Current directions in autoimmunity最新文献

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BLyS and B cell autoimmunity. BLyS和B细胞自身免疫

Current directions in autoimmunity

Pub Date : 2003-01-01 DOI: 10.1159/000066854

Tong Zhou, Jun Zhang, Robert Carter, Robert Kimberly

引用次数: 25

Apoptosis and B cell tolerance. 凋亡与B细胞耐受。

Current directions in autoimmunity

Pub Date : 2003-01-01 DOI: 10.1159/000066855

Jeffrey C Rathmell

引用次数: 10

Toll-like receptors and activation of autoreactive B cells. toll样受体和自身反应性B细胞的激活。

Current directions in autoimmunity

Pub Date : 2003-01-01 DOI: 10.1159/000066858

Elizabeth A Leadbetter, Ian R Rifkin, Ann Marshak-Rothstein

引用次数: 66

Signaling mutations and autoimmunity. 信号突变和自身免疫

Current directions in autoimmunity

Pub Date : 2003-01-01 DOI: 10.1159/000066856

Calvin C K Yu, Alusha A Mamchak, Anthony L DeFranco

Mutations in a number of signaling components in mice can lead to strong autoimmune phenotypes. In some cases, these mutations likely compromise important feedback inhibitory pathways that downregulate antigen receptor signaling. For example, a deficiency of Lyn leads to a severe lupus-like autoimmunity. This autoimmunity may result from loss of a feedback inhibitory pathway in which Lyn phosphorylates CD22, triggering recruitment of the tyrosine phosphatase SHP-1 to the plasma membrane, which then dampens BCR signaling. Loss of Lyn also compromises an inhibitory pathway involving Fc gamma RIIb and SHIP, an inositol phosphatase. Mutation of Fyn exacerbates the autoimmunity caused by loss of Lyn. This may be due in part to a nonimmunological compromise in the integrity of the podocytes in the kidney, which may make the kidneys more susceptible to immune complex-induced damage. Fyn-deficient mice exhibit a number of immunological abnormalities and also exhibit some autoimmunity, although this is less severe than what is seen in Lyn-deficient mice. Recently a gain of function mutation in CD45 that may enhance activity of Src family tyrosine kinases has also been found to cause autoimmune disease, suggesting that the level of Src family tyrosine kinase activity is an important determinant of immune tolerance. Finally, several studies suggest that there is a significant interaction between Src family tyrosine kinases and the Fas pathway that is important for self-tolerance. Although these studies are still at an early stage, it seems clear that alterations in regulators of antigen receptor signaling can contribute to autoimmunity.

小鼠中许多信号成分的突变可导致强自身免疫表型。在某些情况下，这些突变可能损害了下调抗原受体信号的重要反馈抑制途径。例如，Lyn缺乏会导致严重的狼疮样自身免疫。这种自身免疫可能是由于Lyn磷酸化CD22，触发酪氨酸磷酸酶SHP-1向质膜募集，从而抑制BCR信号传导的反馈抑制途径的丧失。Lyn的缺失也破坏了Fc γ RIIb和SHIP(一种肌醇磷酸酶)的抑制途径。Fyn突变加剧了Lyn缺失引起的自身免疫。这可能部分是由于肾脏足细胞完整性的非免疫性损害，这可能使肾脏更容易受到免疫复合物引起的损伤。fyn缺陷小鼠表现出许多免疫异常，也表现出一些自身免疫，尽管这比在lyn缺陷小鼠中所见的要轻。最近，CD45功能突变的增加可能增强Src家族酪氨酸激酶的活性，也被发现引起自身免疫性疾病，这表明Src家族酪氨酸激酶活性水平是免疫耐受的重要决定因素。最后，一些研究表明Src家族酪氨酸激酶和Fas途径之间存在重要的相互作用，这对自我耐受很重要。虽然这些研究仍处于早期阶段，但抗原受体信号调节因子的改变可能有助于自身免疫似乎很清楚。

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引用次数: 32

Abnormal B cell signal transduction in systemic lupus erythematosus. 系统性红斑狼疮患者B细胞信号转导异常。

Current directions in autoimmunity

Pub Date : 2003-01-01 DOI: 10.1159/000066857

Islam U Khan, George C Tsokos, Gary M Kammer

引用次数: 16

TGF-beta: receptors, signaling pathways and autoimmunity. tgf - β:受体、信号通路和自身免疫。

Current directions in autoimmunity

Pub Date : 2002-01-01 DOI: 10.1159/000060548

Wanjun Chen, S. Wahl

引用次数: 78

Interleukin-2 signaling and the maintenance of self-tolerance. 白细胞介素-2信号传导与自我耐受性的维持。

