Impaired humoral immunity in X-linked lymphoproliferative disease is associated with defective IL-10 production by CD4+ T cells
Impaired humoral immunity in X-linked lymphoproliferative disease is associated with defective IL-10 production by CD4+ T cells
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DOI：
10.1172/jci23139
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发表时间：
2005-04-01
影响因子：
15.9
通讯作者：
Tangye, SG
中科院分区：
文献类型：
--
作者：
Ma, CS;Hare, NJ;Tangye, SG
X连锁淋巴增殖性疾病（XLP）是一种常致命的免疫缺陷病，其特征为低丙种球蛋白血症、暴发性传染性单核细胞增多症和/或淋巴瘤。XLP的遗传缺陷基因SH2D1A编码衔接蛋白SAP（信号淋巴细胞激活分子相关[SLAM相关]蛋白）；然而，SH2D1A突变导致低丙种球蛋白血症的机制尚不清楚。我们对14例XLP患者的分析显示，B细胞发育正常，但记忆B细胞数量显著减少。检测到的少数记忆细胞为IgM阳性，表明体内同种型转换缺陷。然而，XLP的B细胞在体外增殖和分化的效率与对照B细胞相同，这表明体内分化受阻是B细胞外源性的。XLP的CD4⁺T细胞在体外不能有效分化为IL - 10⁺效应细胞或不能为B细胞提供最佳辅助这一发现支持了上述可能性。重要的是，通过提供外源性IL - 10或异位表达SAP可改善SAP缺陷型CD4⁺T细胞对B细胞的辅助作用，从而使T细胞产生更多的IL - 10。XLP的CD4⁺T细胞也不能有效上调诱导性共刺激分子（ICOS）的表达，而ICOS是CD4⁺T细胞产生IL - 10的强效诱导剂。因此，IL - 10产生不足可能导致XLP中的低丙种球蛋白血症。这一发现为治疗这种免疫缺陷病提出了新的策略。
X-linked lymphoproliferative disease (XLP) is an often-fatal immunodeficiency characterized by hypogammaglobuhnemia, fulminant infectious mononucleosis, and/or lymphoma. The genetic lesion in XLP, SH2D1A, encodes the adaptor protein SAP (signaling lymphocytic activation molecule-associated [SLAM-associated] protein); however, the mechanism(s) by which mutations in SH2D1A causes hypogammaglobulinemia is unknown. Our analysis of 14 XLP patients revealed normal B cell development but a marked reduction in the number of memory B cells. The few memory cells detected were IgM(+), revealing deficient isotype switching in vivo. However, XLP B cells underwent proliferation and differentiation in vitro as efficiently as control B cells, which indicates that the block in differentiation in vivo is B cell extrinsic. This possibility is supported by the finding that XLP CD4(+) T cells did not efficiently differentiate into IL-10(+) effector cells or provide optimal B cell help in vitro. Importantly, the B cell help provided by SAP-deficient CD4(+) T cells was improved by provision of exogenous IL-10 or ectopic expression of SAP, which resulted in increased IL-10 production by T cells. XLP CD4(+) T cells also failed to efficiently upregulate expression of inducible costimulator (ICOS), a potent inducer of IL-10 production by CD4(+) T cells. Thus, insufficient IL-10 production may contribute to hypogammaglobulinemia in XLP. This finding suggests new strategies for treating this immunodeficiency.