Transglutaminase-6 is an autoantigen in progressive multiple sclerosis and is upregulated in reactive astrocytes

Cristofanilli, Massimiliano; Gratch, Daniel; Pagano, Benjamin; McDermott, Kelsey; Huang, Jessie; Jian, Jeffrey; Bates, D; Sadiq, Saud

doi:10.1177/1352458516684022

Cited by 14 publications

(15 citation statements)

References 23 publications

(24 reference statements)

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“…Several identified mutations of TGM6 gene were reported to be prone to cause death of primary neurons resulting from unfolded protein reaction activation, which may contribute to pathogenesis of SCA35 33 . As an autoimmune target, anti-TGM6 antibodies were presented at a higher level in patients with progressive multiple sclerosis (MS) 34 , amyotrophic lateral sclerosis 35 , and gluten-sensitive cerebellar ataxia 36 , 37 . In this study, we identify a mutation in TGM6 associated with TB; our eQTL analysis showed that the rs6114027C allele was associated with significantly lower expression levels of TGM6 in PBMCs from TB patients.…”

Section: Discussionmentioning

confidence: 99%

“…By analyzing the association of polymorphism of rs6114027 with clinical indices, we found that the rs6114027C allele is associated with severer pulmonary TB disease as manifested with higher frequencies of mycobacteria in the sputum smear. Notably, the elevated TGM6 in astrocytes was found to regulate the expression of glial fibrillary acidic protein (GFAP) in progressive MS 34 . As a marker of astrocyte activation, GFAP reflects the level of damage to the blood–brain barrier to some extent.…”

Section: Discussionmentioning

confidence: 99%

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Genome-wide association study identifies two risk loci for tuberculosis in Han Chinese

Zheng

et al. 2018

Nat Commun

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Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb), and remains a leading public health problem. Previous studies have identified host genetic factors that contribute to Mtb infection outcomes. However, much of the heritability in TB remains unaccounted for and additional susceptibility loci most likely exist. We perform a multistage genome-wide association study on 2949 pulmonary TB patients and 5090 healthy controls (833 cases and 1220 controls were genome-wide genotyped) from Han Chinese population. We discover two risk loci: 14q24.3 (rs12437118, Pcombined = 1.72 × 10−11, OR = 1.277, ESRRB) and 20p13 (rs6114027, Pcombined = 2.37 × 10−11, OR = 1.339, TGM6). Moreover, we determine that the rs6114027 risk allele is related to decreased TGM6 transcripts in PBMCs from pulmonary TB patients and severer pulmonary TB disease. Furthermore, we find that tgm6-deficient mice are more susceptible to Mtb infection. Our results provide new insights into the genetic etiology of TB.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Genome-wide association study identifies two risk loci for tuberculosis in Han Chinese

Zheng

et al. 2018

Nat Commun

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“…However, the causative link between neuro-coeliac disease and circulating TG6 antibodies is questionable [5]. Aside from gluten ataxia, elevated TG6 antibodies have been observed in patients with other neurological diseases such a Multiple Sclerosis and Amyotrophic Lateral Sclerosis [6,7]. Interestingly, the prevalence of DQ2 and DQ8 haplotypes was also increased compared to TG6 negative patients in these studies.…”

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confidence: 60%

“…Recently, a real debate about the role of Helicobacter pylori (HP) infection in CD has been generated: some authors report a very high histological or serological evidence of HP infection in CD patients (even 82% of untreated and 95% of treated CD patients), although data may be also discordant [6]. Specifically, HP is suspected to influence the inflammatory and immune responses also in the small intestine, leading to the onset of a gluten related enteropathy, which can be reversed by the eradication of HP [7]. Moreover, some authors suggest that the gastric mucosal lymphocyte infiltration could be even secondary to the combination of HP infection and chronic gluten ingestion in gluten-sensitive subjects [8].…”

Section: Culture Of Gastric Biopsies In Celiac Disease and Its Relatimentioning

confidence: 99%

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Transglutaminase 6 antibodies are not yet mainstream in neuro-coeliac disease

