Apoptosis and systemic lupus erythematosus.
Reduced clearance of dying cells by macrophages or increased apoptosis provokes accumulation of cellular fragments in various tissues. This process seems to induce the uptake of autoantigens from apoptotic nuclei or chromatin by dendritic cells (DCs). Then, the DCs present altered self-epitopes to naive T cells. Thus, autoreactive T cells are activated accidentally and may now provide T-cell help for B cells that present peptides processed from secondary necrotic/late apoptotic prey. Impaired phagocytic removal of early apoptotic cells may cause accumulation of secondary necrotic cells and debris in the germinal centers of secondary lymph organs. The latter bind complement and can, therefore, be trapped on the surfaces of follicular DCs (FDCs). B cells may get in contact with intracellular autoantigens that had been released during late stages of apoptotic cell death and are immobilized by FDCs. Consecutively, B cells that had, for example, gained specificity for nuclear auto-antigens during random somatic mutations can receive a short-term survival signal. After migration into the mantle zone, these autoreactive B cells may finally be activated by autoreactive CD4+ T helper cells. B cells then differentiate into memory or plasma cells. The plasma cells produce those pathogenic nuclear autoantibodies. Many defects are known with respect to the clearance of apoptotic cells and cell material, especially that of nuclear origin. Reflecting on the plethora of defects of clearance of apoptotic material already demonstrated in systemic lupus erythematosus, it is reasonable to argue that, for many patients, failure of clearance is at the heart of their disease.
Sheriff
Ahmed
A
Institute for Clinical Immunology and Rheumatology, Medical Department III, University of Erlangen-Nüremberg, Glueckstrasse 4a, 91054 Erlangen, Germany.
Gaipl
Udo S
US
Voll
Reinhard E
RE
Kalden
Joachim R
JR
Herrmann
Martin
M
D017209:Apoptosis / Q000276:immunology*; D015551:Autoimmunity; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D010587:Phagocytosis / Q000276:immunology*