REVIEW

CURRENT
OPINION Mechanisms of immune regulation by IVIG
Mark Ballow

Purpose of review
In the past few years there have been many advances in our understanding of the mechanisms by which
intravenous immune globulin (IVIG) modulates immune function in autoimmune disorders.
Recent findings
Previous investigations have focused on the Fc domain of the IgG molecule, and the role of the FcgRIIB
receptor and the sialylated Fc domain that have been show to mediate the anti-inflammatory effects in
certain murine models of autoantibody-mediated diseases. More recent findings have implicated the F(ab’)2
domain in IVIG-induced immune modulation in T-cell-mediated autoimmune disease models in which
upregulation of T-regulatory cells and downregulation of the Th17 pathways are important components of
this mechanism. The prostaglandin E pathway may be playing a role in the IVIG-induced changes in the
T-regulatory pathway.
Summary
Many of the mechanisms proposed for the immune-modulating effects of IVIG demonstrate the complexity of
immune effector functions in disease processes. Although controversy exists on the role of the FcgRIIB
receptor and the importance of the sialylated Fc domain in human autoimmune disorders, probably no one
single mechanism is responsible for the effects of IVIG in autoimmune and inflammatory diseases. The
potential role of the prostaglandin E pathway may offer alternative treatments.
Keywords
FcgRIIB receptor, intravenous immune globulin, neonatal Fc receptor, prostaglandin E, sialylation,
Th17 cells, T-regulatory cells

INTRODUCTION the immunomodulatory effects of immunoglobulin.

In 1981, Imbach et al. [1] were treating immune Mechanisms of action of IGIV are as follows:
deficiency patients with intravenous immune glob-
ulin (IVIG). Several of these patients concomitantly (1) blockade of Fc receptors on macrophages of the
had idiopathic thrombocytopenia purpura (ITP) and reticuloendothelial system of liver and spleen,
after treatment with IVIG, the platelet counts (2) restoration of idiotypic-antiidiotypic network,
increased dramatically immediately after the IVIG (3) suppression or neutralization of cytokines by
infusion. These observations led to a subsequent specific antibodies in the IGIV,
study [1] in children with ITP, which demonstrated (4) block binding of adhesion molecules on leu-
that the administration of high-dose IVIG led to a kocytes to vascular endothelium,
dramatic increase in platelet count and often the (5) inhibit complement uptake on target tissues,
resolution of the disease process. Subsequently to (6) neutralize microbial toxins,
these observations by Imbach in the early 1980s, (7) block Fas ligand-mediated apoptosis by anti-
there has been an explosion in the use of IVIG in Fas antibodies in the IGIV,
patients with a variety of autoimmune and inflam-
matory disorders. Today, more than 70% of the IVIG
Division of Allergy and Immunology, University of South Florida, Morsani
utilized in the United States is for immune modu-
College of Medicine, Children’s Research Institute, All Children’s Hos-
lation in patients with autoimmune and inflamma- pital, St Petersburg, Florida, USA
tory disorders. This review will examine the more Correspondence to Mark Ballow, MD, Division of Allergy and Immuno-
recent literature on the mechanisms of action of IgG logy, Children’s Research Institute, 140 7th Ave South, All Children’s
in the modulation of the immune system, and Hospital, St Petersburg, FL 33701-4. 899, USA. Tel: +1 727 553 3519;
will focus on those mechanisms that affect the e-mail: [email protected]
Fcg receptors and T-regulatory (Treg) pathways. A Curr Opin Allergy Clin Immunol 2014, 14:509–515
number of mechanisms have been postulated for DOI:10.1097/ACI.0000000000000116

