Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) is characterized by prepubertal abrupt onset of obsessive-compulsive disorder (OCD). The sine qua non is group A streptococcus (GAS) infection, which is hypothesized to elicit an IgG-class anti-GAS antibody response that cross-reacts with antigens in the basal ganglia. However, the association between GAS antibody (GAS-IgG) levels and PANDAS has been inconsistent, and qualitative differences in GAS-IgG profiles have not been carefully evaluated in well-phenotyped cohorts. Moreover, independent studies have yet to converge on anti-neural autoantibodies that are specific to PANDAS. Here, we used phage display immunoprecipitation sequencing (PhIP-Seq) to perform ultra-deep anti-pathogen antibody repertoire profiling of serum from definitive pediatric PANDAS patients (N = 34) collected as part of a prior double-blind, placebo-controlled clinical trial of intravenous immunoglobulin (IVIg). PANDAS cases were compared to pediatric controls without a history of neuropsychiatric illness (N = 31). To assess for objective evidence of neuroglial injury, serum neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) levels were compared to healthy pediatric controls. Within PANDAS, NfL and GFAP levels were compared between pre- and post-treatment sera. To evaluate for central autoantibodies, a subset of baseline cerebrospinal fluid (CSF) samples (N = 25) was profiled by full-length human protein microarray. Though GAS reactivity by PhIP-Seq was well correlated with clinical anti-DNaseB and anti-streptolysin O titers, there were no quantitative or qualitative differences in GAS-IgG profiles between PANDAS and controls. Furthermore, NfL and GFAP levels did not differ between cases and controls. Within PANDAS, changes in NfL or GFAP levels at six weeks did not differ between placebo and IVIg groups. However, CSF autoantibody profiling by protein microarray revealed infrequent but notable candidate autoantibodies. In one patient, we identified autoantibodies against Argonaute family proteins (AGO-IgG), a marker of autoimmune sensory neuropathy. Longitudinal measurement of AGO-IgG in sera revealed that titers were unchanged after placebo, but decreased after IVIg, coinciding with symptomatic improvement, including a decrease in that patient's CY-BOCS score. Overall, these results do not support an etiologic role for GAS-IgG in PANDAS. However, some individuals diagnosed with PANDAS may harbor anti-neural autoantibodies.

There is growing evidence that immune dysfunction interacts with genetic predisposition to increase vulnerability to autism spectrum disorders (ASD). However, few studies have extensively profiled the autoantibody repertoire from children with ASD. Here, we utilized unbiased approaches to identify the antigenic targets of autoantibodies from cerebrospinal fluid (CSF) and blood collected from children with ASD compared to typically developing controls. In a cohort of children with ASD, we identified 6 of 61 participants (9.8%) harbored anti-neural autoantibodies in their CSF with distinct immunoreactivity patterns by tissue-based immunofluorescence screening on murine brain sections. In one participant, two CSF samples collected 2.3 years apart showed persistent anti-neural immunofluorescence. Phage display immunoprecipitation sequencing (PhIP-seq) and immunoprecipitation mass spectrometry (IP-MS) were utilized to screen for the antigenic targets of these CSF immunoreactivities, which revealed that each of these 6 cases have unique autoreactivities in their CSF as well as their peripheral blood. Our screening techniques identified several candidate autoantigens that have strong genetic associations with ASD, including ANK2/3, BCL11A, CHD3/8, NRXN1/2, RUNX1T1, and ZNF292. Broadly, these candidate autoantigens participate in several pathways that may contribute to ASD, including synaptic connectivity, neuronal scaffolding, and transcriptional regulation. While the autoantibody specificities remain to be validated through orthogonal assays, these data demonstrate the potential for parallel unbiased screens to identify autoantibodies with relevance to ASD.

N-methyl-d-aspartate (NMDA) receptor-mediated autoimmune encephalitis (NMDAR-AE) frequently results in persistent sensory-motor deficits, especially in children, yet the underlying mechanisms remain unclear. This study investigated the long-term effects of exposure to a patient-derived GluN1-specific mAb during a critical developmental period (from postnatal day 3 to day 12) in mice. We observed long-lasting sensory-motor deficits characteristic of NMDAR-AE, along with permanent changes in callosal axons within the primary somatosensory cortex (S1) in adulthood, including increased terminal branch complexity. This complexity was associated with paroxysmal recruitment of neurons in S1 in response to callosal stimulation. Particularly during complex motor tasks, mAb3-treated mice exhibited significantly reduced interhemispheric functional connectivity between S1 regions, consistent with pronounced sensory-motor behavioral deficits. These findings suggest that transient exposure to anti-GluN1 mAb during a critical developmental window may lead to irreversible morphological and functional changes in callosal axons, which could significantly impair sensory-motor integration and contribute to long-lasting sensory-motor deficits. Our study establishes a new model of NMDAR-AE and identifies novel cellular and network-level mechanisms underlying persistent sensory-motor deficits in this context. These insights lay the foundation for future research into molecular mechanisms and the development of targeted therapeutic interventions

Cytokines are immune signaling molecules that also function as neuromodulators. Cytokines are elevated in the peripheral blood of some individuals with mental disorders, suggesting that inflammation may contribute to their illness. Furthermore, immune therapy trials for systemic inflammatory disorders have reported improvements in anxiety and depression as secondary end points. These findings bolster the salutary potential for anti-inflammatory treatment of primary psychiatric populations. However, immunotherapeutic trials in depression and other psychiatric disorders have largely yielded inconclusive or negative results. One possibility is the reliance of clinical trial designs on cross-sectional measurements of inflammatory markers in blood. Peripheral cytokine profiles may not reflect central inflammatory states and cannot disclose dynamic relationships between compartments. Because central cytokines directly modulate neural activity, mapping their dynamic relationships between the periphery and central nervous system may improve future clinical trial designs. Therefore, we performed a systematic search for studies that measured cytokines at multiple time points in paired blood and cerebrospinal fluid samples from humans and nonhuman primates. Our narrative synthesis of these studies found that peripheral and central cytokine fluctuations are uncorrelated in humans under basal conditions. Moreover, an evoked increase in a cytokine's level peripherally may provoke a dramatic increase in a distinct cytokine centrally without eliciting a meaningful change in its own central level (cross-correlation in the absence of autocorrelation). Furthermore, physical and psychological stressors can induce compartment-specific cytokine changes and correlations. These initial observations highlight the need for a more complete map of cytokine dynamics in humans with and without mental illness.

