Elevated densities of CD163+ perivascular macrophages have been reported in schizophrenia post-mortem brain tissue, particularly in regions involved in neurodevelopment, dopaminergic signaling, and blood-brain barrier (BBB) regulation. However, the biological significance and developmental lineage of these findings remain unclear. While CD163 is linked to regulatory and scavenging functions, macrophage activation states form a continuum and cannot be inferred from any single marker. This Perspective outlines a structured, testable research framework to determine whether this accumulation reflects altered responsiveness to persistent intracellular, inflammatory, systemic, or treatment-related signals. To test this, we propose sequential methodological aims, including defining CD163+ cell localization and phenotypes in predefined brain regions, and assessing viral and non-viral molecular signals using spatial transcriptomic and cell-specific methods. This framework also involves comparing macrophage activation states across schizophrenia and other psychiatric and non-psychiatric control groups, using single-cell and single-nucleus sequencing. By not presuming a specific infectious aetiology, this approach will provide a general methodology to investigate macrophage-related mechanisms across diverse potential triggers. Within this model, HSV-1 is evaluated strictly as an illustrative proof-of-concept candidate for testing intracellular pathogen responses, rather than an exclusive cause, as epidemiological associations have been inconsistent and localization of viral materials within these cells has not been demonstrated. Similarly, Bacille Calmette-Guérin (BCG)-associated trained immunity is introduced strictly as a preliminary, ex vivo/in vitro approach to probe macrophage reprogramming and plasticity. Ultimately, this framework provides a systematic approach for investigating macrophage-related mechanisms and their potential drivers in schizophrenia without presupposing a specific underlying aetiology.

Virus-associated chronic inflammation may contribute to autoimmunity in a number of diseases. In the brain, autoimmune encephalitis appears related to fluctuating reactivation states of neurotropic viruses. In addition, viral miRNAs and proteins can be transmitted via exosomes, which constitute novel but highly relevant mediators of cellular communication. The current study questioned the role of HSV-1-encoded and host-derived miRNAs in cerebrospinal fluid (CSF)-derived exosomes, enriched from stress-induced neuroinflammatory diseases, mainly subarachnoid hemorrhage (SAH), psychiatric disorders (AF and SZ), and various other neuroinflammatory diseases. The results were compared with CSF exosomes from control donors devoid of any neuroinflammatory pathology. Serology proved positive, but variable immunity against herpesviruses in the majority of patients, except controls. Selective ultrastructural examinations identified distinct, herpesvirus-like particles in CSF-derived lymphocytes and monocytes. The likely release of extracellular vesicles and exosomes was most frequently observed from CSF monocytes. The exosomes released were structurally similar to highly purified stem-cell-derived exosomes. Exosomal RNA was quantified for HSV-1-derived miR-H2-3p, miR-H3-3p, miR-H4-3p, miR-H4-5p, miR-H6-3p, miR-H27 and host-derived miR-21-5p, miR-146a-5p, miR-155-5p, and miR-138-5p and correlated with the oxidative stress chemokine IL-8 and the axonal damage marker neurofilament light chain (NfL). Replication-associated miR-H27 correlated with neuronal damage marker NfL, and cell-derived miR-155-5p correlated with oxidative stress marker IL-8. Elevated miR-138-5p targeting HSV-1 latency-associated ICP0 inversely correlated with lower HSV-1 antibodies in CSF. In summary, miR-H27 and miR-155-5p may constitute neuroinflammatory markers for delineating frequent and fluctuating HSV-1 replication and NfL-related axonal damage in addition to the oxidative stress cytokine IL-8 in the brain. Tentatively, HSV-1 remains a relevant pathogen conditioning autoimmune processes and a psychiatric clinical phenotype.

BACKGROUND:Obsessive-compulsive disorder (OCD) and Tourette syndrome (TS) are related mental disorders that share genetic, neurobiological, and phenomenological features. Pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS) is a neuropsychiatric autoimmune disorder with symptoms of OCD and/or TS associated with streptococcal infections. Therefore, PANDAS represents a strong link between OCD, TS, and autoimmunity. Notably, cerebrospinal fluid (CSF) analyses can provide insight into the central nervous processes in OCD, TS, and PANDAS.METHODS:A systematic literature search according to the PRISMA criteria was conducted to collect all CSF studies in patients with OCD, TS, and PANDAS. The total number of cases and the heterogeneity of the low number of studies were not sufficient for a meta-analysis to provide a high level of evidence. Nevertheless, meta-analytical statistics could be performed for glutamate, 5-hydroxyindoleacetic acid (degradation product of serotonin), homovanillic acid (degradation product of dopamine), 3-methoxy-4-hydroxyphenylglycol (major metabolite of noradrenaline), and corticotropin-releasing hormone (CRH) in OCD. A risk-of-bias assessment was implemented using the Cochrane ROBINS-E tool.RESULTS:Meta-analytical testing identified elevated glutamate levels in the CSF of OCD patients compared with healthy controls, while no significant differences were found in other neurotransmitters or CRH. Single studies detected novel neuronal antibodies in OCD patients and elevated oligoclonal bands in TS patients. For TS and PANDAS groups, there was a dearth of data. Risk of bias assessment indicated a substantial risk of bias in most of the included studies.CONCLUSIONS:This systematic review of available CSF data shows that too few studies are currently available for conclusions with good evidence. The existing data indicates glutamate alterations in OCD and possible immunological abnormalities in OCD and TS. More CSF studies avoiding sources of bias are needed.

