A critical role for IL-21 receptor signaling in the pathogenesis of systemic lupus erythematosus in BXSB-Yaa mice.

Abstract

Interleukin 21 (IL-21) is a pleiotropic cytokine produced by CD4 T cells that affects the differentiation and function of T, B, and NK cells by binding to a receptor consisting of the common cytokine receptor gamma chain and the IL-21 receptor (IL-21R). IL-21, a product associated with IL-17-producing CD4 T cells (T(H)17) and follicular CD4 T helper cells (T(FH)), has been implicated in autoimmune disorders including the severe systemic lupus erythematosus (SLE)-like disease characteristic of BXSB-Yaa mice. To determine whether IL-21 plays a significant role in this disease, we compared IL-21R-deficient and -competent BXSB-Yaa mice for multiple parameters of SLE. The deficient mice showed none of the abnormalities characteristic of SLE in IL-21R-competent Yaa mice, including hypergammaglobulinemia, autoantibody production, reduced frequencies of marginal zone B cells and monocytosis, renal disease, and premature morbidity. IL-21 production associated with this autoimmune disease was not a product of T(H)17 cells and was not limited to conventional CXCR5(+) T(FH) but instead was produced broadly by ICOS(+) CD4(+) splenic T cells. IL-21 arising from an abnormal population of CD4 T cells is thus central to the development of this lethal disease, and, more generally, could play an important role in human SLE and related autoimmune disorders.

• Authors: Jason A Bubier, Thomas J Sproule, Oded Foreman, Rosanne Spolski, Daniel J Shaffer, Herbert C Morse 3rd, Warren J Leonard, Derry C Roopenian
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 106 Issue 5 Pg. 1518-23 (Feb 03 2009) ISSN: 1091-6490 [Electronic] United States
• PMID: 19164519 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• DNA Primers
• Interleukins
• Receptors, Interleukin-21
• interleukin-21

Topics

• Animals
• Antibody Formation
• Base Sequence
• DNA Primers
• Enzyme-Linked Immunosorbent Assay
• Flow Cytometry
• Interleukins (genetics)
• Kidney Diseases (prevention & control)
• Lupus Erythematosus, Systemic (etiology, immunology, metabolism)
• Lymphocyte Subsets
• Mice
• Receptors, Interleukin-21 (genetics, metabolism)
• Signal Transduction