Date of Award

Spring 5-1-2005

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Life Sciences

First Advisor

Swapan K. Ghosh

Second Advisor

Kathleen Dannelly

Third Advisor

William H. Flurkey

Abstract

Objectives: Little is known of the role of specific environmental factors in promoting autoimmune disorders such as systemic lupus erythematosus (SLE). The broad objective of this study was to address how exposure to phthalates, common environmental factors m foods, and biomedical devices could affect the immune functions of resistant and autoimmune-prone mice. Methods: The environmental chemical model used in this study is phthalates, which are widely used in various forms and readily occur during day-to-day human contacts. Groups of nonautoimmune-prone (BALB/c, DBA/2 and C57BL/6) and susceptible (NZB, NZB/W Fl) mice were immunized with phthalates ( ortho, meta and para) conjugated to keyhole lymphet hemocyanin (KLH) protein. Sera of immunized mice were assayed for anti-DNA Ab levels by ELISA, and their kidneys were assessed for the progression of pathologic lupus-like syndromes by histology. Isotypic profiles of anti-DNA Abs and cytokine levels induced by immunizations with phthalate in different strains of mice were determined using standard sandwich-ELISA. Results: This study clearly demonstrates that phthalates are capable of inducing cross-reactive Abs that strongly bind phthalate, DNA, or both in all groups of mice. Strain differences, however, exist in terms of amplitude induced anti-DNA responses. Interestingly, repeated immunization with phthalate significantly reduces anti-DNA antibody response in both BALB/c and DBA/2, whereas, in C57BL/6 and NZB/W Fl mice, the response is further heightened. Resistant BALB/C & DBA/2 mice develop specific suppressor T cells (Ts) to down regulate anti-DNA response. In vivo depletion of CD8+ T cells in both BALB/c and DBA/2 mice significantly decreased this CTL activity but increased anti-DNA humeral response. Both C57BL/6 and NZB/W Fl mice mount significantly higher anti-DNA antibody levels along with nephritis and other histopathologic changes in kidney. But only NZB/W Fl mice immunized with phthalate experience high mortality. Anti-DNA antibodies in affected NZB/W Fl are largely IgG2a-type, while in BALB/c and DBA/2, IgG 1-type. Moreover, cytokine analyses indicate that the subclasses of anti-DNA Ab induced correlate with the Thl/Th2 cytokine profiles. Discussion: To our knowledge, this is the first systemic study examining the complex issues of phthalates as environmental chemicals at induction of lupus-type autoimmunity, and differences in susceptibility to phthalates among various mouse strains. In summary, the commonly used phthalates appear harmful to susceptible strains, BALB/c and DBA/2 are spared due to induction of Ts cells.

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