By routine high standard CSF analysis as used in neurology (compare textbook Wildemann et al 2010, Springer) we found in more than 40% of therapy resiatnt cases of both, affective and schizophrenic spectrum disoders, some minor CSF abnormalities (CSF analyses performed in specialised neurological CSF laboratory under continued independent blinded quality control) including increased CSF albumin, increased cell numbers, increased immune globulin fractions, CSF specific oligoclonal bands and rarely specific antibodies (Bechter et al 2010). These findings where recently confirmed in large patient groups, investigated mainly the schizophrenic spectrum, in studies of various University clinics in Germany (Endres et al 2016a,b &2018, Rattay et al 2019, Oviedo-Salcedo et al 2021, Räuber et al 2021). When including additional non-routine CSF parameters, like neopterin (marker of the tryptophan pathway, increased CSF neopterin considered yet an established sign of neuroinflammtion in various neuroinflammatory neurological disorders) (Kühne et al 2013), or determining in addition activated CSF cells (Maxeiner et al 2009, Räuber et al 2021), or CSF cytokines (Maxeiner et al 2014, Scheiber et al 2022), the share of abnormal CSFs in such cohorts was further increased. Also, increased agent specific antibody indices were found in such patinet cohorts (Bechter et al 1995, Runge et al 2022). When summing up the CSF results from various laboratory methods applied (studies were often focused on limited number of methods applied at once beyond the routine), we found the percentage of any CSF pathologies in schizophrenic spectrum psychosis or severe depression may totally involve 70% to 100% of cases. Also autism cases may present with CSF abnormalities (Runge et al. 2020). However, there are also conflicting study results, but divergence may heavily depend from the methods used. Insofar, surely a rigorous control and further critical development of laboratory methods for CSF analysis is required in psychiatric research. Nevertheless, available evidence is strong yet, in that considerable subgroups of schizophrenic and affective spectrum disorders demonstrate minor and presumably definite CSF abnormalities, similar to CSF abnormalities known from well-defined neuroinflammatory disorders. Beyond, the overall variance of CSF abnormalities found in these psychiatric cohorts appears comparable, at least in type, to what was found in neurological disorders considered as “classical” neuroinflammatory disorders, although in such neurological disorders, not surprising, respective CSF abnormalities were usually stronger expressed.

•Over the last 30 years neuropsychiatry has provided important new insights into the pathogenesis /causality of psychiatric disorders.•Developed as psychoneuroimmunology the new field of Immuno-Psychiatry provides greater clinical relevance including new therapies.•The newly introduced diagnosis of autoimmune psychosis is of great therapeutic relevance and appears paradigmatic for future options of Immuno-Psychiatry.•Psychiatric research should focus more on mild and further expanded forms of neuroinflammation, such as parainflammation, because the accumulating evidence is relevant in psychiatric disorders.

Background: Hyperinflammatory, so-called M1 macrophages play a major role in chronic inflammatory diseases often linked to impaired well-being as well as fatigue and sarkopenia. Cytokines such as IL-1, IL-6 play a role in polarizing the differentiation into M1 macrophages and simultanously inhibit the differentiation of anti-inflammatory M2 macrophages. Methods: We enriched blood derived macrophages from peripheral blood and characterized their phenotypes by flow cytometry. The purinergic receptor P2 × 7 was tested by patch clamping and ion flux measurement. Microparticle and exosome release was induced by exogenous ATP-stimulation and qualified by trans-electorn microscopy as well as by nanosizer measurements. Results: M1 macrophages typically lacked surface CD163 and P2 × 7, but M2 macrophages expressed both markers. ATP stimulation induced cell death in M1 but microparticle and exosome release in M2 macrophages. Ion channel measurement confirmed the hypersensitivity of M1 and impaired ion flux by ATP. These result imply that chronic inflammatory diseases linked to highly elevated M1 type macrophages are highly sensitive to exogenous ATP, the most important danger signal in physical and psychiatric trauma. By contrast, anti-inflammatory, M2 macrophages mediate Calcium-signaling and exosome release upon ATP stimulation. MiRNA expression analysis further demonstrated that Let7b-5p discriminates between M1 and M2 macrophage polarization. Conclusion: M1 macrophage and microglia polarization may explain the detrimental response against ATP related trauma in a number of inflammatory conditions which may fuel into fatigue and sarkopenia.

