Date of Award

12-2011

Level of Access Assigned by Author

Campus-Only Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biochemistry and Molecular Biology

Advisor

Derry Roopenian

Second Committee Member

David Serrez

Third Committee Member

Keith Hutchinson

Abstract

Systemic lupus erythematosus (SLE) is a common and devastating autoimmune disease that inflicts damage via autoantibody complexes that results in multi-organ damage and renal failure. The BXSB.Yaa mouse is a well-established model of SLE. We show that genetic disruption of multiple components of the MHC class I axis greatly accelerates autoimmune disease in this model. Mice lacking both CD8+ T cells and IL-15 succumb to SLE-like disease early (mean age 14 wks). This implies a protective role for the immune cells, CD8+ T cells and natural killer cells, that are dependent on IL-15. BXSB.Yaa mice develop an expanded population of central memory (CM) CD8+ T cells with increased expression of the IL-15 receptor (IL-15R). CD8+ T cell immunological memory is critical for adequate suppression and development of this memory is dependent on the cytokine, IL-21. Disease suppression is occurring partially through a perforin-dependent mechanism and also partially through the immunosuppressive cytokine IL-10. IL-21 appears to be a double-edged sword as it is necessary for lupus-like disease to develop in these mice. We show that B cells and not T cells require IL-21 signaling for disease to occur. IL-21 is acting early in disease as IL-21R is upregulated on splenic B cell populations in very young mice. Another cytokine receptor, IL-6R, is also increased early on CD4+ T cells in the spleen, and BXSB.Yaa mice deficient in IL-6 do not develop disease. Our results suggest that IL-6 and IL-21 are active and required early in disease for lupus-like symptoms to develop. Additionally, our results suggest that a T follicular helper (Tfh)-like cell is driving this disease, differing from classical Tfh cells in that it is CXCR5 independent. Normal germinal center reactions are also not necessary for disease to proceed and an extrafollicular response exists with many plasma cells and plasmablasts located in the periarteriole lymphoid sheath of these mice. These results support a model of BXSB.Yaa lupus dependent on IL-21 and IL-6 with abnormal splenic organization of B cells and atypical Tfh cell phenotypes that is being suppressed by regulatory populations of IL-21-dependent CM CD8+ T cells and NK cells partially through perforin-mediated cell lytic mechanisms.

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