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. 2013 Aug:32:51-62.
doi: 10.1016/j.bbi.2013.01.087. Epub 2013 Feb 8.

Expression of immune genes on chromosome 6p21.3-22.1 in schizophrenia

Melissa L Sinkus  1 , Catherine E Adams, Judith Logel, Robert Freedman, Sherry Leonard
Affiliations

Expression of immune genes on chromosome 6p21.3-22.1 in schizophrenia

Melissa L Sinkus et al. Brain Behav Immun. 2013 Aug.

Abstract

Schizophrenia is a common mental illness with a large genetic component. Three genome-wide association studies have implicated the major histocompatibility complex gene region on chromosome 6p21.3-22.1 in schizophrenia. In addition, nicotine, which is commonly abused in schizophrenia, affects the expression of central nervous system immune genes. Messenger RNA levels for genes in the 6p21.3-22.1 region were measured in human postmortem hippocampus of 89 subjects. The effects of schizophrenia diagnosis, smoking and systemic inflammatory illness were compared. Cell-specific expression patterns for the class I major histocompatibility complex gene HLA-A were explored utilizing in situ hybridization. Expression of five genes was altered in schizophrenic subjects. Messenger RNA levels for the class I major histocompatibility complex antigen HLA-B were increased in schizophrenic nonsmokers, while levels for smokers were indistinguishable from those of controls. β2 microglobulin, HLA-A and Notch4 were all expressed in a pattern where inflammatory illness was associated with increased expression in controls but not in subjects with schizophrenia. Schizophrenia was also associated with increased expression of Butyrophilin 2A2. HLA-A was expressed in glutamatergic and GABAergic neurons in the dentate gyrus, hilus, and the stratum pyramidale of the CA1-CA4 regions of the hippocampus, but not in astrocytes. In conclusion, the expression of genes from the major histocompatibility complex region of chromosome 6 with likely roles in synaptic development is altered in schizophrenia. There were also significant interactions between schizophrenia diagnosis and both inflammatory illness and smoking.

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Conflict of interest statement

Conflict of interest statement:

All authors declare that there are no conflicts of interest.