Background: A number of results emphasize autoimmune characteristics in psychiatric diseases, including Affective (AF) and Schizophrenic (SZ) Spectrum Disorders. Study subjects and methods: In this study, serum/plasma samples of n=34 AF (ICD-10 F30-F33) and n=47 SZ (ICD-10 F20-F25) patients, as well as n=10 healthy controls (HDs), were tested for autoantibodies directed against cytokines and different Type I, Type II and Type III interferons using Luminex® technology. Results: Significant amounts of autoantibodies against cytokines were found. Specifically, IFN- λ (AF n=4, SZ n=4), IFN- ω (AF n=2, SZ n=3), and TNF-α (AF n=4, SZ n=1) were selectively increased. Conclusion: The results support autoimmune dysregulation as a contributing factor in psychiatric diseases. Interestingly, the detected patterns were not different between AF and SZ patients. The humoral immunity against common virus infections such as EBV, CMV, HSV-1 and HHV-6 is currently tested.

Affective (AF) and Schizophrenic (SZ) Spectrum disorders manifest with risk factors, involving inflammatory processes linked to infections and autoimmunity. This study searched for novel biomarkers in cerebrospinal fluid (CSF) and peripheral blood. A total of 29 AF and 39 SZ patients with treatment-resistant disease were included. In CSF, the chemokine IL-8 was significantly elevated in AF and SZ patients. IL-8 promotes chemotaxis by neutrophils and may originate from different tissues. S100B, a glia-derived brain damage marker, was higher in CSF from AF than SZ patients. Among the plasma-derived biomarkers, ferritin was elevated in AF and SZ. Soluble CD25, indicating Treg dysfunction, was higher in SZ than in AF patients. Interferon-γ, implying virus-specific immune activation, was positive in selective AF patients, only. Both groups showed elevated expression of immunosuppressive CD33 on monocytes, but higher amounts of CD123+ plasmacytoid dendritic cells were restricted to SZ. In conclusion, chemotactic IL-8 indicates neuronal stress and inflammation in the CSF of both groups. Novel plasma-derived biomarkers such as sCD25 and monocytic CD33 distinguish SZ from AF with an autoimmune phenotype.

Introduction The mild encephalitis hypothesis(ME) ( Bechter 2001, NPBR; updated Bechter 2013,Progr NP&BP) proposed that mild neuroinflammation triggered by infections, autoimmunity, trauma or toxicity (including from stress) might causally underly a spectrum of severe mental disorders (SMDs), especially disorders of the schizophrenic and affective spectrum. Objectives The development from ME hypothesis to the new diagnoses of Autoimmune Psychosis (AP) and a subgroup of Autoimmune Encephalitis (AE) and beyond into future research is reviewed and discussed. Methods Expert review Results The subgroup of AE with exclusive or predominant psychiatric symptoms ( compare Graus et al 2016) and all cases of AP ( Pollak et al,Lancet Psychiatry 2020) match the previous poposed ME criteria. AE and AP can now successfully be treated in majority of cases by immune modulatory treatments. These new insights challenge both, the implementation of diagnosis and treatment into clinical reality and forthcoming research on the causality underlying severe mental disorders (SMDs). CSF studies showed in 50-70% of therapy resistant cases of affective and schizophrenic spectrum disorders some abnormalities compatible with mild neuroinflammation ( Bechter et al 2010, J Psych Res), recently confirmed in large patient samples from various university hospitals in Germany ( Endres et al 2018 aso., Rattay et al 2021, aso.).Also post mortem findings are compatible with ME hypothesis in a larger subgroup of SMDs. Open questions of new clinical categorization by refined grading of mild neuroinfalmmation by improved diagnostic methods appear increasingly required, which will be discussed ( Bechter Frontiers Psychiatry 2020). Conclusions Mild neuroinflammation appears causally involved in SMD Disclosure No significant relationships.

