Enhancing and neutralizing anti‐coxsackievirus activities in serum samples from patients prior to development of type 1 diabetes

Abstract

Background Studies in prospective cohorts have suggested that enterovirus infections are associated with the appearance of islet autoantibodies that precede later appearance of type 1 diabetes (T1D). It was shown that in addition to an antibody‐mediated anti‐coxsackievirus (CV)‐B neutralizing activity of serum from patients with T1D, there was also enhancing anti‐CV‐B activity in vitro. In this study, the patterns of enhancing and neutralizing anti‐CV activities were analysed from consecutive serum samples collected from children who were followed from birth until they developed T1D in the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study and compared to those in non‐diabetic control children. Methods The titres of serum neutralizing activity were analysed against those CVs which were detected in the stools in these children (CV‐B3, CV‐B5 or CV‐A4) using plaque assay. The enhancing activity of these serum samples was analysed by measuring interferon‐alpha (INF‐α) production in cultures of peripheral blood mononuclear cells (PBMC) inoculated with a mixture of these viruses and diluted serum. Results A sustained anti‐CV enhancing activity was observed in consecutive serum samples in patients with T1D. The pattern of responses differed between children who developed T1D and control children. In patients, the anti‐CV enhancing activity was predominant or even exclusive over the neutralizing activity, whereas in controls the enhancing and neutralising activities were more balanced or the neutralizing activity was largely predominant. Conclusions Evaluating the anti‐enterovirus neutralizing and enhancing activity of serum samples can be useful to investigate further the relationship between enteroviruses and the development of T1D.

Persistent coxsackievirus B infection and pathogenesis of type 1 diabetes mellitus

“…In addition, high levels of IFNα were found in the plasma of 75% of patients with T1DM at various stages of the disease (of whom 50% were infected with CVB), but not in the plasma of control individuals 65 . In a 2020 study in patients prior to the development of autoantibodies and T1DM, patient serum showed a predominant enhancing activity, as opposed to neutralizing activity, against CVB3, CVB5 and CVA4 strains, which represent viruses identified in patient stool samples 186 . Interestingly, young mice infected with CVB4 E2 for the first time generated enhancing antibodies against CVB4 (refs 187 , 188 ); reinfection with the same virus at a later age caused pancreatic tissue damage accompanied by hyperglycaemia and a high viral load in the pancreas.…”

The Role of Inflammation in Diabetic Retinopathy

“…Of the two main major forms of diabetes, Type 2 far outweighs Type 1 diabetes (T1D) in prevalence and presents modern health care systems with the greater challenge ( 3 – 5 ). T1D is considered an autoimmune disease ( 6 – 8 ), possibly induced by a viral infection ( 9 , 10 ) with an acute onset involving insulitis and islet cell infiltration but persisting as a chronic disease ( 11 , 12 ), while Type 2 diabetes (T2D) is a chronic disease, brought on by metabolic dysregulation and insulin resistance ( 13 , 14 ). Although etiologically different, both conditions are characterized by hyperglycemia and dyslipidemia which are considered major risk factors for development of the shared macrovascular and microvascular complications as well as neurological dysfunction ( 15 ); moreover, the two conditions can co-exist ( 4 ).…”

Enteroviruses and Type 1 Diabetes: Multiple Mechanisms and Factors?

“…The pattern of responses differed between children who developed T1D and control children. In T1D patients, the anti-Coxsackie virus enhancing activity was predominant or even exclusive over the neutralizing activity, whereas in controls the enhancing and neutralizing activities were more balanced or the neutralizing activity was predominant (70). In summary, the impact of enterovirus infection on APC functions in immune activation or regulation is not well understood and remains a crucial open question in the search for viral triggering mechanisms.…”