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.

FIG. 1.

Ljungan virus antibodies (LVAb) in U/mL in relation to normal distribution of all 676 type 1 diabetes patients newly diagnosed in 1996–2005 (a). The LVAb levels in 309 healthy controls obtained in 1989 are shown for comparison, demonstrating a similar distribution of possible LV exposure (b). The 4^th quartile LVAb was>90 U/mL. Note: the y-axis with (a) max 4000, (b) max 1000 U/mL.

FIG. 2.

Ljungan virus antibodies (LVAb) in U/mL (log scale) in relation to age at diagnosis (years), HLA-DQ genotypes and levels IAA RU/mL (log scale). Young age at onset (0—4.99 years of age) among the HLA-DQ2/8 subjects correlated to high level LVAb and positive IAA (p=0.0001).

FIG. 3.

Ljungan virus antibodies (LVAb) in U/mL (log scale) in relation to DADA, IAA, IA-2A, ZnT8RA, ZnT8WA, and ZnT8QA (log scales). The vertical lines represent the cut-off for a positive autoantibody and the horizontal line the 4th quartile LVAb level. IAA (p=0.006) but not the other islet autoantibody levels correlated to high level LVAb.

FIG. 4.

Mean levels of Ljungan virus antibodies (LVAb) in U/mL within the 4th quartile (__ solid line) and in the 1st—3rd quartiles (….dotted line), respectively, in relation to season. Seasons from February 1996 until April 2005 are indicated as uneven numbers (1, 3, 5, etc) for the winter (October—March), and even numbers for the summer (April—September) seasons. The fluctuating levels of LVAb in the 4th quartile are compared to the increasing incidence (- - - -semi-dotted line) of T1D among children in Skåne.