自然性免疫力為人類免疫系統的第一道防線且與後天性免疫一樣重要。 當自然性免疫力出現缺失的時候，人們會變得容易遭受到病源的感染。 在過去的報導中，前人曾提到抗原辨認受器、細胞激素受器或其相關的訊息傳遞分子若發生基因突變，則會導致病人容易遭受到細菌、結核菌、病毒、或者是黴菌感染。 因此，我們假設這些易遭受感染的病人在自然性免疫力中是有缺失的。 所以，我們試著利用系統性的方法來證明這個假設。 我們利用了抗原辯認受器的刺激物(toll-like receptor agonists)、肺結核桿菌疫苗(BCG)加上 IL-12或 IFN-γ、PMA結合 ionomycin 或小兒麻痺疫苗株第二型病毒 (poliovirus type II) 來刺激病人的白血球藉以觀察其細胞激素的分泌。 我們偵測的細胞激素包括 IFN-γ, IFN-alpha, IL-12, IL-6, IL-1β, IL-10 以及 TNF-alpha，欲藉著比較病人與正常人的細胞激素有何差異來找出免疫缺失之處。 我們共試驗了一位 hyper-IgM sydrome病人、兩位 chronic granulomatous disease 病人、一位CD4 T cells 低下的病人。 我們發現 hyper-IgM sydrome病人表現了低量的IL-12和IFN-γ以及IFN-α，還有較高的IL-10表現，顯示了病人可能有免疫系統不平衡的現象。 而Chronic granulomatous disease 病人因為較大量的IL-6和IL-1beta表現，而顯示了過度發炎 (hyper-inflammatory) 的現象。 另一位CD4 T cells低下的病人，根據他低下的IFN-γ, IL-12 以及IFN-α表現，加上肺結核菌疫苗結合IFN-γ或IL-12的刺激，病人的反應雖然比正常人略低，但是也證實了病人的 IFN-γ 及 IL-12 受器應該是沒有發生突變。 此外，我們也證實了這位病人並沒有 IFN-γ的自體抗體 (autoantibody) 。 我們利用這個方法發現的一些結果可以呼應病人的狀況，也希望可以更進一步的利用這個方法來找到病人可能突變的基因或者可以使這個方法可以有臨床上的應用。

Innate immunity, as well as acquired immune response, has been documented to be important for host defense. Induction of the innate immune responses depends on recognition of pathogen components by host pattern-recognition receptors including Toll-like receptors (TLRs). Many TLR signaling-related (IRAK-4, NEMO, et al) and cytokine-related (IFN-γ, STAT-1, et al) gene mutations have been found to lead to susceptibility to infections. Some patients are repeatedly infected with bacteria, mycobacteria or viruses. We hypothesize that these patients may have deficiencies in their innate immune responses. In this project, we tried to identify the mechanism underlying the infection susceptibility in these immunodeficient patients using a systematic approach. We took whole blood from susceptible patients and stimulate that with poliovirus sabin type 2 strain, TLR agonists, BCG combined with IL-12 or IFN-, or PMA/ionomycin. A comprehensive panel of cytokines including IFN-α, IFN-γ, IL-12, IL-6, IL-1, IL-10 and TNF-α was measured in the same sample by using a multiple cytokines suspension array system. Therefore, these cytokine responses in susceptible patients including hyper-IgM (HIGM) syndrome, chronic granulomatous disease (CGD), and selective CD4 cells deficiency patients were addressed. In our results, the hyper-inflammatory phenotype of CGD patients after stimulations was showed by higher IL-1beta and IL-6 productions. Cytokine profiles of the HIGM patient showed impaired T-helper-1 immunity because of very low IL-12 production, lower IFN-, IFN-, and higher IL-10 productions. By analyzing the cytokine response of a “selective CD4 T cells deficiency” patient, we found that the patient has impaired IFN- and IL-12 productions. Potential defects including IFN-gamma receptor deficiency, IL-12 receptor deficiency, and IFN- autoantibody have been excluded. The method we established in this study will help to identify the cellular defects and gene mutations involved in deficiency of innate immunity. The results will unravel innate immune responses to pathogenic microorganisms and may provide useful information for future clinical applications.

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