Peripheral blood cellular immunophenotype in suicidal ideation, suicide attempt, and suicide: a systematic review and meta-analysis.

Previous meta-analyses have documented the association of immune-inflammatory pathways with the pathophysiology of Major Depressive Episode (MDE), as reflected by alterations in peripheral blood immune cell counts. However, it remains unclear whether these immunological changes are distinct in individuals experiencing suicidal ideation (SI) or suicidal behavior (SB), beyond the context of an MDE. This systematic review and meta-analysis aimed to examine peripheral immune cell profiles across samples with SI/SB and compare them to healthy controls or patients with MDE. A systematic literature search was conducted in MEDLINE, Embase, and PsycINFO for articles published from inception until June 12, 2023. Two independent reviewers screened the articles for inclusion, extracted data, and assessed the risk of bias using the Newcastle-Ottawa scale. Meta-analyses were performed using a random-effects model to calculate standardized mean differences (SMDs) and 95% confidence intervals (CIs) for immune cell counts or ratios between groups with and without SI/SB. Heterogeneity across studies was assessed using the restricted maximum-likelihood estimator for tau statistic and I2-statistic and tested by the Q test. Publication bias was evaluated using the Egger´s test and funnel plots. Meta-regression analyses were conducted to explore the potential moderating effects of age, gender, current or lifetime SI/SB, and the type of self-harming behavior (SI or SB). The study was registered with PROSPERO (CRD42023433089). The systematic review included 30 studies, with data from 19 studies included in the meta-analyses comprising 139 unique comparisons. Eleven different cell populations or ratios were included, comprising 1973 individuals with SI/SB and 5537 comparison subjects. White blood cell (WBC) and neutrophil counts were higher in individuals with SI/SB than in controls (WBC: SMD = 0.458; 95% CI = 0.367-0.548; p value ≤ 0.001; I2 = 0.002% and; Neutrophils: SMD = 0.581; 95% CI = 0.408-0.753; p < 0.001), indicating an inflammatory process. The neutrophil-to-lymphocyte ratio (NLR) emerged as a potential marker, demonstrating a notable elevation in individuals with SI/SB (SMD = 0.695; 95% CI = 0.054-1.335; p value = 0.033; I2 = 94.281%; Q test p value ≤ 0.001). The elevated NLR appears to be primarily driven by the increase in neutrophil counts, as no significant differences were found in lymphocyte counts between groups. Comparisons among participants with and without SI/SB and depression revealed similar trends with increased NLR, monocyte-to-lymphocyte ratio (MLR), and platelet-to-lymphocyte ratio (PLR) observed in depressed individuals with SI/SB compared to those without SI/SB. Broad alteration in the peripheral immune cell populations and their ratios were observed in individuals with SI/SB, indicating an immune activation or dysfunction. Notably, these immunological changes were also evident when comparing MDE individuals with and without SI/SB, suggesting that such immune dysfunction associated with suicidality cannot be solely attributed to or explained by depressive symptoms. The NLR, MLR, and PLR ratios, in combination with novel immune cellular and protein biomarkers, open new avenues in understanding the immunological underpinnings of SI/SB. These findings highlight the potential utility of immune markers as part of a multi-modal approach for risk stratification and therapeutic monitoring in SI/SB.

Duodenal mucosa of untreated celiac disease patients has altered expression of the GAS6 and PROS1 and the negative regulator tyrosine kinase TAM receptors subfamily.

Celiac disease (CD) is an immune-driven disease characterized by tissue damage in the small intestine of genetically-susceptible individuals. We evaluated here a crucial immune regulatory pathway involving TYRO3, AXL, and MERTK (TAM) receptors and their ligands PROS1 and GAS6 in duodenal biopsies of controls and CD patients. We found increased GAS6 expression associated with downregulation of PROS1 and variable TAM receptors levels in duodenum tissue of CD patients. Interestingly, CD3+ lymphocytes, CD68+, CD11c+ myeloid and epithelial cells, showed differential expressions of TAM components comparing CD vs controls. Principal component analysis revealed a clear segregation of two groups of CD patients based on TAM components and IFN signaling. In vitro validation demonstrated that monocytes, T lymphocytes and epithelial cells upregulated TAM components in response to IFN stimulation. Our findings highlight a dysregulated TAM axis in CD related to IFN signaling and contribute to a deeper understanding of the pathophysiology of CD.

Increased AXLhigh myeloid cells as pathognomonic marker in Langerhans cell histiocytosis and Langerin expression dependence of mTOR inhibition.

Langerhans cell histiocytosis (LCH) is characterized by an expansion and accumulation of pathological histiocytes expressing langerin (CD207) and CD1a in different organs under an inflammatory milieu. The origin of pathognomonic precursors of LCH is widely debated, but monocytes and pre-dendritic cells (pre-DC) play a significant role. Remarkably, we found an expansion of AXLhigh cells in the CD11c+ subset of patients with active LCH, which also express the pathognomonic CD207 and CD1a. Moreover, we obtained a monocyte-derived LC-like (mo-LC-like) expressing high levels of AXL when treated with inflammatory cytokine, or plasma of patients with active disease. Intriguingly, inhibiting the mTOR pathway at the initial stages of monocyte differentiation to LC-like fosters the pathognomonic LCH program, highly increasing CD207 levels, together with NOTCH1 induction. We define here that AXLhigh could also be taken as a strong pathognomonic marker for LCH, and the release of Langerin and NOTCH1 expression depends on the inhibition of the mTOR pathway.