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 Primary immune deficiency disease

half-life of serum IgG is markedly decreased. Yu and

KEY POINTS Lennon [5] postulated that the administration of
 Although saturation of the FcRn receptor may be an IVIG saturates this FcRn receptor found in the endo-
important component of IVIG-induced modulation of somes of endothelial cells, resulting in the enhanced
antibody-mediated autoimmune disease in experimental catabolism of the autoantibodies in antibody-medi-
models, more studies are needed in human disease. ated autoimmune diseases. In mouse models of
bullous pemphigoid and arthritis, IVIG treatment
 Studies in splenectomized mice, with ITP and in patients
with immune deficiency and autoimmune disease, have resulted in a reduction in pathogenic antibodies to
questioned the role of the FcgRIIB receptor and the levels beneath the disease-causing threshold, and
C-type lectin receptor DC-SIGN in IVIG-induced immune this effect was attenuated in FcRn-deficient mice [6].
modulation. Hansen and Balthasar [7] reported that high-dose
IVIG in a rat model of immune thrombocytopenia
 Although the importance of sialylation of the IgG
molecule especially of the Fc domain is important in enhanced the clearance of antiplatelet antibodies by
murine models of autoantibody-mediated disease, this saturation of the FcRn receptor by immunoglobulin,
mechanism remains controversial in other animal and that this mechanism may account for 50% of
models and in human disease. the total protective effects of IVIG. These studies
were supported by additional observations by Han-
 IVIG-induced Treg cells and inhibition of the Th17
pathway appear to be important mechanisms of action sen and Balthasar [7] that in an FcRn knockout
of IVIG. mouse, IVIG therapy failed to increase the clearance
of antiplatelet antibodies. Similarly, using FcRn
 Several studies have demonstrated the role of the PGE (
/
) knockout mice Li et al. [6] reported that the
pathway in the immune modulation of IVIG in certain
FcRn receptor saturation by immunoglobulin was
disease models.
critical to protect neonatal mice in a bullous pem-
phigoid mouse model. However, in these FcRn (
/
)
mice models it is difficult to assess the pathogenicity
(8) induce apoptosis with anti-Fas antibodies at of the autoantibody-inducing disease. In the absence
high concentrations of IGIV, of the FcRn receptor, the clearance of these autoanti-
(9) neutrophil apoptosis by anti-Siglec-9 anti- bodies in these disease models is modified, which
bodies in IGIV, affects their pathologic effects. Furthermore, in a
(10) saturate the FcRn receptors to enhance the different mouse ITP model with absent FcRn, IVIG
clearance of autoantibodies, was still effective in increasing platelet counts [8].
(11) induction of inhibitory FcgRIIB receptors on Thus, the role of the FcRn receptor in human auto-
effector macrophages, antibody-mediated diseases modulated by IVIG is
(12) neutralization of growth factors for B-cells, for unclear (Fig. 1).
example, B-cell activating factor,
(13) inhibit T-cell proliferative responses,
(14) expand and/or activating a population of Treg Fc RECEPTOR BLOCKADE
cells, Following the administration of 1 to 2 g/kg of IVIG
(15) downregulate the Th17 pathway, platelet counts rise rapidly in patients with ITP [9].
(16) inhibit the differentiation and maturation of Fc receptor blockade of the reticuloendothelial
dendritic cells. system was suggested as the mechanism by which
platelet counts rapidly increase after the adminis-
The reader is referred to other reviews on this tration of IVIG [10,11]. Autoantibody-opsonized
topic for a more comprehensive and complete platelets are destroyed in the spleen and liver by
review of the mechanisms of action of immunoglo- FcgR-mediated phagocytic clearance [8]. Fehr et al.
&&
bulin [2,3 ]. [11] showed that the administration of IVIG in
patients with ITP prolonged the in-vivo clearance
of radiolabeled antibody sensitized red blood cells.
THE ROLE OF THE NEONATAL Fc Further supporting evidence for Fc receptor block-
RECEPTOR ON IMMUNE MODULATION ade on macrophages in the spleen and in other
The neonatal Fc receptor (FcRn) is a specialized parts of the reticuloendothelial system was reported
receptor that binds serum IgG, protects the IgG from by Clarkson et al. [12] who demonstrated a marked
degradation inside the lysosomes and returns the increase in platelet counts in patients with ITP
IgG intact to the plasma circulation. These special- using a monoclonal antibody directed against the
ized receptors account for the long half-life of serum FcgRIIIA receptor. Intravenous administration in
IgG of 21–25 days [4]. In FcRn knockout mice the children with acute ITP of Fcg fragments prepared

