Detection of Serum Antibodies Cross-Reacting with Mycobacterium avium Subspecies paratuberculosis and Beta-Cell Antigen Zinc Transporter 8 Homologous Peptides in Patients with High-Risk Proliferative Diabetic Retinopathy

Pinna, Antonio; Masala, Speranza; Blasetti, Francesco; Maiore, Irene; Cossu, Davide; Paccagnini, Daniela; Mameli, Giuseppe; Sechi, Leonardo Antonio

doi:10.1371/journal.pone.0107802

Cited by 15 publications

(16 citation statements)

References 23 publications

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“…In light of our previous finding reporting an elevated sero‐prevalence of MAP in patients with T1D from Sardinia and continental Italy , we here show that two epitopes belonging to different MAP proteins (MAP2404c and MAP 1,4‐α‐gbp) are targets of an Ab mediated response that cross‐recognize the homologous PI sequences. MAP was called into question as one of the possible candidate initiator of T1D , a triggering role in β‐cell mediated aAbs production has also been surmised for insulin .…”

Section: Discussionsupporting

confidence: 70%

Proinsulin and MAP3865c homologous epitopes are a target of antibody response in new-onset type 1 diabetes children from continental Italy

et al. 2015

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Mycobacterium avium subspecies paratuberculosis (MAP) asymptomatic infection is speculated to play a role in type 1 diabetes (T1D) among Sardinian subjects. Data obtained analyzing a pediatric population from mainland Italy lends support to the hypothesis, which envisions MAP as an environmental factor at play in T1D pathogenesis. Aiming to investigate the likelihood of cross-recognition between linear determinants shared by self (proinsulin) and non-self (MAP) proteins, 59 children with new onset T1D and 60 healthy controls (HCs) from continental Italy were enrolled in the study. Serum samples were subjected to indirect enzyme-linked immunosorbent assay (ELISA) for the presence of antibodies (Abs) toward four homologues MAP/proinsulin epitopes. The rate of MAP infection (42.4% in T1D children and 5% in HCs; p < 0.0001) was estimated searching for Abs against MAP specific protein MptD. The homologous MAP2404c70-85 and proinsulin (PI)46-61 peptides were recognized by 42.4 and 39% of new-onset T1D children and only in 5% of HCs (AUC = 0.76, AUC = 0.7, p < 0.0001); whereas the prevalence of Abs against MAP 1,4-α-gbp157-173 and PI64-80 peptides was 45.7 and 49.1% in new-onset T1D children, respectively, compared with 3.3% of HCs (AUC = 0.74 and p < 0.0001 in both). Pre-incubation of MAP Ab-positive sera with proinsulin peptides was able to block the binding to the correspondent MAP epitopes, thus showing that Abs against these homologous peptides are cross-reactive. MAP/Proinsulin Ab mediated cross-recognition, most likely via molecular mimicry, maybe a factor in accelerating and/or initiating T1D in MAP-infected children. Indeed, it is known that anti-proinsulin and anti-Insulin autoantibodies are the earliest to appear.

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Section: Discussionsupporting

confidence: 70%

Proinsulin and MAP3865c homologous epitopes are a target of antibody response in new-onset type 1 diabetes children from continental Italy

et al. 2015

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“…In autoimmune diabetes, thyroiditis, and MS, MAP is thought to induce pathology due to molecular mimicry between protein elements of itself and the targeted organ elements of the host, e.g., MAP 3865c and Znt8 in autoimmune (type 1) diabetes and thyroiditis (31, 35, 36). Figure 1 shows how MAP may trigger autoimmune diseases.…”

Section: Map and Human Diseasesmentioning

confidence: 99%

Mycobacterium avium ss. paratuberculosis Zoonosis – The Hundred Year War – Beyond Crohn’s Disease

