Requirement of dying cells and environmental adjuvants for the induction of autoimmunity.
OBJECTIVE
Cells commonly die without eliciting autoimmunity. However, dying cells are a potential initiating stimulus for systemic lupus erythematosus (SLE). Our goal was to verify whether immune adjuvants influence the autoimmunity induction that ensues following in vivo injection of dying cells.


METHODS
Mice were immunized with apoptotic thymocytes in the presence of artificial moieties, such as Freund's incomplete adjuvant (IFA), or natural adjuvants, such as dendritic cells (DCs). Renal involvement and the development of autoantibodies were monitored.


RESULTS
Apoptotic cells failed to induce clinical disease or to sustain production of autoantibodies in (NZB x NZW)F(1) mice. In contrast, autoimmunity developed in the presence of IFA or DCs. The characteristics of the adjuvant influenced the array of autoantibodies, the kinetics of their development, and the severity of the disease. DCs were required for induction of anti-beta(2)-glycoprotein I IgG. Adjuvants alone did not elicit disease.


CONCLUSIONS
A "two-hit" signal composed of autoantigens and adjuvants initiates systemic autoimmunity. Moreover, environmental signals at the site of clearance of dead cells shape the features and the severity of the autoimmune disease. Strategies aimed at preventing the accumulation of dying cells and at modulating endogenous adjuvants may be beneficial for the treatment of SLE.
Bondanza
Attilio
A
H. San Raffaele Scientific Institute and University, Via Olgettina 58, Milan 20132, Italy.
Zimmermann
Valérie S
VS
Dell'Antonio
Giacomo
G
Cin
Elena Dal
ED
Balestrieri
Genesio
G
Tincani
Angela
A
Amoura
Zahir
Z
Piette
Jean-Charles
JC
Sabbadini
Maria Grazia
MG
Rovere-Querini
Patrizia
P
Manfredi
Angelo A
AA
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology / Q000637:transplantation; D005260:Female; D005620:Freund's Adjuvant / Q000494:pharmacology; D006023:Glycoproteins / Q000276:immunology; D007114:Immunization; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008814:Mice, Inbred NZB; D012720:Severity of Illness Index; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology; D053482:beta 2-Glycoprotein I
D001323:Autoantibodies; D006023:Glycoproteins; D053482:beta 2-Glycoprotein I; D005620:Freund's Adjuvant