Although B cells are implicated in multiple sclerosis (MS) pathophysiology, a predictive or diagnostic autoantibody remains elusive. Here, the Department of Defense Serum Repository (DoDSR), a cohort of over 10 million individuals, was used to generate whole-proteome autoantibody profiles of hundreds of patients with MS (PwMS) years before and subsequently after MS onset. This analysis defines a unique cluster of PwMS that share an autoantibody signature against a common motif that has similarity with many human pathogens. These patients exhibit antibody reactivity years before developing MS symptoms and have higher levels of serum neurofilament light (sNfL) compared to other PwMS. Furthermore, this profile is preserved over time, providing molecular evidence for an immunologically active prodromal period years before clinical onset. This autoantibody reactivity was validated in samples from a separate incident MS cohort in both cerebrospinal fluid (CSF) and serum, where it is highly specific for patients eventually diagnosed with MS. This signature is a starting point for further immunological characterization of this MS patient subset and may be clinically useful as an antigen-specific biomarker for high-risk patients with clinically- or radiologically-isolated neuroinflammatory syndromes.

Vitamin B12 is critical for hematopoiesis and myelination. Deficiency can cause neurologic deficits including loss of coordination and cognitive decline. However, diagnosis relies on measurement of vitamin B12 in the blood, which may not accurately reflect the concentration in the brain. Using programmable phage display, we identified an autoantibody targeting the transcobalamin receptor (CD320) in a patient with progressive tremor, ataxia, and scanning speech. Anti-CD320 impaired cellular uptake of cobalamin (B12) in vitro by depleting its target from the cell surface. Despite a normal serum concentration, B12 was nearly undetectable in her cerebrospinal fluid (CSF). Immunosuppressive treatment and high-dose systemic B12 supplementation were associated with increased B12 in the CSF and clinical improvement. Optofluidic screening enabled isolation of a patient-derived monoclonal antibody that impaired B12 transport across an in vitro model of the blood-brain barrier (BBB). Autoantibodies targeting the same epitope of CD320 were identified in seven other patients with neurologic deficits of unknown etiology, 6% of healthy controls, and 21.4% of a cohort of patients with neuropsychiatric lupus. In 132 paired serum and CSF samples, detection of anti-CD320 in the blood predicted B12 deficiency in the brain. However, these individuals did not display any hematologic signs of B12 deficiency despite systemic CD320 impairment. Using a genome-wide CRISPR screen, we found that the low-density lipoprotein receptor serves as an alternative B12 uptake pathway in hematopoietic cells. These findings dissect the tissue specificity of B12 transport and elucidate an autoimmune neurologic condition that may be amenable to immunomodulatory treatment and nutritional supplementation.

Ataxia with anti-regulator of G-protein signaling 8 autoantibodies (RGS8-Abs) is an autoimmune disease recently described in four patients. The present study aimed to identify other patients with RGS8-Abs, describe their clinical features, including the link between RGS8-related autoimmune cerebellar ataxia (ACA) and cancer. Patients with RGS8-Abs were identified retrospectively in the biological collections of the French Reference Center for Paraneoplastic Neurological Syndrome and the University of California San Francisco Center for Encephalitis and Meningitis. Clinical data were collected, and cerebrospinal fluid, serum, and tumor pathological samples were retrieved to characterize the autoantibodies and the associated malignancies. Only three patients with RGS8-Abs were identified. All of them presented with a pure cerebellar ataxia of mild to severe course, unresponsive to current immunotherapy regimens for ACA. Two patients presented with a Hodgkin lymphoma of the rare specific subtype called nodular lymphocyte-predominant Hodgkin lymphoma, with very mild extension. Autoantibodies detected in all patients enriched the same epitope on the RGS8 protein, which is an intracellular protein physiologically expressed in Purkinje cells but also ectopically expressed specifically in lymphoma cells of patients with RGS8-related ACA. The present results and those of the four cases previously described suggest that RGS8-Abs define a new paraneoplastic neurological syndrome of extreme rarity found mostly in middle-aged males that associates pure cerebellar ataxia and a particular lymphoma specifically expressing the RGS8 antigen. As in other paraneoplastic ACA with intracellular antigen, the disease course is severe, and patients tend to exhibit a poor response to immune therapy.

