Immune modulation of i.v. immunoglobulin in women with reproductive failure

Abstract

BackgroundThe mechanism of maternal immune tolerance of the semi‐allogenic fetus has been explored extensively. The immune reaction to defend from invasion by pathogenic microorganisms should be maintained during pregnancy. An imbalance between the immune tolerance to the fetus and immune activation to the pathogenic organisms is associated with poor pregnancy outcomes. This emphasizes that the immune mechanism of successful reproduction is not just immune suppression, but adequate immune modulation.MethodsIn this review, the action of i.v. immunoglobulin G (IVIg) on the immune system and its efficacy in reproductive failure (RF) was summarized. Also suggested is the indication of IVIg therapy for women with RF.Main findings (Results)Based on the mechanism of the immune regulation of IVIg and following confirmation of the immune modulation effects of it in various aberrant immune parameters in patients with RF, it is obvious that IVIg is effective in recurrent pregnancy losses and repeated implantation failures with immunologic disturbances.ConclusionThe authors recommend IVIg therapy in patients with RF with aberrant cellular immunologic parameters, including a high natural killer cell proportion and its cytotoxicity or elevated T helper 1 to T helper 2 ratio, based on each clinic's cut‐off values. Further clinical studies about the safety of IVIg in the fetus and its efficacy in other immunologic abnormalities of RF are needed.

Modulatory effect of intravenous immunoglobulin on Th17/Treg cell balance in women with unexplained recurrent spontaneous abortion

“…25 IgG is divided into a F(ab')2 fragment that contains two antigen-binding sites and one Fc fragment which binds to its receptors (FcR) on the immune cells and complements. 27 Neonatal FcR (FcRn) plays a role in extending the half-life of IgG. In humans, FcγRIA, FcγRIIA, FcγRIIC, FcγRIIIA, and FcγRIIIB activate the immune system, while FcγRIIB suppresses immune reactions.…”

“…27 Neonatal FcR (FcRn) plays a role in extending the half-life of IgG. 27 Indeed, using IgG passive transfer models of autoimmune skin blistering diseases pemphigus and pemphigoid, characterized by the linear deposition of IgG autoantibodies at the basement membrane zone, Li et al showed that a high dose of IVIG saturates FcRn binding sites, and hence, the pathogenic antibodies lose FcRn protection and are more rapidly degraded. Into the low pH conditions, IgG bind to FcRn bind and is endocytosed into the cells.…”

“…In humans, FcγRIA, FcγRIIA, FcγRIIC, FcγRIIIA, and FcγRIIIB activate the immune system, while FcγRIIB suppresses immune reactions. 27 Neonatal FcR (FcRn) plays a role in extending the half-life of IgG. 28,29 Neonatal Fc receptors are located on the cell surface of endothelial or myeloid cells.…”

“…30 By competition with pathogenic IgG autoantibodies for binding to FcRn, IVIg decreased endocytosis of autoantibodies and leads to a decreased half-life of autoantibodies and blocks tissue inflammation. 27 Indeed, using IgG passive transfer models of autoimmune skin blistering diseases pemphigus and pemphigoid, characterized by the linear deposition of IgG autoantibodies at the basement membrane zone, Li et al showed that a high dose of IVIG saturates FcRn binding sites, and hence, the pathogenic antibodies lose FcRn protection and are more rapidly degraded. The faster degradation prevents pathogenic antibody from reaching its tissue targets in the skin, and skin blistering is abolished.…”

“…137 Several mechanisms of action have been described during the last 25 years, including (a) modulation of Fcγ receptor expression on leukocytes and endothelial cells; (b) interaction with complement proteins; (c) modulation of cytokines and chemokines synthesis and release; (d) modulation of cell proliferation and apoptosis; (e) remyelination; (f) neutralization of circulating antibodies; (g) selection of immune repertoires; and (h) interaction with other cell surface molecules on lymphocytes and monocytes 27,126,127,138,139. 137 Several mechanisms of action have been described during the last 25 years, including (a) modulation of Fcγ receptor expression on leukocytes and endothelial cells; (b) interaction with complement proteins; (c) modulation of cytokines and chemokines synthesis and release; (d) modulation of cell proliferation and apoptosis; (e) remyelination; (f) neutralization of circulating antibodies; (g) selection of immune repertoires; and (h) interaction with other cell surface molecules on lymphocytes and monocytes 27,126,127,138,139.…”