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"INTERFERON ALPHA/LAMBDA INDUCED EFFECTS ON microRNAS, LYMPHOID SUBPOPULATIONS AND AUTOIMMUNE DISEASE IN NZB/NZW F1 MURINE MODEL OF SYSTEMIC LUPUS ERYTHEMATOSUS"

by
Yao Yuan
Molecular Pathology and Immunology Program
Bachelor of Medicine (B.Med), 2006, Southeast University, Nanjing, China



Thesis Advisor: Elizabeth Raveche, Ph.D.
Professor
Department of Pathology and Laboratory Medicine

Wednesday, April 18, 2012
1:30 P.M., MSB Room C-555


Abstract

The effects of chronic exposure to interferons on the development of autoantibodies, ultimately leading to kidney glomerulonephritis and proteinuria, were assessed in NZB/NZW F1 (B/W) mice, a de novo model of systemic lupus erythematosus (SLE). IFNalpha (IFN-) augments autoimmunity, however, the effects of a newly discovered related type III interferon, IFNlambda (IFN-f) on autoimmune disease progression are unknown. In this study, chronic high dose IFN- greatly accelerated autoimmunity manifested by early occurrence of proteinuria as well as elevated autoantibodies. In contrast, IFN-f at the same dose did not augment B/W autoimmunity. Analysis of lymphoid subpopulations in the spleens revealed that in vivo IFN-z shortly after initiation of treatment, increased activated autoreactive CD4+ T cells (CD134+), however, IFN-f did not. In contrast, B regulatory or B10 cells (B220lowCD5+CD1dhi), which are a subset of B1 cells producing IL-10 and suppress autoimmunity, are elevated early by IFN-f. When autoimmunity fully developed, mice receiving all IFNs had decreased Breg (B10) compared to control B/W mice receiving PBS, however, IFN-f treatment showed the least reduction in B10 cells. Although IFN-f alone did not accelerate autoimmunity, the addition of IFN-fnn to even low dose IFN- enhanced the disease progression. MicroRNAs (miRNAs), because they can target mRNA involved in immune responses, may be involved in autoimmunity. It has been shown that decreased miR-15a is associated with increased survival and proliferation of B1 cells. In the study, elevated miR-15a was found in both spleen and plasma with disease development and this was significantly correlated to the increase in autoantibody levels regardless of treatment. Analysis of B cell subpopulations obtained by flow cytometric sorting showed that miR-15a was highly expressed in the B10 subset independent of disease status, suggesting that miR-15a has an intrinsic negative effect on the B10 subset. In conclusions, IFN-f had no effect on activation of T cells, and less suppression of Breg (B10) compared to IFN-n at the same dose treatment in diseased B/W mice. The study suggests that IFN-f has a reduced potential to accelerate autoimmunity or may have a positive regulatory effect in autoimmune diseases in B/W mice. Our data also support the involvement of elevated miR-15a in autoimmune disease development in B/W mice and suggest that decreasing this microRNA might be beneficial in B/W mice.


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