Anti-ganglioside antibodies and celiac disease,Allergy, Asthma & Clinical Immunology

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Anti-ganglioside antibodies and celiac disease
Allergy, Asthma & Clinical Immunology ( IF 2.6 ) Pub Date : 2021-05-28 , DOI: 10.1186/s13223-021-00557-y
Alessandro Granito , Francesco Tovoli , Alberto Raiteri , Umberto Volta

Dear Editor,

We read with great interest the article by Cutillo et al. analyzing the multiple roles of gangliosides and their key components, sialic acids, in the protection of human and microbial cells from host immune response, and their potential to serve as targets for autoimmunity [1].

In their discussion of anti-ganglioside antibodies and analysis of the various human pathologies in which anti-ganglioside antibodies have been reported, the authors mention celiac disease (CD) as a condition associated with the presence of anti-GM1 antibodies. They also state that the triggering factor that induces anti-ganglioside antibodies generation is unknown. However, the authors support the hypothesis that the formation of complexes between gliadin and GM1 ganglioside leads to the generation of antibodies to GM1 as a “secondary product”. In this respect, CD can be considered an autoimmune disease where, unusually, several pathogenetic factors are well known, i.e., the extrinsic trigger (gliadin), a close genetic background (HLA-DQ2 or -DQ8), and a highly specific immune response directed to a well-characterized autoantigen (tissue transglutaminase). Our data on the presence of anti-neuronal antibodies to central/enteric nervous systems provide further support for the autoimmune hypothesis of neurological dysfunction in CD patients [2,3,4].

We have previously described in 2006 our own experience on the prevalence of a wider range of anti-ganglioside antibodies and their clinical significance in CD patients [5, 6].

Using a commercially available ELISA kit (IMMCO Diagnostics, Buffalo, NY, USA), we studied anti-GM1, anti-GD1b, and anti-GQ1b serum IgG and IgM antibodies in 22 adult patients (median age 35, range: 19–56 years; three males, 19 females) with CD and neurological manifestations, including eight cases of idiopathic cerebellar ataxia, seven cases with epilepsy (without cerebral calcifications), two with multiple sclerosis, three with attention/memory impairment, and two with peripheral neuropathies.

In all cases, diagnosis of CD was confirmed by endoscopic duodenal biopsy, revealing different grades of villous atrophy (from 3a to 3c, according to the modified Marsh classification). In all CD patients, intestinal villous atrophy was associated with a positivity for serological CD markers (anti-endomysial and/or anti-tissue transglutaminase antibodies) further supporting the diagnosis of CD. All available data, regarding CD diagnosis, diagnostic work-up, histopathology and treatment were obtained from the hospital digital database.

In addition, anti-ganglioside antibodies status was assessed in 30 patients with CD without neurological dysfunction (median age 37 years, range 17–59 years, eight males, 22 females), 20 patients with neurological disorders (seven with idiopathic cerebellar ataxia, seven with epilepsy, four with peripheral neuropathy, one with paraneoplastic syndrome and subacute cerebellar atrophy, and one with amyotrophic lateral sclerosis), 50 patients with immune system disorders (six with Crohn’s disease, four with ulcerative colitis, 10 with autoimmune hepatitis, 20 with primary biliary cholangitis, and 10 with the calcifications, Raynaud’s phenomenon, esophageal hypomotility, sclerodactyly, and telangiectasia (CREST) syndrome, and 20 blood donors with comparable age and sex demographics. The study was approved by the local Ethics Committee and all patients and controls gave their informed consent before.

Our anti-ganglioside antibodies assessment results are summarized in Fig. 1. At least one of the three anti-ganglioside IgG antibodies tested for (anti-GM1, anti-GD1b, anti-GQ1b) was found in 64% of CD patients with neurological dysfunction compared to 30% of CD patients without neurological symptoms, 50% of neurological patients without CD, 20% of autoimmune controls and none of the healthy controls (p = 0.02, p = ns, p = 0.003 and p = 0.0001, respectively).

Analysis of individual reactive antibody types showed that both anti-GM1 and anti-GD1b IgG were significantly more frequent in CD patients with neurological dysfunction than in CD patients without neurological symptoms, autoimmune controls, and blood donors. No significant difference between groups was found for anti-GQ1b IgG.

Among the neurological patients with CD, six of the seven with epilepsy, two of the three with attention deficit/memory impairment syndrome, three of the eight with idiopathic cerebellar ataxia, one of the two with multiple sclerosis, and both patients with peripheral neuropathy had anti-ganglioside IgG antibodies.

Of these 14 patients, 11 showed reactivity against only one ganglioside, two showed reactivity to two gangliosides, and one patient showed reactivity to all three gangliosides. Within the group with neurological disorders but without CD, four of the seven with idiopathic cerebellar ataxia, four of the seven with epilepsy, and two of the four with peripheral neuropathy were positive for IgG antibodies to gangliosides.

