Do Defective Immune System-Mediated Myelination Processes Increase Postpartum Psychosis Risk?
Authors: Paola Dazzan, Montserrat Fusté, William Davies
Journal: Trends in Molecular Medicine (2018)

Postpartum psychosis (PP) is a rare, severe psychiatric disorder affecting some women shortly after childbirth. While the risk factors for PP are relatively well understood, our knowledge of the underlying pathophysiology is extremely poor; however, there is some evidence that immune system dysregulation may play a role. A recent study has shown that regulatory T cells (Tregs) may promote remyelination via the CCN family of proteins. Here, we argue, on the basis of emerging immunological, animal model, and neuroimaging findings, that PP risk may be elevated due to abnormalities in the Treg–CCN–(re)myelination axis and that risk and protective/treatment factors for the disorder may influence this axis. Postpartum (or puerperal) psychosis (PP) is a rare, severe psychiatric disorder that affects women shortly after childbirth; risk is particularly high in individuals with a history of bipolar disorder or PP, but the underlying pathophysiology remains poorly understood. Emerging evidence suggests that immune system (dys)function plays an important role in disorder onset. On the basis of new findings from clinical and animal model studies, we hypothesise that the abundance and/or activity of regulatory T cells, and the efficacy of consequent (re)myelination processes in the brain mediated by CCN proteins, is perturbed in PP; this pathway may be modulated by risk and protective/treatment factors for the disorder, and identifying abnormalities within it could signpost novel predictive biomarkers and therapeutic targets. Postpartum (or puerperal) psychosis (PP) is a rare, severe psychiatric disorder that affects women shortly after childbirth; risk is particularly high in individuals with a history of bipolar disorder or PP, but the underlying pathophysiology remains poorly understood. Emerging evidence suggests that immune system (dys)function plays an important role in disorder onset. On the basis of new findings from clinical and animal model studies, we hypothesise that the abundance and/or activity of regulatory T cells, and the efficacy of consequent (re)myelination processes in the brain mediated by CCN proteins, is perturbed in PP; this pathway may be modulated by risk and protective/treatment factors for the disorder, and identifying abnormalities within it could signpost novel predictive biomarkers and therapeutic targets. Postpartum psychosis (PP) is a severe psychiatric disorder affecting approximately one or two of every 1000 women shortly after childbirth (most often within 6 weeks); the main symptoms include hallucinations, delusions, cognitive disorganisation, and mood abnormalities [1Bergink V. et al.Postpartum psychosis: madness, mania, and melancholia in motherhood.Am. J. Psychiatry. 2016; 173: 1179-1188Crossref PubMed Scopus (69) Google Scholar]. PP risk is highly predictable, with a risk recently reported to be ∼35% for women with a history of either bipolar affective disorder or previous PP [2Wesseloo R. et al.Risk of postpartum relapse in bipolar disorder and postpartum psychosis: a systematic review and meta-analysis.Am. J. Psychiatry. 2016; 173: 117-127Crossref PubMed Scopus (155) Google Scholar]. Although PP occurs concomitantly with the biological sequelae of childbirth, its neurobiological basis remains poorly understood. The most intensively studied biological changes in PP have been those that occur in maternal reproductive hormones shortly after childbirth; however, no differences in absolute levels of oestrogen or progesterone have been identified in women who develop an episode of PP [3Kumar R. et al.Neuroendocrine and psychosocial mechanisms in post-partum psychosis.Prog. Neuropsychopharmacol. Biol. Psychiatry. 1993; 17: 571-579Crossref Scopus (14) Google Scholar, 4Wisner K.L. Stowe Z.N. Psychobiology of postpartum mood disorders.Semin. Reprod. Endocrinol. 1997; 15: 77-89Crossref PubMed Scopus (84) Google Scholar]. A genetic liability to PP has also been suggested: a linkage study in women with bipolar affective PP implicated chromosomal regions 16p13 and 8q24 (regions previously associated with bipolar disorder vulnerability) [5Jones I. et al.Bipolar affective puerperal psychosis: genome-wide significant evidence for linkage to chromosome 16.Am. J. Psychiatry. 