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 Mechanisms of immune regulation by IVIG Ballow

Modulating activities of IVIG

Autoantibody-mediated disease Cell-mediated autoimmune disease

DCIR
DC
Fc F(ab’)2
Saturation of the FcRn receptor
PGE2
Fc
Fc sialylated enriched IgG

SIGN-R1

Treg cell TH17 cell pathway

FoxP3+
IL-33
Macrophage

IL-4 Tregitopes
Inhibitory FcγR

Decrease inflammation
Basophil
Effector macrophage

FIGURE 1. Immune modulating activities of IVIG in antibody mediated and cell mediated autoimmune disease.

from IVIG resulted in a rapid increase in platelet effects of IVIG. The protective effects of IVIG were
counts [13]. The efficacy of using Fcg fragment associated with the increased expression of the
therapy in ITP strengthens the hypothesis that FcgRIIB receptor on splenic macrophages [17]. Sub-
Fcg receptor blockade is the main mechanism of sequently, Kaneko et al. [18] showed that the inhibi-
action of IVIG for the immediate rapid increase in tory properties of IVIG was linked to the sialylation
platelet counts in ITP. However, this mechanism of the glycan component in the CH2 domain of the
does not explain the longer-term immune-modulat- Fc fragment. Using a K/BxN serum-induced arthritis
ing effects of IVIG therapy in these autoantibody- murine model, Kaneko et al. [18] showed that IVIG
mediated diseases. at 1 g/kg inhibited the inflammatory arthritic
process. Deglycosylated or neuraminidase-treated
IVIGs were unable to inhibit this inflammation.
MODULATION OF IMMUNOREGULATORY IVIG enriched for the sialylated glycan moiety
FUNCTION THROUGH THE Fc RECEPTOR had comparable inhibitory effects on the inflamma-
Although Fc receptor blockade with the adminis- tory process at only 1/10th of the dosage used with
tration of IVIG may result in the rapid rise in platelet intact IVIG. This inhibitory activity was dependent
counts in patients with ITP, studies [10,14] have on FcgRIIB expression on effector macrophages.
shown that the levels of antiplatelet antibodies Anthony et al. [19] engineered a recombinant/sialy-
decrease over time. Studies [15,16] addressing these lated human IgG1 Fc protein that had a 35-fold
observations suggest that the inhibitory FcgRIIB enhanced immune-modulating activity compared
receptors found on a variety of cell types including with native IVIG. However, antibodies enriched
macrophages, B-cells and a subpopulation of T-cells for the sialic acid moiety have reduced binding to
may be playing a role in the immune modulation of the FcgRs [20] that suggested that other receptor(s)
IVIG. This FcgRIIB receptor provides an inhibitory are involved in the inhibitory or anti-inflammatory
signal to cells through a pathway mediated by an properties of IVIG.
immunoregulatory tyrosine-based inhibition motif. Although in these mouse models of auto-
In a murine model of immune thrombocytopenia antibody mediated disease the role of the sialylated
Samuelsson et al. [17] reported that the protective IgG molecule resulting in an increase in the FcgRIIB
effects of IVIG required this inhibitory Fcg receptor, receptor on effector macrophages was important,
for example, in which either disruption of Fcg RIIB the intermediary steps leading to changes in this
receptors in knockout mice or blocking with a receptor were not clear. Anthony et al. [21] per-
monoclonal antibody reversed the therapeutic formed studies to examine the mechanism by which