NMDA receptor antibody encephalitis (NMDAR-AE) is characterized by cerebrospinal fluid (CSF)-resident anti-NMDA receptor autoantibodies that cause a wide range of neurological manifestations. Although many symptoms are responsive to immunotherapy, behavioral deficits persist, especially in young patients. However, the underlying mechanisms of these long-lasting impairments are unknown. Here, we used a patient-derived GluN1-specific monoclonal antibody (mAb) to interrogate the underlying mechanisms of long-lasting sensory-motor impairments. Transient exposure to this mAb led to excess callosal projections in somatosensory cortex and resulted in permanent callosal axon alterations in mice. Importantly, these mice displayed persistent fine movement impairments which were similar to those in NMDAR-AE patients. Notably, the severity of these behavioral deficits was tightly correlated with the severity of callosal axon alterations. At the injection site, the anti-GluN1 autoantibody significantly decreased EPH receptor B2 (EPHB2) expression, a regulator of commissural projections, indicating EPHB2’s essential role in this phenotype. Our studies reveal important insights into the cellular and molecular basis for persistent sensory-motor deficits in NMDAR-AE.

A major aim of neuroscience is to identify and model the functional properties of neural cells whose dysfunction underlie neuropsychiatric illness. In this article, we propose that human-derived monoclonal autoantibodies (HD-mAbs) are well positioned to selectively target and manipulate neural subpopulations as defined by their protein expression; that is, cellular proteotypes. Recent technical advances allow for efficient cloning of autoantibodies from neuropsychiatric patients. These HD-mAbs can be introduced into animal models to gain biological and pathobiological insights about neural proteotypes of interest. Protein engineering can be used to modify, enhance, silence, or confer new functional properties to native HD-mAbs, thereby enhancing their versatility. Finally, we discuss the challenges and limitations confronting HD-mAbs as experimental research tools for neuroscience.

TANK-binding kinase 1 (TBK1) missense mutations predispose to neurologic disease including frontotemporal dementia and amyotrophic lateral sclerosis (FTD-ALS). FTD-ALS TBK1 variants have also been observed in patients with a primary schizophrenia diagnosis. TBK1 upregulates the transcription of type I interferon genes in response to bacteria including B. burgdorferi, which causes Lyme disease. Among the many functional consequences of TBK1 missense variants, a reduction in protein expression by more than 50% is considered pathogenic.

Objective Co‐occurring anti‐tripartite motif‐containing protein 9 and 67 autoantibodies (TRIM9/67‐IgG) have been reported in only a very few cases of paraneoplastic cerebellar syndrome. The value of these biomarkers and the most sensitive methods of TRIM9/67‐IgG detection are not known. Methods We performed a retrospective, multicenter study to evaluate the cerebrospinal fluid and serum of candidate TRIM9/67‐IgG cases by tissue‐based immunofluorescence, peptide phage display immunoprecipitation sequencing, overexpression cell‐based assay (CBA), and immunoblot. Cases in which TRIM9/67‐IgG was detected by at least 2 assays were considered TRIM9/67‐IgG positive. Results Among these cases (n = 13), CBA was the most sensitive (100%) and revealed that all cases had TRIM9 and TRIM67 autoantibodies. Of TRIM9/67‐IgG cases with available clinical history, a subacute cerebellar syndrome was the most common presentation (n = 7/10), followed by encephalitis (n = 3/10). Of these 10 patients, 70% had comorbid cancer (7/10), 85% of whom (n = 6/7) had confirmed metastatic disease. All evaluable cancer biopsies expressed TRIM9 protein (n = 5/5), whose expression was elevated in the cancerous regions of the tissue in 4 of 5 cases. Interpretation TRIM9/67‐IgG is a rare but likely high‐risk paraneoplastic biomarker for which CBA appears to be the most sensitive diagnostic assay. ANN NEUROL 2023;94:1086–1101

Neuroinvasive infection is the most common cause of meningoencephalitis in people living with human immunodeficiency virus (HIV), but autoimmune etiologies have been reported. We present the case of a 51-year-old man living with HIV infection with steroid-responsive meningoencephalitis whose comprehensive pathogen testing was non-diagnostic. Subsequent tissue-based immunofluorescence with acute-phase cerebrospinal fluid revealed anti-neural antibodies localizing to the axon initial segment (AIS), the node of Ranvier (NoR), and the subpial space. Phage display immunoprecipitation sequencing identified ankyrinG (AnkG) as the leading candidate autoantigen. A synthetic blocking peptide encoding the PhIP-Seq-identified AnkG epitope neutralized CSF IgG binding to the AIS and NoR, thereby confirming a monoepitopic AnkG antibody response. However, subpial immunostaining persisted, indicating the presence of additional autoantibodies. Review of archival tissue-based staining identified candidate AnkG autoantibodies in a 60-year-old woman with metastatic ovarian cancer and seizures that were subsequently validated by cell-based assay. AnkG antibodies were not detected by tissue-based assay and/or PhIP-Seq in control CSF ( N = 39), HIV CSF ( N = 79), or other suspected and confirmed neuroinflammatory CSF cases ( N = 1,236). Therefore, AnkG autoantibodies in CSF are rare but extend the catalog of AIS and NoR autoantibodies associated with neurological autoimmunity.

