Environmental adjuvants, apoptosis and the censorship over autoimmunity.
Alterations during apoptosis lead to the activation of autoreactive T cells and the production of autoantibodies. This article discusses the pathogenic potential of cells dying in vivo, dissecting the role of signals that favor immune responses (adjuvants) and the influence of genetic backgrounds. Diverse factors determine whether apoptosis leads or not to a self-sustaining, clinically apparent autoimmune disease. The in vivo accumulation of uncleared dying cells per se is not sufficient to cause disease. However, dying cells are antigenic and their complementation with immune adjuvants causes lethal diseases in predisposed lupus-prone animals. At least some adjuvant signals directly target the function and the activation state of antigen presenting cells. Several laboratories are aggressively pursuing the molecular identification of endogenous adjuvants. Sodium monourate and the high mobility group B1 protein (HMGB1) are, among those identified so far, well known to rheumatologists. However, even the complementation of apoptotic cells with potent adjuvant signals fail to cause clinical autoimmunity in most strains: autoantibodies generated are transient, do not undergo to epitope/spreading and do not cause disease. Novel tools for drug development will derive from the molecular identification of the constraints that prevent autoimmunity in normal subjects.
Rovere-Querini
Patrizia
P
H San Raffaele Scientific Institute and Vita-Salute San Raffaele University, DIBIT 3A1, Via Olgettina 58, 20132 Milano, Italy. rovere.patrizia@hsr.it
Manfredi
Angelo A
AA
Sabbadini
Maria Grazia
MG
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D001323:Autoantibodies / Q000097:blood* / Q000276:immunology; D015551:Autoimmunity / Q000187:drug effects* / Q000276:immunology; D016207:Cytokines / Q000097:blood; D004777:Environment; D006801:Humans
D000276:Adjuvants, Immunologic; D001323:Autoantibodies; D016207:Cytokines