Background Bipolar disorder is a debilitating mood disorder associated with a high risk of suicide and characterized by immune dysregulation. In this study, we used a multi-faceted approach to better distinguish the pattern of dysregulation of immune profiles in individuals with BD.

Methods We analyzed peripheral blood mononuclear cells (bipolar disorder N=39, control N=30), serum cytokines (bipolar disorder N=86, control N=58), whole blood RNA (bipolar disorder N=25, control N=25), and whole blood DNA (bipolar disorder N=104, control N=66) to identify immune-related differences in participants diagnosed with bipolar disorder compared to controls.

Results Flow cytometry revealed a higher proportion of monocytes in participants with bipolar disorder together with a lower proportion of T helper cells. Additionally, the levels of 18 cytokines were significantly elevated, while two were reduced in participants with bipolar disorder. Most of the cytokines altered in individuals with bipolar disorder were proinflammatory. Forty-nine genes were differentially expressed in our bipolar disorder cohort and further analyses uncovered several immune-related pathways altered in these individuals. Genetic analysis indicated variants associated with inflammatory bowel disease also influences bipolar disorder risk.

Discussion Our findings indicate a significant immune component to bipolar disorder pathophysiology and genetic overlap with inflammatory bowel disease. This comprehensive study supports existing literature, whilst also highlighting novel immune targets altered in individuals with bipolar disorder. Specifically, multiple lines of evidence indicate differences in the peripheral representation of monocytes and T cells are hallmarks of bipolar disorder.

The authors have declared no competing interest.

This study was supported by an Iowa Neuroscience Institute Research Program of Excellence grant with philanthropy from the Roy J. Carver Charitable Trust (JAW), a US Department of Veterans Affairs Merit Review Award (JAW) and a US Department of Veterans Affairs Senior Clinician Scientist (JAW). It was also supported by an EHSRC Career Enhancement award and a EHSRC Pilot grant (NIH P30 ES005605; MEG) and by the National Center for Advancing Translational Sciences of the National Institutes of Health (UL1TR002537) and the National Institute of Mental Health (NIMH R01MH125838 and R01MH111578 to VAM and JAW). Funding for this work was given to SS through the OB/GYN department at the University of Iowa Hospitals & Clinics, as well as the AHA with grant 19IPLOI34760288, and the NIH with grants NCATS 3UL1TR002537-03W1, NHLBI 1KO1HL155240-01, and NCATS UL1TR002494. Additional funding for this work came from the National Institutes of Health through a Predoctoral Training Grant (T32GM008629 to LGC).

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The Institutional Review Board of the University of Iowa gave ethical approval for this work.

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