Antiretroviral therapy (ART) suppresses plasma and cerebrospinal fluid (CSF) HIV replication. Neurosymptomatic (NS) CSF escape is a rare exception in which CNS HIV replication occurs in the setting of neurologic impairment. The origins of NS escape are not fully understood. We performed a case-control study of asymptomatic (AS) escape and NS escape subjects with HIV-negative subjects as controls in which we investigated differential immunoreactivity to self-antigens in the CSF of NS escape by employing neuroanatomic CSF immunostaining and massively multiplexed self-antigen serology (PhIP-Seq). Additionally, we utilized pan-viral serology (VirScan) to deeply profile the CSF anti-viral antibody response and metagenomic next-generation sequencing (mNGS) for pathogen detection. We detected Epstein-Barr virus (EBV) DNA more frequently in the CSF of NS escape subjects than in AS escape subjects. Based on immunostaining and PhIP-Seq, there was evidence for increased immunoreactivity against self-antigens in NS escape CSF. Finally, VirScan revealed several immunodominant epitopes that map to the HIV envelope and gag proteins in the CSF of AS and NS escape subjects. Whether these additional inflammatory markers are byproducts of an HIV-driven process or whether they independently contribute to the neuropathogenesis of NS escape will require further study.

Patients with COVID-19 are at increased risk for developing new or recurrent psychosis (1Taquet M. Luciano S. Geddes J.R. Harrison P.J. Bidirectional associations between COVID-19 and psychiatric disorder: Retrospective cohort studies of 62 354 COVID-19 cases in the USA.Lancet Psychiatry. 2021; 8: 130-140Abstract Full Text Full Text PDF PubMed Scopus (700) Google Scholar,2Taquet M. Sillett R. Zhu L. Mendel J. Camplisson I. Dercon Q. Harrison P.J. Neurological and psychiatric risk trajectories after SARS-CoV-2 infection: An analysis of 2-year retrospective cohort studies including 1 284 437 patients.Lancet Psychiatry. 2022; 9: 815-827Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar). Viral infections—including SARS-CoV-2 (3Panariello A. Bassetti R. Radice A. Rossotti R. Puoti M. Corradin M. et al.Anti-NMDA receptor encephalitis in a psychiatric Covid-19 patient: A case report.Brain Behav Immun. 2020; 87: 179-181Crossref PubMed Scopus (90) Google Scholar, 4Monti G. Giovannini G. Marudi A. Bedin R. Melegari A. Simone A.M. et al.Anti-NMDA receptor encephalitis presenting as new onset refractory status epilepticus in COVID-19.Seizure. 2020; 81: 18-20Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, 5Alvarez Bravo G. Ramió i Torrentà L. Anti-NMDA receptor encephalitis secondary to SARS-CoV-2 infection.Neurología (Engl Ed). 2020; 35: 699-700Crossref PubMed Scopus (21) Google Scholar)—can cause psychosis in the context of autoimmune encephalitis (6Linnoila J.J. Binnicker M.J. Majed M. Klein C.J. McKeon A. CSF herpes virus and autoantibody profiles in the evaluation of encephalitis.Neurol Neuroimmunol Neuroinflamm. 2016; 3: e245Crossref PubMed Scopus (79) Google Scholar). However, some individuals with parainfectious psychosis do not meet criteria for autoimmune encephalitis, yet they respond to immunotherapy (7Gungor İ. Derin S. Tekturk P. Tüzün E. Bilgiç B. Çakır S. First-episode psychotic disorder improving after immunotherapy.Acta Neurol Belg. 2016; 116: 113-114Crossref PubMed Scopus (5) Google Scholar,8Graus 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: 391-404Abstract Full Text Full Text PDF PubMed Scopus (2055) Google Scholar). We identified anti-SARS-CoV-2 and candidate autoantibodies in the serum and cerebrospinal fluid (CSF) of a case of COVID-19–associated subacute psychosis that did not meet criteria for autoimmune or infectious encephalitis yet remitted after treatment with intravenous immunoglobulin (IVIg). A 30-year-old man without medical, psychiatric, or substance use history developed fever and malaise. The following day, he developed a delusion that the rapture was imminent. On day 2, a nasopharyngeal swab was positive for SARS-CoV-2 by real-time reverse transcription–polymerase chain reaction. He began a 14-day isolation but maintained daily contact with family. He did not have anosmia, ageusia, or respiratory symptoms, nor did he receive treatment for COVID-19. He initially suffered from hypersomnia and slept 22 hours/day. He then developed insomnia, sleeping only 3 to 4 hours/day. During this time, he paced, rambled, and believed that he was dying and communicating with deceased relatives and God. On day 22, he kicked through a door and pushed his mother, prompting an emergency department evaluation. In the emergency department, he falsely claimed to be a veteran, and worried about being experimented on with radiation. He did not have suicidal ideation, homicidal ideation, or hallucinations. Noncontrast head computed tomography was normal, and urine toxicology was negative. He was started on