Rethinking the red wolf disease: does Protein S suppress systemic lupus erythematosus clinical activity?

Systemic lupus erythematosus (SLE) is the prototypic chronic inflammatory systemic autoimmune disease, but many aspects of its pathogenesis remain poorly understood. As described in the following sections, the recent report from Suh and colleagues [1] may help us to integrate an understanding of how innate immune pathways affect autoimmune pathogenesis.One of the most fundamental challenges to the immune system is the efficient recognition and clearance of the body's own cells when senescence, injury or other causes lead to their entry into programmed death pathways, which are a normal outcome of cell and tissue turnover. Apoptotic cell (AC) clearance is therefore important for resolving the cellular consequences of normal development during embryogenesis, and for cellular proliferation and differentiation that continues throughout life.The homeostatic pathways that regulate apoptotic clearance are also involved in the resolution of inflammation. Yet inflammation is a beneficial host response to foreign challenge or tissue injury, representing a tightly choreographed sequence of changes in tissue and blood factors and cellular recruitment and subsequent clearance that ultimately restores tissue structure and function. Both exposure to ACs and the clearance of ACs have been recognized as important mechanisms for the resolution of inflammation in vivo (reviewed in [2]), while an inability to control inflammatory responses is at the root of many chronic diseases.Conditions associated with defects in phagocytic clearance of dead and dying host cells, and especially C1q and IgM deficiency states, may lead to lupus-like disease [2]. These associated clearance defects may also result in cellular progression to secondary necrosis and the release of self-ligands (such as High-mobility group protein B1 (HMGB-1) and heat shock protein (HSP)) for inflammatory innate receptors and of self-antigens that drive stimulation and selection of autoreactive lymphocytes.Discovered in 199