This is going to be a rather technical post about the Fas and FasL cell surface receptors and what happens when the genes that produce them are defective. I offer it because Fas is so often mentioned in research studies related to cancers, auto-immune diseases and, in fact, in most discussions of molecular pathways concerned with cell birth, reproduction and death.
Fas is a glycoprotein molecule, 43 kDa in size. It is a surface receptor molecule that is expressed on the surface of Fas-activated lymphocytes. When Fas is paired up with another surface molecule, the ligand Fas L sitting on the surface of another cell, the lymphocyte cell bearing Fas commits apoptosis; it kills itself(ref). So, a cell with Fas mating with another cell with Fas L is a dance of death.
Well-functioning of Fas and FasL is important for health. “In the immune system, Fas and FasL are involved in down-regulation of immune reactions as well as in T cell-mediated cytotoxicity. Malfunction of the Fas system causes lymphoproliferative disorders and accelerates autoimmune diseases, whereas its exacerbation may cause tissue destruction(ref).”
Here are some examples of disease conditions in relationship tp defects in the Fas/ FasL system:
· Going back to 1998 it was observed “Germline mutations in the Fas gene have been associated with autoimmune lymphoproliferative syndrome, and somatic Fas mutations have been found in multiple myeloma.” – “Our data indicate that somatic disruption of Fas may play a role in the pathogenesis of some lymphomas, and suggest a link between Fas mutation, cancer and autoimmunity(ref).”
· Fas and FasL are implicated in many lymphoma cancers. “FasL mRNA was detected by reverse transcriptase-polymerase chain reaction in 38 out of 63 lymphoma biopsy specimens representative of various subtypes of non-Hodgkin’s lymphoma (NHL) and Hodgkin’s disease. FasL was co-expressed with Fas mRNA in most cases(ref).” It appears that if there is a defect in Fas/FasL pathway, the normal reactive cells are more sensitive to Fas-induced apoptosis than the cancerous ones in the case of lymphomas(ref).
· A 2008 study was coducted “to investigate the impact of functional polymorphisms in the Fas and Fas L genes on the survival of early stage non–small cell lung cancer (NSCLC) patients.” 338 patients with NSCLC were involved. The authors concluded “The Fas -670A>G polymorphism may affect survival in early-stage NSCLC. The analysis of the Fas -670A>G polymorphism can help identify patients at high risk for a poor disease outcome(ref).”
· “A polymorphism in the Fas gene promoter region influences the susceptibility to systemic sclerosis(ref).”
· Defects in the Gene encoding Fas is correlated with systemic lupus erythematosus (SLE). “In the murine MRL/Ipr-Ipr model of systemic lupus erythematosus (SLE), the lymphoproliferation (lpr) mutation results in defective transcription of the gene that codes for the Fas protein.” – “Interest in the importance of Fas in SLE has risen with the observation that 60% of human subjects with lupus have elevated levels of the soluble Fas receptor in their serum and that the abnormal presence of this molecule may protect lymphocytes from undergoing apoptosis(ref).” The link of FAS to autoimmune diseases goes back over a decade, considering the 1998 paper Human autoimmune lymphoproliferative syndrome, a defect in the apoptosis-inducing Fas receptor: a lesson from the mouse model.
· Another 2008 study, Differential expression of Fas system apoptotic molecules in peripheral lymphocytes from patients with Graves’ disease and Hashimoto’s thyroiditis, looked at whether whether “the Fas system apoptotic molecules are differentially expressed in Graves’ disease (GD) and Hashimoto’s thyroiditis (HT), the two opposite phenotypes of autoimmune thyroid disease (AITD).” The conclusion was “The Fas system apoptotic molecules appear to be differentially expressed on peripheral lymphocytes in the two opposite phenotypes of AITD.”
The above is just a sampler. Polymorphism veriations of the Fas and Fas L genes are also implicated in and perhaps causative of many other cancers and pathological processes. For a background discussion of gene veriations and how they impact disease processes see the blog post Gene variations and diseases – far from simple.
What can be done for people with defective Fas or FasL genes? I think the ultimate solution will involve gene splicing. See the following blog post Treating genetic diseases with corrected induced pluripotent stem cells.
