介白質素-22與發炎體相關基因多形性對於台灣人僵直性脊椎炎發展的效應

僵直性脊椎炎 (ankylosing spondylitis) 病患已經被觀察到其周邊血液單核球細胞 (peripheral blood mononuclear cell) 第二十二型輔助T細胞 (T helper cell 22) 相較於健康對照是顯著增加的，其所分泌的介白質素 (interleukin；IL)-22與其接受器的結合可以活化訊號轉導和轉錄活化因子3 (signal transducer and activactor of transcription 3)、Akt和有絲分裂活化蛋白質激酶 (mitogen-activated protein kinase) 路徑，並且調節細胞的免疫反應以及參與組織的修復。介白質素IL-1β的高度表現也相關於僵直性脊椎炎的發生，並且發炎體 (inflammasome) 在IL-1β的生成過程中扮演重要的修飾者。成熟的IL-1β是由透過caspase-1所切割的pro-IL-1β而產生，caspase-1表現則分別受到核區域化富含白氨酸重複蛋白1 (nuclear localization leucine-rich-repeat protein 1；NLRP1) inflammasome (NLRP1、ASC、pro-caspase-1與pro-caspase-5蛋白複合體)、NLRP3 inflammasome (NLRP3、ASC、CARD8與procaspase-1蛋白複合體)、核苷酸結合低聚化區域類受體C4 (nucleotide-binding oligomerization domain receptors-like C4；NLRC4) inflammasome (NLRC4、ASC、NAIPs與pro-caspase-1蛋白複合體)、與黑色素瘤缺乏因子2 (absent in melanoma 2；AIM2) inflammasome (AIM2、ASC與pro-caspase-1蛋白複合體) 路徑所影響，導致caspase-1與IL-1β的高度表現。然而，IL-22以及發炎體相關基因對於僵直性脊椎炎發展的效應是尚未被探討的。因此，我們設計一項以醫院為基礎的病例對照研究，評估IL-22、NLRP1、NLRP3、NLRC4與CARD8基因多形性在僵直性脊椎炎發生與疾病進展上的效應。總計，有300名僵直性脊椎炎病患與300名以性別及年齡配對的健康對照被納入。利用聚合酶鏈鎖反應-限制酵素片段長度多形性 (polymorphism chain reaction [PCR]-restriction fragment length polymorphism) 與即時定量聚合酶鏈鎖反應 (real-time PCR) 來判定IL-22 rs1012356、rs1026786、rs1179246、rs2046068、rs2227484、rs2227485、rs2227501、rs2227503、以及rs2227513、NLRP1 rs878329與rs6502867、NLRP3 rs10754558、NLRC4 rs212713、rs430759與rs455060、以及CARD8 rs2043211基因型；僵直性脊椎炎病患之疾病活性與功能狀態則藉由巴斯僵直性脊椎炎疾病活性指數 (Bath Ankylosing Spondylitis Disease Activity Index；BASDAI)、巴斯僵直性脊椎炎功能性指數 (Bath Ankylosing Spondylitis Functional Index)、以及巴斯僵直性脊椎炎健康綜合評分 (Bath Ankylosing Spondylitis Global；BAS-G) 來評估。結果顯示，攜帶IL-22 rs2227485 CT基因型 (relative risk；RR = 0.67；95% confidence interval；95% C.I. = 0.44-1.01) 與CARD8 rs2043211 AA基因型者 (RR = 0.59；95% C.I. = 0.36-0.96)，分別相較於攜帶IL-22 rs2227485 TT與CARD8 rs2043211 TT基因者型具有較低的僵直性脊椎炎發生危險性。同時攜帶IL-22 rs2227485 CT+CC與NLRC4 rs212713 TT+CT基因型者 (RR = 0.62；95% C.I. = 0.44-0.87)、同時攜帶IL-22 rs2227485 CT+CC基因型與CARD8 rs2043211 AA+AT基因型者 (RR = 0.41；95% C.I. = 0.19-0.89)、以及同時攜帶NLRC4 rs212713 TT+CT與CARD8 rs2043211 AA+AT基因型者 (RR = 0.66；95% C.I. = 0.47-0.94) 分別相較於攜帶其他合併基因型者，對於僵直性脊椎炎具有顯著的保護效應。此外，攜帶IL-22 rs1026786 AG、rs2227503 AG、以及rs2227501 AC基因型者分別具有顯著較高的BASDAI數值，攜帶NLRP1 rs6502867 CT基因型者也具有顯著較高的BAS-G數值。因此，IL-22與發炎體相關基因多形性相關於僵直性脊椎炎病患的疾病發展與嚴重程度。