AbstractBackgroundAutoimmune encephalitis (AE) is an important consideration during the diagnostic work-up of secondary mental disorders. Indeed, isolated psychiatric syndromes have been described in case reports of patients with underlying AE. Therefore, the authors performed a systematic literature review of published cases with AE that have predominant psychiatric/neurocognitive manifestations. The aim of this paper is to present the clinical characteristics of these patients.MethodsThe authors conducted a systematic Medline search via Ovid, looking for case reports/series of AEs with antineuronal autoantibodies (Abs) against cell surface/intracellular antigens combined with predominant psychiatric/neurocognitive syndromes. The same was done for patients with Hashimoto encephalopathy/SREAT. Only patients with signs of immunological brain involvement or tumors in their diagnostic investigations or improvement under immunomodulatory drugs were included.ResultsWe identified 145 patients with AE mimicking predominant psychiatric/neurocognitive syndromes. Of these cases, 64% were female, and the mean age among all patients was 43.9 (±22.1) years. Most of the patients had Abs against neuronal cell surface antigens (55%), most frequently against the NMDA-receptor (N= 46). Amnestic/dementia-like (39%) and schizophreniform (34%) syndromes were the most frequently reported. Cerebrospinal fluid changes were found in 78%, electroencephalography abnormalities in 61%, and magnetic resonance imaging pathologies in 51% of the patients. Immunomodulatory treatment was performed in 87% of the cases, and 94% of the patients responded to treatment.ConclusionsOur findings indicate that AEs can mimic predominant psychiatric and neurocognitive disorders, such as schizophreniform psychoses or neurodegenerative dementia, and that affected patients can be treated successfully with immunomodulatory drugs.

The discovery of anti–NMDA receptor encephalitis in 2007 provided enormous boosts to immunological research in neurology and psychiatry. Anti–NMDA receptor encephalitis is associated with severe neurological and a plethora of psychiatric symptoms, including psychotic and affective phenomena ( 1 Prüss H. Autoantibodies in neurological disease. Nat Rev Immunol. 2021; 21: 798-813 Crossref PubMed Scopus (52) Google Scholar , 2 Graus F. Titulaer M.J. Balu R. Benseler S. Bien C.G. Cellucci T. et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016; 15: 391-404 Abstract Full Text Full Text PDF PubMed Scopus (1828) Google Scholar ). To date, several more well-characterized neuronal autoantibodies have been described ( 1 Prüss H. Autoantibodies in neurological disease. Nat Rev Immunol. 2021; 21: 798-813 Crossref PubMed Scopus (52) Google Scholar , 2 Graus F. Titulaer M.J. Balu R. Benseler S. Bien C.G. Cellucci T. et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016; 15: 391-404 Abstract Full Text Full Text PDF PubMed Scopus (1828) Google Scholar ). According to current international consensus criteria, a diagnosis of possible autoimmune encephalitis (AE) should be considered in the presence of a subacute neuropsychiatric syndrome (with severe working memory deficits, an altered mental state, or psychiatric symptoms) in combination with at least one further organic sign, such as inflammatory cerebrospinal fluid (CSF) changes with an increased white blood cell (WBC) count, suspicious magnetic resonance imaging (MRI) changes, epileptic seizures, or focal neurological signs ( 2 Graus F. Titulaer M.J. Balu R. Benseler S. Bien C.G. Cellucci T. et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016; 15: 391-404 Abstract Full Text Full Text PDF PubMed Scopus (1828) Google Scholar ). SEE CORRESPONDING ARTICLE ON PAGE 563 SEE CORRESPONDING ARTICLE ON PAGE 563 SEE CORRESPONDING ARTICLE ON PAGE 563 Neuroinflammatory Biomarkers in Cerebrospinal Fluid From 106 Patients With Recent-Onset Depression Compared With 106 Individually Matched Healthy Control SubjectsBiological PsychiatryVol. 92Issue 7PreviewNeuroinflammation has been linked to depression; however, neuroinflammatory biomarkers in the cerebrospinal fluid (CSF) have not previously been thoroughly investigated in a large group of patients with recent-onset depression compared with healthy control subjects. Full-Text PDF Open Access

