HERV-W and Mycobacterium avium subspecies paratuberculosis Are at Play in Pediatric Patients at Onset of Type 1 Diabetes

Abstract

The etiology of T1D remains unknown, although a variety of etiological agents have been proposed as potential candidates to trigger autoimmunity in susceptible individuals. Emerging evidence has indicated that endogenous human retrovirus (HERV) may play a role in the disease etiopathogenesis; although several epigenetic mechanisms keep most HERVs silenced, environmental stimuli such as infections may contribute to the transcriptional reactivation of HERV-Wand thus promote pathological conditions. Previous studies have indicated that also Mycobacterium avium subspecies paratuberculosis (MAP) could be a potential risk factor for T1D, particularly in the Sardinian population. In the present study, the humoral response against HERV-W envelope and MAP-derived peptides was analyzed to investigate their potential role in T1D etiopathogenesis, in a Sardinian population at T1D onset (n = 26), T1D (45) and an age-matched healthy population (n = 45). For the first time, a high serum-prevalence of anti-Map and anti-HERV-W Abs was observed in pediatric patients at onset of T1D compared to T1D patients and healthy controls. Our results support the hypothesis that external infections and internal reactivations are involved in the etiology of T1D, and that HERV-W activation may be induced by infectious agents such as MAP.

Expression of Human Endogenous Retroviruses in the Human Thymus Along T Cell Development

“…Moreover, our finding of HERV protein expression in the thymic medulla further reinforces their possible role in negative selection, with implications for autoimmune diseases (15). We found high levels of HERV-W in the BDCA-3 + dendritic cells isolated from the 3 thymuses evaluated which deserves confirmation and exploration given the recent association of HERV-W with pediatric onset of type 1 Diabetes (17). The relative high levels of HERV expression in TECs point to the relevance of investigating their contribution to the transcriptional regulation in these cells central for T cell selection (7).…”

“…Moreover, several HERV families have been shown to be expressed in the human thymus (10)(11)(12)(13)(14). The association of HERV expression with the development of autoimmune diseases has been suggested to be also linked to T cell selection in the thymus (8,(15)(16)(17), but there are no detailed studies on HERV expression throughout human thymocyte development as well as on thymic stromal cells.…”

Systematic and meta-analysis of Mycobacterium avium subsp. paratuberculosis related type 1 and type 2 diabetes mellitus

“…Based on selection quality of cases, 37.5% of the studies accompanied case definition adequately with laboratory diagnosis/validation (item 1a) 42 , 44 , 49 – 51 , 56 while 68.8% 41 – 43 , 45 , 47 , 52 , 54 , 57 – 59 relied on hospital records for case definition (item 1b); in term of representativeness of the cases, 93.8% 42 – 45 , 47 , 50 – 52 , 54 , 57 – 61 represent representative series of cases (item 2a), 6.1% 41 had or did not stated potential for selection biases (item 2b). On selection of controls, 18.8% of the studies 51 , 54 , 58 were based on community controls (item 3a), while 68.8% studies were hospital-based controls 42 – 44 , 47 , 50 , 52 , 57 – 61 (item 3b). All the studies (100%) defined controls based on no history of DM 12 , 41 – 45 , 47 , 49 – 52 , 54 , 57 – 61 (item 4a).…”

“…No further efforts to assay/validate the true non-DM statuses of the controls via diabetic diagnosis test in most cases. For quality based on comparability of design and analysis to control for confounders, 81.3% of the studies 12 , 41 – 45 , 47 , 49 , 50 , 52 , 58 , 60 , 61 controls for age and 25.0% 42 , 46 , 49 , 57 further control for other sources of confounders. For exposure quality, ascertainment of MAP exposure in DM cases and controls was based on anti-MAP antibodies (abs)/MAP DNA diagnostic approach (PCR) in all the studies (100%; item 1a) and the same for both DM cases and controls (100%, item 1b) 12 , 41 – 45 , 47 , 49 – 52 , 54 , 57 – 61 , and non-response rate was generally not reported but the same in both cases and controls in 12.5% 45 , 51 of the studies (item 3a) and different between the groups with no description in 6.3% 49 (item 3c).…”

Hermon-Taylor: M. paratuberculosis and Crohn’s Disease—The Book of Revelation According to John

“…To date, MAP has been causally associated with granulomatous diseases besides Crohn's: sarcoidosis [12,13] and Blau syndrome [14]. Through molecular mimicry from mycobacterial protein elements, MAP is found to induce autoantibodies in autoimmune diabetes (T1D) [15], multiple sclerosis [16], autoimmune thyroiditis [17], lupus [18] and rheumatoid arthritis [19,20].…”