In patients with autoimmune diseases, anti-ganglioside antibodies were found in three of the six with Crohn’s disease, one of the four with UC, two of the 10 with AIH, two of the 20 with PBC, and two of the 10 with CREST syndrome.

Ganglioside reactivity, expressed in terms of Enzymatic Units (AEU) associated with anti-GM1 and anti-GD1b IgG were significantly higher in CD patients with neurological disorders (anti-GM1: median 20.35 AEU, range 2.6–136.5 AU; anti-GD1b: median 16.5 AEU, range 5.9–79.4 AEU) than in CD patients without neurological disorders (anti-GM1: median 16.2 AEU, range 5.9–35.5 AEU; anti-GD1b: median 12.05 AEU, range 5.9–33.1 AEU) (p = 0.04 and p = 0.02, respectively), autoimmune control patients (anti-GM1: median 13.1 AEU, range 5.3–41.2 AEU; anti-GD1b: median 11.1 AEU, range 5.9–33.1 AEU) (p = 0.007 and p = 0.02, respectively) and healthy blood donors (anti-GM1: median 12.5 AEU, range 5.0–24.0; anti-GD1b: median 9.4 AEU, range 1.1–18.0 AEU) (p = 0.009 and p = 0.0001, respectively).

No correlation was found between AEU of antibodies to gangliosides and the severity of villous atrophy. Of note, 8 (47%) of the 17 patients with CD and neurological manifestations who were positive for at least one anti-ganglioside IgG antibody became negative for the antibody after 1 year of strict adherence to a gluten-free diet.

Interestingly, anti-ganglioside IgM antibodies, although at a lower prevalence than anti-ganglioside IgG antibodies and without any significant difference among the various groups studied, were confined to three cases of epilepsy within the CD group with neurological dysfunction.

CD patients without neurological manifestations, as expected, during follow-up under gluten free diet tested negative for autoantibody markers of CD and exhibited no other autoantibodies.

The first description of anti-ganglioside antibodies in CD patients dates back to 2002 by Alaidini et al. who reported a positivity for at least one autoantibody directed against GM1, GM2, GD1a, GD1b, GT1b, and GQ1b gangliosides in 6 CD patients with peripheral neuropathy, thus assuming that neuropathy of CD may be autoimmune and associated with anti-ganglioside antibodies [7].

After our 2006 study, other authors confirmed the presence of anti-ganglioside antibodies in celiac disease and their potential pathogenetic role in other autoimmune and non-autoimmune neurological disorders (Table 1).

Table 1 Prevalence of antiganglioside antibodies in celiac disease and other autoimmune and non-autoimmune diseases

Full size table

Interestingly, a molecular mimicry between some microbial antigens, such as lipo-oligosaccharides of Campylobacter jejuni and the gangliosides has been hypothesized as a possible mechanism by which anti-ganglioside antibodies are generated, thus reflecting an abnormal immune response to microbiota antigens [8, 9].

Our results, which detected anti-ganglioside antibodies beyond anti-GM1, confirm and expand upon previously identified antineuronal antibodies (e.g., Hu-like and Yo-like detected by indirect immunofluorescence) in patients with CD and neurological complications, confirming the hypothesis that anti-ganglioside antibodies may result from an immunological disorder underlying CD [2, 4, 10].

In conclusion, our data support data described by Cutillo et al. on a potential pathogenic role of anti-ganglioside antibodies in immuno-mediated neurological disorders and provide evidence that detection of anti-ganglioside antibodies could indicate associated neurological symptoms in CD patients. Anti-ganglioside antibodies may therefore represent immunological markers for neurological dysfunction in CD patients and should be included in the work-up of CD patients.

Not applicable.

CD:: Celiac disease
AEU:: Antiganglioside enzymatic units
CREST:: The calcifications, Raynaud’s phenomenon, esophageal hypomotility, sclerodactyly, and telangiectasia syndrome

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Affiliations

Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
Alessandro Granito, Francesco Tovoli, Alberto Raiteri & Umberto Volta
Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
Alessandro Granito, Francesco Tovoli & Alberto Raiteri

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Contributions

AG, FT, AR, UV analysed and interpreted the patient data. AG was a major contributor in writing the manuscript. All authors read and approved the final manuscript.

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Correspondence to Alessandro Granito.

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All subjects gave their consent to publish clinical data.

