Apoptosis impairment

An important animal model of lupus is the lpr mouse. It was discovered that the abnormality leading to autoimmunity in this model is a defect in the gene coding for Fas protein and this leads to impaired apoptosis [103], This, in turn, leads to lymphade-nopathy and prevents elimination of autoimmune T cells, thus interfering with tolerance. Minocycline inhibits apoptosis, and it has been postulated that this contributes to the mechanism of minocycline-induced lupus [104],... 

However it was later shown that fumonisin B1 treatment does not impair receptor- or dmg-induced apoptosis (Jaffrezou et al 1996), strenghtening the notion that sphingomyelin breakdown plays the major part in the generation of the biologically relevant ceramide. 

Programmed cell death plays an important role during lymphocyte development, by eliminating autoreactive cells, as well as in the effector phase of the immune response, when antigen induced cell death halt cell activation. Several groups have been studied the function of PTEN in the immune response. PTEN heterozygous (PTEN+/-) mutants develop a lethal polyclonal autoimmune disorder with features reminiscent of those observed in Fas-deficient mutants. Fas-mediated apoptosis was impaired in Pten+/-mice, and T lymphocytes from these mice show reduced activation-induced cell death and increased proliferation upon activation. PI3-K inhibitors restored Fas responsiveness in PTEN+/- cells. These results indicate that PTEN is an essential mediator of the Fas response and a repressor of autoimmunity, thus implicate the P13-Kinase/Akt pathway in Fas-mediated apoptosis (DiCristofano et al, 1999)... 

Wang, J., Koizumi, T., and Watanabe, T., 1996, Altered antigen receptor signaling and impaired Fas-mediated apoptosis of B cells in Lyn-deficient mice. J.Exp. Med. 184 831-838. 

Mechanisms involved in UV-B-induced immune tolerance are multiple. UV-B irradiation strongly affects the viability and function of skin DCs [6]. UV-B irradiation causes DNA damage and apoptosis in LCs, while promoting their migration to regional lymph nodes [7]. This effect is paralleled by the reduced expression of MHC and costimulatory molecules, which results in an impaired antigen presenting capability. The release of IL-10 by resident skin cells, ker-atinocytes and mast cells, also contributes to dampen DC function [8, 9]. Thus, upon UV-B irradiation, immature or partially mature DCs,... 

The clinical spectrum in a large kindred with autoimmune lymphoprolif-erative syndrome caused by a Fas mutation that impairs lymphocyte apoptosis. J Pediatr 1998 133 629-633. 

Apoptosis Damage to mitochondria can also result in the release of cytochrome c and other factors into the cytosol, which can initiate the process of apoptosis. If a sufficient number of cells in a tissue or organ is lost, the function of the organ or tissue can be impaired, so that it would be less... 

Thus, the KOB cells have been demonstrated ex vivo to prevent apoptosis by expression on their surfaces of function-ablating Fas antigen, which lacks the entire death domain. These aberrant Fas molecules probably behave as decoy receptors and interfere with the trimerization of normal Fas in a dominant negative manner, resulting in the impairment of signal transduction. 

Masuda A, Maeno K, Nakagawa T et al. Association between mitotic spindle checkpoint impairment and susceptibility to the induction of apoptosis by anti-microtubule agents in human lung cancers. Am... 

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