Introduction The mild encephalitis (ME) hypothesis of severe mental disorders, ME to be caused by infections, autoimmunity , toxicity and trauma ( Bechter 2001, updated Bechter 2013), is now emergingly supported from neuroimaging and CSF and postmorten findings. Objectives Review about the present status of ME hypothesis and autoimmune psychosis and remainig challenges to assess and categorize mild neuroinflammation. Methods expert review Results Autoimmune Encephalitis presenting with exclusive psychiatric symptoms and all cases of Autoimmune Psychosis (international consensus criteria in Pollak et al, Lancet Psychiatry, 2020) match the proposed ME criteria ( Bechter 2001 & 2013). Majority of these cases of an autoimmune type of ME are well treatable with immune modulatory treatments. It remained unclear, whether CNS antibodies are causal or contributive by shaping the observed clinical syndrome. The increasing evidence of mild neuroinflammation present in considerable subgroup of schizophrenia or psychosis spectrum cases from ongoing clinical studies, including CSF ( Bechter et al 2010, Endres et al 2018, 2020, aso.) and neuroimaging plus the observed clinical improvement with immune modulytory therapies, strongly support ME hypothesis, potentialy even in considerably larger subgroup of SMDs,supported by brain biopsy (Najjar et al ,several papers) and post mortem studies (Bogerts et al group ,Weickert et al group, several papers). Conclusions Beyond ME even more refined categories of mild neuroinflammation, including parainflammation ( proposed by Medzhitov 2008) and neuroprogression ( proposed by Berk et al 2010/11) need to be considered in further research on the possible role of mild neuroinflammation in SMDs (Bechter 2020, Frontiers Psychiatry). Disclosure No significant relationships.

Obsessive-compulsive disorder (OCD) is a highly disabling mental illness that can be divided into frequent primary and rarer organic secondary forms. Its association with secondary autoimmune triggers was introduced through the discovery of Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal infection (PANDAS) and Pediatric Acute onset Neuropsychiatric Syndrome (PANS). Autoimmune encephalitis and systemic autoimmune diseases or other autoimmune brain diseases, such as multiple sclerosis, have also been reported to sometimes present with obsessive-compulsive symptoms (OCS). Subgroups of patients with OCD show elevated proinflammatory cytokines and autoantibodies against targets that include the basal ganglia. In this conceptual review paper, the clinical manifestations, pathophysiological considerations, diagnostic investigations, and treatment approaches of immune-related secondary OCD are summarized. The novel concept of “autoimmune OCD” is proposed for a small subgroup of OCD patients, and clinical signs based on the PANDAS/PANS criteria and from recent experience with autoimmune encephalitis and autoimmune psychosis are suggested. Red flag signs for “autoimmune OCD” could include (sub)acute onset, unusual age of onset, atypical presentation of OCS with neuropsychiatric features (e.g., disproportionate cognitive deficits) or accompanying neurological symptoms (e.g., movement disorders), autonomic dysfunction, treatment resistance, associations of symptom onset with infections such as group A streptococcus, comorbid autoimmune diseases or malignancies. Clinical investigations may also reveal alterations such as increased levels of anti-basal ganglia or dopamine receptor antibodies or inflammatory changes in the basal ganglia in neuroimaging. Based on these red flag signs, the criteria for a possible, probable, and definite autoimmune OCD subtype are proposed.

Encephalitis has an estimated prevalence of ≤0.01%. Even with extensive diagnostic work-up, an infectious etiology is identified or suspected in <50% of cases, suggesting a role for etiologically unclear, noninfectious processes. Mild encephalitis runs frequently unnoticed, despite slight neuroinflammation detectable postmortem in many neuropsychiatric illnesses. A widely unexplored field in humans, though clearly documented in rodents, is genetic brain inflammation, particularly that associated with myelin abnormalities, inducing primary white matter encephalitis. We hypothesized that “autoimmune encephalitides” may result from any brain inflammation concurring with the presence of brain antigen-directed autoantibodies, e.g., against N-methyl-D-aspartate-receptor NR1 (NMDAR1-AB), which are not causal of, but may considerably shape the encephalitis phenotype. We therefore immunized young female Cnp −/− mice lacking the structural myelin protein 2′-3′-cyclic nucleotide 3′-phosphodiesterase (Cnp) with a “cocktail” of NMDAR1 peptides. Cnp −/− mice exhibit early low-grade inflammation of white matter tracts and blood–brain barrier disruption. Our novel mental-time-travel test disclosed that Cnp −/− mice are compromised in what–where–when orientation, but this episodic memory readout was not further deteriorated by NMDAR1-AB. In contrast, comparing wild-type and Cnp −/− mice without/with NMDAR1-AB regarding hippocampal learning/memory and motor balance/coordination revealed distinct stair patterns of behavioral pathology. To elucidate a potential contribution of oligodendroglial NMDAR downregulation to NMDAR1-AB effects, we generated conditional NR1 knockout mice. These mice displayed normal Morris water maze and mental-time-travel, but beam balance performance was similar to immunized Cnp −/− . Immunohistochemistry confirmed neuroinflammation/neurodegeneration in Cnp −/− mice, yet without add-on effect of NMDAR1-AB. To conclude, genetic brain inflammation may explain an encephalitic component underlying autoimmune conditions.