title: 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.
authors.affiliation: INSERM, Unité 872, Paris 75006, France.
authors.forename: Shivashankar
authors.initials: S
authors.lastname: Othy
authors.forename: Pushpa
authors.initials: P
authors.lastname: Hegde
authors.forename: Selma
authors.initials: S
authors.lastname: Topçu
authors.forename: Meenu
authors.initials: M
authors.lastname: Sharma
authors.forename: Mohan S
authors.initials: MS
authors.lastname: Maddur
authors.forename: Sebastien
authors.initials: S
authors.lastname: Lacroix-Desmazes
authors.forename: Jagadeesh
authors.initials: J
authors.lastname: Bayry
authors.forename: Srini V
authors.initials: SV
authors.lastname: Kaveri
mesh_terms: D061605:Administration, Intravenous / Q000379:methods; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D004660:Encephalitis / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology / Q000378:metabolism; D016756:Immunoglobulins, Intravenous / Q000276:immunology / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D017452:Receptors, IgG / Q000276:immunology / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000276:immunology / Q000378:metabolism*; D000081025:Sphingosine-1-Phosphate Receptors; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000276:immunology / Q000378:metabolism*; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D000098853:Podoplanin
chemical_list: D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D016756:Immunoglobulins, Intravenous; D008562:Membrane Glycoproteins; D017452:Receptors, IgG; D049349:Receptors, Lysosphingolipid; D000081025:Sphingosine-1-Phosphate Receptors; D058570:TOR Serine-Threonine Kinases; C499172:Fcgr2b protein, mouse; C490441:Pdpn protein, mouse; D000098853:Podoplanin; C556330:S1pr1 protein, mouse; C546843:mTOR protein, mouse