2013年7月20日 訊 /生物谷BIOON/ --近日，來(lái)自悉尼Garvan醫(yī)學(xué)研究所的研究人員通過(guò)研究表示，對(duì)單一基因突變的免疫缺陷患者進(jìn)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(dāng)患者實(shí)際的針狀和臨床預(yù)期不太一樣的時(shí)候，就更要去深入研究其中的機(jī)制，相關(guān)研究刊登于國(guó)際雜志Journal of Allergy and Clinical Immunology上,。
文章中,，研究者對(duì)常染色體顯性高IgE綜合征進(jìn)行了研究，該疾病是基因STAT3發(fā)生突變導(dǎo)致的,，這使得患者更易發(fā)生淋巴瘤,，實(shí)驗(yàn)室和動(dòng)物模型研究預(yù)測(cè)這種疾病的患者對(duì)病毒和癌癥會(huì)更加易感，而實(shí)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(gè)體相比預(yù)期來(lái)說(shuō)，其免疫系統(tǒng)具有更強(qiáng)的代償能力,，研究者預(yù)測(cè)患者機(jī)體中會(huì)較少產(chǎn)生具有功能的殺傷性T細(xì)胞,，殺傷性T細(xì)胞是一種可以殺滅入侵微生物和癌癥細(xì)胞的機(jī)體免疫細(xì)胞。
研究者Elissa Deenick說(shuō)道,，在正常情況下STAT3分子可以在T細(xì)胞中傳輸生化信號(hào),，這種信號(hào)可以指導(dǎo)STAT3分子開(kāi)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(hào)大部分時(shí)間采用“聲東擊西的策略”，看似工作實(shí)際上并無(wú)功能,。殺傷性T細(xì)胞需要特定的分子來(lái)變得更為有效,，尤其是對(duì)付病毒和淋巴瘤；而高IgE患者就不能產(chǎn)生必備的信號(hào)來(lái)產(chǎn)生這些效應(yīng)分子,。
研究者認(rèn)為這項(xiàng)研究非常重要,，因?yàn)槠浣沂玖送ㄟ^(guò)小鼠模型獲得的結(jié)果和人類(lèi)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(duì)其病情的預(yù)測(cè)而已,；研究結(jié)果對(duì)于臨床研究非常重要，因?yàn)槠錇槲覀兲峁┝瞬∪藢?shí)際的情況,，方便醫(yī)生們根據(jù)實(shí)際病情進(jìn)行治療,。（生物谷Bioon.com）
doi:10.1016/j.jaci.2013.05.029
PMC:
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.