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 Primary immune deficiency disease

the sialylated Fc fragment could mediate its anti- blocking antibody, IVIG still enhanced IL-33 mRNA
inflammatory activity, and identify the target cell production by macrophages in vitro. These data and
that initiates this anti-inflammatory pathway. They other studies [26,27] suggest a DC-SIGN and FcgRIIB
showed that a C-type lectin receptor, for example, receptor independent pathway for the effects of
specific intercellular adhesion molecule 3-grabbing IVIG. In contrast, observations in patients with
nonintegrin-related 1 (SIGN-R1) which is expressed chronic inflammatory demyelinating polyneuro-
primarily on splenic marginal zone macrophages pathy treated with high-dose IVIG demonstrated
was required for the anti-inflammatory activity of upregulation of this FcgRIIB receptor on peripheral
IVIG in concert with its ability to bind to sialylated blood monocytes [28]. Therefore, the pathways by
Fc domains. Furthermore, the 2,6 linkage of the which IVIG modulated immune function may be
sialylated moiety in the Fc domain was important different in humans compared with mice, a theme
for the modulating effects of IVIG. Anthony et al. that will be expanded upon below in other models
[22] demonstrated that the interaction between sia- on the effects of IVIG-induced immune modulation.
lylated IgG Fc and SIGN-R1 leads to the upregulation
of the inhibitory FcgRIIB receptor on effector macro-
phages, and that this effect of IVIG was abrogated in THE SIALYLATION CONTROVERSY
SIGN-R1 knockout mice. Using their K/BxN serum- The experimental models of Ravetch and colleagues
induced arthritis model in mice, Anthony et al. [22] clearly outline the role of sialylated IgG on the Fc
showed that IVIG induced the production of IL-33 domain in the immunomodulatory properties of
from dendritic cells, by binding of the sialylated Fc IVIG on murine models of antibody-mediated auto-
domain to SIGN-R1, which in turn increased the immune disease. IgG is glycosylated in the constant
production of IL-4 from basophils, and upregulated region in the CH2 domain at Asn 297. Glycosylation
the expression of the FcgRIIB receptor on effector in the IgG Fc domain modifies antibody effector
macrophages. It had been demonstrated by others function by modifying its binding affinity to Fcg
that Th2 derived cytokines, and IL-4 in particular, receptors. A fully processed form of the carbo-
increase the expression of the FcgRIIB receptor on hydrate component with a terminal sialic acid
effector cells. moiety is present in only 5% of the total serum
Does this mechanism of action for IVIG reported IgG. Is this the reason why such large doses of IVIG
by Ravetch and colleagues in several autoantibody- are required to achieve efficacy in human auto-
mediated mouse models [18,19,21,22] play a role in immune diseases? Several studies have suggested
humans? In particular is dendritic cell-specific inter- that the Fc sialylated portions of the IgG molecule
cellular adhesion molecule-3-grabbing nonintegrin were not critical for the activity of IVIG. Leontyev
(DC-SIGN), the human orthologue of SIGN-R1 in et al. [23] described a sialylation-independent mech-
the mouse, involved in the immune-modulating anism for the effects of IVIG in a murine ITP model.
effects of IVIG in man? Others have questioned Campbell et al. [29] explored the effects of high-dose
whether this lectin receptor has a comparable role IVIG in two murine models of antibody-mediated
for the anti-inflammatory effects of the IgG Fc inflammation of the joints, models for rheumatoid
domain on human macrophages and dendritic cells. arthritis: the K/BxN serum transfer murine model
SIGN-R1 is mainly expressed on mouse splenic used by Ravitch and colleagues, and the collagen
marginal zone macrophages, an important aspect antibody-induced arthritis murine model. IVIG was
of the model proposed by Ravetch and colleagues. protective in a dose-dependent manner, and the
The human spleen differs from that in mice with protective effect was linked to the Fc domain of
regard to the presence of marginal zone macro- IgG. However, sialylation was not required for effi-
phages. Splenectomized patients with ITP still cacy. Also, in contrast to the studies by Anthony
respond to IVIG therapy. In an ITP mouse model, et al. [22], depleting basophils with a monoclonal
IVIG still showed efficacy when splenectomized antibody did not abrogate the effects of IVIG on its
&&
[23,24]. Tjon et al. [25 ] studied these proposed immune-modulating activities. These authors also
pathways in patients receiving IVIG treatment for called into question the role of IL-33 in the immune-
primary immune deficiency disease and auto- modulating process by IVIG. IL-33Ra
/
mice, but
immune disease. IVIG therapy increased plasma not IL-33
/
mice were protected from K/BxN serum
levels of IL-33, IL-4 and IL-13, but the FcgRIIB transfer-induced arthritis [30]. Bayry et al. [26] found
receptor was not upregulated on peripheral blood that sialylated IgG Fc fragments were not involved
myeloid dendritic cells. There was decreased expres- in the anti-inflammatory activity of IVIG on human
sion of the activating FcgRIIA receptor and of the dendritic cells. Furthermore, the variable region
IFN-gR2 subunit on myeloid dendritic cells in those domains also have sialic acid rich glycan moieties
patients receiving high-dose IVIG. Using a DC-SIGN [31,32] that may be important in engaging C-type

