Circulating granulocytes consist of three major myeloid cell subsets, namely basophils, eosinophils, and neutrophils. While the first two are rarely discussed in the context of neuropsychiatric illnesses, an increase in neutrophil-related parameters represents one of the most consistent findings regarding changes in peripheral immune cells in SCZ (
Figure 2).
3.3. Natural Killer Cells
NK cells are a type of immune cell with both adaptive and innate features. They have been implicated in a wide range of human diseases, ranging from infection and cancer to CNS disorders. Potential abnormalities in both NK cell count and function have been documented in SCZ, although with significant discrepancies among studies. Flow cytometric analysis showed increased counts of NK cells in clozapine-treated chronic SCZ blood samples compared to HCs
[34][67]. In contrast, computational deconvolution based on gene expression yielded lower NK cell numbers in both drug-naïve and medicated SCZ patients
[43][44][125,126], and this decrease was uncorrelated to psychotic relapse/remission. A different flow cytometric study confirmed these lower NK cell counts in chronic SCZ; however, medication appeared to increase NK cell numbers
[45][127]. These differences could be due to the different quantification methods used (flow cytometry vs. gene expression, whole blood vs. peripheral mononuclear cells). Chronic SCZ subpopulations who received differing regimens of antipsychotic drugs may exhibit distinct NK cell profiles. In fact, an earlier study involving a heterogenous SCZ cohort (more than four subtypes and treatment modalities) failed to detect any abnormalities in immune cell counts in blood samples
[46][128]. Regarding the function of NK cells in SCZ, there have been conflicting reports on NK cell cytolytic activity, possibly related to significant variations in general NK cell lytic function, medication regimes, and SCZ subtypes
[47][48][49][50][129,130,131,132]. With regard to phenotypes, some studies suggested that an elevated expression of NK-cell-activation markers, such as HLA-DR and natural killer group 2C (NKG2C), might be associated with the first episode of psychosis in SCZ patients compared to HCs.
3.4. B Lymphocytes
Considering that various autoantibody types have been found to be elevated in serum and CSF samples of SCZ patients, B cells, as producers of antibodies, have long been implicated in the autoimmune hypothesis of SCZ (
Figure 2). For instance, several small-cohort studies suggested that autoantibodies may act against anti-glutamic acid decarboxylase (GAD), γ-aminobutyric acid A receptor 1 (GABAR1), anti-acetylcholine receptor (A7ChR), and N-metil-D-aspartato receptor (NMDAR) in SCZ pathogenesis
[51][52][53][54][136,137,138,139]. However, large-scale studies (
n > 150) failed to confirm the biological significance of these autoantibodies in this disorder
[55][56][57][140,141,142], or they detected only a small range of autoantibodies in low concentrations in certain SCZ subsets, such as clinically high-risk SCZ, SCZ with the first episode of psychosis, and SCZ with tardive dyskinesia.
3.5. T Lymphocytes
Numerous phenotypic studies of various circulating T cell subsets have been conducted in SCZ (
Figure 2). While the findings were inconsistent with regard to the distribution of total CD3+ T cells, CD4+ helper T cells, and CD8+ cytotoxic T cells
[45][58][59][60][61][127,156,160,161,162], they mostly agreed with regard to increased T cell activation
[33][62][63][66,163,164]. Furthermore, activated T cells in medicated SCZ patients appeared to have higher levels of CD25 than drug-naïve patients. Along with this ex vivo-activated phenotype, several studies observed a reduced responsiveness to in vitro stimulation of IL-2 production in T cells from drug-naïve SCZ patients compared to HCs
[64][65][66][165,166,167]. However, this decrease in IL-2 production was not observed in a study of paranoid and residual SCZ
[67][99], possibly due to how patients were stratified in this study and/or the use of purified T cells/peripheral blood mononuclear cells vs. whole blood for in vitro assays. Regarding T-helper (Th) cell subtypes, an increase in Th2 cells was reportedly associated with the SCZ subtype with a pro-inflammatory monocyte feature
[33][66]; however, this alteration could not be confirmed by a different study
[67][99]. The same two studies also yielded inconsistent findings regarding the role of Th1 cells. In contrast, consensus exists regarding the elevated numbers of regulatory T cells (Treg) and IL-17-producing Th cells (Th17) in SCZ
[33][62][68][69][70][71][66,135,163,168,169,170].
4. Implications for Mechanistic Studies and Therapeutic Development
To explore disease mechanisms of SCZ, various in vitro and animal studies have been established, with induced pluripotent stem cells derived from SCZ patients and rodent strains based on human genetics as the most clinically relevant attempts to model SCZ-associated pathology
[72][73][178,179]. However, most immune-related studies to date have focused exclusively on the role of microglia, but not other peripheral immune cell subsets, in this psychiatric illness.
Anomalies in various immune cell subsets and their trafficking patterns in SCZ also suggest the potential utility of cell-type-specific immunotherapy as a novel pharmacological approach for this psychiatric illness
[74][75][184,185]. In this regard, immunomodulators aiming to inhibit lymphocyte trafficking (fingolimod) and deplete B cells (anti-CD20 monoclonal antibody, rituximab) could significantly improve negative symptoms and general psychopathology of SCZ, respectively
[76][77][186,187].
Besides these classical immunotherapies, the potential clinical efficacy in SCZ of other anti-inflammatory treatments, including aspirin, minocycline, N-acetylcysteine, estrogens, telmisartan (an angiotensin receptor 1 antagonist), and pioglitazone (a PPAR-γ antagonist)
[78][79][80][193,194,195], has been observed. Interestingly, other anti-inflammatory medications, such as celecoxib, davunetide, dextromethorphan, fatty acids, pregnenolone, statins, and varenicline, did not have a significant impact on SCZ symptoms in a recent meta-analysis, highlighting the presence of inflammatory-pathway-specific abnormalities in SCZ development.