Figures

Figure 1
Figure 1. Relative expression levels of B2M and three HLA genes in control subjects without an inflammatory condition
Mean expression compared to GAPDH, expressed as a percentage. Bars are one S.E.M. HLA-G does not have a bar because there was no detectable expression of this gene.
Figure 2
Figure 2. Interactive effects of schizophrenia and inflammatory illness on HLA-A levels
Least squares means of log transformed expression relative to GAPDH. Means are adjusted for all other effects in the model. A. Controls with inflammatory illness had significantly increased HLA-A expression compared to those with no inflammatory illness [F(1,87)= 12.77; p = 0.002; fold Δ = 1.6]. This difference in expression did not occur in the schizophrenic subjects. B. Smokers had significantly lower HLA-A expression [F(1,87) = 5.26; p = 0.038; fold Δ = 1.2]. Bars are one S.E.M.
Figure 3
Figure 3. Interactive effects of schizophrenia, smoking and inflammatory illness on HLA-B expression
Least squares means of log transformed expression relative to GAPDH. Means are adjusted for all other effects in the model. A. Schizophrenic nonsmokers had significantly increased HLA-B expression compared Control nonsmokers [F (1,87)= 10.69; p = 0.005; fold Δ = 2.3], and compared to schizophrenic smokers [F(1,87) = 22.99; p < 0.001; fold Δ = 2.7]. B. Nonsmokers with an inflammatory illness had significantly increased HLA-B expression compared to those with no inflammatory illness [F(1,87) = 18.15; p = 0.001; fold Δ = 2.4]. This difference in expression did not occur in the smokers. Bars are one S.E.M.
Figure 4
Figure 4. Interactive effects of schizophrenia, smoking and inflammatory illness on B2M expression
Least squares means of log transformed expression relative to GAPDH. Means are adjusted for all other effects in the model. A. Controls with an inflammatory illness had significantly increased B2M expression compared to those with no inflammatory illness [F(1,87) = 24. 21; p < 0.001; fold Δ = 1.8]. This difference in expression did not occur in the schizophrenic subjects. B. Nonsmokers with an inflammatory illness had significantly increased B2M expression compared to those with no inflammatory illness [F(1,87) = 18.15; p = 0.001; fold Δ = 1.8). This difference in expression did not occur in the smokers. Bars are one S.E.M.
Figure 5
Figure 5. Interactive effects of schizophrenia and smoking on Notch4 expression
Least squares means of log transformed expression relative to GAPDH. Means are adjusted for all other effects in the model. A. Controls with inflammation had significantly increased Notch4 expression compared to those with no inflammation [F(1,87) = 11.1; p = 0.004; fold Δ = 1.8]. This difference in expression did not occur in the schizophrenic subjects. B. Smokers had significantly lower expression than nonsmokers [F(1,87) = 5.85; p = 0.031; fold Δ = 1.3]. Bars are one S.E.M.
Figure 6
Figure 6. Effects of schizophrenia and smoking BTN2A2 expression
A. Subjects with schizophrenia had significantly higher levels of BTN2A2 mRNA [F(1,87) = 6.56; p = 0.023; fold Δ = 1.4]. B. Smokers had lower BTN2A2 levels [F(1,87) = 4.28; p = 0.057; fold Δ = 1.3]. Bars are 1 S.E.M.
Figure 7
Figure 7. Interactive effects of Smoking and inflammatory illness on HLA-DRA and TAP1 expression
Least squares means of log transformed expression relative to GAPDH. Means are adjusted for all other effects in the model. A. Effects on HLA-DRA expression. Nonsmokers with an inflammatory illness had significantly increased HLA-DRA expression compared to those with no inflammatory illness (t = 3.67; p = 0.002; fold Δ = 3.3). This difference in expression did not occur in the smokers. B. Effects on TAP1 expression. Nonsmokers with an inflammatory illness had significantly increased TAP1 expression compared to those with no inflammatory illness [F(1,87) = 14.47; p = 0.002; fold Δ = 2.0]. This difference in expression did not occur in the smokers. Bars are one S.E.M.
Figure 8
Figure 8. HLA-A mRNA in the Human Hippocampus
This slice was taken from a control nonsmoking subject (subject SL283, see Table S1) but the qualitative pattern in all subjects tested was the same. DG = dentate gyrus; gc = granule cells; CA1-4 = cornu ammonis areas 1–4. SI = subiculum. This image is a composite of 85 photomicrographs taken at 4X magnification. Bar = 1mm.
Figure 9
Figure 9. Double Labeling for HLA-A and Cell Specific Markers in the Hippocampus
(A–C) Double Labeling for HLA-A and GFAP in a group of cells in the CA3 region. HLA-A mRNA was detected by in situ hybridization and labeling with a DyLight 549 conjugated antibody (red). GFAP was detected by FITC labeled antibodies (green). Nuclei were labeled with DAPI nuclear stain (blue). A. Fluorescence microscopy image showing HLA-A positive cells. B. Fluorescence microscopy showing intermediate filaments labeled for GFAP. C. Merged image with all three wavelengths. HLA-A labeled cells do not appear to contain filaments labeled for GFAP. (D–F) Double Labeling for HLA-A and Glutamate in a group of cells is in the CA3 region. HLA-A mRNA was detected by in situ hybridization and labeling with a DyLight 549 conjugated antibody (red). Glutamate was detected with a FITC labeled antibody (green). Nuclei were labeled with DAPI nuclear stain (blue). D. Fluorescence microscopy image showing HLA-A positive cells. E. Fluorescence microscopy showing glutamate labeled cells. F. Merged image with all three wavelengths. (G–I) Double labeling for HLA-A and GAD65/GAD67 in the dentate gyrus polymorphic layer. HLA-A mRNA was detected by in situ hybridization and labeling with a DyLight 549 conjugated antibody (red). GAD65 and GAD67 were detected by a FITC labeled antibody (green). Nuclei were labeled with DAPI nuclear stain (blue). G. Fluorescence microscopy image showing HLA-A positive cells. H. Fluorescence microscopy showing GAD65/GAD67 labeled cells. I. Merged image with all three wavelengths. Bar = 25 microns.
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