haloperidol 5 mg by mouth twice daily with significant improvement of his agitation and delusions. After 48 hours, he was discharged to outpatient follow-up. Outpatient magnetic resonance imaging of the brain with and without gadolinium was unremarkable. After discharge, his restlessness, insomnia, and cognitive slowing recurred, as did his fears that he would be experimented on "like a guinea pig." On day 34, he punched through a wall and was hospitalized and evaluated for autoimmune encephalitis. A detailed neurological exam was unremarkable. He had a flat affect, slowed speech, and akathisia, which resolved after decreasing haloperidol and starting benztropine and lorazepam. A 12-hour video electroencephalogram was normal. CSF studies, including a clinical autoimmune encephalitis autoantibody panel, were notable only for an elevated IgG of 4.8 mg/dL (reference 1.0–3.0 mg/dL) with a normal IgG index (see Table 1).Table 1Clinical StudiesSourceTestResult (Reference)Nasopharyngeal SwabSARS-CoV-2 RNA PCRDay 2: positiveDay 34: negativeUrine9-drug toxicology screenNegativeSerumBasic metabolic panelWithin acceptable limits:Sodium 146 mmol/L (136–144 mmol/L)Potassium 3.1 mmol/L (3.3–5.1 mmol/L)Prothrombin time11.5 seconds (9.6–12.3 seconds)International normalized ratio1.07Complete blood countDay 24 WBC: 6.9 × 1000/μL (4.0–10.0 × 1000/μL)Day 34 WBC: 5.4 × 1000/μL (4.0–10.0 × 1000/μL)MPV 11.6 fL (6.0–11.0 fL)Thyroid-stimulating hormone2.520 μIU/mL (0.270–4.200 μIU/mL)D-dimer1.89 mg/L (≤0.50 mg/L)Liver enzymesAST 156 U/L (<35 U/L)ALT 372 U/L (<59 U/L)C-reactive protein1.7 mg/L (<1.0 mg/L)Ferritin1124 ng/mL (30–400 mg/mL)Ammonia27 μmol/L (11–35 μmol/L)Albumin4.2 g/dL (3.6–4.9 g/dL)IgG1230 mg/dL (700–1600 mg/dL)CSFCell count0 nucleated cellsProtein41.2 mg/dL (15–45 mg/dL)Glucose60 mg/dL (40–70 mg/dL)CultureNo growthOligoclonal bandingNoneAlbumin25.8 mg/dL (10–30 mg/dL)IgG4.8 mg/dL (1.0–3.0 mg/dL)IgG index0.67 (<0.7)Autoimmune encephalopathy panelNegative for AMPA Ab, amphiphysin Ab, anti-glial nuclear Ab, neuronal nuclear Ab (types 1, 2, and 3), CASPR2, CRMP–5, DPPX, GABA-B receptor, GAD65, GFAP, IgLON5, LGI1-IgG, MGLUR1, NIF, NMDA receptor, Purkinje cell cytoplasmic Ab (types Tr, 1, and 2)ImagingCT head without contrastNo acute intracranial findingsMRI brain with contrastNo acute intracranial abnormality or definitive structural abnormality identified; specifically, no imaging findings suggestive of encephalitis or acute demyelinationElectroencephalographyNormal prolonged (>12 hours) awake and asleep inpatient video EEGAb, antibody; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CSF, cerebrospinal fluid; CT, computed tomography; EEG, electroencephalogram; MPV, mean platelet volume; MRI, magnetic resonance imaging; PCR, polymerase chain reaction. Open table in a new tab Ab, antibody; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CSF, cerebrospinal fluid; CT, computed tomography; EEG, electroencephalogram; MPV, mean platelet volume; MRI, magnetic resonance imaging; PCR, polymerase chain reaction. Lacking focal neurologic symptoms, seizures, magnetic resonance imaging abnormalities, or CSF pleocytosis, his presentation did not meet consensus criteria for autoimmune encephalitis (8Graus 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: 391-404Abstract Full Text Full Text PDF PubMed Scopus (2055) Google Scholar). Nevertheless, his subacute psychosis, cognitive slowing, and recent SARS-CoV-2 infection raised concern for autoimmune-mediated psychosis. Therefore, starting on day 35, he received a total of 2 g/kg of IVIg over 3 days. His cognitive slowing and psychotic symptoms remitted after the first day of treatment. His sleep cycle normalized, and he was discharged without scheduled antipsychotics. He returned to work immediately after discharge and remained symptom-free 3 months later. Because his robust response to IVIg suggested an underlying neuroinflammatory process, we tested for anti-SARS-CoV-2 and anti-neural autoantibodies. Using a Luminex SARS-CoV-2 antigen panel (9Zamecnik C.R. Rajan J.V. Yamauchi K.A. Mann S.A. Loudermilk R.P. Sowa G.M. et al.ReScan, a multiplex diagnostic pipeline, pans human sera for SARS-CoV-2 antigens.Cell Rep Med. 2020; 1100123Google Scholar,10Sabatino Jr., J.J. Mittl K. Rowles W.M. McPolin K. Rajan J.V. Laurie M.T. et al.Multiple sclerosis therapies differentially affect SARS-CoV-2 vaccine-induced antibody and T cell immunity and function.JCI Insight. 2022; 7e156978Crossref PubMed Scopus (29) Google Scholar), we detected anti-spike, anti-receptor binding domain, and anti-nucleocapsid protein antibodies in his serum and CSF (Figure 1A) (9Zamecnik C.R. Rajan J.V. Yamauchi K.A. Mann S.A. Loudermilk R.P. Sowa G.M. et al.ReScan, a multiplex diagnostic pipeline, pans human sera for SARS-CoV-2 antigens.Cell Rep Med. 2020; 1100123Google Scholar,10Sabatino Jr., J.J. Mittl K. Rowles W.M. McPolin K. Rajan J.V. Laurie M.T. et al.Multiple sclerosis therapies differentially affect SARS-CoV-2 vaccine-induced antibody and T cell immunity and function.JCI Insight. 