Exposure of anionic phospholipids serves as anti-inflammatory and immunosuppressive signal--implications for antiphospholipid syndrome and systemic lupus erythematosus.
In contrast to necrotic cells, the clearance of apoptotic ones usually is an anti-inflammatory process which elicits only a marginal immune response. During apoptosis phosphatidylserine (PS) is exposed on the outer leaflet of the cytoplasmic membrane and serves as target for the PS receptor of phagocytes. The latter is responsible for anti-inflammatory signalling and the induction of TGFbeta. We were interested whether the immunogenicity of apoptotic cells can be increased by masking PS. We observed that treatment of xenogeneic apoptotic cells with annexin V (AxV) significantly increased the humoral immune response against surface epitopes of these cells. Furthermore, AxV-coated irradiated tumour cells were able to elicit a long lasting tumour specific cytotoxic T lymphocyte response. AxV efficiently blocked the uptake of irradiated cells by macrophages but not by dendritic cells. Furthermore, AxV skewed the phagocytosis of irradiated cells towards inflammation. Investigation of patients with autoimmune diseases further supported the role of anionic surface phospholipids for anti-inflammatory clearance of apoptotic cells. Impaired clearance and opsonisation with anti-phospholipid-antibodies are discussed to be responsible for the development of systemic lupus erythematosus and anti-phospholipid-syndrome, respectively. Presentation of cryptic epitopes from late apoptotic cells in a proinflammatory context may challenge T cell tolerance. In addition, accumulation of uncleared apoptotic debris in the germinal centres of lymph nodes may result in the survival of autoreactive B cells.
Gaipl
Udo S
US
Institute for Clinical Immunology and Rheumatology, Department of Internal Medicine III, Erlangen, Germany
Beyer
Thomas D
TD
Baumann
Irith
I
Voll
Reinhard E
RE
Stach
Christian M
CM
Heyder
Petra
P
Kalden
Joachim R
JR
Manfredi
Angelo
A
Herrmann
Martin
M
D000818:Animals; D000838:Anions; D017304:Annexin A5 / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D016736:Antiphospholipid Syndrome / Q000276:immunology*; D017209:Apoptosis; D002460:Cell Line; D002478:Cells, Cultured; D002645:Chickens; D003593:Cytoplasm / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D020287:In Situ Nick-End Labeling; D007249:Inflammation; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008198:Lymph Nodes / Q000473:pathology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008856:Microscopy, Fluorescence; D010586:Phagocytes / Q000378:metabolism; D010587:Phagocytosis; D010718:Phosphatidylserines / Q000378:metabolism; D010743:Phospholipids / Q000737:chemistry / Q000276:immunology*; D011485:Protein Binding; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000838:Anions; D017304:Annexin A5; D000893:Anti-Inflammatory Agents; D007166:Immunosuppressive Agents; D010718:Phosphatidylserines; D010743:Phospholipids; D016212:Transforming Growth Factor beta