Combined deficiency in CD44 and Fas leads to exacerbation of lymphoproliferative and autoimmune disease.
Combined deficiency in CD44 and Fas leads to exacerbation of lymphoproliferative and autoimmune disease.
复制标题
CD44 和 Fas 的联合缺乏会导致淋巴增殖性疾病和自身免疫性疾病的恶化。
DOI：
10.1093/intimm/dxg132
复制
发表时间：
2003
影响因子：
4.4
通讯作者：
Nagarkatti,Mitzi
中科院分区：
文献类型：
--
作者：
Do,Yoonkyung;Rafi-Janajreh,AsimahQ;McKallip,RobertJ;Nagarkatti,PrakashS;Nagarkatti,Mitzi
Fas基因突变的患者会患上自身免疫性淋巴增殖性疾病(Alps)，而他们有类似突变的家庭成员通常是正常的，从而表明额外的因素可能在Alps的发展中发挥作用。在本研究中，我们通过建立不表达CD44和Fas的CD44-/-/Fas-/-小鼠，并与表达CD44但不表达Fas的CD44+/+/Fas-/-小鼠进行比较，以检验CD44在淋巴增殖性疾病发展中的作用。结果表明，与CD44+/+/Fas-/-小鼠相比，CD44-/-/Fas-/-小鼠发生了更严重的淋巴增生性疾病和自身免疫性疾病。这表现为淋巴结中细胞数量的增加，以及B220+CD4-CD8-(双阴性)T细胞的更大比例，以及针对单链DNA和染色质的抗体。CD44-/-/Fas-/-小鼠淋巴增殖性疾病的严重程度与T细胞对活化诱导细胞死亡(AICD)的抵抗力增加有关，但与B细胞无关。目前的研究表明，CD44的缺陷和死亡受体家族中的一个分子(如Fas)的缺陷可以进一步下调AICD，并加剧淋巴增生性和自身免疫性疾病。
Patients with mutations in Fas develop autoimmune lymphoproliferative disease (ALPS), while their family members with similar mutations are often normal, thereby suggesting that additional factors may play a role in the development of ALPS. In the current study, we tested the role of CD44 in the development of lymphoproliferative disease by generating CD44–/–/Fas–/–mice, which failed to express CD44 and Fas, and compared them to CD44+/+/Fas–/–mice that expressed CD44, but not Fas. The results showed that CD44–/–/Fas–/–mice developed a more severe lymphoproliferative and autoimmune disease when compared to CD44+/+/Fas–/–mice. This was indicated by increased numbers of cells in their lymph nodes, and a greater proportion of B220+CD4–CD8–(double‐negative) T cells as well as antibodies against single‐stranded DNA and chromatin. The heightened severity of lymphoproliferative disease seen in CD44–/–/Fas–/–mice correlated with increased resistance of T cells, but not B cells, to undergo activation‐induced cell death (AICD). The current study suggests that deficiency in CD44 in combination with a defect in one of the molecules involved in the death receptor family such as Fas can further down‐regulate AICD, and exacerbate the lymphoproliferative and autoimmune disease.