Effects of recurrence of illness and adverse childhood experiences on effector, cytotoxic, and regulatory T cells, and cannabinoid receptor-bearing B cells in major depression, an autoimmune disorder

Background Major depressive disorder (MDD) is characterized by increased T helper (Th)1 polarization, T cell activation (e.g., CD71+ and CD40L+), and cannabinoid receptor type 2 bearing CD20+ B cells; and lower T regulatory (Treg) numbers. Aims To delineate the effects of adverse childhood experiences (ACEs) and recurrence of illness (ROI) on activated T and CB2-bearing B populations, and Tregs, including FoxP3+CD152+, FoxP3+GARP+, and FoxP3+CB1+ cells. Methods We measured ROI, ACEs, the number of activated T cells, Tregs, and CD20+CB2+ B cells, in 30 MDD patients and 20 healthy controls. Results A larger part of the variance in the depression phenome (40.8%) was explained by increased CD20+CB2+ and activated T cells, and lowered Tregs. ROI and lifetime suicidal behaviors were significantly and positively associated with CD20+CB2+, CD3+CD71+, CD3+CD40L+, CD4+CD71+, CD4+CD40L+, and CD4HLADR+ numbers. ROI was significantly correlated with CD8+CD40L+ numbers. The sum of ACEs was significantly associated with CD20+CB2+, CD3+CD40L+, CD4+40L+ numbers, T cell activation (positively) and Treg (inversely) indices. One replicable latent vector could be extracted from activated T cells, lifetime and current suicidal behaviors, number of depressive episodes, and severity of depression, and 48.8% of its variance was explained by ACEs. Conclusions ACE-induced activation of T effector and cytotoxic cells and B cells with autoimmune potential, coupled with lowered Treg numbers are a key component of depression. The findings indicate that increasing ROI, the phenome of depression and suicidal behaviors, are caused by autoimmune processes, which are the consequence of ACEs and increasing sensitization of immune responses. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The work was supported by AMERI-ASIA MED CO, Ltd; the Thailand Science research and Innovation Fund Chulalongkorn University (HEA663000016) to MM, and a grant from H.M. the King Bhumibol Adulyadej's 72nd Birthday Anniversary Scholarship to MR. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was conducted in accordance with the Declaration of Helsinki of 1975, revised in 2013, and the protocol was approved by the Ethics Committee of the Institutional Review Board of the Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand (#528/63). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The dataset generated during and/or analyzed during the current study will be available from the corresponding author (M.M.) upon reasonable request and once the authors have fully exploited the dataset.