Intravenous immunoglobulin (IVIG) is a polyspecific pooled immunoglobulin G preparation and one of the commonly used therapeutics for autoimmune diseases including those of neurological origin. A recent report in murine model proposed that IVIG expands regulatory T (Treg) cells via induction of interleukin 33 (IL-33). However, translational insight on these observations is lacking.
Ten newly diagnosed Guillain-Barré syndrome (GBS) patients were treated with IVIG at the rate of 0.4 g/kg for three to five consecutive days. Clinical evaluation for muscular weakness was performed by Medical Research Council (MRC) and modified Rankin scoring (MRS) system. Heparinized blood samples were collected before and 1, 2, and 4–5 weeks post-IVIG therapy. Peripheral blood mononuclear cells were stained for surface CD4 and intracellular Foxp3, IFN-γ, and tumor necrosis factor alpha (TNF-α) and were analyzed by flow cytometry. IL-33 and prostaglandin E2 in the plasma were measured by ELISA.
The fold changes in plasma IL-33 at week 1 showed no correlation with the MRC and MRS scores at weeks 1, 2, and ≥4 post-IVIG therapy. Clinical recovery following IVIG therapy appears to be associated with Treg cell response. Contrary to murine study, there was no association between the fold changes in IL-33 at week 1 and Treg cell frequency at weeks 1, 2, and ≥4 post-IVIG therapy. Treg cell-mediated clinical response to IVIG therapy in GBS patients was associated with reciprocal regulation of effector T cells-expressing TNF-α.
Treg cell expansion by IVIG in patients with autoimmune diseases lack correlation with IL-33. Treg cell frequency, but not plasma IL-33 levels, represents potential immunological biomarker to predict clinical response to IVIG therapy.
Hughes RA, Swan AV, van Doorn PA. Intravenous immunoglobulin for Guillain-Barre syndrome. Cochrane Database Syst Rev. 2012;7:CD002063.
Sharma M, Schoindre Y, Hegde P, Saha C, Maddur MS, Stephen-Victor E, Gilardin L, Lecerf M, Bruneval P, Mouthon L, et al. Intravenous immunoglobulin-induced IL-33 is insufficient to mediate basophil expansion in autoimmune patients. Sci Rep. 2014;4:5672. PubMed
Ephrem A, Chamat S, Miquel C, Fisson S, Mouthon L, Caligiuri G, Delignat S, Elluru S, Bayry J, Lacroix-Desmazes S, et al. Expansion of CD4 + CD25+ regulatory T cells by intravenous immunoglobulin: a critical factor in controlling experimental autoimmune encephalomyelitis. Blood. 2008;111:715–22. CrossRefPubMed
Maddur MS, Trinath J, Rabin M, Bolgert F, Guy M, Vallat JM, Magy L, Balaji KN, Kaveri SV, Bayry J. Intravenous immunoglobulin-mediated expansion of regulatory T cells in autoimmune patients is associated with increased prostaglandin E2 levels in the circulation. Cell Mol Immunol. 2015;12:650–2. CrossRefPubMed
Savenije OE, Mahachie John JM, Granell R, Kerkhof M, Dijk FN, de Jongste JC, Smit HA, Brunekreef B, Postma DS, Van Steen K, et al. Association of IL33-IL-1 receptor-like 1 (IL1RL1) pathway polymorphisms with wheezing phenotypes and asthma in childhood. J Allergy Clin Immunol. 2014;134:170–7. CrossRefPubMed
Besnard AG, Guabiraba R, Niedbala W, Palomo J, Reverchon F, Shaw TN, Couper KN, Ryffel B, Liew FY. IL-33-mediated protection against experimental cerebral malaria is linked to induction of type 2 innate lymphoid cells, M2 macrophages and regulatory T cells. PLoS Pathog. 2015;11(2):e1004607. CrossRefPubMedPubMedCentral
Franca RF, Costa RS, Silva JR, Peres RS, Mendonca LR, Colon DF, Alves-Filho JC, Cunha FQ. IL-33 signaling is essential to attenuate viral-induced encephalitis development by downregulating iNOS expression in the central nervous system. J Neuroinflammation. 2016;13(1):159. CrossRefPubMedPubMedCentral
- Regulatory T cell frequency, but not plasma IL-33 levels, represents potential immunological biomarker to predict clinical response to intravenous immunoglobulin therapy
Mohan S. Maddur
Varun K. Sharma
Kithiganahalli N. Balaji
Srini V. Kaveri
- BioMed Central