The clearance of apoptotic cells: implications for autoimmunity.
Apoptosis has been clearly characterised by the ability to limit the activation of inflammatory responses through the disposal of the apoptotic cell by rapid uptake by phagocytes. The exposure of phosphatidylserine deriving from the loss of plasma lipid asymmetry is the early membrane signal which alerts the phagocyte about the imminent apoptotic death of the cell. Also modifications of membrane carbohydrate groups on apoptotic cells contribute to phagocyte recognition. Soluble proteins such as C1q, mannose-binding lectin, surfactant proteins A and D, C-reactive protein, C3bi, beta2-glycoprotein I and growth arrest specific gene-6 bind to apoptotic cells and act as "opsonins" thus favouring their clearance. A redundant and promiscuous system of receptors including integrins, scavenger receptors, CR3 and CR4, calreticulin, CD14 and Mer receptor ensures an efficient and rapid uptake of apoptotic cells. In animal models and in human pathology, single genetic defects of molecules involved in apoptotic cell clearance seem to be the main determinant in the development of autoimmunity. The uptake of apoptotic cells by phagocytes provides an immunomodulatory effect in that it triggers the release of anti-inflammatory cytokines, inhibits the production of inflammatory cytokines and leads to T cell tolerance. Impaired clearance of apoptotic cells or the presence of 'danger' signals may modify the balance between tolerance induction and activation of T cells leading to an effective autoimmune response.
Pittoni
Valerio
V
Dipartimento di Terapia Medica, Cattedra di Reumatologia, Università di Roma La Sapienza, Policlinico Umberto I, 00161 Rome, Italy.
Valesini
Guido
G
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology*; D015922:Complement C1q / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D016167:Integrin alphaXbeta2 / Q000276:immunology; D016177:Macrophage-1 Antigen / Q000276:immunology; D051379:Mice; D010586:Phagocytes / Q000276:immunology; D010718:Phosphatidylserines / Q000276:immunology
D016167:Integrin alphaXbeta2; D016177:Macrophage-1 Antigen; D010718:Phosphatidylserines; D015922:Complement C1q