Mulder

Rouvroye

Dam

2018

Digestive and Liver Disease

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Transglutaminase 6 antibodies are not yet mainstream in neuro-coeliac disease Worldwide 1% of the population suffers from a gluten related disorder (GRD) that severely impacts ones life, and no therapeutic treatment, except a gluten-free diet, is available. GRD's are a group of immune mediated diseases triggered by the ingestion of gluten. Well known is coeliac disease (CD) that presents with enteropathy. Some patients present exclusively with extra-intestinal manifestations such as skin involvement in dermatitis herpetiformis (DH). Over the last fifty years, patients with gluten sensitivity presenting with neurological symptoms have been described more and more. These symptoms include e.g. cerebellar ataxia and peripheral neuropathies and were thus far considered to be a rare manifestation of GRD. Thus, the diagnosis of neuro-coeliac disease is not yet based on objective and verifiable clinical and/or pathological criteria set by international working groups, such as those of the international Society for the Study of Celiac Disease, the European Society of Pediatric Gastroenterology and Nutrition or Neurological Societies. It would be recommended that groups working on neuro-coeliac disease bundle their forces to obtain a large international cohort of patients to standardize the clinical and pathological picture of this disease. The Sheffield group, led by professor Hadjivassiliou, is one of the leading groups working on neuro-coeliac disease. In the past they have shown that cerebellar ataxia in gluten sensitive patients coincides with white matter abnormalities and neuropathology. Moreover, they found that Transglutaminase (TG) 6 antibodies are overrepresented in the serum of these patients [1]. Serum markers in CD include the presence of TG2 antibodies, and in DH elevated levels of TG3 antibodies can be found [2,3]. In a previous issue of this journal, Panagiotis Zis et al. present a cross-sectional study on 28 patients with peripheral neuropathies, i.e. sensory ganglionopathy, symmetrical axonal neuropathy or mononeuritis multiplex. The notion that TG6 antibodies were enhanced in cerebellar ataxia patients, and that TG6 is considered to be a Transglutaminase more specific to the central nervous system, they now questioned whether TG6 antibodies were elevated in gluten sensitive patients with peripheral neuropathy. The prevalence of TG6 antibodies was 50% compared to 4% in the healthy population, suggesting that TG6 involvement is not confined to the central nervous system alone, but also can affect the peripheral nervous system. In addition, in CD more than 95% of patients share the HLA DQ2 or DQ8 haplotype, whereas of the patients in this study only 62% shared those HLA haplotypes. Moreover, TG2 antibodies were also elevated in this population [4]. As mentioned the so-called neuro-coeliac disease manifestations are not well studied by neurologists and neuroscientists and

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Pathogenesis of autoimmune demyelination: from multiple sclerosis to neuromyelitis optica spectrum disorders and myelin oligodendrocyte glycoprotein antibody‐associated disease

et al. 2021

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Autoimmunity plays a significant role in the pathogenesis of demyelination. Multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are now recognised as separate disease entities under the amalgam of human central nervous system demyelinating disorders. While these disorders share inherent similarities, investigations into their distinct clinical presentations and lesion pathologies have aided in differential diagnoses and understanding of disease pathogenesis. An interplay of various genetic and environmental factors contributes to each disease, many of which implicate an autoimmune response. The pivotal role of the adaptive immune system has been highlighted by the diagnostic autoantibodies in NMOSD and MOGAD, and the presence of autoreactive lymphocytes in MS lesions. While a number of autoantigens have been proposed in MS, recent emphasis on the contribution of B cells has shed new light on the well-established understanding of T cell involvement in pathogenesis. This review aims to synthesise the clinical characteristics and pathological findings, discuss existing and emerging hypotheses regarding the aetiology of demyelination and evaluate recent pathogenicity studies involving T cells, B cells, and autoantibodies and their implications in human demyelination.

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Transglutaminase-6 is an autoantigen in progressive multiple sclerosis and is upregulated in reactive astrocytes

Abstract: TGM6-IgG may be a candidate CSF biomarker to predict and monitor disease activity in progressive MS patients. Furthermore, TGM6 expression by reactive astrocytes within both human and mouse lesions suggests its involvement in the mechanisms of glial scar formation.

Cited by 14 publications

References 23 publications

Genome-wide association study identifies two risk loci for tuberculosis in Han Chinese

Genome-wide association study identifies two risk loci for tuberculosis in Han Chinese

Transglutaminase 6 antibodies are not yet mainstream in neuro-coeliac disease

Pathogenesis of autoimmune demyelination: from multiple sclerosis to neuromyelitis optica spectrum disorders and myelin oligodendrocyte glycoprotein antibody‐associated disease

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