Intravenous Gammaglobulin Inhibits Encephalitogenic Potential of Pathogenic T Cells and Interferes with their Trafficking to the Central Nervous System, Implicating Sphingosine-1 Phosphate Receptor 1–Mammalian Target of Rapamycin Axis

Abstract

Despite an increasing use of high-dose therapy of i.v. gammaglobulin (IVIg) in the treatment of various T cell– and Ab-mediated inflammatory and autoimmune diseases, comprehension of the mechanisms underlying its therapeutic benefit has remained a major challenge. Particularly, the effect of IVIg in T cell–mediated autoimmune conditions remains unexplored. Using an actively induced experimental autoimmune encephalomyelitis model, a T cell–mediated autoimmune condition, we demonstrate that IVIg inhibits the differentiation of naive CD4 T cells into encephalitogenic subsets (Th1 and Th17 cells) and concomitantly induces an expansion of Foxp3+ regulatory T cells. Further, IVIg renders effector T cells less pathogenic by decreasing the expression of encephalitogenic molecular players like GM-CSF and podoplanin. Intriguingly and contrary to the current arguments, the inhibitory FcγRIIB is dispensable for IVIg-mediated reciprocal modulation of effector and regulatory CD4 subsets. Additionally, F(ab′)2 fragments also retained this function of IVIg. IVIg or F(ab′)2 fragments decrease the sphingosine-1 phosphate receptor on CD4 cells, thus sequestering these cells in the draining lymph nodes and decreasing their infiltration into the CNS. Our study reveals a novel role of Igs in the modulation of polarization and trafficking of T lymphocytes, accounting for the observed beneficial effect in IVIg therapy.

Intravenous immunoglobulin expands regulatory T cells via induction of cyclooxygenase-2–dependent prostaglandin E2 in human dendritic cells

“…[15][16][17][18][19][20][21][22][23][24][25][26] However, the cellular and molecular mechanisms by which IVIg expands Tregs are relatively unknown. As Treg expansion in the periphery requires signaling by antigen-presenting cells such as dendritic cells (DCs) 27,28 and IVIg has been demonstrated to modulate DC functions, [29][30][31][32] we hypothesized that IVIg induces distinct signaling events in DCs.…”

“…EAE was induced in 10-weekold female C57BL/6J mice (Janvier, Saint Berthevin, France) and evolution of disease was followed as previously reported. 15,26 EAE was induced in 3 different groups and each group included 6 to 8 mice. Mice were immunized with 200 mg of MOG peptide (MEVGWYRSPFSRVVHLYRNGK; PolyPeptide laboratory, Strasbourg, France) emulsified in complete Freund's adjuvant (Sigma-Aldrich) containing 880 mg of nonviable Mycobacterium tuberculosis H37RA.…”

“…Previous studies have demonstrated that IVIg protects mice from EAE and was associated with an expansion of Tregs. 15,26 Twelve days following the induction of EAE that corresponded to the onset of disease in the control group, mice were sacrificed and analyzed for Tregs in the spleen. In line with previous reports, we confirm that IVIg therapy in EAE is associated with significant expansion of Tregs ( Figure 5A).…”

Polyclonal immunoglobulin G for autoimmune demyelinating nervous system disorders

“…In addition, it was demonstrated that polyclonal IgG inhibits the in vitro proliferation of human T cell lines reactive against myelin basic protein (MBP) [42]. As recently shown, it may impede lymph node egression of encephalitogenic T cells by downregulation of sphingosine-1-phosphate receptor 1 [43]. Furthermore, polyclonal IgG may inhibit T cell migration across the blood-nerve barrier [44,45].…”

Intravenous immunoglobulins (IVIG) in systemic sclerosis: a challenging yet promising future

“…[51][52][53][54][55][56][57][58][59][60]. To date, IVIGs' beneficial effects areTable 1Selected mechanisms of action of IVIG in human disease and experimental models of autoimmune diseases (reviewed by[55])…”