2007; 164: 1099-1104Crossref PubMed Scopus (57) Google Scholar], while genetic association studies have provided suggestive, albeit inconclusive, evidence of risk variants within candidate genes involved in serotonergic, hormone-dependent, or stress-response pathways [6Jones I. et al.Bipolar disorder, affective psychosis, and schizophrenia in pregnancy and the post-partum period.Lancet. 2014; 384: 1789-1799Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar, 7Kumar H.B. et al.Serotonergic candidate genes and puerperal psychosis: an association study.Psychiatr. Genet. 2007; 17: 253-260Crossref PubMed Scopus (22) Google Scholar, 8Thippeswamy H. et al.Estrogen pathway related genes and their association with risk of postpartum psychosis: a case control study.Asian J. Psychiatry. 2017; 26: 82-85Crossref PubMed Scopus (5) Google Scholar]. Key obstacles in identifying biological risk and protective factors for PP include low disorder prevalence, high between-patient symptom heterogeneity, lack of accessibility to patient brain tissue, and a historical lack of amenable model systems [9Davies W. Understanding the pathophysiology of postpartum psychosis: challenges and new approaches.World J. Psychiatry. 2017; 7: 77-88Crossref Scopus (12) Google Scholar]. However, understanding the pathophysiology of PP is crucial for identifying both novel therapeutic targets (for more efficacious drugs with fewer adverse effects) and predictive biomarkers (for identification of the most 'at risk' women before, or during, pregnancy, thereby facilitating earlier, more individualised clinical interventions). Recent evidence has highlighted a potentially important role for the immune system in the onset of PP: women with the disorder have higher rates of autoimmune thyroid dysfunction and pre-eclampsia (considered a disease of immunological maternal-fetal incompatibility) [1Bergink V. et al.Postpartum psychosis: madness, mania, and melancholia in motherhood.Am. J. Psychiatry. 2016; 173: 1179-1188Crossref PubMed Scopus (69) Google Scholar, 10Bergink V. et al.Pre-eclampsia and first-onset postpartum psychiatric episodes: a Danish population-based cohort study.Psychol. Med. 2015; 45: 3481-3489Crossref PubMed Scopus (43) Google Scholar], and some cases of PP involve an autoimmune response against the N-methyl-d-aspartic acid receptor [11Bergink V. et al.Autoimmune encephalitis in postpartum psychosis.Am. J. Psychiatry. 2015; 172: 901-908Crossref PubMed Scopus (53) Google Scholar]. The link between PP pathophysiology and the immune system may not be surprising, given that immune system dysregulation, characterised by elevated levels of serum proinflammatory cytokines such as interleukin (IL)-6, IL-1, and tumour necrosis factor-α, and alterations in the expression of associated genes now features prominently in pathophysiological models of depression (including in the postpartum period) [12Boufidou F. et al.CSF and plasma cytokines at delivery and postpartum mood disturbances.J. Affect. Disord. 2009; 115: 287-292Crossref PubMed Scopus (60) Google Scholar, 13Kohler C.A. et al.Peripheral cytokine and chemokine alterations in depression: a meta-analysis of 82 studies.Acta Psychiatr. Scand. 2017; 135: 373-387Crossref PubMed Scopus (423) Google Scholar], bipolar affective disorder [14Drexhage R.C. et al.Inflammatory gene expression in monocytes of patients with schizophrenia: overlap and difference with bipolar disorder. A study in naturalistically treated patients.Int. J. Neuropsychopharmacol. 2010; 13: 1369-1381Crossref PubMed Scopus (112) Google Scholar], and psychosis [15Bergink V. et al.Autoimmunity, inflammation, and psychosis: a search for peripheral markers.Biol. Psychiatry. 2014; 75: 324-331Abstract Full Text Full Text PDF PubMed Scopus (167) Google Scholar, 16Miller B.J. et al.Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects.Biol. Psychiatry. 