Page 1184 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPTEr 84 Immunoglobulin Therapy: Replacement and Immunomodulation 1149

These antiidiotypic antibodies may also act in concert with to the sialylation of the glycan component of the Fc fragment.
their effects on the FcγRIIB receptor on B cells to produce a The important glycan moiety in the IgG molecule is located at
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negative “off signal” to the B cells synthesizing these autoimmune the asparagine (Asn ) site in the second domain of the constant
antibodies. Thus the antiidiotypic antibodies in IVIG may be region. Using a K/BxN serum-induced arthritis model in mice,
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beneficial by restoring the idiotypic control network in these Kaneko et al. showed that IVIG at 1 g/kg inhibited the inflam-
autoimmune diseases. matory arthritic process. Deglycosylated or neuraminidase-treated
IVIGs were unable to inhibit this inflammation. IVIG enriched
The Role of the FcRn Receptor on Immune Modulation for the sialylated glycan moiety had comparable inhibitory effects
The FcRn receptor (neonatal Fc receptor) was identified as the on the inflammatory process at only one-10th of the dosage
receptor responsible for protecting IgG from catabolism in the used with intact IVIG. This inhibitory activity was dependent
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endocytic vesicles of the endosome, and this explains the relatively on FcγRIIB expression on effector macrophages. Anthony et al.
long half-life of this plasma protein. IVIG may accelerate the engineered a recombinant/sialylated human IgG1 Fc protein that
catabolism of IgG autoantibodies by saturating these protective had 35-fold enhanced immune-modulating activity compared
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receptors in direct proportion to the relative concentration of with native IVIG. Anthony et al. performed studies to examine
exogenous plasma levels of IgG from IVIG. In mouse models the mechanism by which the sialylated Fc fragment could mediate
of bullous pemphigoid and arthritis, IVIG treatment resulted its antiinflammatory activity and to identify the target cell that
in a reduction in pathogenic antibodies to levels below the initiates this antiinflammatory pathway. A splenic marginal zone
disease-causing threshold, and this effect was attenuated in macrophage expressing the C-type lectin receptor (i.e., SIGN-R1)
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FcRn-deficient mice. Hansen and Balthasar showed in a rat was required for the antiinflammatory activity of IVIG in concert
model of immune thrombocytopenia that IVIG enhanced the with its ability to bind to sialylated Fc domains. These authors
clearance of antiplatelet antibodies in a dose-dependent manner proposed that the interaction between sialylated IgG Fc and
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by saturation of the FcRn receptor. These same investigators SIGN-R1 leads to the upregulation of the inhibitory FcγRIIB
estimated that approximately 50% of the overall effect of IVIG receptor on effector cells. They suggested that DC-SIGN (dendritic
in ITP may be attributed to IVIG-mediated acceleration of the cell–specific intercellular adhesion molecule-grabbing noninte-
elimination of antiplatelet antibodies by the FcRn saturation grin), the human orthologue of SIGN-R1, has a comparable role
mechanism and showed that in FcRn knock-out mice, IVIG in the antiinflammatory effects of IgG Fc fragment on human
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failed to increase the clearance of antiplatelet antibodies. However, macrophages and dendritic cells (DCs). Anthony et al. presented
very little data, if any, are available in human autoimmune disease data in their murine model that this immune-modulating pathway
to support this mechanism. may be mediated by the production of interleukin-33 (IL-33)
by DCs, which, in turn, produce IL-4 from basophils, leading
KEY CONCEPTS 4 to the increased expression of the FcγRIIB receptor on effector
macrophages. Of note, observations in patients with chronic
Proposed Mechanisms of Action of intravenous inflammatory demyelinating polyneuropathy (CIDP) treated
immunoglobulin (IVIG) in Autoimmune Idiopathic with high-dose IVIG demonstrated upregulation of the FcγRIIB
Thrombocytopenic Purpura receptor on peripheral blood monocytes. Others, however, have
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questioned whether this pathway of immune modulation is
• Fc receptor blockade of reticuloendothelial system important in humans. 37-39 Nevertheless, these exciting studies
• Fcγ receptor downregulation
• Idiotype–antiidiotype interaction between antiplatelet GPIIb/IIa auto- define, at least in mice, an important mechanism by which IVIG
antibodies and the antiidiotypic antibodies in IVIG modulates immune processes mediated through sialylated Fc
• Activation of inhibitory receptor FcγRIIB on the IgG molecule and the receptors on DCs and effector
• Saturation of FcRn receptor to accelerate the catabolism of antiplatelet macrophages (i.e., SIGN-R1 and FcγRIIB) involved in this
autoantibodies antiinflammatory process.

Modulation of Immunoregulatory Function Through KEY CONCEPTS 5
the Fc Receptor Proposed Mechanisms of Action of IVIG in
The FcγRIIB receptor provides an inhibitory signal to cells through Neuromuscular Diseases
a pathway mediated by an immunoregulatory tyrosine-based • Modulation of proinflammatory cytokines, e.g., TNF-GR α, IL-1GR β
inhibition motif (ITIM). Studies have shown that IVIG stimulates in GBS
these inhibitory FcγRIIB receptors found on a variety of cell • Reduction in muscle levels of ICAM-1, TGF-GR β, and TGF-GR β
types, including macrophages, B cells, and a subpopulation of mRNA in dermatomyositis
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T cells. Samuelsson et al., using a murine model of ITP, showed • Neutralization by antiidiotypic antibodies in IVIG of potentially pathogenic
autoantibodies, e.g., anti-Gm1 antibodies in GBS and CIDP, and anti-
that the administration of IVIG prevented platelet destruction AchR in MG
by a pathogenic monoclonal autoantibody. Protection was • IVIG saturation of FcRn receptors to accelerate degradation of IgG
associated with the induction of the expression of FcγRIIB autoantibodies
receptors on splenic macrophages. This inhibitory FcγRIIB • Inhibition of complement deposition and formation of MAC on
receptor was required for the protection of the animals against endomysial capillaries in dermatomyositis
the monoclonal autoantibody, since disruption of the receptor AchR, acetylcholine nicotinic receptor; CIDP, chronic inflammatory
by either genetic deletion or a blocking monoclonal antibody demyelinating polyneuropathy; FcRn, neonatal Fc receptor;
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(mAb) reversed the therapeutic effects of IVIG. Kaneko et al. GBS, Guillain-Barré syndrome; MAC, membranolytic attack complex;
showed that that the inhibitory properties of IVIG were linked MG, myasthenia gravis.