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 Mechanisms of immune regulation by IVIG Ballow

&&
lectin receptors. In several murine and in-vitro cells [38]. In their model system Massoud et al. [39 ]
human models (see below), the F(ab’)2 fragment reported that sialylated IgG bound to a novel C-type
of IVIG was involved in the immune modulation lectin receptor, that is the dendritic cell immuno-
of the disease process. receptor (DCIR), induced Treg cells and attenuated
airway hyperresponsiveness. Interestingly, transfer
of IVIG treated myeloid dendritic cell from Fcg
EFFECTS OF IMMUNOGLOBULIN G ON THE receptor knockout mice still increased Treg cells
T-REGULATORY PATHWAYS and abrogated airway hyperresponsiveness. These
Although many labs have focused on antibody- observations suggest that in this asthma model the
mediated autoimmune disease, other labs have effects of IVIG were independent of Fcg receptors.
focused on the effects of IVIG on cell-mediated The importance of Treg cells in the immune
immune autoimmune disease. One such T-cell- modulation induced by IVIG is also underscored
mediated model is experimental autoimmune ence- by the studies of de Groot et al. [40]. These investi-
phalomyelitis, a murine animal model of multiple gators identified epitopes, that is Tregitopes in both
sclerosis in which IVIG abrogates the disease pro- the Fc and F(ab’)2 regions that bind to multiple
gression by expanding CD4þCD25þ forkhead box human leucocyte antigen class II determinants that
P3 (FoxP3) Treg cells. Using this animal model, Othy results in the expansion and activation of FoxP3þ
&&
et al. [33 ] showed that IVIG inhibits the differen- Treg cells. Coincubation of these Tregitopes with
tiation of Th17 and Th1 cells, and increases the house dust mite antigen led to expansion of
number of CD4þCD25þ FoxP3þ Treg cells. Even CD4þCD25high Treg cells, and suppressed IL-5 and
in FcgRIIB
/
mice IVIG decreased the number of IFN-g cytokine secretion, but upregulated IL-10
Th17 cells, while expanding the number of FoxP3þ from peripheral blood mononuclear cells of house
Treg cells. Furthermore, this process induced by dust mites-sensitive individuals. Although not
IVIG was not dependent on the Fc domain as studied directly in their model, antigen-presenting
F(ab’)2 fragments led to similar changes in Th17 cells or dendritic cells presumably play an important
cells, Treg cells and clinical efficacy in this exper- role in this pathway of inducing Treg cells.
imental autoimmune encephalomyelitis model. In Kawasaki disease and in patients with a
Desialylated IVIG had the same immune-modulat- vasculitis, clinical improvement with IVIG therapy
ing effects as ‘native’ IVIG [34]. Kaveri and col- correlated with increased Treg number and function
&&
leagues [35 ] demonstrated that the mechanism [41,42]. Tjon et al. [43] reported that high-dose,
by which IVIG induces Treg cells was by the induc- but not low-dose IVIG treatment in patients with
tion of cyclo-oxygenase dependent prostaglandin immunodeficiency and autoimmune disease
E2 (PGE2) from human dendritic cells. This process enhanced the activation of circulating Treg cells,
was mediated by F(ab’)2 fragments, but not Fc but the numbers of circulating Treg cells remained
fragments. In a different in-vitro model, Wiedeman unchanged. Thus, depending on the animal model