關鍵字

僵直性脊椎炎；介白素-22 ；核區域化富含白氨酸重複蛋白1 ；核區域化富含白氨酸重複蛋白3 ；核苷酸結合低聚化區域類受體C4 ； Caspase相關的募集區域8

並列摘要

It has been observed that T helper 22 (Th22) cells were significantly elevated in the peripheral blood mononuclear cells of patients with ankylosing spondylitis (AS) compared with those in healthy controls. Binding of interleukin-22 (IL-22) secreted by Th22 cells to its receptors could activate signal transducer and activactor of transcription 3, Akt, and mitogen-activated protein kinase pathways; and regulate cellular immune responses and involve in tissue repair. Higher expression of IL-1β was also associated with AS development, and inflammasomes played an important modifier in the generation of IL-1β. Mature IL-1β is generated by pro-IL-1β through cleavage by caspase-1. Expression of caspase-1 was affected by nuclear localization leucine-rich-repeat protein 1 (NLRP1) inflammasome (NLRP1, ASC, pro-caspase-1 and pro-caspase-5 protein complexs), NLRP3 inflammasome (NLRP3, ASC, CARD8 and procaspase-1 protein complexs), nucleotide-binding oligomerization domain receptors-like C4 (NLRC4) inflammasome (NLRC4, ASC, NAIPs and pro-caspase-1 protein complexs), and absent in melanoma 2 (AIM2) inflammasome (AIM2, ASC and pro-caspase-1 protein complexs) pathways, respectively; leading to higher expression of caspase-1 and IL-1β. However, the effects of IL-22 and inflammasome related genes on AS development have not been investigated. Therefore, we designed a hospital-based case-control study to evaluate the effects of IL-22, NLRP1, NLRP3, NLRC4 and CARD8 genetic polymorphisms on AS occurrence and disease progression. A total of 300 AS patients and 300 age and gender-matched healthy controls were recruited. Polymerase chain reaction (PCR)-restriction fragment length polymorphism and real-time PCR were applied to identify the IL-22 rs1012356, rs1026786, rs1179246, rs2046068, rs2227484, rs2227485, rs2227501, rs2227503 and rs2227513, NLRP1 rs87832 and rs6502867, NLRP3 rs10754558, NLRC4 rs212713, rs430759 and rs455060, and CARD8 rs2043211 genotypes. The disease activity and functional status of AS patients were evaluated by Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index, and Bath Ankylosing Spondylitis Global (BAS-G). Results showed that those who carried IL-22 rs2227485 CT genotype (relative risk [RR] = 0.67, 95% confidence interval [95% C.I.] = 0.44-1.01) and CARD8 rs2043211 AA genotype (RR = 0.59, 95% C.I. = 0.36-0.96) had a decreased risk for AS occurrence, compared to IL-22 rs2227485 TT and CARD8 rs2043211 TT genotype; respectively. Those who carried both IL-22 rs2227485 CT+CC and NLRC4 rs212713 TT+CT genotypes (RR = 0.62, 95% C.I. = 0.44-0.87), IL-22 rs2227485 CT+CC and CARD8 rs2043211 AA+AT genotypes (RR = 0.41, 95% C.I. = 0.19-0.89), NLRC4 rs212713 TT+CT and CARD8 rs2043211 AA+AT genotypes (RR = 0.66, 95% C.I. = 0.47-0.94) had a significantly protective effect on AS occurrence, compared to those carried other combined genotypes; respectively. In addition, those carried IL-22 rs1026786 AG, rs2227503 AG, and rs2227501 AC genotype had a significantly higher BASDAI score; respectively. Those carried NLRP1 rs6502867 CT genotype also had a significantly higher BAS-G score. Therefore, IL-22 and inflammasome related genetic polymorphisms were associated with disease development and severity in AS patients.

並列關鍵字

ankylosing spondylitis ； interleukin-22 ； nuclear localization leucine-rich-repeat protein 1 ； nuclear localization leucine-rich-repeat protein 3 ； nucleotide-binding oligomerization domain receptors-like C4 ； CARD8

參考文獻

56. Shih HC. Liu SC. Chang CP. Tschen JS. Chiu HY. Liu HC. Chang JG. Positive association of ankylosing spondylitis with homozygous HLA-B2704, but protection with B2705 in Taiwan Chinese. Kaohsiung J Med Sci. 17(10):509-16, 2001.

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介白質素-22與發炎體相關基因多形性對於台灣人僵直性脊椎炎發展的效應

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