: Compelling evidence links the initiation and progression of Systemic Lupus Erythematosus (SLE) and Anti-Phospholipid Syndrome (APS) to aberrant immune responses to apoptotic cells. However, the circumstances that lead to the production of anti-nuclear autoantibodies, the hallmark of SLE, and of autoantibodies to complexes between serum proteins and membrane phospholipids, the serologicalI markers for APS, remain poorly understood. B cells with Ig receptors for apoptotic cells may be in a position to gain access to relevant autoantigens. Following positive selection by autoreactive T cells, such B cells may be induced to secrete autoantibodies to apoptotic cells (ATAC), and disrupt normal clearance mechanisms, thus perpetuating and even expanding the autoimmune response. Alternatively, ATAC may arise secondary to defects in clearance, or an overabundance of apoptotic cell remnants. To distinguish between these possibilities, more detailed information on the genetics, regulation, and function of ATAC is needed. This proposal aims to derive ATAC from mice with defects in phagocytosis of apoptotic cells.
The specific aims are: 1) Test sera of Mer, Axl, Tyro3 triply nullizygous mice for the expression of ATAC, and construct hybridomas from positive mice; 2) Screen hybridomas for ATAC specificity by flow cytometry and confocal microscopy and survey their relationship to other autoreactive hybridomas from the same fusions; 3) Determine the genetic basis for ATAC specificity and compare the contributions of immunoglobulin heavy and light chain V gene use, junctional diversity, and somatic mutations to the recognition of apoptotic cells. Future studies will explore the contribution of ATAC-bearing B cells to autoimmune responses against nuclear and cell surface antigens, the effect of soluble ATAC on the clearance of apoptotic cells by macrophage, and the regulation of ATAC-bearing B cells. The results of these studies will allow a fuller assessment of the role of apoptotic cells in the induction of B cell tolerance or autoimmunity.
| Neeli, Indira; Richardson, Mekel M; Khan, Salar N et al. (2007) Divergent members of a single autoreactive B cell clone retain specificity for apoptotic blebs. Mol Immunol 44:1914-21 |
| Radic, Marko Z; Shah, Kinjal; Zhang, Wenguang et al. (2006) Heterogeneous nuclear ribonucleoprotein P2 is an autoantibody target in mice deficient for Mer, Axl, and Tyro3 receptor tyrosine kinases. J Immunol 176:68-74 |
| Cline, Amy M; Radic, Marko Z (2004) Murine lupus autoantibodies identify distinct subsets of apoptotic bodies. Autoimmunity 37:85-93 |
| Cline, Amy M; Radic, Marko Z (2004) Apoptosis, subcellular particles, and autoimmunity. Clin Immunol 112:175-82 |
| Radic, Marko; Marion, Tony; Monestier, Marc (2004) Nucleosomes are exposed at the cell surface in apoptosis. J Immunol 172:6692-700 |
