Neuronal MHC/HLA regulates the synapses of the central nervous system (CNS). The expression of MHC/HLA is, in turn, regulated by immune
cytokines. We were therefore interested in the regulation of
schizophrenia-associated
HLA antigens, specifically their regulation of expression by
interferons. We had previously observed a moderately increased frequency of
HLA-A10 expression in schizophrenic patients. While searching for the "true" disease gene near the
HLA-A gene, we discovered that homozygosity of the HLA-J M80469 pseudogene allele, in combination with
HLA-A10 or
HLA-A9, was associated with a high risk of
schizophrenia (
HLA-A10 relative risk = 29.33, p = 0.00019, patients N = 77, controls N = 214). The allele HLA-J M80468, which codes for
interferon-inducible
mRNA, conferred protection on carriers of
HLA-A9 and
HLA-A10 (
HLA-A10 relative risk = 0.022, p = 0.00017). Functional analysis revealed that
interferon γ (IFNγ) downregulated the expression of
HLA-A9 and
HLA-A10 in monocytes from HLA-J M80469 homozygous patients but not from carriers of the HLA-J M80468 allele. This is the first demonstration of an inverse effect of IFNγ on HLA expression that is associated with non-coding gene variants and
schizophrenia. Our findings suggest that the
interferons secreted during acute and
chronic infections may interfere in synaptic regulation via neuronal HLA and that this disturbance in synaptic regulation may induce the symptoms of
mental illness.