2011; 70: 663-671Abstract Full Text Full Text PDF PubMed Scopus (1046) Google Scholar]. PP occurs at a time of naturally heightened immune responsiveness. In pregnancy, a predominant anti-inflammatory T helper (Th)2-type immunity (whereby Th2 cell activity, including cytokine expression, is favoured over that from Th1 cells), has been historically considered responsible for maternal tolerance toward fetal alloantigens to protect the foetus from maternal Th1 cell-mediated immunity and subsequent attack [17Mor G. et al.Inflammation and pregnancy: the role of the immune system at the implantation site.Ann. N. Y. Acad. Sci. 2011; 1221: 80-87Crossref PubMed Scopus (511) Google Scholar]. However, more recent models of immunity function in pregnancy also implicate other T cell types, including regulatory T cells (Tregs; see Glossary), cytotoxic natural killer (NK) cells, and Th17 cells [18Kraus T.A. et al.Characterizing the pregnancy immune phenotype: results of the viral immunity and pregnancy (VIP) study.J. Clin. Immunol. 2012; 32: 300-311Crossref PubMed Scopus (106) Google Scholar, 19Wegienka G. et al.Within-woman change in regulatory T cells from pregnancy to the postpartum period.J. Reprod. Immunol. 2011; 88: 58-65Crossref PubMed Scopus (31) Google Scholar]. Treg levels typically increase in late pregnancy and peak early in the postpartum period, to be followed by later depletion [19Wegienka G. et al.Within-woman change in regulatory T cells from pregnancy to the postpartum period.J. Reprod. Immunol. 2011; 88: 58-65Crossref PubMed Scopus (31) Google Scholar]. Not only may Treg cells be important for regulating immunity and mediating self-tolerance in pregnancy but also for moderating the course of autoimmune disorders during this period. For example, the proliferation of Tregs that occurs during pregnancy is thought to mitigate acute exacerbations of multiple sclerosis (MS), an immune system-mediated demyelinating disease [20Iorio R. et al.T-bet, pSTAT1 and pSTAT3 expression in peripheral blood mononuclear cells during pregnancy correlates with post-partum activation of multiple sclerosis.Clin. Immunol. 2009; 131: 70-83Crossref PubMed Scopus (18) Google Scholar]. Two recent studies have reported that women with PP have lower levels of Th1, Th17, and Tregs [21Bergink V. et al.Immune system dysregulation in first-onset postpartum psychosis.Biol. Psychiatry. 2013; 73: 1000-1007Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar] and a lower proportion of naïve Tregs (but a higher proportion of memory Tregs) [22Kumar M.M. et al.Immune system aberrations in postpartum psychosis: an immunophenotyping study from a tertiary care neuropsychiatric hospital in India.J. Neuroimmunol. 2017; 310: 8-13Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar] than healthy postpartum women. These findings may reflect the disrupted function of one or more subpopulations of Tregs in this clinical group, although the mechanisms underlying group differences in T cell proportions, and their precise functional relevance, are currently unclear. In addition, women with PP have been reported to exhibit lower numbers of NK cells [21Bergink V. et al.Immune system dysregulation in first-onset postpartum psychosis.Biol. Psychiatry. 2013; 73: 1000-1007Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar] but increased regulatory NK cells [22Kumar M.M. et al.Immune system aberrations in postpartum psychosis: an immunophenotyping study from a tertiary care neuropsychiatric hospital in India.J. Neuroimmunol. 2017; 310: 8-13Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar] that counterbalance the cytotoxic NK response and are suggestive of a possible defect in the immune restoration normally present in the postpartum period. Furthermore, women with PP show a reduction in numbers of dendritic cells [22Kumar M.M. et al.Immune system aberrations in postpartum psychosis: an immunophenotyping study from a tertiary care neuropsychiatric hospital in India.J. Neuroimmunol. 2017; 310: 8-13Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar]; these cells are known to secrete higher levels of IL-12 and IL-6 in MS by inducing proinflammatory Th1 and Th17 cells, and their reduced numbers in women with PP could theoretically result in the persistence of immunosuppressive cells in the postpartum period. Finally, monocyte and macrophage levels have also been found to be significantly higher in women with PP than in those without PP. Although Kumar and colleagues [22Kumar M.M. et al.Immune system aberrations in postpartum psychosis: an immunophenotyping study from a tertiary care neuropsychiatric hospital in India.J. Neuroimmunol. 