2015

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The factitive role of Mycobacterium avium ss. paratuberculosis (MAP) in Crohn’s disease has been debated for more than a century. The controversy is due to the fact that Crohn’s disease is so similar to a disease of MAP-infected ruminant animals, Johne’s disease; and, though MAP can be readily detected in the infected ruminants, it is much more difficult to detect in humans. Molecular techniques that can detect MAP in pathologic Crohn’s specimens as well as dedicated specialty labs successful in culturing MAP from Crohn’s patients have provided strong argument for MAP’s role in Crohn’s disease. Perhaps more incriminating for MAP as a zoonotic agent is the increasing number of diseases with which MAP has been related: Blau syndrome, type 1 diabetes, Hashimoto thyroiditis, and multiple sclerosis. In this article, we debate about genetic susceptibility to mycobacterial infection and human exposure to MAP; moreover, it suggests that molecular mimicry between protein epitopes of MAP and human proteins is a likely bridge between infection and these autoimmune disorders.

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“…In 2012, DeNiro et al have suggested that ischemic retinopathy may be mediated by aberrant Zn 2+ homeostasis caused by ZnT8 downregulation 23 . Later on, Pinna et al have showed that T1DM patients have higher rates of positive antibodies against MAP/ZnT8 peptides, but failed to find the correlation between the presence of these antibodies and the severity degree of high-risk proliferative diabetic retinopathy 24 . Xu et al have demonstrated that erythropoietin (EPO) maintains zinc homeostasis through activating the ERK pathway and downregulating HIF-1α (hypoxia inducible factor-1α), and thus upregulating ZnT8 expression in diabetic retinas 25 .…”

Section: Introductionmentioning

confidence: 99%

Effects of ZnT8 on epithelial-to-mesenchymal transition and tubulointerstitial fibrosis in diabetic kidney disease

Zhang¹,

Guan²,

Yang³

et al. 2020

Cell Death Dis

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Zinc transporter 8 (ZnT8) transports zinc ions for crystallization and storage of insulin in pancreatic beta-cells and ZnT8 dysfunction is involved in pathogenesis of diabetes. The current study aimed to investigate whether ZnT8 has effects in pathophysiology of diabetic kidney disease (DKD) by using animal models for diabetes, including STZ-induced diabetic, db/db, ZnT8-KO, ZnT8-KO-STZ and ZnT8-KO-db/db mice. Results demonstrated that urine albumin to creatinine ratio and epithelial-to-mesenchymal transition (EMT) were increased in kidneys of ZnT8-KO-STZ and ZnT8-KO-db/db mice compared with C57BL/6 J and ZnT8-KO mice, while serum TGF-β1, IL-6, and TNF-α levels were elevated in parallel. In kidneys of mice intercrossed between ZnT8-KO and STZ-induced diabetic or db/db mice, these three inflammatory factors, ACR and EMT were also found to be increased compared with C57BL/6J, db/db and ZnT8-KO mice. Furthermore, ZnT8 up-regulation by hZnT8-EGFP reduced the levels of high glucose (HG)-induced EMT and inflammatory factors in normal rat kidney tubular epithelial cell (NRK-52E cells). Expression of phosphorylated Smad2/Smad3 was up-regulated after HG stimulation and further enhanced by ZnT8 siRNA but down-regulated after hZnT8-EGFP gene transfection. The current study thus provides the first evidence that ZnT8 protects against EMT-tubulointerstitial fibrosis though the restrain of TGF-β1/Smads signaling activation in DKD.

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Detection of Serum Antibodies Cross-Reacting with Mycobacterium avium Subspecies paratuberculosis and Beta-Cell Antigen Zinc Transporter 8 Homologous Peptides in Patients with High-Risk Proliferative Diabetic Retinopathy

Cited by 15 publications

References 23 publications

Proinsulin and MAP3865c homologous epitopes are a target of antibody response in new-onset type 1 diabetes children from continental Italy

Proinsulin and MAP3865c homologous epitopes are a target of antibody response in new-onset type 1 diabetes children from continental Italy

Mycobacterium avium ss. paratuberculosis Zoonosis – The Hundred Year War – Beyond Crohn’s Disease

Effects of ZnT8 on epithelial-to-mesenchymal transition and tubulointerstitial fibrosis in diabetic kidney disease

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