Current directions in autoimmunity

Pub Date : 2002-01-01 DOI: 10.1159/000060549

B. Nelson

IL-2 plays an important and complex role in the immune system, serving as a growth factor, a differentiation factor, and a regulator of cell death. It shares many of these functions with other cytokines such as IL-15, which complicates the interpretation of the IL-2-deficient phenotype. Nonetheless, it is clear that a major indispensable role of IL-2 signaling, at least in mice, is to limit the number of activated T cells in the periphery after exposure to self- or environmental antigens. Although we still do not understand the mechanism by which this occurs, there emerge several general conclusions that provide a foundation for future work on this issue. The autoimmune phenotype associated with IL-2 deficiency results from the dysregulated activity of thymus-derived TCR alpha beta CD4+ and/or CD8+ T cells. The process requires an initial antigenic stimulus (e.g., from intestinal flora or self-antigens), but can then spread to naive bystander T cells by an undefined mechanism. A key observation is that neighboring T cells with intact IL-2 signaling can suppress the dysregulated activity of IL-2- or IL-2R-deficient T cells in a dominant manner, indicating that IL-2-based immune regulation is a systemic rather than cell autonomous property. The IL-2R signal responsible for maintaining homeostasis is not dependent on either the Shc or Stat5 pathways, therefore AICD, which is Stat5-dependent in vitro, cannot be the critical mechanism. Finally, expression of the IL-2R in the thymus and not the periphery appears sufficient to suppress the autoimmune phenotype, suggesting that IL-2 signaling may be required for some aspect of thymocyte selection and/or differentiation that has so far gone undetected. These observations can be combined into a unified model wherein IL-2 signaling is required for the development of a regulatory T-cell subset that serves to terminate antigen-induced responses of TCR alpha beta T cells. On the other hand, the role of IL-2 in the maintenance of self-tolerance could be multifaceted, with no single model accounting for all experimental findings. Of note, most of our knowledge regarding IL-2 signaling and tolerance has come from studies of knockout mice. Conceptually, it is important to remember that the function of a molecule such as IL-2 is not simply the inverse of the phenotype seen when that molecule is absent, since necessity and sufficiency are not always coupled in physiological processes. In this regard, perhaps new insights into this important issue can be gained by better defining when and where IL-2 signaling normally occurs in wild-type animals and the functional status of the T cells involved.

IL-2在免疫系统中发挥着重要而复杂的作用，是一种生长因子、分化因子和细胞死亡的调节剂。它与其他细胞因子(如IL-15)共享许多这些功能，这使il -2缺陷表型的解释变得复杂。尽管如此，很明显，至少在小鼠中，IL-2信号的一个重要的不可缺少的作用是在暴露于自身或环境抗原后限制外周活化T细胞的数量。虽然我们仍然不了解发生这种情况的机制，但已经出现了几个一般性结论，为今后在这个问题上的工作提供了基础。与IL-2缺乏相关的自身免疫表型是由胸腺源性TCR α β CD4+和/或CD8+ T细胞活性失调引起的。这个过程需要一个初始的抗原刺激(例如，来自肠道菌群或自身抗原)，但随后可以通过一种未定义的机制扩散到幼稚的旁观者T细胞。一个关键的观察结果是，具有完整IL-2信号的邻近T细胞可以以显性方式抑制IL-2或il - 2r缺陷T细胞的失调活性，这表明基于IL-2的免疫调节是一种全身性而非细胞自主特性。负责维持体内平衡的IL-2R信号不依赖于Shc或Stat5通路，因此体外依赖Stat5的AICD不可能是关键机制。最后，IL-2R在胸腺而非外周的表达似乎足以抑制自身免疫表型，这表明IL-2信号可能在胸腺细胞选择和/或分化的某些方面是必需的，而这些方面迄今尚未被发现。这些观察结果可以结合成一个统一的模型，其中IL-2信号是调节性T细胞亚群发育所必需的，该T细胞亚群用于终止抗原诱导的TCR α - β T细胞反应。另一方面，IL-2在维持自我耐受性中的作用可能是多方面的，没有一个单一的模型可以解释所有的实验结果。值得注意的是，我们关于IL-2信号传导和耐受性的大部分知识都来自基因敲除小鼠的研究。从概念上讲，重要的是要记住，像IL-2这样的分子的功能并不是简单地与该分子缺失时所见的表型相反，因为在生理过程中必要性和充分性并不总是耦合的。在这方面，也许通过更好地定义IL-2信号在野生型动物中正常发生的时间和地点以及所涉及的T细胞的功能状态，可以获得对这一重要问题的新见解。

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引用次数: 54

Abnormal T lymphocyte signal transduction in systemic lupus erythematosus. 系统性红斑狼疮患者T淋巴细胞信号转导异常。

Current directions in autoimmunity

Pub Date : 2002-01-01 DOI: 10.1159/000060555

G. Kammer, G. Tsokos

引用次数: 16

Role of the B7-CD28/CTLA-4 pathway in autoimmune disease. B7-CD28/CTLA-4通路在自身免疫性疾病中的作用

Current directions in autoimmunity

Pub Date : 2002-01-01 DOI: 10.1159/000060550

Tammy T. Chang, V. Kuchroo, A. Sharpe

引用次数: 47

Keeping the T-cell immune response in balance: role of protein tyrosine phosphatases in autoimmunity. 保持t细胞免疫反应平衡:蛋白酪氨酸磷酸酶在自身免疫中的作用。

Current directions in autoimmunity

Pub Date : 2002-01-01 DOI: 10.1159/000060553

T. Mustelin

引用次数: 12

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