2013年7月20日 訊 /生物谷BIOON/ --近日,，來自悉尼Garvan醫(yī)學研究所的研究人員通過研究表示，對單一基因突變的免疫缺陷患者進行研究或許可以獲取更多關(guān)于免疫系統(tǒng)研究的信息,，尤其是當患者實際的針狀和臨床預期不太一樣的時候,，就更要去深入研究其中的機制，相關(guān)研究刊登于國際雜志Journal of Allergy and Clinical Immunology上,。
文章中,，研究者對常染色體顯性高IgE綜合征進行了研究，該疾病是基因STAT3發(fā)生突變導致的,，這使得患者更易發(fā)生淋巴瘤,，實驗室和動物模型研究預測這種疾病的患者對病毒和癌癥會更加易感，而實際情況并不是這樣,。
研究人員Megan Ives及其同事研究發(fā)現(xiàn),，常染色體顯性高IgE綜合征個體相比預期來說，其免疫系統(tǒng)具有更強的代償能力,，研究者預測患者機體中會較少產(chǎn)生具有功能的殺傷性T細胞,，殺傷性T細胞是一種可以殺滅入侵微生物和癌癥細胞的機體免疫細胞。
研究者Elissa Deenick說道,，在正常情況下STAT3分子可以在T細胞中傳輸生化信號,，這種信號可以指導STAT3分子開啟其殺滅功能，但是在高IgE病人中,，其由于缺少STAT3基因,，這種信號大部分時間采用“聲東擊西的策略”,，看似工作實際上并無功能。殺傷性T細胞需要特定的分子來變得更為有效,，尤其是對付病毒和淋巴瘤,；而高IgE患者就不能產(chǎn)生必備的信號來產(chǎn)生這些效應(yīng)分子。
研究者認為這項研究非常重要,，因為其揭示了通過小鼠模型獲得的結(jié)果和人類真正感染后的結(jié)果二者之間的差異,；研究者的研究工作可以幫助我們理解為何高IgE病人的情況并不是不好，不好的情況只是研究者對其病情的預測而已,；研究結(jié)果對于臨床研究非常重要,，因為其為我們提供了病人實際的情況，方便醫(yī)生們根據(jù)實際病情進行治療,。（生物谷Bioon.com）
doi:10.1016/j.jaci.2013.05.029
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PMID:
Signal transducer and activator of transcription 3 (STAT3) mutations underlying autosomal dominant hyper-IgE syndrome impair human CD8+ T-cell memory formation and function
Megan L. Ives, BAdvSc , Cindy S. Ma, PhD , Umaimainthan Palendira, PhD , Anna Chan, MSc , Jacinta Bustamante, MD, PhD , Stephanie Boisson-Dupuis, PhD , Dan Engelhard, MD , Diana Averbuch, MD , Klaus Magdorf, MD , Joachim Roesler, MD, PhD , Jane Peake, MBBS , Melanie Wong, MBBS, PhD, FRCPA , Sharon Choo, MBBS, FRACP, FRCPA , Matthew C. Cook, MBBS, PhD, FRACP, FRCPA , Capucine Picard, MD, PhD , Anne Durandy, MD, PhD , Miyuki Tsumura, MSc , Masao Kobayashi, MD, PhD , Gulbu Uzel, MD , Jean-Laurent Casanova, MD, PhD , Stuart G. Tangye, PhD , Elissa K. Deenick, PhD
Background The capacity of CD8+ T cells to control infections and mediate antitumor immunity requires the development and survival of effector and memory cells. IL-21 has emerged as a potent inducer of CD8+ T-cell effector function and memory development in mouse models of infectious disease. However, the role of IL-21 and associated signaling pathways in protective CD8+ T-cell immunity in human subjects is unknown. Objective We sought to determine which signaling pathways mediate the effects of IL-21 on human CD8+ T cells and whether defects in these pathways contribute to disease pathogenesis in patients with primary immunodeficiencies caused by mutations in components of the IL-21 signaling cascade. Methods Human primary immunodeficiencies resulting from monogenic mutations provide a unique opportunity to assess the requirement for particular molecules in regulating human lymphocyte function. Lymphocytes from patients with loss-of-function mutations in signal transducer and activator of transcription 1 (STAT1), STAT3, or IL-21 receptor (IL21R) were used to assess the respective roles of these genes in human CD8+ T-cell differentiation in vivo and in vitro. Results Mutations in STAT3 and IL21R, but not STAT1, led to a decrease in multiple memory CD8+ T-cell subsets in vivo, indicating that STAT3 signaling, possibly downstream of IL-21R, regulates the memory cell pool. Furthermore, STAT3 was important for inducing the lytic machinery in IL-21–stimulated naive CD8+ T cells. However, this defect was overcome by T-cell receptor engagement. Conclusion The IL-21R/STAT3 pathway is required for many aspects of human CD8+ T-cell behavior but in some cases can be compensated by other signals. This helps explain the relatively mild susceptibility to viral disease observed in STAT3- and IL-21R–deficient subjects.