2022; 7e156978Crossref PubMed Scopus (29) Google Scholar). We then screened for anti-neural autoantibodies using anatomic mouse brain tissue staining (11Ricken G. Schwaiger C. De Simoni D. Pichler V. Lang J. Glatter S. et al.Detection methods for autoantibodies in suspected autoimmune encephalitis.Front Neurol. 2018; 9: 841Crossref PubMed Scopus (45) Google Scholar), a validated and standard method performed by incubating rodent brain sections with CSF. At a 1:4 dilution, his CSF IgG produced prominent punctate immunostaining of the accessory olfactory bulb, cytoplasmic and neuropil staining in upper layers of the cortex and thalamus, and cytoplasmic staining of hilar and granule neurons in the hippocampus (Figure 1B). We next used whole human peptidome phage display immunoprecipitation sequencing (PhIP-Seq) (12O'Donovan B. Mandel-Brehm C. Vazquez S.E. Liu J. Parent A.V. Anderson M.S. et al.High-resolution epitope mapping of anti-Hu and anti-Yo autoimmunity by programmable phage display.Brain Commun. 2020; 2 (fcaa059)PubMed Google Scholar) to screen for candidate autoantigens. Similar to COVID-19 patients with neurological symptoms (13Song E. Bartley C.M. Chow R.D. Ngo T.T. Jiang R. Zamecnik C.R. et al.Divergent and self-reactive immune responses in the CNS of COVID-19 patients with neurological symptoms.Cell Rep Med. 2021; 2100288Google Scholar), the patient's CSF enriched a diverse set of candidate autoantigens (n = 27), including multiple peptides mapping to MCTP1, a protein implicated in neurotransmitter release (Figure 1C) (14Genç Ö. Dickman D.K. Ma W. Tong A. Fetter R.D. Davis G.W. MCTP is an ER-resident calcium sensor that stabilizes synaptic transmission and homeostatic plasticity.Elife. 2017; 6e22904Crossref PubMed Scopus (25) Google Scholar,15Téllez-Arreola J.L. Silva M. Martínez-Torres A. MCTP-1 modulates neurotransmitter release in C. elegans.Mol Cell Neurosci. 2020; 107103528Crossref PubMed Scopus (2) Google Scholar). The top PhIP-Seq–enriched peptide is encoded by 11 MCTP1 isoforms—but not the canonical isoform MCTP1L (National Center for Biotechnology Information RefSeq [https://www.ncbi.nlm.nih.gov/refseq/]). Surprisingly, MCTP1 autoantibodies did not validate by overexpression cell-based assay or immunoprecipitation using a representative isoform (isoform 3). However, an expanded PhIP-Seq comparison revealed that the patient enriched MCTP1 significantly more than a combined 3408 healthy CSF and sera and 808 negative control samples (Figure 1D). Finally, we evaluated whether PhIP-Seq candidate antigen enrichment was due to sequence similarity with SARS-CoV-2. We mapped our patient's anti-SARS-CoV-2 target epitopes by SARS-CoV-1/2 phage display (9Zamecnik C.R. Rajan J.V. Yamauchi K.A. Mann S.A. Loudermilk R.P. Sowa G.M. et al.ReScan, a multiplex diagnostic pipeline, pans human sera for SARS-CoV-2 antigens.Cell Rep Med. 2020; 1100123Google Scholar) and compared viral epitopes with PhIP-Seq–identified candidate autoantigens using National Center for Biotechnology Information BlastP (https://blast.ncbi.nlm.nih.gov/Blast.cgi). Among the top 10 CSF- and serum-enriched SARS-CoV-2 peptides, we identified 15 unique peptides, none of which aligned to PhIP-Seq candidate autoantigens (Figure 1E). In this correspondence, we have profiled the antibody response of a COVID-19 patient with antipsychotic-refractory subacute psychosis whose symptoms rapidly and completely remitted after treatment with IVIg. We identified and mapped the epitope specificity of anti-SARS-CoV-2 antibodies in the patient's CSF and characterized autoantibodies by rodent brain tissue staining and PhIP-Seq. Although anti-neural autoantibodies have been described in neurologically impaired COVID-19 patients (16Song E. Bartley C.M. Chow R.D. Ngo T. Jiang R. Zamecnik C.R. et al.Exploratory neuroimmune profiling identifies CNS-specific alterations in COVID-19 patients with neurological involvement.bioRxiv. 2020; https://doi.org/10.1101/2020.2009.2011.293464Crossref Google Scholar, 17Franke C. Ferse C. Kreye J. Momsen Reincke S. Sanchez-Sendin E. Rocco A. et al.High frequency of cerebrospinal fluid autoantibodies in COVID-19 patients with neurological symptoms.Brain Behav Immun. 2021; 93: 415-419Crossref PubMed Scopus (123) Google Scholar, 18Severance E.G. Dickerson F.B. Viscidi R.P. Bossis I. Stallings C.R. Origoni A.E. et al.Coronavirus immunoreactivity in individuals with a recent onset of psychotic symptoms.Schizophr Bull. 2011; 37: 101-107Crossref PubMed Scopus (124) Google Scholar), autoantibody screening is rarely performed in COVID-19–associated psychosis (19Parra A. Juanes A. Losada C.P. Álvarez-Sesmero S. Santana V.D. Martí I. et al.Psychotic symptoms in COVID-19 patients. A retrospective descriptive study.Psychiatry Res. 2020; 291113254Crossref PubMed Scopus (99) Google Scholar, 20Smith C.M. Komisar J.R. Mourad A. Kincaid B.R. COVID-19-associated brief psychotic disorder.BMJ Case Rep. 2020; 13e236940Crossref Scopus (74) Google Scholar, 21Ferrando S.J. Klepacz L. Lynch S. Tavakkoli M. Dornbush R. 