2017; 310: 8-13Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar] found no difference in total monocyte numbers between women with PP and healthy postpartum women, their study did find lower levels of the non-classical monocyte subtype, which display inflammatory characteristics upon activation, in the former group. The parallel findings of higher blood levels of chemokine CCL2 (produced by monocytes during tissue infiltration) in women with PP, and of a robustly upregulated immune system-related gene expression profile in this clinical group, strongly support the relevance of monocyte alterations in this disorder [21Bergink V. et al.Immune system dysregulation in first-onset postpartum psychosis.Biol. Psychiatry. 2013; 73: 1000-1007Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar]. Collectively, the above-mentioned data support a model for PP whereby an imbalance between proinflammatory and immunosuppressive cells of the immune system in the postpartum period may be strongly associated, possibly causally, with the development of the disorder. It remains to be established whether, and how, peripheral immune activation might affect the maternal brain processes that underlie PP onset. However, data relevant to the pathophysiology of MS and other psychiatric conditions, discussed in the subsequent sections, suggest that an influence on myelination processes is possible. While gray and white matter abnormalities have been consistently reported in psychoses not related to the puerperium [23De Peri L. et al.Brain structural abnormalities at the onset of schizophrenia and bipolar disorder: a meta-analysis of controlled magnetic resonance imaging studies.Curr. Pharm. Des. 2012; 18: 486-494Crossref PubMed Scopus (115) Google Scholar], until very recently, brain structure had never been investigated in PP. To date, only one study (from our group) has systematically evaluated gray matter structure using magnetic resonance imaging in women at risk of PP [24Fuste M. et al.Brain structure in women at risk of postpartum psychosis: an MRI study.Transl. Psychiatry. 2017; 7: 1286-1294Crossref Scopus (16) Google Scholar]. In brief, this study found that 'at risk' women who developed PP had smaller volumes of the anterior cingulate, superior temporal, and parahippocampal gyri compared to women at risk who did not develop PP, a pattern of alterations resembling that often found in patients with psychoses not related to the puerperium. Using a different imaging sequence, we also showed in this sample that women at risk of PP have reduced myelin content in the temporal lobes and sublobar areas relative to healthy women [25Giordano A. et al.SA86. Neuroinflammation in puerperal psychosis: the relationship between myelin content and peripheral inflammatory markers.Schizophr. Bull. 2017; 43: S144Crossref Google Scholar]. A case report in which PP was associated with white matter pathology in the corpus callosum [26Udaya S.C. et al.Bright splenium of a psychotic mind.Ann. Indian Acad. Neurol. 2015; 18: 80-83PubMed Google Scholar] adds further weight to a possible link between PP risk and abnormal myelination processes. Studying white matter structure using sufficiently sensitive methods may be particularly informative in the context of PP, given evidence that maternal brain structure and associated physiology change substantially during pregnancy and into the postpartum period [27Hoekzema E. et al.Pregnancy leads to long-lasting changes in human brain structure.Nat. Neurosci. 2017; 20: 287-296Crossref PubMed Scopus (226) Google Scholar, 28Kim P. et al.The plasticity of human maternal brain: longitudinal changes in brain anatomy during the early postpartum period.Behav. Neurosci. 2010; 124: 695-700Crossref PubMed Scopus (234) Google Scholar] and that there are notable sex differences in white matter structure, both in healthy individuals and in those affected by psychosis [29Cosgrove K.P. et al.Evolving knowledge of sex differences in brain structure, function, and chemistry.Biol. Psychiatry. 