Relationship Between Ljungan Virus Antibodies, HLA-DQ8, and Insulin Autoantibodies in Newly Diagnosed Type 1 Diabetes Children

Abstract

Environmental factors, including viral infections, may explain an increasing and fluctuating incidence of childhood type 1 diabetes (T1D). Ljungan virus (LV) isolated from bank voles have been implicated, but it is unclear whether LV contributes to islet autoimmunity, progression to clinical onset, or both, of T1D. The aim was to test whether LV antibodies (LVAb) were related to HLA-DQ and islet autoantibodies in newly diagnosed T1D patients (n = 676) and controls (n = 309). Patients, 0-18 years of age, diagnosed with T1D in 1996-2005 were analyzed for LVAb, HLA-DQ genotypes, and all seven known islet autoantibodies (GADA, IA-2A, IAA, ICA, ZnT8RA, ZnT8WA, and ZnT8QA).LVAb at 75 th percentile, defined as cut off, was 90 (range 6-3936) U/mL and 4 th quartile LVAb were found in 25% (170/676) of which 64% were < 10 (n = 108, p < 0.0001), and 27% were < 5 (n = 45; p < 0.0001) years old. The 4 th quartile LVAb in children < 10 years of age correlated to HLA DQ2/8, 8/8, and 8/X ( p < 0.0001). Furthermore, in the group with 4 th quartile LVAb, 55% were IAA positive ( p = 0.01) and correlation was found between 4 th quartile LVAb and IAA in children < 10 years of age ( p = 0.035). It is concluded that 1) LVAb were common among the young T1D patients and LVAb levels were higher in the younger age groups; 2) 4 th quartile LVAb correlated with IAA; and 3) there was a correlation between 4 th quartile LVAb and HLA-DQ8, particularly in the young patients. The presence of LVAb supports the notion that prior exposure to LV may be associated with T1D.

Islet autoantibodies present in association with Ljungan virus infection in bank voles (Myodes glareolus) in northern Sweden

“…The Finnish study used the same LV isolate (LV 87‐012G) as in the present study to determine LVA by indirect immunofluorescence in infected cell‐lines. The RBA in the present study is based on the LV 87‐012G cDNA [Niklasson et al, ], with the difference that the cDNA was re‐cloned into the high efficiency expression vector TnT [Nilsson et al, ]. In the Finnish bank voles LVA, detected by immunofluorescence, was found in 18% of the animals, which is comparable to the upper quartile of LVA detected in the RBA in the present study.…”

“…In humans, previous studies on Swedish children and young adults (0–18 years old) indicate that children with newly diagnosed type 1 diabetes had higher levels of LVA than healthy controls, suggesting that LV could possibly contribute to type 1 diabetes in humans [Nilsson et al, , , ]. These studies also implied that LVA levels were higher in young children and that the incidence of type 1 diabetes seemed to co‐vary with subjects with high LVA levels [Nilsson et al, , , ].…”

“…The etiology of type 1 diabetes is not clarified but virus infections remain a possible trigger of islet autoimmunity [Tauriainen et al, 2011]. It has previously been suggested that Ljungan virus (LV), which is carried by bank voles (Myodes glareolus) may be associated with type 1 diabetes [Niklasson et al, 2003b;Nilsson et al, 2009Nilsson et al, , 2013Nilsson et al, , 2015. Zoonotic agents have in common that one or more animal species function as a reservoir during at least some part of the life cycle.…”

Pet exposure in the family during pregnancy and risk for type 1 diabetes-The prospective ABIS study

“…This virus seems to be especially diabetogenic when the infection is combined with stress, which makes it more interesting as stress for several reasons is suspected to contribute to development of T1D in humans . As antibodies against Ljungan virus seem to be quite common in children with diabetes even though no Ljungan virus RNA was discovered in stool samples from a Norwegian type 1 diabetes cohort, it cannot be excluded that this virus plays a role for the development of some cases of T1D. As the virus is found in rodents we found it relevant to look into the registration of pet animals which the mothers of ABIS babies made in the birth questionnaire when the ABIS children were born October 1, 1997 to October 1, 1999.…”

“…Ljungan virus has also been identified in several other species of voles, lemmings as well as yellow‐neck mouse (Apodemus), a hamster relative . Particular attention was paid when an epidemiological association between the periodic increase in number of lemmings and similar variation in incidence of T1D the following years, and antibodies to the virus were found to be quite common in diabetic children . It has been suggested that LV is involved in the pathogenesis of diabetes in BB‐rats .…”