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Granito, A., Tovoli, F., Raiteri, A. et al. Anti-ganglioside antibodies and celiac disease. Allergy Asthma Clin Immunol 17, 53 (2021). https://doi.org/10.1186/s13223-021-00557-y

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Received: 23 June 2020
Accepted: 10 May 2021
Published: 28 May 2021
DOI: https://doi.org/10.1186/s13223-021-00557-y

中文翻译：

抗神经节苷脂抗体与乳糜泻

亲爱的编辑，

我们饶有兴趣地阅读了 Cutillo 等人的文章。分析神经节苷脂及其关键成分唾液酸在保护人类和微生物细胞免受宿主免疫反应中的多种作用，以及它们作为自身免疫靶点的潜力 [1]。

在他们对抗神经节苷脂抗体的讨论和对已报道抗神经节苷脂抗体的各种人类病理的分析中，作者提到乳糜泻 (CD) 作为与抗 GM1 抗体存在相关的疾病。他们还指出，诱导抗神经节苷脂抗体生成的触发因素尚不清楚。然而，作者支持这样的假设，即麦醇溶蛋白和 GM1 神经节苷脂之间复合物的形成导致产生针对 GM1 的抗体作为“次级产物”。在这方面，CD 可以被认为是一种自身免疫性疾病，其中一些致病因素是众所周知的，即外源性触发因素（麦胶蛋白）、密切的遗传背景（HLA-DQ2 或 -DQ8）、以及针对充分表征的自身抗原（组织转谷氨酰胺酶）的高度特异性免疫反应。我们关于中枢/肠神经系统抗神经元抗体存在的数据为 CD 患者神经功能障碍的自身免疫假说提供了进一步支持 [2,3,4]。

我们之前曾在 2006 年描述了我们自己在 CD 患者中更广泛的抗神经节苷脂抗体的流行情况及其临床意义的经验 [5, 6]。

使用市售的ELISA试剂盒（IMMCO Diagnostics，美国纽约州布法罗），我们在22位成年患者（年龄中位数35岁，范围：19–56）中研究了抗GM1，抗GD1b和抗GQ1b血清IgG和IgM抗体。年；男 3 例，女 19 例）伴 CD 和神经系统表现，其中特发性小脑共济失调 8 例，癫痫（无脑钙化）7 例，多发性硬化 2 例，注意力/记忆障碍 3 例，周围神经病变 2 例。

在所有病例中，内窥镜十二指肠活检证实了 CD 的诊断，揭示了不同程度的绒毛萎缩（根据改良的 Marsh 分类，从 3a 到 3c）。在所有 CD 患者中，肠绒毛萎缩与血清学 CD 标志物（抗肌内膜和/或抗组织转谷氨酰胺酶抗体）阳性相关，进一步支持 CD 的诊断。所有有关 CD 诊断、诊断检查、组织病理学和治疗的可用数据均来自医院数字数据库。

此外，还评估了 30 名无神经功能障碍的 CD 患者（中位年龄 37 岁，范围 17-59 岁，8 名男性，22 名女性）、20 名神经系统疾病患者（7 名患有特发性小脑共济失调，7癫痫，4 名周围神经病变，1 名副肿瘤综合征和亚急性小脑萎缩，1 名肌萎缩侧索硬化症），50 名免疫系统疾病患者（6 名克罗恩病，4 名溃疡性结肠炎，10 名自身免疫性肝炎，20 名原发性胆汁性胆管炎，10 名钙化、雷诺现象、食道动力不足、硬化症和毛细血管扩张 (CREST) 综合征，以及 20 名年龄和性别相近的献血者。该研究获得了当地伦理委员会的批准，所有患者和对照组均事先知情同意。

我们的抗神经节苷脂抗体评估结果总结在图 1 中。在 64% 的神经系统疾病 CD 患者中发现了至少一种测试的抗神经节苷脂 IgG 抗体（抗 GM1、抗 GD1b、抗 GQ1b）。与30％的无神经系统症状的CD患者，50％的无CD的神经系统患者，20％的自身免疫对照以及健康对照者相比，机能障碍（分别为p = 0.02，p = ns，p = 0.003和p = 0.0001） .

对个体反应性抗体类型的分析表明，在有神经功能障碍的 CD 患者中，抗 GM1 和抗 GD1b IgG 的发生频率明显高于无神经系统症状、自身免疫控制和献血者的 CD 患者。对于抗 GQ1b IgG，未发现组间显着差异。

在患有 CD 的神经系统患者中，7 人中有 6 人患有癫痫症，3 人中有 2 人患有注意力缺陷/记忆障碍综合征，8 人中有 3 人患有特发性小脑共济失调症，2 人中有 1 人患有多发性硬化症，并且两名周围神经病患者都有抗神经节苷脂 IgG 抗体。

在这 14 名患者中，11 名仅对一种神经节苷脂表现出反应性，2 人对两种神经节苷脂表现出反应性，1 名患者对所有三种神经节苷脂表现出反应性。在有神经系统疾病但没有 CD 的组中，7 人中有 4 人有特发性小脑共济失调，7 人中有 4 人有癫痫症，4 人中有 2 人有周围神经病，神经节苷脂 IgG 抗体呈阳性。

在自身免疫性疾病患者中，6 名克罗恩病患者中的 3 名、4 名 UC 患者中的 1 名、10 名 AIH 患者中的 2 名、20 名 PBC 患者中的 2 名和 10 名 CREST 综合征患者中发现了抗神经节苷脂抗体.

