Richard M. Siegel, MD, PhD, Thomas A. Fleisher, MD

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Presentation transcript:

The role of Fas and related death receptors in autoimmune and other disease states Richard M. Siegel, MD, PhD, Thomas A. Fleisher, MD Journal of Allergy and Clinical Immunology Volume 103, Issue 5, Pages 729-738 (May 1999) DOI: 10.1016/S0091-6749(99)70412-4 Copyright © 1999 Mosby, Inc. Terms and Conditions

Fig. 1 Signaling by the Fas death receptor. The major steps in initiation of the apoptosis pathway by the Fas receptor are shown. The purple spheres in the extracellular region of the Fas receptor schematic indicate cysteine-repeat domains of the receptor. The oval spheres indicate the death domains in Fas and FADD. Negative regulatory proteins described in the text are shown in red. Journal of Allergy and Clinical Immunology 1999 103, 729-738DOI: (10.1016/S0091-6749(99)70412-4) Copyright © 1999 Mosby, Inc. Terms and Conditions

Fig. 2 The role of Fas and Fas ligand in the immune response. T-cell activation is depicted in the center of the figure, with antigen stimulation driving resting T cells (grey cell) into the cell cycle (yellow cell). Restimulation through the T-cell antigen receptor leads to expression of Fas ligand and sensitivity to apoptosis through the Fas receptor (red cell). Fas-mediated killing of B cells and antigen-presenting cells (APC) is illustrated, as well as the possible killing of T cells by APCs. Journal of Allergy and Clinical Immunology 1999 103, 729-738DOI: (10.1016/S0091-6749(99)70412-4) Copyright © 1999 Mosby, Inc. Terms and Conditions

Fig. 3 The role of the Fas system in T cell/target cell interactions. The 4 possible outcomes of Fas/Fas ligand interactions between T cells and nonimmune cells are depicted. Note that interactions may be enhanced by recognition of antigens presented by the target cell by the T-cell antigen receptor (not shown). Target cell killing results from ligation of Fas on target cells. Immune privilege is thought to result from the opposite interaction, killing of T cells through engagement of their Fas receptors by Fas ligand from the target cell, although other factors may be necessary for this to occur (see text). Both T cells and target cells can commit suicide through autocrine Fas/Fas ligand stimulation. Interactions that would enhance inflammation and autoimmune disease are shown in red, and negative regulatory interactions are shown in green. Journal of Allergy and Clinical Immunology 1999 103, 729-738DOI: (10.1016/S0091-6749(99)70412-4) Copyright © 1999 Mosby, Inc. Terms and Conditions

Fig. 4 Clinical manifestations of ALPS. A computed tomography scan of the neck is shown at the top left, demonstrating enlarged preauricular, cervical, and occipital lymph nodes. Arrowheads denote the most prominent lymph nodes. The top right panel shows flow-cytometric analysis of peripheral blood T cells from a patient with ALPS, with CD8 expression on the vertical axis and CD4 on the horizontal axis. The lower left quadrant contains CD4–CD8– cells, which are usually present as less than 1% of T cells expressing the αβ TCR. The bottom panels show CD3, CD4, and CD8 staining (blue) on serial sections of a lymph node biopsy specimen from a patient with ALPS and also shows the large numbers of CD3+CD4–CD8– T cells present in the interfollicular areas of the lymph node. Journal of Allergy and Clinical Immunology 1999 103, 729-738DOI: (10.1016/S0091-6749(99)70412-4) Copyright © 1999 Mosby, Inc. Terms and Conditions