An artical showing the expression of Fas (tumor necrosis factor) on both cd4+ and CD8+ T cells in PM and DM. (Sugiura, Murakawa 1999). [1]

Fas ligand

Fas ligand (FasL; CD95L), a cytotoxic cytokine belonging to the TNF superfamily, acts through Fas, a death receptor of the TNFR superfamily, to induce programed cell death via caspase signaling (1). Local expression of FasL in immunoprivileged organs including eyes, testis, and placenta is essential for deletion of infiltrating inflammatory cells (2). Fas/FasL interaction is of particular importance for homeostasis of the immune system and its dysregulation has been implicated in various autoimmune diseases. Mice carrying autosomal recessive mutations in the Fas (lpr) and FasL (gld) genes develop a spontaneous autoimmune syndrome similar to human systemic lupus erythematosus (3). Fas and FasL are also involved in the pathogenesis of EAE, as EAE is dramatically ameliorated in lpr and gld mice in terms of disease incidence and mean clinical score (4). Intrathecal infusion of recombinant FasL induces apoptosis of CNS-infiltrating inflammatory cells, including T cells and macrophages, but does not exert cytotoxicity against CNS-resident cells, resulting in mitigated EAE manifestations(5).

Microenvironment

The FAS receptor is homotrimeric and activated by the cognate FAS ligand (FASL), another homotrimeric protein complex homologous to TNF . Following stimulation, the intracellular death domain (DD) portion of FAS nucleates an extended helical complex of the FADD adaptor protein and caspases-8 and −10. These caspases undergo proteolytic autoprocessing and cleave, in a signaling cascade, downstream effector caspases and other targets, leading to apoptosis. The FAS gene contains nine exons spanning 26 kb on chromosome 10q24. The first 5 exons encode the extracellular portion containing 3 cysteine-rich domains that control receptor trimerization and FASL binding. Exon 6 represents the transmembrane domain (TM), and the intracellular portion is encoded by exons 7 through 9. The FAS DD encoded by exon 9 is 85 amino acids long and critical for apoptosis signaling ALPS-FAS is most frequently caused by heterozygous mutations that generate mutant FAS proteins, often with defective DDs. The defective FAS chains associate with wild-type chains via the pre-ligand assembly domain (PLAD), resulting in functionally defective receptor trimers, a phenomenon termed “dominant interference” Less frequently, heterozygous mutations cause decreased FAS protein and haploinsufficiency. Mutations in genes encoding FASL, FADD, and CASP10 also cause ALPS termed ALPS-FASL, ALPS-FADD, and ALPS-CASP10, respectively. Germ-line mutations in CASP8 or somatic mutations in NRAS and KRAS cause ALPS-related syndromes with distinct clinical phenotypes. Importantly, FASmutations are associated with in vitro lymphocyte apoptosis defects but may show variable clinical penetrance, and this mechanism has not been fully defined.

Chemical signals

S ystemic infusion of bone marrow mesenchymal stem cells (BMMSCs) yields therapeutic benefit for a variety of autoimmune diseases. The apoptotic T cells subsequently triggered macrophages to produce high levels of TGFβ, which in turn led to the upregulation of CD4⁺CD25⁺Foxp3⁺ regulatory T cells and, ultimately, immune tolerance.

Fas-mediated apoptosis of muscle fibres occurs in both PM and DM. Immunohistochemical analysis has revealed that Fas-expressing muscle fibres are surrounded by FasL-expressing mononuclear cells. Fas, which is a 45-kDa membrane protein that belongs to the tumour necrosis factor (TNF) receptor superfamily, is constitutively expressed in many cell types.The ligand for Fas, FasL, is expressed on activated T cells and natural killer (NK) cells, as well as at some immune-privileged sites.When cross-linked with FasL, Fas transduces an apoptotic signal. The Fas/FasL system is essential for homeostasis of the immune system, and its impairment leads to autoimmune disease. Several reports suggest a stimulatory function for Fas-mediated signalling. Murine macrophages can be activated by FasL stimulation, and Fas-mediated signalling can induce human dendritic cells (DCs) to produce proinflammatory cytokines.These lines of evidence suggest the possibility that the Fas/FasL interaction in inflamed tissues of inflammatory myopathies results not only in muscle fiber apoptosis but also in the promotion of inflammatory responses.

One study reveals that proinflammatory cytokines enhance Fas-mediated apoptosis of muscle cells, and that the Fas/FasL interaction between invading DCs and CD4⁺ T cells induces the local production of IL-23 and proinflammatory cytokines, which in turn promote the proliferation of Th17 cells and enhance Fas-mediated apoptosis of muscle cells, respectively. (6)

Footnotes:

1. Rie Watanabe-Fukunaga, , Neal G. Copeland*,Brannan C,Copeland N,Kenkins N, Nagata S. Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature, 356, 314 - 317, 1992 as found at VIEW

2. Tomohiro Takahashi, Tanaka M,Brannan C,Jenkins N,Copeland N,Suda T,Nagata S. Generalized lymphoproliferative disease in mice, caused by a point mutation in the fas ligand. Cell, Volume 76, Issue 6, p969–976, 1994 as found at VIEW

3. H Waldner, Sobel RA,Howard E,Kuchroo VK. Fas- and FasL-deficient mice are resistant to induction of autoimmune encephalomyelitis. Journal of Immunology, 159:3100-3, 1997 as found at VIEW

4. B Zhu, Luo L,Chen Y,Paty DW, Cynader MS. Intrathecal Fas ligand infusion strengthens immunoprivilege of central nervous system and suppresses experimental autoimmune encephalomyelitis. J Immunol, Aug 1;169(3):1561-9, 2002 as found at VIEW

5. XU Wang, Haroon F,Karray S,Deckert M,Schluter D. Astrocytic Fas ligand expression is required to induce T-cell apoptosis and recovery from experimental autoimmune encephalomyelitis. Eur. J. Immunol, 013. 43: 115–124, 2012 as found at VIEW

6. Masahiro Kondo, Murakawa Y,Harashima N,Kobayashi S,Yamaguchi S, Harada M. Roles of proinflammatory cytokines and the Fas/Fas ligand interaction in the pathogenesis of inflammatory myopathies. Immunology, Volume 128, Issue 1pt2, , 2008 as found at VIEW

7. Sugiura, T, Y.,Nagai,A.,Kondo,Murakawa Y.,Nagai A.,Kondo M., Kobayash. Fas and Fas ligand interaction induces apoptosis in inflammatory myopathies: CD4+ T cells cause muscle cell injury directly in polymyositis. Arthritis & Rheumatism, 42: 291–298, 1999 as found at VIEW