Department of Rheumatology and Clinical Immunology, University Medical Center Freiburg, Freiburg, Germany.
J Clin Immunol. 2013 Jul;33(5):909-16. doi: 10.1007/s10875-013-9892-3. Epub 2013 Apr 23.
OBJECTIVES: Gastrointestinal manifestations are frequent in patients with common variable immunodeficiency (CVID), and some of the patients present with celiac-like features. Diagnosing celiac disease (CD) in CVID however is challenging, as autoantibody detection and histopathology of the small intestine cannot reliably discriminate between classic CD and a celiac-like disease in these individuals. For the development of classic gluten-sensitive CD a certain HLA haplotype involving the loci DQA1* and DQB1* and encoding two different HLA DQ heterodimers is the prerequisite. We aimed to determine the frequency of these haplotypes in CVID patients with suspected CD. Furthermore, we report on autoimmune manifestations and the lymphocyte phenotype in these patients. METHODS: By retrospective analysis data on gastrointestinal symptoms, diet, concurrent autoimmune diseases, and routine laboratory values were collected. CVID patients were classified according to their B-cell phenotype. Expression of HLA-DQA1* and HLA-DQB1* alleles were determined by genetic analysis. RESULTS: Twenty out of 250 CVID patients presented with a clinical phenotype resembling celiac disease. Four (20%) out of these CVID patients carried the CD-associated HLA DQ2.5 or DQ8 heterodimer, while HLA DQ2.5 was present in 100% of a CD control cohort. Gluten-free diet (GFD) resulted in a clinical and histological response in two out of four patients with HLA high-risk alleles for CD. The response could not be assessed in the remaining two patients, as these patients did not adhere sufficiently long to GFD. The percentage of autoimmune manifestations other than CD was high (50%) in CVID patients presenting with a CD-like enteropathy, and most of these patients had an expansion of B-cells with low expression of CD21 (CD21low B-cells). CONCLUSIONS: In CVID patients with suspected celiac disease typing of the HLA loci DQA1 and DQB1 can help to identify those that have a genetic susceptibility for CD. In CVID patients with a celiac-like phenotype but negative for CD-associated HLA-DQ markers, an autoimmune enteropathy (AIE) as part of an extended autoimmune dysregulation needs to be considered. This has important implications for further diagnostics and therapy of these patients.
目的：胃肠道表现是普通可变免疫缺陷（CVID）患者的常见症状，其中一些患者表现出类似乳糜泻的特征。然而，在 CVID 患者中诊断乳糜泻具有挑战性，因为自身抗体检测和小肠组织病理学不能可靠地区分这些患者中的经典乳糜泻和类似乳糜泻的疾病。对于经典麸质敏感 CD 的发展，涉及 DQA1和 DQB1基因座的特定 HLA 单倍型以及编码两种不同 HLA DQ 异二聚体是前提。我们旨在确定疑似 CD 的 CVID 患者中这些单倍型的频率。此外，我们报告了这些患者的自身免疫表现和淋巴细胞表型。
方法：通过回顾性分析胃肠道症状、饮食、同时存在的自身免疫性疾病和常规实验室值的数据。根据 B 细胞表型对 CVID 患者进行分类。通过遗传分析确定 HLA-DQA1和 HLA-DQB1等位基因的表达。
结果：250 例 CVID 患者中有 20 例表现出类似乳糜泻的临床表型。其中 4 例（20%）患者携带 CD 相关的 HLA DQ2.5 或 DQ8 异二聚体，而 CD 对照组中 HLA DQ2.5 存在于 100%的患者中。在携带 CD 高危 HLA 等位基因的 4 例患者中，2 例患者接受无麸质饮食（GFD）后出现临床和组织学反应。其余 2 例患者由于未能长期坚持 GFD，无法评估反应。在表现出类似乳糜泻的肠病的 CVID 患者中，除 CD 以外的自身免疫表现的比例很高（50%），其中大多数患者的 B 细胞表达 CD21 减少（CD21low B 细胞）。
结论：在疑似乳糜泻的 CVID 患者中，DQA1 和 DQB1 基因座的 HLA 分型有助于识别具有 CD 遗传易感性的患者。在 HLA 标志物与 CD 无关的 CVID 患者中，表现出类似乳糜泻的表型但无 CD 相关 HLA-DQ 标志物时，需要考虑作为扩展自身免疫失调一部分的自身免疫性肠病（AIE）。这对这些患者的进一步诊断和治疗具有重要意义。
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