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Runge K. et al.Spectrum of novel anti-central nervous system autoantibodies in the cerebrospinal fluid of 119 patients with schizophreniform and affective disorders.Biol Psychiatry. 2022; 92: 261-274Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar,30Ehrenreich H. Gastaldi V.D. Wilke J.B.H. Quo vaditis anti-brain autoantibodies: Causes, consequences, or epiphenomena?.Biol Psychiatry. 2022; 92: 254-255Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar). By PhIP-Seq, our patient's CSF and serum significantly enriched MCTP1. MCTP1 enrichment was not explained by sequence similarity with SARS-CoV-2 proteins, suggesting a distinct antibody response, rather than molecular mimicry. Although anti-MCTP1 autoantibodies did not validate by cell-based assay or immunoprecipitation, neither method is dispositive (11Ricken G. Schwaiger C. De Simoni D. Pichler V. Lang J. 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Cellucci T. et al.A clinical approach to diagnosis of autoimmune encephalitis.Lancet Neurol. 2016; 15: 391-404Abstract Full Text Full Text PDF PubMed Scopus (2055) Google Scholar). To identify individuals with potentially immune-responsive acute psychosis without neurological impairment, Pollak et al. (32Pollak T.A. Lennox B.R. Müller S. Benros M.E. Prüss H. Tebartz van Elst L. et al.Autoimmune psychosis: An international consensus on an approach to the diagnosis and management of psychosis of suspected autoimmune origin.Lancet Psychiatry. 2020; 7: 93-108Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar) proposed criteria for autoimmune psychosis. While "possible" autoimmune psychosis relies solely on clinical factors, "probable" and "definite" autoimmune psychosis require abnormal imaging or laboratory studies. Our patient's subacute psychosis and cognitive dysfunction qualified him for possible autoimmune psychosis. However, he had several red flags for autoimmune psychosis: infectious prodrome, rapid progression, and insufficient response to antipsychotics (32Pollak T.A. Lennox B.R. Müller S. Benros M.E. Prüss H. Tebartz van Elst L. et al.Autoimmune psychosis: An international consensus on an approach to the diagnosis and management of psychosis of suspected autoimmune origin.Lancet Psychiatry. 2020; 7: 93-108Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar). Moreover, his mood dysregulation, cognitive slowing, and hypersomnia were evocative of the mixed symptomatology more typical of autoimmune encephalitis (33Muñoz-Lopetegi A. Graus F. Dalmau J. Santamaria J. Sleep disorders in autoimmune encephalitis.Lancet Neurol. 2020; 19: 1010-1022Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar,34Al-Diwani A. Handel A. Townsend L. Pollak T. Leite M.I. Harrison P.J. et al.The psychopathology of NMDAR-antibody encephalitis in adults: A systematic review and phenotypic analysis of individual patient data.Lancet Psychiatry. 2019; 6: 235-246Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar). Given his overall clinical picture, we administered IVIg with apparent clinical response. Only by relying on ancillary criteria were we able to justify immunotherapy for our patient, suggesting that re-evaluating the criteria for autoimmune psychosis may improve its sensitivity (35Franke C. Prüss H. Letter to the Editor: Comment on Mulder J et al. (2021) Indirect Immunofluorescence for Detecting Anti-Neuronal Autoimmunity in CSF after COVID-19 - Possibilities and pitfalls.Brain Behav Immun. 2021; 94: 473-474Crossref PubMed Scopus (3) Google Scholar). Even so, this case should be interpreted with caution. Psychotic disorders are protean by nature, mixed symptomatology does occur, and most psychotic presentations are unlikely to be immune mediated. However, given the scale of the COVID-19 pandemic, psychiatric practitioners should consider autoimmune psychosis in patients with COVID-19–associated psychosis. This work was supported by National Institute of Mental Health Grant Nos. R01MH122471 (to SJP, MRW), R01MH125396 (to SSS), K23MH118999 (to SFF), and R21MH118109 (to SS); National Institute of Neurological Disorders and Stroke Grant No. R01NS118995-14S (to SJP); the Brain Research Foundation (to SJP); the National Intitute of Allergy and Infectious Diseases Grant No. R01AI157488 (to SFF); the Hanna H. Gray Fellowship of the Howard Hughes Medical Institute (to CMB); the President's Postdoctoral Fellowship Program of the University of California (to CMB); the John A. Watson Scholar Program of the University of California, San Francisco (to CMB); and the Deeda Blair Research Initiative for Disorders of the Brain of the Foundation for the National Institutes of Health (to CMB). Sequencing