ARRA: The Role of C 1 q in Regulation of Monocyte to Dendtritic Cell Transition

longer than 30 lines of text. ate gym, I Enter the text here that is the new abstract information for your application. This section must be no The association of Clq with autoimmune diseases in genera!, and with systemic lupus erythematosus (SLE) in particular, has been firmly established. Genetic deficiency of Clq is in 3L? fact considered to be a strong susceptibility factor for SLE. Of the known congenital Clq deficient individuals, 95%, have developed early-onset photosensitive SLE. A prevailing hypothesis, which is supported by recent in vivo data, stipulates that in Clq deficient individuals, failure to clear apoptotic cells may provide persistently high loads of potentially immunogenic 'T' ,1, a-. G1' self-antigens that trigger autoimmune responses by non-tolerant I cells. Implicit in this hypothesis is the notion that CIq-{and Clq receptors (CIqR)]-is the primary mediator of apoptotic cell uptake, which we think is not. While Clq undoubtedly plays an important role in the removal of apoptotic cells-an event that is critical for host survival-this process is perforce redundant, i.e., multiple ligand-receptor combinations exist as alternative mechanisms to dispose self-waste. Our own observations in the past 10 years lead us to believe that locally synthesized Clq plays a fundamental role in regulating dendritic cell (DC) differentiation and function at the earliest stages of DC growth. Implied in this novel hypothesis is the notion that the Clq/ClqR system is actively engaged in avoiding self-directed adaptive immune response. Critical events in E.0 two G'. 010 ;,r0 such a system would include regulation of DC activity mediated by distinct Clq/ClqR interactions. The present proposal is therefore designed to test this novel hypothesis by focusing primarily on the events that occur during the narrow window of the inonocyte to DC transition. During this period Cl q and Cl qR interactions are predicted to regulate early processes that signal progression from the monocyte lineage (innate immunity) toward the DC lineage (adaptive immunity). To test this hypothesis, wetropose to: (1) Determine the synthesis and expression of Clq during the monocyte to DC transition, (2) Evaluate the consequence of inhibition of Clq synthesis on DC differentiation and function, and to (3) Assess the effect of exogenously added Clq during the monocyte to DC transition. Together, the proposed studies will not only provide information for developing a comprehensive model of the role of Cl q in autoimmunity, but also `.G w1' 0.N ..r v0, .a. ?'? in the long term, may provide firm grounds for the development of innovative therapeutic intervention strategies. ..O (.) '-" .?+ 4?U 4.' .U- 0_0