Allelic frequencies of 3' Ig heavy chain locus enhancer HS1,2-A associated with Ig levels in patients with schizophrenia

Infectious and autoimmune pathogenic hypotheses of schizophrenia have been proposed, prompting searches for antibodies against viruses or brain structures, and for altered levels of immunoglobulins. Previous experiments have shown that allele frequencies of the Ig heavy chain 3' enhancer HS1,2*A are associated with several autoimmune diseases, suggesting a possible correlation between HS1,2 alleles and Ig production. To test this, we analyzed levels of serum Igs and HS1,2*A genotypes in two independent cohorts, one of 88 schizophrenic inpatients (24 women) and a second of 133 healthy subjects (59 women). Both groups were similar in the frequency of individuals with altered serum concentration of Ig classes and IgG subclasses (schizophrenia panel-80%; controls-68%). With the possible exception of a stabilizing effect of olanzapine, no psychopharmacological drug consumed during the month prior to serum sampling in the schizophrenia group significantly affected Ig levels. In both patient and control cohorts, an increased frequency of the HS1,2*2A allele corresponded to increased Ig plasma levels, while an increased frequency of the HS1,2*1A allele corresponded to decreased Ig plasma levels. EMSA analysis with nuclear extracts from human B cells showed that the transcription factor SP1 bound to the polymorphic region of both HS1,2*1A and HS1,2*2A while NF-kappa B bound only to the HS1,2*2A. We predict that differences in transcription factor binding sites in the two allelic variants of the 3' IgH enhancer HS1,2 may provide a mechanism by which differences in Ig expression are affected.