特发性1型糖尿病患者免疫病因学探讨
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摘要
目的：从锌转运体8自身抗体(ZnT8A)、分泌干扰素γ的谷氨酸脱羧酶65反应性T细胞(GAD65-IFN-y-T细胞)及免疫遗传基因标志HLA-DQ易感单体型三个方面,探讨特发性1型糖尿病患者的免疫病因学证据。
方法：52例以自发酮症或酮症酸中毒起病,胰岛自身抗体谷氨酸脱羧酶抗体(GADA)、蛋白酪氨酸磷酸酶自身抗体(IA-2A)及胰岛素自身抗体(IAA)均阴性,且依赖胰岛素治疗的湖南汉族新发1型糖尿病患者纳入本研究。放射配体法检测ZnT8A, ELISPOT技术检测ZnT8A阴性患者GAD65-IFN-y-T细胞,PCR直接测序法进行HLA-DQ基因型检测。据是否携带1型糖尿病的易感单体型,将研究对象分为HLA-DQ易感单体型携带组和HLA-DQ易感单体型不携带组两组,并对接受HLA-DQ基因检测患者以年为间隔随访3年。比较携带组与不携带组起病初期的临床特征、ZnT8A及GAD65-IFN-y-T细胞检测情况,随访时胰岛自身抗体及胰岛β细胞功能的变化。
结果：1)52例特发性1型糖尿病患者中有5例ZnT8A检测阳性,ZnT8A阳性率为9.6%；2)16例ZnT8A阴性且接受GAD65-IFN-y-T细胞检测的特发性1型糖尿病患者中,2例呈GAD65-IFN-y-T细胞检测阳性,阳性率为12.5%；3)与HLA-DQ易感单体型不携带组相比,携带组起病初期的酮症程度更严重,空腹C肽水平更低(P<0.05),更类似于经典1型糖尿病(P>0.05),其他临床特征携带组与不携带组两组无统计学差异；3)起病初期,]HLA-DQ易感单体型携带组与不携带组的ZnT8A阳性率和ZnT8A滴度相比无统计学差异。4)HLA-DQ易感单体型携带组中检测到1例GAD65-IFN-y-T细胞呈阳性反应的患者(1/5),但在不携带组未有检测到GAD65-IFN-y-T细胞呈阳性反应的患者；5)HLA-DQ易感单体型携带组中检测到1例患者在随访中ZnT8A由阴转阳(1/18),但在不携带组中未有检测到抗体转阳患者。6)随访第1年时,HLA-DQ易感单体型携带组与不携带组空腹C肽(FCP)水平均较基线时升高(P<0.05),但在随访第2、3年时两组FCP水平均较基线水平无统计学差异,两组随访各年的餐后2小时C肽水平(2hCP)、△CP (△CP=2hCP-FCP)均较基线水平无统计学差异；两组随访各年的FCP、2hCP、△CP及其分别的年变化率均无统计学差异。
结论：1)部分特发性1型糖尿病患者体内存在锌转运体8抗体和分泌Y干扰素的GAD65反应性T细胞；2)携带HLA-DQ易感单体型特发性1型糖尿病患者,起病时空腹C肽水平更低,酮症程度更严重,更类似自身免疫性1型糖尿病患者,目前的诊断标准低估了自身免疫性1型糖尿病的发病情况。
Objective:To investigate potential autoimmune characteristics of idiopathic type1diabetes by detection of zinc transporter8autoantibodies (ZnT8A), GAD65-reactive IFN-y secreting T cells (GAD65-IFN-y-T cells), and HLA-DQ susceptible haplotypes.
Methods:Fifty-two patients of Hunan Han origin with newly onset idiopathic type1diabetes were enrolled in this study. The criteria for enrolment of idiopathic type1diabetes included:①New-onset, unprovoked ketosis or ketoacidosis at onset;②Negative GADA, IA-2A and IAA;③Prmanent insulinopenia. ZnT8A were detected in all patients with radioligand assay. GAD65-IFN-y-T cells were then determined by enzyme linked immune spot (ELISPOT) in ZnT8A-negative patients. HLA-DQA1and DQB1alleles were identified with PCR sequence-based genotyping (SBT). According to the situation of HLA-DQ susceptible haplotypes, patients with HLA-DQ genotyping were categorized into two groups, and were all visited annually for3consecutive years. Comparisons were made between the two groups in their clinical characteristics, ZnT8A and GAD65-IFN-y-T cell status, and isletβ cell function.
Results:1) In this study group, ZnT8A was positive in5cases out of52(9.6%).2) GAD65-IFN-y-T cells were positive in2cases out of16patients with negative ZnT8A(12.5%).3) More severe DKA and lower FCP levels at onset (P<0.05) were observed in patients with HLA-DQ susceptible haplotypes.4) There was no significant difference in the positive rate and index of ZnT8A between patients with and without HLA-DQ susceptible haplotypes.5) GAD65-IFN-γ-T cells was positive in1patient carrying HLA-DQ susceptible haplotypes, while there was none in patients with non-susceptible HLA-DQ haplotypes.6) Islet autoantibodies (ZnT8A and IA-2A) turned positive in1patient with HLA-DQ susceptible haplotypes (1/18), while none was observed in patients with non-HLA-DQ susceptible haplotypes during the3-year visiting.7) There was no significant association between FCP and disease duration.
