The HLA-DR phenotype modulates the humoral immune response to enterovirus antigens.
OBJECTIVE
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
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.
Sadeharju
K
K
Department of Virology, Medical School, University of Tampere, PO Box 33014, Tampere, Finland.
Knip
M
M
Hiltunen
M
M
Akerblom
H K
HK
Hyöty
H
H
D000917:Antibody Formation; D000956:Antigens, Viral / Q000097:blood / Q000276:immunology*; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D004770:Enterovirus / Q000276:immunology*; D004769:Enterovirus Infections / Q000276:immunology*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006684:HLA-DR Antigens / Q000235:genetics*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007070:Immunoglobulin A / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D008297:Male; D009109:Mumps virus / Q000276:immunology; D010641:Phenotype; D035781:Siblings; D013548:Sweden
D000956:Antigens, Viral; D006684:HLA-DR Antigens; D007070:Immunoglobulin A; D007074:Immunoglobulin G