T-helper cell intrinsic defects in lupus that break peripheral tolerance to nuclear autoantigens.
Special populations of T helper cells drive B cells to produce IgG class switched, pathogenic autoantibodies in lupus. The major source of antigenic determinants (epitopes) that trigger interactions between lupus T and B cells is nucleosomes of apoptotic cells. These epitopes can be used for antigen-specific therapy of lupus. Secondly, the autoimmune T cells of lupus are sustained because they resist anergy and activation-induced programmed cell death by markedly upregulating cyclooxygenase (COX) 2 along with the antiapoptotic molecule c-FLIP. Only certain COX-2 inhibitors block pathogenic anti-DNA autoantibody production in lupus by causing death of autoimmune T helper cells. Hence COX-2 inhibitors may work independently of their ability to block the enzymatic function of COX-2, and structural peculiarities of these select inhibitors may lead to better drug discovery and design.
Datta
Syamal K
SK
Department of Medicine, Feinberg School of Medicine, Northwestern University, 240 East Huron St., Chicago, IL 60611, USA. skd257@northwestern.edu
Zhang
Li
L
Xu
Luting
L
D000818:Animals; D017209:Apoptosis / Q000276:immunology / Q000502:physiology; D001324:Autoantigens / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D023201:CD40 Ligand / Q000378:metabolism; D017635:Clonal Anergy; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology / Q000378:metabolism; D008177:Lupus Vulgaris / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D008565:Membrane Proteins; D009707:Nucleosomes / Q000276:immunology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000473:pathology*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
D001324:Autoantigens; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009707:Nucleosomes; D011518:Proto-Oncogene Proteins; D023201:CD40 Ligand; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; C067419:CBL protein, human