2007; 62: 847-855Abstract Full Text Full Text PDF PubMed Scopus (570) Google Scholar, 30Domen P.A. et al.Microstructural white matter alterations in psychotic disorder: a family-based diffusion tensor imaging study.Schizophr. Res. 2013; 146: 291-300Crossref PubMed Scopus (15) Google Scholar]. Of relevance to our proposed model, pregnancy is a time of considerable change in women with MS and in animal models of the condition, whereby symptom severity and the number/size of active white matter lesions are reduced [31Voskuhl R. Momtazee C. Pregnancy: effect on multiple sclerosis, treatment considerations, and breastfeeding.Neurotherapeutics. 2017; 14: 974-984Crossref PubMed Scopus (29) Google Scholar]; this may be explained by the hormonal changes that physiologically occur in pregnancy (notably changes in prolactin levels), which can stimulate the maternal central nervous system (CNS) to generate new myelinating oligodendrocytes and facilitate partial remyelination, even in the presence of immune activation [32Gregg C. Pregnancy, prolactin and white matter regeneration.J. Neurol. Sci. 2009; 285: 22-27Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar]. We propose that the (re)myelination processes that occur during pregnancy and the postpartum period in MS patients (and possibly also in healthy individuals) are compromised in women at risk of PP; this may explain why bipolar disorder symptoms do not improve significantly during pregnancy [33Driscoll K.E. et al.Mood symptoms in pregnant and postpartum women with bipolar disorder: a naturalistic study.Bipolar Disord. 2017; 19: 295-304Crossref PubMed Scopus (10) Google Scholar, 34Bergink V. et al.Prevention of postpartum psychosis and mania in women at high risk.Am. J. Psychiatry. 2012; 169: 609-615Crossref PubMed Scopus (102) Google Scholar]. The recent publication of a study examining the cellular and molecular underpinnings of MS prompted us to consider previously unexplored mechanisms that may contribute to PP vulnerability. This new study elegantly demonstrated that Tregs can promote oligodendrocyte differentiation and (re)myelination within the CNS independently of inflammatory processes via secretion of the protein CCN3 (also known as nephroblastoma-overexpressed protein, or NOV) [35Dombrowski Y. et al.Regulatory T cells promote myelin regeneration in the central nervous system.Nat. Neurosci. 2017; 20: 674-680Crossref PubMed Scopus (173) Google Scholar]. This finding was of particular interest to us given that the CCN protein family member CCN3 had been suggested as a candidate mediator of PP risk by our work in a novel pharmacological mouse model [36Humby T. et al.A pharmacological mouse model suggests a novel risk pathway for postpartum psychosis.Psychoneuroendocrinology. 2016; 74: 363-370Crossref PubMed Scopus (12) Google Scholar]. In our model, Ccn3 expression was upregulated in whole brain tissue from new mouse mothers acutely administered an inhibitor of steroid sulfatase (to mimic the putative PP risk factor maternal steroid sulfatase deficiency [37Davies W. Does steroid sulfatase deficiency influence postpartum psychosis risk?.Trends Mol. Med. 2012; 18: 256-262Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar]); these mice exhibited abnormal postpartum anxiety-related and startle behaviours of possible relevance to PP. The behavioural abnormalities and the Ccn3 overexpression in the mouse model could be attenuated through administration of the antipsychotic drug ziprasidone, supporting its face and predictive validity. The finding that manipulation of placental gene activity in mice gives rise to altered maternal behaviours and increased brain (hippocampal) Ccn3 expression [38Creeth H.D.J. et al.Maternal care boosted by paternal imprinting in mammals.PLoS Biol. 2018; 16e2006599Crossref PubMed Scopus (23) Google Scholar] further supports the notion of CCN3 as a mediator of postpartum psychopathology [9Davies W. Understanding the pathophysiology of postpartum psychosis: challenges and new approaches.World J. Psychiatry. 2017; 7: 77-88Crossref Scopus (12) Google Scholar, 36Humby T. et al.A pharmacological mouse model suggests a novel risk pathway for postpartum psychosis.Psychoneuroendocrinology. 