在患有神经系统疾病的 CD 患者中，以与抗 GM1 和抗 GD1b IgG 相关的酶单位 (AEU) 表示的神经节苷脂反应性显着更高（抗 GM1：中位数 20.35 AEU，范围 2.6-136.5 AU；抗 GD1b：中位数 16.5 AEU，范围 5.9-79.4 AEU）比没有神经系统疾病的 CD 患者（抗 GM1：中位数 16.2 AEU，范围 5.9-35.5 AEU；抗 GD1b：中位数 12.05 AEU，范围 5.9-33.1 AEU）（p = 0.04和 p = 0.02），自身免疫对照患者（抗 GM1：中值 13.1 AEU，范围 5.3-41.2 AEU；抗 GD1b：中值 11.1 AEU，范围 5.9-33.1 AEU）（分别为 p = 0.007 和 p = 0.02 ) 和健康献血者（抗 GM1：中值 12.5 AEU，范围 5.0-24.0；抗 GD1b：中值 9.4 AEU，范围 1.1-18.0 AEU）（分别为 p = 0.009 和 p = 0.0001）。

未发现神经节苷脂抗体的 AEU 与绒毛萎缩严重程度之间存在相关性。值得注意的是，在 17 名至少一种抗神经节苷脂 IgG 抗体阳性的 CD 和神经系统表现患者中，有 8 名 (47%) 在严格坚持无麸质饮食 1 年后变为阴性。

有趣的是，尽管抗神经节苷脂 IgM 抗体的流行率低于抗神经节苷脂 IgG 抗体，并且在所研究的各组之间没有任何显着差异，但仅限于 CD 组中具有神经功能障碍的三例癫痫病例。

正如预期的那样，没有神经系统表现的 CD 患者在无麸质饮食的随访期间检测出 CD 自身抗体标记物呈阴性，并且没有表现出其他自身抗体。

CD 患者中抗神经节苷脂抗体的首次描述可追溯到 2002 年 Alaidini 等人。谁报告了 6 名患有周围神经病变的 CD 患者中至少一种针对 GM1、GM2、GD1a、GD1b、GT1b 和 GQ1b 神经节苷脂的自身抗体呈阳性，因此假设 CD 的神经病变可能是自身免疫性的并与抗神经节苷脂抗体相关 [7] ]。

在我们 2006 年的研究之后，其他作者证实了抗神经节苷脂抗体在乳糜泻中的存在及其在其他自身免疫性和非自身免疫性神经系统疾病中的潜在致病作用（表 1）。

表 1 抗神经节苷脂抗体在乳糜泻及其他自身免疫和非自身免疫疾病中的患病率

全尺寸表

有趣的是，一些微生物抗原（如空肠弯曲杆菌的低聚糖和神经节苷脂）之间的分子模拟被假设为产生抗神经节苷脂抗体的可能机制，从而反映了对微生物群抗原的异常免疫反应 [8, 9 ]。

我们的结果检测到抗 GM1 以外的抗神经节苷脂抗体，证实并扩展了先前在 CD 和神经系统并发症患者中发现的抗神经元抗体（例如，通过间接免疫荧光检测到的 Hu 样和 Yo 样），证实了抗神经元抗体的假设-神经节苷脂抗体可能由 CD 的免疫系统疾病引起 [2, 4, 10]。

总之，我们的数据支持 Cutillo 等人描述的数据。抗神经节苷脂抗体在免疫介导的神经系统疾病中的潜在致病作用，并提供证据表明抗神经节苷脂抗体的检测可以指示 CD 患者的相关神经系统症状。因此，抗神经节苷脂抗体可能代表 CD 患者神经功能障碍的免疫标志物，应包括在 CD 患者的检查中。

不适用。

光盘：: 乳糜泻
AEU：: 抗神经节苷脂酶单位
波峰：: 钙化、雷诺现象、食道动力不足、硬化症和毛细血管扩张综合征

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隶属关系

意大利博洛尼亚博洛尼亚大学医学和外科科学系
亚历山德罗·格拉尼托、弗朗切斯科·托沃利、阿尔贝托·雷特里和翁贝托·沃尔特
意大利博洛尼亚 IRCCS Azienda Ospedaliero-Universitaria Di Bologna 内科、肝胆和免疫过敏性疾病科
亚历山德罗·格拉尼托、弗朗切斯科·托沃利和阿尔贝托·雷特里

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