Biological relevance of citrullinations: diagnostic, prognostic and therapeutic options

Gudmann, N.S.; Hansen, N.U.B.; Jensen, A.-C. Bay; Karsdal, Morten A.; Siebuhr, Anne Sofie

doi:10.3109/08916934.2014.962024

Cited by 48 publications

(33 citation statements)

References 54 publications

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“…T and B cell reactivity to post-translationally modified epitopes 16 has been detected in the context of rheumatoid arthritis 17 , celiac disease 18 and T1D 19–26 : for example, (pre)proinsulin and IA-2 peptides in the context of the high-risk DQ8- trans class II molecule 10,27 . In previous studies, human peripheral autoreactive T cells responded to epitopes containing post-translational modifications such as a vicinal disulfide bond in insulin 20 , citrullination or deamidation 19,21–27 , or islet-derived T cells with hybrid insulin–peptide fusions of proinsulin C peptide with islet amy-loid polypeptide (IAPP) or neuropeptide Y 28 (Supplementary Fig.…”

mentioning

confidence: 99%

Analysis of self-antigen specificity of islet-infiltrating T cells from human donors with type 1 diabetes

Babon

DeNicola

Blodgett

et al. 2016

Nat Med

247

271

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A major therapeutic goal for type 1 diabetes (T1D) is to induce autoantigen-specific tolerance of T cells. This could suppress autoimmunity in those at risk for the development of T1D, as well as in those with established disease who receive islet replacement or regeneration therapy. Because functional studies of human autoreactive T cell responses have been limited largely to peripheral blood–derived T cells1–3, it is unclear how representative the peripheral T cell repertoire is of T cells infiltrating the islets. Our knowledge of the insulitic T cell repertoire is derived from histological and immunohistochemical analyses of insulitis4–8, the identification of autoreactive CD8+ T cells in situ, in islets of human leukocyte antigen (HLA)-A2+ donors9 and isolation and identification of DQ8 and DQ2–DQ8 heterodimer–restricted, proinsulin-reactive CD4+ T cells grown from islets of a single donor with T1D10. Here we present an analysis of 50 of a total of 236 CD4+ and CD8+ T cell lines grown from individual handpicked islets or clones directly sorted from handpicked, dispersed islets from nine donors with T1D. Seventeen of these T cell lines and clones reacted to a broad range of studied native islet antigens and to post-translationally modified peptides. These studies demonstrate the existence of a variety of islet-infiltrating, islet-autoantigen reactive T cells in individuals with T1D, and these data have implications for the design of successful immunotherapies.

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mentioning

confidence: 99%

Analysis of self-antigen specificity of islet-infiltrating T cells from human donors with type 1 diabetes

Babon

DeNicola

Blodgett

et al. 2016

Nat Med

247

271

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“…At first sight, this finding was somewhat surprising taking into account previous studies which have highlighted the role of PADI activity, in particular PADI4 in inflammatory processes (reviewed in ref. 39). In the context of ulcerative colitis, the pan-PADI inhibitor CI-amidine was found to be effective in a mouse model where it reduced inflammation (40).…”

Section: Does Padi2 Serve As Early Diagnosis Biomarker?mentioning

confidence: 99%

Downregulation of the Deiminase PADI2 Is an Early Event in Colorectal Carcinogenesis and Indicates Poor Prognosis

Cantariño

Musulén

Valero

et al. 2016

Molecular Cancer Research

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Peptidyl arginine deiminases (PADI) are a family of enzymes that catalyze the poorly understood posttranslational modification converting arginine residues into citrullines. In this study, the role of PADIs in the pathogenesis of colorectal cancer was investigated. Specifically, RNA expression was analyzed and its association with survival in a cohort of 98 colorectal cancer patient specimens with matched adjacent mucosa and 50 controls from donors without cancer. Key results were validated in an independent collection of tumors with matched adjacent mucosa and by mining of a publicly available expression data set. Protein expression was analyzed by immunoblotting for cell lines or IHC for patient specimens that further included 24 cases of adenocarcinoma with adjacent dysplasia and 11 cases of active ulcerative colitis. The data indicate that PADI2 is the dominantly expressed PADI enzyme in colon mucosa and is upregulated during differentiation. PADI2 expression is low or absent in colorectal cancer. Frequently, this occurs already at the stage of low-grade dysplasia. Mucosal PADI2 expression is also low in ulcerative colitis. The expression level of PADI2 in tumor and adjacent mucosa correlates with differential survival: low levels associate with poor prognosis.Implications: Downregulation of PADI2 is an early event in the pathogenesis of colorectal cancer associated with poor prognosis and points toward a possible role of citrullination in modulating tumor cells and their microenvironment.

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“…The elevation of the molecular mass of heavy chains of IgGs caused by glycosylation was earlier described in patients with the rheumatoid arthritis [15,16]. Interestingly, the anticitrullinated protein antibodies detected in the MS patients acquired a pro-inflammatory Fc glycosylation phenotype prior to the onset of the rheumatoid arthritis [17]. To address potential clinical reasons for appearance of unique IgGs and their heavy chains in blood serum of some MS patients, we investigated their history presented below.…”

Section: Resultsmentioning

confidence: 99%

Identification of the Unique Properties of IgGs and their Heavy chains in Blood Serum of Multiple Sclerosis Patients

Negrych¹,

Myronovskij²

2016

J Autoimmune Disord

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Monitoring of multiple sclerosis (MS) requires of molecular markers. Recently, using TCA-precipitation/ extraction and MALDI TOF/TOF mass-spectrometry, we identified in blood serum of multiple sclerosis (MS) patients earlier unknown 46 kDa form of human unconventional myosin IC isoform b (Myo1C) (Myronovskij et al., 2015). During SDS-electrophoresis of TCA-extracted proteins of blood serum of 28 MS patients, 3 additional polypeptides with 55, 50 and 25 kDa molecular masses were detected. Western-blot analysis using monospecific anti-human IgG rabbit HRP-conjugated antibodies showed that 55 and 25 kDa polypeptides belong to heavy and light chains of IgG molecules, while 50 kDa protein corresponds to free heavy chains of IgGs. None of these polypeptides was found in fractions of TCAextracted polypeptides isolated from blood serum of healthy human donors or patients with systemic lupus erythematosis and rheumatoid arthritis.

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Biological relevance of citrullinations: diagnostic, prognostic and therapeutic options

Cited by 48 publications

References 54 publications

Analysis of self-antigen specificity of islet-infiltrating T cells from human donors with type 1 diabetes

Analysis of self-antigen specificity of islet-infiltrating T cells from human donors with type 1 diabetes

Downregulation of the Deiminase PADI2 Is an Early Event in Colorectal Carcinogenesis and Indicates Poor Prognosis

Identification of the Unique Properties of IgGs and their Heavy chains in Blood Serum of Multiple Sclerosis Patients

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