2016; 74: 363-370Crossref PubMed Scopus (12) Google Scholar]. Our pharmacological model also revealed increased brain gene expression for putative CCN protein interactors, including the pro-depressant CCN2(CTGF) [39Turner C.A. et al.Connective tissue growth factor is a novel prodepressant.Biol. Psychiatry. 2018; 84: 555-562Abstract Full Text Full Text PDF Scopus (8) Google Scholar], which may heterodimerise with CCN3 and exert antagonistic effects [40Hoshijima M. et al.Roles of heterotypic CCN2/CTGF-CCN3/NOV and homotypic CCN2-CCN2 interactions in expression of the differentiated phenotype of chondrocytes.FEBS J. 2012; 279: 3584-3597Crossref PubMed Scopus (27) Google Scholar], and the PP-relevant CCL2 protein [36Humby T. et al.A pharmacological mouse model suggests a novel risk pathway for postpartum psychosis.Psychoneuroendocrinology. 2016; 74: 363-370Crossref PubMed Scopus (12) Google Scholar, 41Le Dreau G. et al.NOV/CCN3 upregulates CCL2 and CXCL1 expression in astrocytes through beta1 and beta5 integrins.Glia. 2010; 58: 1510-1521Crossref PubMed Scopus (36) Google Scholar]. CCN2 blocks oligodendrocyte differentiation to reduce myelination levels [42Ercan E. et al.Neuronal CTGF/CCN2 negatively regulates myelination in a mouse model of tuberous sclerosis complex.J. Exp. Med. 2017; 214: 681-697Crossref PubMed Scopus (50) Google Scholar, 43Lamond R. Barnett S.C. Schwann cells but not olfactory ensheathing cells inhibit CNS myelination via the secretion of connective tissue growth factor.J. Neurosci. 2013; 33: 18686-18697Crossref Scopus (16) Google Scholar] while CCL2 (monocyte chemoattractant protein-1) can influence blood–brain barrier permeability [44Yadav A. et al.MCP-1: chemoattractant with a role beyond immunity: a review.Clin. Chim. Acta. 2010; 411: 1570-1579Crossref PubMed Scopus (326) Google Scholar] and mobilisation of oligodendrocyte progenitor cells [45Moyon S. et al.Demyelination causes adult CNS progenitors to revert to an immature state and express immune cues that support their migration.J. Neurosci. 2015; 35: 4-20Crossref PubMed Scopus (132) Google Scholar]. The CCN3 protein is present in the extracellular matrix, the cytoplasm, and the nucleus, and is involved in many diverse cellular processes including cell adhesion, migration, proliferation, differentiation, and survival [46Malik A.R. et al.Matricellular proteins of the Cyr61/CTGF/NOV (CCN) family and the nervous system.Front. Cell. Neurosci. 2015; 9: 237Crossref PubMed Scopus (31) Google Scholar]; it possesses multiple functional characteristics that support its candidacy as a mediator of PP risk, and its associated gene is located within the candidate PP genetic risk locus at 8q24 [9Davies W. Understanding the pathophysiology of postpartum psychosis: challenges and new approaches.World J. Psychiatry. 2017; 7: 77-88Crossref Scopus (12) Google Scholar, 36Humby T. et al.A pharmacological mouse model suggests a novel risk pathway for postpartum psychosis.Psychoneuroendocrinology. 2016; 74: 363-370Crossref PubMed Scopus (12) Google Scholar]. In adult human brain, CCN gene family members, including CCN3, are highly expressed throughout the cortex and the limbic system [46Malik A.R. et al.Matricellular proteins of the Cyr61/CTGF/NOV (CCN) family and the nervous system.Front. Cell. Neurosci. 2015; 9: 237Crossref PubMed Scopus (31) Google Scholar], and their expression in these, and other tissues, may be modulated by several PP-relevant molecules such as oestrogen, serotonin, cytokines, psychotomimetics, and the mood-stabilising drug lithium [9Davies W. Understanding the pathophysiology of postpartum psychosis: challenges and new approaches.World J. Psychiatry. 2017; 7: 77-88Crossref Scopus (12) Google Scholar, 36Humby T. et al.A pharmacological mouse model suggests a novel risk pathway for postpartum psychosis.Psychoneuroendocrinology. 