Peripheral Blood Cell–Stratified Subgroups of Inflamed Depression

Abstract

BACKGROUND: Depression has been associated with increased inflammatory proteins, but changes in circulating immune cells are less well defined. METHODS: We used multiparametric flow cytometry to count 14 subsets of peripheral blood cells in 206 depression cases and 77 age-and sex-matched controls (N = 283). We used univariate and multivariate analyses to investigate the immunophenotypes associated with depression and depression severity. RESULTS: Depression cases, compared with controls, had significantly increased immune cell counts, especially neutrophils, CD4 1 T cells, and monocytes, and increased inflammatory proteins (C-reactive protein and interleukin-6). Within-group analysis of cases demonstrated significant associations between the severity of depressive symptoms and increased myeloid and CD4 1 T-cell counts. Depression cases were partitioned into 2 subgroups by forced binary clustering of cell counts: the inflamed depression subgroup (n = 81 out of 206; 39%) had increased monocyte, CD4 1 , and neutrophil counts; increased C-reactive protein and interleukin-6; and more severe depression than the uninflamed majority of cases. Relaxing the presumption of a binary classification, data-driven analysis identified 4 subgroups of depression cases, 2 of which (n = 38 and n = 100; 67% collectively) were associated with increased inflammatory proteins and more severe depression but differed in terms of myeloid and lymphoid cell counts. Results were robust to potentially confounding effects of age, sex, body mass index, recent infection, and tobacco use. CONCLUSIONS: Peripheral immune cell counts were used to distinguish inflamed and uninflamed subgroups of depression and to indicate that there may be mechanistically distinct subgroups of inflamed depression.

Major Depressive Disorder Is Associated With Differential Expression of Innate Immune and Neutrophil-Related Gene Networks in Peripheral Blood: A Quantitative Review of Whole-Genome Transcriptional Data From Case-Control Studies

“…We were unable to explore this issue any further immediately owing to lack of cell count data provided by the primary studies. There is prior evidence that MDD is associated with increased numbers of neutrophils (52) and increased neutrophil/lymphocyte ratio (53)(54)(55). Flow cytometry and transcriptional analysis of sorted cell classes or single cells could be used in the future to resolve the immune cellular phenotype and its relationship to transcriptional changes more precisely.…”

“…In relation to pathogenesis of MDD, these case-control differences in innate immune gene expression (SMD approximately 0.2-0.5) ( Figure 4) are of the same order of magnitude as previously reported case-control differences in CRP and inflammatory cytokines (SMD approximately 0.1-0.5). There is some prior evidence that increased neutrophil counts are positively correlated with increased inflammatory proteins in MDD (52), and neutrophils are known to produce many cytokines and chemokines (56). Thus, neutrophil expansion and/or activation may constitute at least one of the cellular sources of peripherally increased proinflammatory cytokines in MDD, which in turn could communicate across the blood-brain barrier to cause central immune state changes and depressive behaviors (10)(11)(12)(13).…”

Inflammatory phenotype of depression symptom structure: A network perspective

“…This has led to calls for the inflammatory phenotyping of depression (Felger et al, 2018) and increased modeling of specific symptoms and symptom subtypes in immunopsychiatry . These pursuits have included profiling symptoms associated with inflammation (Fried et al, 2019;Jokela et al, 2016;Kappelmann et al, 2020;Moriarity et al, 2020a) as well as inflammatory proteins and cell counts associated with MDD (Lynall et al, 2020). Although there are many different inflammatory proteins, CRP, an acute phase reactant, arguably is the most widely studied.…”

Polygenic risk for immuno-metabolic markers and specific depressive symptoms: A multi-sample network analysis study

“…Regarding immunological complexity, studies have reported various associations of serum inflammatory proteins with depression, including among others CRP, interleukin (IL)-6, IL-10, and tumour necrosis factor (TNF)-α (Goldsmith et al, 2016;Haapakoski et al, 2015;. Evidence from in-depth immunophenotyping further suggests that there may be distinct subgroups of inflammation-related depression as shown by immune cell count clustering and transcriptome analyses (Cattaneo et al, 2020;Lynall et al, 2020). These studies suggest that acutely elevated levels of inflammatory markers are associated with depression, but associations of depression with genetic/lifetime predisposition to higher inflammatory markers has been studied less frequently and primarily for CRP (Badini et al, 2020;Kappelmann et al, 2020;Milaneschi et al, 2017bMilaneschi et al, , 2016.…”