&
et al. [36 ] showed that a F(ab’)2 fragment of IVIG for autoimmune disease and the human auto-
inhibited toll-like receptor (TLR)-7 and TLR-9 ago- immune disorder, IVIG appears to have reciprocal
nist-induced IFN-a production. This inhibitory immune-modulating effects by downregulating the
activity of IgG was mediated by PGE2 production Th17 pathway [44] and enhancing or expanding
by monocytes. CD4þCD25þ FoxP3 Treg cells.
Mazer and colleagues have extensively studied
the effects of IVIG therapy in an ovalbumin sensi-
tized mouse model of asthma. IVIG markedly atte- CONCLUSION
nuated lung inflammation and decreased bronchial Clearly, IVIG (IgG) has a number of immune-
hyperresponsiveness to methacholine [37]. IL-13 modulating effects (see the above list given in the
and TNF-a levels diminished, Delta-4 (part of the introduction section). In autoantibody-mediated
Notch pathway that induces Th1 cells) expression disease, the Fc domain appears to be the important
increased whereas Jagged-1 (part of the Notch path- IgG moiety that leads to immune modulation.
way that induces Th2 cells) expression and GATA-3 The importance of sialylation of the Fc fragment
mRNA decreased, suggesting that Th2 responses remains controversial, as do the mediators involved,
were suppressed. The draining pulmonary lymph for example, IL-33 and IL4. Differences in animal
nodes of IVIG treated mice showed a significant models, IVIG source, route and timing of the
increase in CD4þCD25þFoxp3þ regulatory cells. administration of the IVIG, mouse strain and other
IVIG-primed dendritic cells on adoptive transfer variables may account for the differences in experi-
to ovalbumin sensitized and challenged mice abro- mental observations between laboratories. In
gated airway hyperresponsiveness and induced Treg T-cell-mediated animal models of disease, such as

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 Primary immune deficiency disease

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Humans Suppresses Dendritic Cell Function via Stimulation of IL-4 and IL-13
tute of Allergy and Infectious Diseases. M. Ballow is &&

Production. J Immunol 2014; 192:5625–5634.

currently receiving a grant from CSL Behring, and is on An important article using human cells in patients treated with high-dose IVIG
showing that IVIG modulates the inflammatory responsiveness of myeloid dendritic
the speaker’s bureau for CSL Behring, Baxter and Grifols. cell by a DC-SIGN independent process mediated by Th2 cytokines with down-
regulation of FcgRIIa and IFN-gR2 receptors but not FcgRIIB.
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&& modulate the immune system? Nat Rev Immunol 2013; 13:176–189. fractionation does not enhance the efficacy of immunoglobulin G in a murine
Excellent review on the mechanisms of action of IVIG with some intersting insight. model of immune thrombocytopenia. PLoS One 2011; 6:e21246.
4. Junghans R, Anderson C. The protective receptor for IgG catabolism is the 32. Kasermann F, Boerema DJ, Ruegsegger M, et al. Analysis and functional
beta2-microglobulin-containing neonatal intestinal transport receptor. Proc consequences of increased Fab-sialylation of intravenous immunoglobulin
Natl Acad Sci U S A 1996; 93:5512–5516. (IVIG) after lectin fractionation. PLoS One 2012; 7:e37243.