Immunological alterations in patients with current and lifetime suicide ideation and attempts: Examining the relationship with depressive symptoms.

Background: Suicidal ideation and attempt (SI/SA) have been associated with dysregulation of the immune response and inflammation. However, few studies have explored how innate and acquired cellular immunity impact on the peripheral immune response. Our study addresses this gap by examining the composition of peripheral immune cells and humoral markers among individuals with current SI/SA, individuals with a history of SI/SA, and healthy controls (HC). Additionally, we aim to explore whether depressive symptoms settle the relationship between inflammation and SI/SA. Methods: This is a multicenter case-control study that included 105 participants. Clinical and demographic characterists together with hemogram parameters, soluble pro and anti-inflamatory factors, and specific innate and adaptive immune cell populations were compared among patients with current SI/SA (n = 21), a history of lifetime SI/SA (n = 42), and HC (n = 42). Results: Patients with both current and lifetime SI/SA had a significant increase in the absolute count of monocytes and in the monocyte/lymphocyte ratio (MLR). Additionally, patients with current and lifetime SI/SA showed a significant increase in high-sensitivity C- reactive protein (hs-CRP), and patients with lifetime SI/SA also showed higher levels of Erythrocyte Sedimentation Rate (ESR). The cellular inflammatory status of patients with SI/SA was characterized by altered proportions of monocytes with higher levels of nonclassical and intermediate monocytes. No differences were observed in the number of lymphocytes and the proportion of CD4 and CD8 between patients and HC, but we found differences in markers of exhaustion of CD4 lymphocytes, with increased levels of Programmed cell death protein 1 (PD1) in Current SI/SA and Lymphocyte activation gene 3 (LAG3) in Current SI/SA and Lifetime SI/SA compared to HC. The plasmainflammatory status was marked by higher levels of soluble Triggering receptor expressed on myeloid cells 2 (sTREM2) in patients with lifetime SI/SA compared to HC. Finally, the multinomial analysis indicates that inflammation and depressive symptoms are independently associated with SI/SA. Conclusion: This study highlights the association of immunological alterations with SI/SA. Furthremore, SI/SA is independently influenced by depressive symptoms and inflammation. This may have important therapeutic implications, as in these patients, it may be necessary to treat the inflammatory process beyond treating the depressive symptoms.

Decoding the inflammatory signature of the major depressive episode: insights from peripheral immunophenotyping in active and remitted condition, a case-control study.

Depression is a prevalent and incapacitating condition with a significant impact on global morbidity and mortality. Although the immune system's role in its pathogenesis is increasingly recognized, there is a lack of comprehensive understanding regarding the involvement of innate and adaptive immune cells. To address this gap, we conducted a multicenter case-control study involving 121 participants matched for sex and age. These participants had either an active (or current) major depressive episode (MDE) (39 cases) or a remitted MDE (40 cases), including individuals with major depressive disorder or bipolar disorder. We compared these 79 patients to 42 healthy controls (HC), analyzing their immunological profiles. In blood samples, we determined the complete cell count and the monocyte subtypes and lymphocyte T-cell populations using flow cytometry. Additionally, we measured a panel of cytokines, chemokines, and neurotrophic factors in the plasma. Compared with HC, people endorsing a current MDE showed monocytosis (p = 0.001), increased high-sensitivity C-reactive protein (p = 0.002), and erythrocyte sedimentation rate (p = 0.003), and an altered proportion of specific monocyte subsets. CD4 lymphocytes presented increased median percentages of activation markers CD69+ (p = 0.007) and exhaustion markers PD1+ (p = 0.013) and LAG3+ (p = 0.014), as well as a higher frequency of CD4+CD25+FOXP3+ regulatory T cells (p = 0.003). Additionally, patients showed increased plasma levels of sTREM2 (p = 0.0089). These changes are more likely state markers, indicating the presence of an ongoing inflammatory response during an active MDE. The Random Forest model achieved remarkable classification accuracies of 83.8% for MDE vs. HC and 70% for differentiating active and remitted MDE. Interestingly, the cluster analysis identified three distinct immunological profiles among MDE patients. Cluster 1 has the highest number of leukocytes, mainly given by the increment in lymphocyte count and the lowest proinflammatory cytokine levels. Cluster 3 displayed the most robust inflammatory pattern, with high levels of TNFα, CX3CL1, IL-12p70, IL-17A, IL-23, and IL-33, associated with the highest level of IL-10, as well as ß-NGF and the lowest level for BDNF. This profile is also associated with the highest absolute number and percentage of circulating monocytes and the lowest absolute number and percentage of circulating lymphocytes, denoting an active inflammatory process. Cluster 2 has some cardinal signs of more acute inflammation, such as elevated levels of CCL2 and increased levels of proinflammatory cytokines such as IL-1ß, IFNγ, and CXCL8. Similarly, the absolute number of monocytes is closer to a HC value, as well as the percentage of lymphocytes, suggesting a possible initiation of the inflammatory process. The study provides new insights into the immune system's role in MDE, paving the ground for replication prospective studies targeting the development of diagnostic and prognostic tools and new therapeutic targets.