of IVIg-treated patients with ITP exhibit a decreased
ANCA-positive systemic vasculitis ability to form rosettes with IgG-coated erythrocytes [3]; (iii)
Antiphospholipid syndrome the administration of IVIg results in a decreased clearance of
Recurrent spontaneous abortions anti-D-coated autologous erythrocytes in vivo [4]; (iv) the
Rheumatoid arthritis and felty’s syndrome administration of antibodies against FccRIII or of Fc frag-
JRA ments of IVIg to patients with ITP has similar efficacy as
SLE IVIg [5,6]. Recent studies have further suggested that IVIg
Thyroid ophthalmopathy could also be effective in ITP by up-regulating the expression
Birdshot retinochoroidopathya
of FccRIIB. Thus, using a transgenic murine model of ITP, it
Graft vs. host diseasea
has been demonstrated that IVIg mediates its protective ef-
Multiple sclerosis
Insulin-dependent diabetes mellitus
fect, by its ability to induce the expression of the inhibitory
Steroid-dependent asthma FccRIIB on effector cells that otherwise trigger the clearance
Steroid-dependent severe atopic dermatitis of the opsonized platelets [7].
Crohn’s disease Fc-dependent immunomodulation by IVIg may also in-
a
Diseases in which evidence for the effect of IVIg has been obtained in volve secondary cellular events transduced by the interaction
controlled trials. between the Fc portion of immunoglobulin and Fc receptors.
 J. Bayry et al. / Transfusion Clinique et Biologique 10 (2003) 165–169
Thus, the simultaneous ligation of FccRII and of the idiotype
of a B cell antigen receptor may inhibit B cell activation and
induce anergy and/or apoptosis, through phosphorylation of
immune tyrosine inhibitory motifs (ITIM) [8]. The latter
mechanism may provide a basis for IVIg-mediated suppres-
sion of autoantibody production. An additional Fc-dependent
mechanism of action of IVIg has recently been hypothesized,
whereby the binding of IVIg to a “protective” Fc receptor in
endocytotic vesicles, termed FcRn, would result in the accel-
erated clearance of IgG and therefore reduce the levels of
pathogenic antibodies [9].
Anti-inflammatory effects of IVIg depend on both Fc
moiety and variable region of infused Ig. Anti-inflammatory
effects of IVIg include its ability to neutralize microbial
toxins, interfere with complement-mediated damage, alter
the inflammatory potential of soluble immune complexes,
modulate the production of pro-inflammatory and anti-
inflammatory cytokines and of chemokines, and the expres-
sion of adhesion molecules [10–13].
4. V region-mediated interactions of IVIg
Interactions between IVIg and variable regions of autoan-
tibodies provide the basis for the ability of IVIg to regulate
autoreactive B cell clones in vivo. We have accumulated
several lines of evidence demonstrating that IVIg contains
antibodies that recognize idiotypes of disease-associated and
of natural autoantibodies and antigen receptors on B lympho-
cytes [14].
We have shown that intact IVIg and F(ab')2 fragments of
IVIg neutralize the functional activity of various autoanti-
bodies and/or inhibit the binding of the autoantibodies to
their respective autoantigens in vitro [14]. Inhibition of au-
toantibody activity by IVIg has been observed in the case of
autoantibodies to several self antigens. The neutralizing ca-
pacity of IVIg toward autoantibodies likely explains the rapid
fall in the plasma titer of anti-factor VIII and anti-neutrophil
cytoplasmic antigen (ANCA) autoantibodies that has been
seen in patients with anti-factor VIII autoimmune disease and
with ANCA-positive vasculitis following treatment with
IVIg [15,16]. In patients with these diseases, a direct rela-
tionship has been found between the ability of IVIg to neu-
tralize autoantibody activity in vitro and that of IVIg to
decrease autoantibody titers in treated patients in vivo
[16,17]. Evidence that the inhibitory capacity of IVIg is
related to the presence in IVIg of antibodies directed to
idiotypes of autoantibodies came from affinity chromatogra-
phy experiments using columns of F(ab')2 fragments of IVIg
coupled to Sepharose. A 1.3- to 50-fold increase in specific
anti-factor VIII, anti-DNA, anti-thyroglobulin (TG), anti-
peripheral nerve, ANCA, anti-intrinsic factor and anti-retinal
antigen autoantibody activity was observed in the eluates,
demonstrating that F(ab')2 fragments of IVIg specifically
bind idiotypic determinants located in or close to the antigen-
binding site of the autoantibodies, with high affinity. We have
further shown that IVIg share anti-idiotypic reactivity toward
167
idiotypes of autoantibodies with heterologous anti-idiotypic
reagents, as additional evidence that IVIg contains anti-
idiotypes to autoantibodies. Thus, IVIg was shown to com-
pete with monoclonal and polyclonal anti-idiotypic antibod-
ies for the binding to idiotypes expressed by anti-factor VIII
[18] and anti-thyroglobulin autoantibodies [19].