2016; 74: 363-370Crossref PubMed Scopus (12) Google Scholar]. The intriguing findings described above, together with emerging knowledge of immune system and brain structural alterations in PP, have allowed us to generate a novel and testable evidence-based hypothesis regarding PP risk that reconciles these lines of evidence. Generally, we propose that women at risk of PP are more likely than healthy individuals to display abnormalities in the immune system–CCN family (and interactors)–(re)myelination axis and that disruption of this axis is a core pathophysiological feature of PP. Specifically, we propose that a perturbation in Treg abundance/activity in women at risk of PP may be associated with altered expression of the CCN3 protein in the brain and subsequently with reduced levels of myelination in cortical and limbic brain regions exhibiting the highest CCN3 expression and/or with the greatest accessibility to Treg influx. If dysfunction of the aforementioned axis contributes significantly to PP pathophysiology, we might expect key risk and protective factors associated with the condition to impact upon it. Patients with bipolar disorder show consistent evidence for reduced numbers of circulating Tregs [47do Prado C.H. et al.Reduced regulatory T cells are associated with higher levels of Th1/TH17 cytokines and activated MAPK in type 1 bipolar disorder.Psychoneuroendocrinology. 2013; 38: 667-676Crossref PubMed Scopus (66) Google Scholar, 48Vogels R.J. et al.T cell deficits and overexpression of hepatocyte growth factor in anti-inflammatory circulating monocytes of middle-aged patients with bipolar disorder characterized by a high prevalence of the metabolic syndrome.Front. Psychiatry. 2017; 8: 1-11Crossref Scopus (10) Google Scholar], and this is correlated with white matter integrity across much of the brain [49Poletti S. et al.Th17 cells correlate positively to the structural and functional integrity of the brain in bipolar depression and healthy controls.Brain Behav. Immun. 2017; 61: 317-325Crossref Scopus (26) Google Scholar]; the molecular mechanisms underlying this correlation are, as yet, undetermined. Similarly, patients with autoimmune thyroid diseases have been reported to exhibit reduced Treg numbers [50Li C. et al.Imbalance of Th17/Treg in different subtypes of autoimmune thyroid diseases.Cell. Physiol. Biochem. 2016; 40: 245-252Crossref Scopus (55) Google Scholar] or impaired Treg cell function [51Glick A.B. et al.Impairment of regulatory T-cell function in autoimmune thyroid disease.Thyroid. 2013; 23: 871-878Crossref PubMed Scopus (78) Google Scholar]. There is convincing evidence that the thyroid system can affect myelination and neural connectivity processes [52Calza L. et al.Role of the thyroid system in myelination and neural connectivity.Compr. Physiol. 2015; 5: 1405-1421Crossref PubMed Scopus (23) Google Scholar], and rodent work has demonstrated that CCN expression is regulated by the thyroid hormone triiodothyronine in brain cortex [53Berbel P. et al.An evo-devo approach to thyroid hormones in cerebral and cerebellar cortical development: etiological implications for autism.Front. Endocrinol. (Lausanne). 2014; 5: 1-28Crossref Scopus (58) Google Scholar]. Pre-eclampsia is also associated with low levels of circulating Tregs in some cases [54Rahimzadeh M. et al.Regulatory T-cells and preeclampsia: an overview of literature.Expert Rev. Clin. Immunol. 2016; 12: 209-227Crossref PubMed Scopus (44) Google Scholar], with long-term white matter changes (notably in the temporal lobe, an area involved in the pathophysiology of psychosis [55Siepmann T. et al.Long-term cerebral white and gray matter changes after preeclampsia.Neurology. 2017; 88: 1256-1264Crossref Scopus (40) Google Scholar, 56Wiegman M.J. et al.Regional distribution of cerebral white matter lesions years after preeclampsia and eclampsia.Obstet. Gynecol. 2014; 123: 790-795Crossref PubMed Scopus (40) Google Scholar]), and with perturbed expression of CCN family members (including CCN3) in placental tissue and serum [57Winterhager E. Gellhaus A. The role of the CCN family of proteins in female reproduction.Cell. Mol. Life Sci. 2014; 71: 2299-2311Crossref PubMed Scopus (23) Google Scholar]. Moreover, CCN3 has repeatedly been implicated as a risk factor for hypertension [58Wain L.V. et al.Novel blood pressure locus and gene discovery using genome-wide association study and expression data sets from blood and the kidney.Hypertension. 2017; 70: e4-e19Crossref Scopus (75) Google Scholar], a core feature of pre-eclampsia. Interestingly, systemic kynurenine levels (associated with effects on Treg activity [59Mandi Y. Vecsei L. The kynurenine system and immunoregulation.J. Neural Transm. (Vienna). 2012; 119: 197-209Crossref PubMed Scopus (218) Google Scholar]) have been reported