Decades of clinical research has clearly shown that some symptoms can overlap in psychiatric diagnoses as diverse as schizophrenia, depression, and bipolar disorder. With the decoding of the human genome, it has also become possible in the last 15 years to say that disorders including these three share some genetic risk factors. Epidemiological studies have further shown that specific environmental risk factors—stress, for example—can similarly raise individual risk across diagnoses.

These facts suggest that multiple disorders share certain characteristics, and perhaps also causal factors. If they do share some of the same causes, then there is the prospect that a new treatment for one disorder might help patients with other disorders.

A team of researchers led by Mary-Ellen Lynall, MRCPsych, of Cambridge University, UK, has published research results clarifying one likely source of pathology that operates in multiple psychiatric disorders: abnormalities of the body’s immune system. As Dr. Lynall and colleagues point out, immune abnormalities have been reported in schizophrenia, major depressive disorder, bipolar disorder, autism spectrum disorder, and ADHD. Furthermore, they note, environmental exposures that elicit an immune response (stress, again, is a good example) also have been found to be risk factors in multiple psychiatric diagnoses.

On this evidence alone, it’s possible to propose that the immune system is implicated in the biological causation of a number of psychiatric illnesses—but, crucially, the team cautions, so far, “direct evidence of a causal role is limited.”

The team’s senior members included Ed Bullmore, Ph.D., MRCPsych, a 2004 BBRF Distinguished Investigator, and Murray B. Stein, M.D., FRCPC, a member of BBRF’s Scientific Council. The team also included Daniel F. Levey, Ph.D., a 2019 BBRF Young Investigator, and Renato Polimanti, Ph.D., a 2015 BBRF Young Investigator.

The team’s approach was influenced by the fact that past studies have failed to identify which subsets of immune cells are important in the development of psychiatric conditions. Some studies have found abnormalities in both myeloid cells and lymphoid cells in patients with psychiatric conditions compared to healthy controls. Myeloid cells, including monocytes, macrophages, and neutrophils, develop primarily in the bone marrow, the place where nearly all blood cells, including immune cells, are born. Lymphoid cells are also known as lymphocytes and include adaptive immune cells such as T cells and B cells. Lymphoid cells are also usually born in the bone marrow, but mature further in the thymus or spleen.

One key question the team set out to explore was whether DNA variations associated with increased risk for schizophrenia, major depression, bipolar disorder and autism, are capable of driving immune system abnormalities observed in these illnesses. They did indeed find evidence supporting this possibility.

They used data generated by past genome-wide association studies (“GWAS” studies) that searched for DNA risk factors across multiple disorders as well as GWAS studies searching for risk variants within specific disorders. They were particularly interested in DNA variants found in non-coding regions of the genome. These are locations within the genome’s 3 billion pairs of DNA “letters” that are not involved in generating proteins. The bulk of the non-coding genome is thought to be involved in regulating genes that tell cells how to make proteins.

Most of the risk variants for psychiatric illness found in GWAS studies are located in the non-coding portion of the genome. Many of these affect what scientists call epigenetic processes—biological processes in which molecular tags are added to or removed from the DNA double helix, thereby regulating gene activity.

In the journal Nature Communications, Dr. Lynall and colleagues reported two findings of potentially great importance. One is that DNA risk variants for psychiatric disorders frequently occur at gene-regulatory sites in brain tissue and lymphoid cells. In other words, the DNA variations that have been linked with various psychiatric illnesses (and across some of them) frequently occur at “epigenetically active sties” in these places. This is particularly true, the team found, in T cells, especially activated helper T cells. Helper T cells are lymphoid immune cells that, among other things, send signals to other immune cells, including cells capable of destroying infectious agents. No such association was found between psychiatric risk variants and gene-regulatory activity in myeloid cells.

There are various ways to interpret the team’s results. One, they said, is that they are consistent with epidemiological studies finding that increased risk of multiple psychiatric disorders is found following a wide range of infections. The new results, along with these epidemiological findings, support a “two-hit” model where the effects of psychiatric genetic risk variants (the first “hit”) are only revealed following T cell activation (the second “hit,” potentially due to stress or infection).

Genetic variants that give rise to atypical T cells “could conceivably have effects on the brain by at least two broad routes,” the researchers noted. One is when activated T cells possibly alter the function of neurons, perhaps via factors associated with inflammation. Another route is developmental: T cells have an important role normal childhood and adolescent programs of synaptic pruning: the essential process through which a super-abundance of nerve cells and connections between them are reduced as the very young brain matures. The team proposes that “atypical T cells in the brain could lead, via atypical synaptic pruning, to the disrupted brain connectivity seen in schizophrenia and other disorders.”

The research opens the way to a range of investigations. Among these: investigation of the epigenetic profile of T cells in psychiatric patient groups; expansion of the analyses to include GWAS results from non-European individuals, since immune-related risk may vary by ancestry; examination of whether sex differences impact the processes under investigation; and deeper investigation of possible T cell-related involvement in illnesses beyond schizophrenia, which has been the focus of much attention to date.