Pathogenesis of multi-organic failure in autoimmune diseases.
Multi-organic failure in the context of autoimmune diseases is a multi-factorial condition where different pathways concur to produce a global system breakdown. Some of these pathways include the coagulation, fibrinolysis, kinin and complement cascades which in normal conditions work together to provide a comprehensive response to injury. In pathologic conditions these regulatory mechanisms are replaced by positive feed-back loops. The common response pattern is the activation of the immune system via endothelium activation. Furthermore, these different plasma-driven mechanisms may induce standardised endothelial cell responses of which the most relevant are the activation of p38, JNK, NF-kbeta and IRF-3 pathways. In this paper we review the common points between these major pathways and how they become activated, contributing to a global clinical picture. We present two examples of apparently different clinical settings, caused by the same global dysfunction: the Macrophage Activation Syndrome and the iatrogenic "cytokine storm" triggered by the administration of anti-CD28 monoclonal antibody TGN1412 in a phase 1 trial.
Amaral
M C
MC
Department of Pharmacology, Autoimmune Diseases Unit, Faculty of Medical Sciences of Lisbon, Curry Cabral Hospital, Portugal.
Alves
J Delgado
JD
D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D001327:Autoimmune Diseases / Q000276:immunology / Q000503:physiopathology* / Q000628:therapy; D001777:Blood Coagulation; D018106:CD28 Antigens / Q000276:immunology; D002648:Child; D002986:Clinical Trials as Topic; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D003602:Cytotoxicity, Immunologic; D025461:Feedback, Physiological; D006801:Humans; D055501:Macrophage Activation Syndrome / Q000097:blood / Q000276:immunology* / Q000503:physiopathology*; D009102:Multiple Organ Failure; D015398:Signal Transduction / Q000276:immunology; D013927:Thrombosis
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018106:CD28 Antigens; D016207:Cytokines; C509303:TGN-1412