The HLA-DR phenotype modulates the humoral immune response to enterovirus antigens

Abstract

Aims/hypothesis. Enterovirus infections are among the environmental risk factors potentially contributing to the pathogenesis of Type 1 diabetes. The aim of this study was to evaluate virus-host interaction by analysing the enterovirus antibody levels in subjects carrying different HLA-DR alleles associated with either increased or decreased risk of Type 1 diabetes. Methods. Antibodies against coxsackievirus B4 were measured to study immune responses induced by natural enterovirus infections and against poliovirus 1 to study immune responses induced by immunisation by enterovirus antigens (vaccine). Antibodies against the mumps virus were measured as a control. Study subjects included siblings of children with Type 1 diabetes taking part in the Childhood Diabetes in Finland (DiMe) Study and carrying either HLA-DR risk (DR3 and/or DR4) or protective (DR2) alleles. Results. Children with either the HLA-DR3 or HLA-DR4 allele and those with both these risk alleles had higher Coxsackie B4 antibody levels than children carrying the HLA-DR2 allele (p=0.01, p=0.01 and p=0.008, respectively). High responders (IgG levels higher than 75 percent) were also more frequent among genetically susceptible children compared to children with the protective DR2 allele (27% vs 12%) (p<0.009). The same trend was seen for poliovirus antibodies, while mumps antibody levels had a different pattern (high responders more common among DR2-positive subjects). Conclusions/interpretation. Diabetes-associated HLA-DR risk alleles were associated with a strong immune responsiveness and protective alleles with a weak responsiveness against enterovirus antigens. This phenomenon should be taken into consideration in serological case-control studies and it might play a role in virus-induced beta-cell damage. [Diabetologia (2003[Diabetologia ( ) 46:1100[Diabetologia ( -1105

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

“…The two different studies conducted in these two different counties, one in the very South of Sweden (present study) and the other in the northern part of the country therefore showed comparable results. Furthermore, the new finding that high level LVAb were associated with the T1D high risk HLA DQ2/8, 8/8, and 8/X genotypes support the well-known association between HLA and the immune response to virus (33). The association is likely to be explained by HLA-DQ8 as there was no association between HLA-DQ 2/2 or 2/X (X is not 8) subjects.…”

Relationship between the incidence of type 1 diabetes and maternal enterovirus antibodies: time trends and geographical variation

“…These HLA allele combinations vary between countries, and high-risk combinations may be more prevalent in countries with a high diabetes incidence, thus contributing to the international variation in diabetes incidence [45]. However, the difference observed between high-and low-incidence countries is opposite to the expected one if HLA risk genes were involved, as a strong antibody response to enteroviruses is associated with HLA risk alleles for type 1 diabetes [44]. The present observation that Finnish women had a stronger antibody response when positive in the neutralisation assay may reflect the effect of HLA, even though other factors such as a low level of background enterovirus infection in the Finnish population may also play a role, leading to a higher response to the infection.…”

“…In the international comparisons, the distribution of HLA risk alleles for type 1 diabetes is one possible source of bias as HLA can modulate the immune response to enterovirus antigens [42][43][44]. These HLA allele combinations vary between countries, and high-risk combinations may be more prevalent in countries with a high diabetes incidence, thus contributing to the international variation in diabetes incidence [45].…”

Environmental Triggers and Determinants of Type 1 Diabetes

“…A Finnish study indicated that the increased relative risk associated with childhood milk consumption may be higher among siblings of affected children carrying HLA class II genotypes conferring strong or moderate disease susceptibility than among those with low or decreased risk genotypes (63). HLA risk alleles for type 1 diabetes have also been linked to the appearance of autoantibodies subsequent to enterovirus infections (37) and to increased immune responsiveness to enterovirus antigens (90). Another consideration that has to be taken into account is that there may be interactions between two or more environmental factors.…”