Goldman Frederick D, Vibhakar Rajeev, Puck Jennifer M, Straus Stephen E, Ballas Zuhair K, Hollenback Clay, Loew Thomas, Thompson Anthony, Song Kejing, Cook Robert T
Department of Pediatrics, University of Iowa Hospitals and Clinics and Veterans Affairs Medical Center, Iowa City, 52242, USA.
Clin Immunol. 2002 Jul;104(1):31-9. doi: 10.1006/clim.2002.5249.
Autoimmune Lymphoproliferative Syndrome (ALPS) is a disorder of defective lymphocyte apoptosis due to mutations of the Fas receptor and other molecules in the Fas signaling pathway. In addition to accumulation of CD4(-) CD8(-) double-negative (DN) T cells, many patients display a dysregulated cytokine pattern with dysfunctional T cells, suggesting Fas defects may impact pathways of T-cell activation/differentiation. Here, we report two novel mutations in the Fas receptor resulting in an ALPS phenotype. Utilizing flow cytometry, we found anti-CD3 activated CD4(+) T cells from these patients were incapable of fully upregulating activation markers (CD25, CD69, and CD40L) or producing interferon-gamma and IL-2. Additionally, DN T cells were unable to transduce proximal T-cell antigen receptor signals or produce cytokines. Furthermore, DN T cells overexpressed CD57 and phenotypically resembled end-stage effector cells. As DN T cells were essentially anergic, the clinical manifestations of autoimmunity are more likely to be a consequence of aberrant cytokine secretion within the CD4(+) T-cell subpopulation.
自身免疫性淋巴细胞增生综合征（ALPS）是一种由于Fas受体及Fas信号通路中其他分子发生突变导致淋巴细胞凋亡缺陷的疾病。除了CD4(-)CD8(-)双阴性（DN）T细胞积累外，许多患者还表现出细胞因子模式失调以及T细胞功能异常，提示Fas缺陷可能影响T细胞激活/分化途径。在此，我们报告了Fas受体中的两个新突变，其导致了ALPS表型。利用流式细胞术，我们发现来自这些患者的抗CD3激活的CD4(+)T细胞无法完全上调激活标志物（CD25、CD69和CD40L）或产生干扰素-γ和IL-2。此外，DN T细胞无法转导近端T细胞抗原受体信号或产生细胞因子。此外，DN T细胞过度表达CD57，并且在表型上类似于终末效应细胞。由于DN T细胞基本处于无反应状态，自身免疫的临床表现更可能是CD4(+)T细胞亚群内细胞因子分泌异常的结果。