was performed at the University of California, San Francisco (UCSF) Center for Advanced Technology, supported by UCSF Sandler Program for Breakthrough Biomedical Research, Research Resource Program Institutional Matching Instrumentation Awards, and National Institutes of Health (NIH Office of the Director) Grant Nos. 1S10OD028511-01. We thank Trung Huynh and Anne Wapniarski for laboratory assistance. We thank Andrew Kung and Joseph Derisi for use of the PhIP-Seq database. During the course of treatment, we obtained surrogate consent to use surplus cerebrospinal fluid for research. After regaining capacity, the patient provided written informed consent for this case report. This work has not previously been published in any form. MRW received a research grant from Roche/Genentech. All other authors report no biomedical financial interests or potential conflicts of interest.

Background Antiretroviral therapy (ART) suppresses plasma and cerebrospinal fluid (CSF) HIV replication with occasional asymptomatic episodes of detectable HIV RNA known as asymptomatic (AS) escape. Neurosymptomatic (NS) CSF escape is a rare exception in which CNS HIV replication occurs in the setting of neurologic impairment. The origins of NS escape are not fully understood.Methods Using a large cohort of PLWH (n=111), including elite controllers (n=4), viral controllers (n=4), ART untreated subjects (n=18), HIV-associated dementia (n=4), ART suppressed (n=16), AS escape (n=19), NS escape (n=35), secondary escape (n=5) subjects, and HIV-negative controls (n=6), we investigated immunoreactivity to self-antigens in the CSF of NS escape by employing neuroanatomic CSF immunostaining and massively multiplexed self-antigen serology (PhIP-Seq). Additionally, we utilized pan-viral serology (VirScan) to deeply profile the CSF anti-viral antibody response and metagenomic next-generation sequencing (mNGS) for pathogen detection.Results We detected Epstein-Barr virus (EBV) DNA more frequently in the CSF of NS escape subjects than in AS escape controls. Based on immunostaining and PhIP-Seq, there was evidence for increased immunoreactivity against self-antigens in NS escape CSF. Finally, VirScan revealed several immunodominant epitopes that map to the HIV env and gag proteins in the CSF of PLWH.Discussion We deployed agnostic tools to study whether there was evidence for a neuroinvasive co-infection and/or autoimmunity in HIV escape syndromes. We more frequently detected EBV DNA and immunoreactivity to self-antigens in NS escape. Whether these additional inflammatory markers are byproducts of an HIV-driven inflammatory process or whether they independently contribute to the neuropathogenesis of NS escape will require further study.### Competing Interest StatementDr. Joseph DeRisi has received grants from the Chan Zuckerberg Biohub, personal fees from the Public Health Company and from Allen & Company; Dr. Michael Wilson has received unrelated grants from Roche/Genentech and Novartis as well as speaking honoraria from Novartis, Takeda, WebMD and Genentech. Drs. Wilson and DeRisi serve as advisors for Delve Bio. Dr. Christopher Bartley has received an honorarium for speaking to the Commonwealth Club and owns shares in NowRx Inc. M. Gisslen has received research grants from Gilead Sciences and Janssen-Cilag and honoraria as speaker, DSMB committee member and/or scientific advisor from Amgen, AstraZeneca, Biogen, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline/ViiV, Janssen-Cilag, MSD, Novocure, Novo Nordic, Pfizer and Sanofi, all unrelated to the content of this manuscript.### Funding StatementSupported by grant from NIH/NINDS: R01 R01NS094067 and NS 3R01NS094067-05S1 to Dr. Richard W Price and colleagues, K08NS107619 (MRW) and Westridge Foundation (MRW and IAH). CM Bartley was supported by a Hanna H. Gray Fellowship, Howard Hughes Medical Institute, a President Postdoctoral Fellowship Program, the University of California, and the John A. Watson Scholar Program, UCSF.### Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:The samples used in this study were collected between 2000 and 2018 in the context of HIV research studies at two medical centers: Sahlgrenska University Hospital, Gothenburg, Sweden and Zuckerberg San Francisco General Hospital, University of California San Francisco, San Francisco, CA, USA. Samples were obtained in the context of established research approved by the local institutional review boards of these institutions. All participants provided informed consent and, if there was a question regarding their capacity to provide fully consent, consent was also obtained from individuals with power of attorney.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.YesI 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).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAnonymized data not published within this article will be made available by request from any qualified investigator.