5. Interaction of IVIg with membrane molecules
of lymphocytes
In addition to binding to idiotypes of immunoglobulins,
IVIg reacts with a number of membrane molecules of T cells,
B cells and monocytes that are relevant for the control of
autoreactivity and induction of tolerance to self. Thus, IVIg
has been shown to contain antibodies to variable and constant
regions of the human ab T cell receptor, cytokines and
cytokine receptors, CD5, CD4, HLA class I molecules, RGD
adhesion motif, Fas and CCR5 [1,13,20–24]. We believe that
antibodies directed to such functional molecules of lympho-
cytes are important for the immunomodulatory effects of
normal immunoglobulin.
6. Interaction of IVIg with antigen-presenting cells
We have recently examined the effects of IVIg on differ-
entiation, maturation and function of dendritic cells (DC)
[25] (Fig. 1). We have shown that DC are the primary targets
for the immunosuppressive effects of IVIg on T cell activa-
tion. IVIg inhibits the differentiation and maturation of DC in
vitro, and abrogates the capacity of mature DC to secrete
IL-12 upon activation, while enhancing IL-10 production.
IVIg-induced down-regulation of costimulatory molecules
associated with modulation of cytokine secretion resulted in
inhibition of auto- and allo-reactive T cell activation and
proliferation. Modulation of DC maturation and function by
IVIg is of potential relevance to its immunomodulatory ef-
fects in controlling specific immune responses in autoim-
mune diseases, transplantation and other immune-mediated
conditions [25].
7. Concluding remarks
Significant progress has been made in understanding the
mechanisms by which IVIg exerts immunomodulatory func-
tions since its first use in the treatment of ITP. The mode of
action of IVIg is complex, involving modulation of expres-
sion and function of Fc receptors, interference with activa-
tion of complement and the cytokine network, provision of
anti-idiotypic antibodies, regulation of cell growth, and ef-
fects on the activation differentiation and effector functions
of T and B cells. The therapeutic effects of immune globulin
most likely reflect the functions of natural antibodies in
maintaining immune homeostasis in healthy people. Over
the past 20 years, immune globulin has become the preferred
168 J. Bayry et al. / Transfusion Clinique et Biologique 10 (2003) 165–169

Fig. 1. Integrated model of the effect of IVIg on DC. IVIg may induce apoptosis of monocytes, check the number of monocytes differentiating into immature
DC, block the constitutive, or inflammation-dependent maturation of DC. IVIg may block the DC-mediated T cell activation and survival by down-regulating
the expression of CD40 and B7 on DC. IVIg may block Fas-FasL-dependent maturation of DC. By down-regulating the expression of Fas on DC, IVIg may
contribute towards the inhibition of DC maturation, a process that is dependent on Fas engagement through cognate interaction of DC with FasL-expressing T
cells. IVIg-mediated suppression of DC is further assisted by elimination of T cells by IVIg through apoptosis.

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globulin represents a promising but unproved treatment, are
imperative.
Acknowledgements
Supported by Institut National de la Santé et de la Recher-
che Médicale (INSERM) and Centre National de la Recher-
che Scientifique (CNRS) France, by a grant from ZLB Bio-
plasma AG, Bern, Switzerland.
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