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 Mechanisms of immune regulation by IVIG Ballow

33. Othy S, Hegde P, Topcu S, et al. Intravenous gammaglobulin inhibits ence- 38. Massoud AH, Guay J, Shalaby KH, et al. Intravenous immunoglobulin attenu-
&& phalitogenic potential of pathogenic T cells and interferes with their trafficking ates airway inflammation through induction of forkhead box protein 3-positive
to the central nervous system, implicating sphingosine-1 phosphate receptor regulatory T cells. J Allergy Clin Immunol 2012; 129:1656–1665.e3.
1-mammalian target of rapamycin axis. J Immunol 2013; 190:4535–4541. 39. Massoud AH, Yona M, Xue D, et al. Dendritic cell immunoreceptor: a novel
An important article that demonstrates that IVIG inhibits the differentiation of CD4 && receptor for intravenous immunoglobulin mediates induction of regulatory
T-cells into Th17 cells, while inducing the expansion of FoxP3þ Treg cells. The T cells. J Allergy Clin Immunol 2014; 133:853–863.e5.
F(ab’)2 fragments were similar to intact IgG in mediating these effects. An important article that demonstrates that a novel C-type lectin receptor for sialic-
34. Othy S, Topcu S, Saha C, et al. Sialylation may be dispensable for reciprocal acid enriched IVIG, dendritic cell immunoreceptor, is an important component of
modulation of helper T cells by intravenous immunoglobulin. Eur J Immunol IVIG-induced increase in Treg cells and abrogation of the airway hyperrespon-
2014; 44:2059–2063. siveness in a mouse asthma model.
35. Trinath J, Hegde P, Sharma M, et al. Intravenous immunoglobulin expands 40. De Groot A, Moise L, McMurry J, et al. Activation of natural regulatory T cells
&& regulatory T cells via induction of cyclo-oxygenase-2-dependent prostaglan- by IgG Fc-derived peptide ‘Tregitopes’. Blood 2008; 112:3303–3311.
din E2 in human dendritic cells. Blood 2013; 122:1419–1427. 41. Olivito B, Taddio A, Simonini G, et al. Defective FoxP3 expression in patients
A critical article that demonstrates that the IVIG-induced expansion of Treg cells is with acute Kawasaki disease and restoration by intravenous immunoglobulin
mediated by the induction of cyclo-oxygenase dependent prostaglandin E2. therapy. Clin Exp Rheumatol 2010; 28:93–97.
36. Wiedeman A, Santer D, Wei Y, et al. Contrasting mechanisms of interferon-a 42. Tsurikisawa N, Saito H, Oshikata C, et al. High dose intravenous immuno-
& inhibition by intravenous immunoglobulin after induction by immune com- globulin treatment increases regulatory T cells in patients with eosinophilic
plexes versus toll-like receptor agonists. Arthritis Rheum 2013; 65:2713– granulomatosis with polyangitis. J Rheumatol 2012; 39:1019–1025.
2723. 43. Tjon A, Tha-In T, Metselaar H, et al. Patients treated with high-dose intra-
In this article the authors report that the inhibitory activity of IVIG on TLR agonist- venous immunoglobulin show selective activation of regulatory T cells. Clin
induced IFN-a requires monocyte production of PGE2. Exp Immunol 2013; 173:259–267.
37. Kaufman GN, Massoud AH, Audusseau S, et al. Intravenous immunoglobulin 44. Maddur MS, Vani J, Hegde P, et al. Inhibition of differentiation, amplification,
attenuates airway hyperresponsiveness in a murine model of allergic asthma. and function of human TH17 cells by intravenous immunoglobulin. J Allergy
Clin Exp Allergy 2011; 41:718–728. Clin Immunol 2011; 127:823–830; e1-7.

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