Conclusions:1) ZnT8A、GAD65-IFN-γ-T cells exist in some of idiopathic type1diabetes patients.2) Idiopathic type1diabetes patients who carrying HLA-DQ susceptible haplotypes, presented more autoimmune type1diabetes like features, which indicated that the incidence of autoimmune type1diabetes patients is underestimated.
方法：52例以自发酮症或酮症酸中毒起病,胰岛自身抗体谷氨酸脱羧酶抗体(GADA)、蛋白酪氨酸磷酸酶自身抗体(IA-2A)及胰岛素自身抗体(IAA)均阴性,且依赖胰岛素治疗的湖南汉族新发1型糖尿病患者纳入本研究。放射配体法检测ZnT8A, ELISPOT技术检测ZnT8A阴性患者GAD65-IFN-y-T细胞,PCR直接测序法进行HLA-DQ基因型检测。据是否携带1型糖尿病的易感单体型,将研究对象分为HLA-DQ易感单体型携带组和HLA-DQ易感单体型不携带组两组,并对接受HLA-DQ基因检测患者以年为间隔随访3年。比较携带组与不携带组起病初期的临床特征、ZnT8A及GAD65-IFN-y-T细胞检测情况,随访时胰岛自身抗体及胰岛β细胞功能的变化。
结果：1)52例特发性1型糖尿病患者中有5例ZnT8A检测阳性,ZnT8A阳性率为9.6%；2)16例ZnT8A阴性且接受GAD65-IFN-y-T细胞检测的特发性1型糖尿病患者中,2例呈GAD65-IFN-y-T细胞检测阳性,阳性率为12.5%；3)与HLA-DQ易感单体型不携带组相比,携带组起病初期的酮症程度更严重,空腹C肽水平更低(P<0.05),更类似于经典1型糖尿病(P>0.05),其他临床特征携带组与不携带组两组无统计学差异；3)起病初期,]HLA-DQ易感单体型携带组与不携带组的ZnT8A阳性率和ZnT8A滴度相比无统计学差异。4)HLA-DQ易感单体型携带组中检测到1例GAD65-IFN-y-T细胞呈阳性反应的患者(1/5),但在不携带组未有检测到GAD65-IFN-y-T细胞呈阳性反应的患者；5)HLA-DQ易感单体型携带组中检测到1例患者在随访中ZnT8A由阴转阳(1/18),但在不携带组中未有检测到抗体转阳患者。6)随访第1年时,HLA-DQ易感单体型携带组与不携带组空腹C肽(FCP)水平均较基线时升高(P<0.05),但在随访第2、3年时两组FCP水平均较基线水平无统计学差异,两组随访各年的餐后2小时C肽水平(2hCP)、△CP (△CP=2hCP-FCP)均较基线水平无统计学差异；两组随访各年的FCP、2hCP、△CP及其分别的年变化率均无统计学差异。
结论：1)部分特发性1型糖尿病患者体内存在锌转运体8抗体和分泌Y干扰素的GAD65反应性T细胞；2)携带HLA-DQ易感单体型特发性1型糖尿病患者,起病时空腹C肽水平更低,酮症程度更严重,更类似自身免疫性1型糖尿病患者,目前的诊断标准低估了自身免疫性1型糖尿病的发病情况。
Objective:To investigate potential autoimmune characteristics of idiopathic type1diabetes by detection of zinc transporter8autoantibodies (ZnT8A), GAD65-reactive IFN-y secreting T cells (GAD65-IFN-y-T cells), and HLA-DQ susceptible haplotypes.
Methods:Fifty-two patients of Hunan Han origin with newly onset idiopathic type1diabetes were enrolled in this study. The criteria for enrolment of idiopathic type1diabetes included:①New-onset, unprovoked ketosis or ketoacidosis at onset;②Negative GADA, IA-2A and IAA;③Prmanent insulinopenia. ZnT8A were detected in all patients with radioligand assay. GAD65-IFN-y-T cells were then determined by enzyme linked immune spot (ELISPOT) in ZnT8A-negative patients. HLA-DQA1and DQB1alleles were identified with PCR sequence-based genotyping (SBT). According to the situation of HLA-DQ susceptible haplotypes, patients with HLA-DQ genotyping were categorized into two groups, and were all visited annually for3consecutive years. Comparisons were made between the two groups in their clinical characteristics, ZnT8A and GAD65-IFN-y-T cell status, and isletβ cell function.
Results:1) In this study group, ZnT8A was positive in5cases out of52(9.6%).2) GAD65-IFN-y-T cells were positive in2cases out of16patients with negative ZnT8A(12.5%).3) More severe DKA and lower FCP levels at onset (P<0.05) were observed in patients with HLA-DQ susceptible haplotypes.4) There was no significant difference in the positive rate and index of ZnT8A between patients with and without HLA-DQ susceptible haplotypes.5) GAD65-IFN-γ-T cells was positive in1patient carrying HLA-DQ susceptible haplotypes, while there was none in patients with non-susceptible HLA-DQ haplotypes.6) Islet autoantibodies (ZnT8A and IA-2A) turned positive in1patient with HLA-DQ susceptible haplotypes (1/18), while none was observed in patients with non-HLA-DQ susceptible haplotypes during the3-year visiting.7) There was no significant association between FCP and disease duration.
Conclusions:1) ZnT8A、GAD65-IFN-γ-T cells exist in some of idiopathic type1diabetes patients.2) Idiopathic type1diabetes patients who carrying HLA-DQ susceptible haplotypes, presented more autoimmune type1diabetes like features, which indicated that the incidence of autoimmune type1diabetes patients is underestimated.
引文
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