Michael R. Wilson

Schizophrenia spectrum disorders have substantial genetic liability, but their stable incidence and clinical heterogeneity leave open contributions from non-genetic mechanisms. Though autoimmune encephalitis demonstrates that anti-neural antibodies can cause psychosis, encephalitis antibodies are uncommon in schizophrenia. Here we show that multi-platform autoantigen profiling of cerebrospinal fluid and plasma detects rare, anti-neural autoantibodies in schizophrenia spectrum disorders. By antibody profiling the cerebrospinal fluid of 32 schizophrenia spectrum participants and 32 neuropsychiatrically unaffected controls by brain tissue immunostaining, immunoprecipitation–mass spectrometry, phage display immunoprecipitation sequencing, and plasma by complementary protein microarrays, we identify three autoantibodies, including to alpha-crystallin B. The anti-alpha-crystallin B antibody preferentially recognizes phosphorylated serine-45 and is absent from the cerebrospinal fluid of individuals with untreated multiple sclerosis, a disease with frequent antibodies to unphosphorylated alpha-crystallin B. These findings do not define autoimmune psychosis as a new disease but support broader autoantibody searches in psychotic disorders.

Preterm birth is associated with breakdown of maternal–fetal tolerance and remains the leading cause of global mortality in young children. However, the role of self-reactive antibodies has been limited to a handful of pathogenic allo- and autoantibodies linked to pregnancy complications. Here we identify a shared autoreactive signature of pregnancy in pregnant sera ( n = 2,719) relative to never-pregnant controls ( n = 130), using proteome-wide autoantibody profiling. Across eight human pregnancy cohorts, we define autoreactivities associated with preterm birth by comparing preterm ( n = 688) and term ( n = 1,505) pregnancies. Within the signature, antibodies to IL1 receptor antagonist (IL1RA) induce resorption, inflammation and vascular malperfusion in pregnant mice. IL1RA localizes to placental endothelial adherens junctions, suggesting a role in vascular integrity. These findings identify a term pregnancy humoral immune program and shared changes preceding preterm delivery, including anti-IL1RA, which may have direct pathogenic consequences.

Mutations in GRN and C9orf72 are common causes of frontotemporal dementia (FTD). While it is well-recognized that GRN or C9orf72 mutations also increase the risk of autoimmune diseases, the intersection of innate and adaptive immunity, neuroinflammation, and neurodegeneration in FTD remains unclear. Here we show that concurrent loss of Grn and C9orf72 breaks immune tolerance by activating the pattern recognition receptor, TLR7, leading to clonal expansion of age-associated B cells and activated B cells. Grn-/-;C9orf72-/- B cells exhibited heightened responses upon TLR7 activation and produced autoantibodies that target the axon guidance receptor Robo3 to promote astroglial pathology. Interestingly, immunization with Robo3 extracellular domain in young Grn-/-;C9orf72-/- mice accelerated astrogliosis. Conversely, TLR7 antagonist M5049 treatment rescued B cell defects, reduced anti-Robo3 autoantibodies, and mitigated astrogliosis and synaptic loss in Grn-/-;C9orf72-/- mice. Together, these results offer critical insights into how TLR7-mediated autoimmune dysfunction targets Robo3 to drive neuroinflammation and neurodegeneration in FTD.

Systemic lupus erythematosus (SLE) is characterized by diverse autoantibodies, yet established biomarkers capture only a fraction of autoreactivity. We profiled 1,268 plasma samples from 695 patients with SLE and 301 healthy controls using phage immunoprecipitation sequencing (PhIP-seq). Machine learning identified a reproducible autoreactivity signature that discriminated SLE from controls across two validation cohorts. SLE autoreactivities were enriched for RNA-binding proteins, while targets containing Basic Acidic Dipeptide repeat domains were associated with high disease activity. A YTHDF2-derived peptide was the most prevalent shared autoreactivity, occurring in ∼25% of patients and exhibiting sequence similarity to Epstein-Barr virus (EBV) lytic switch protein BZLF1. Competition assays demonstrated higher-affinity binding to the viral peptide, consistent with EBV-associated molecular mimicry. Orthogonal validation using a 10-peptide Luminex panel strongly discriminated SLE from healthy controls. These findings expand the SLE autoantibody landscape, identify disease activity associated autoreactivities and insight linking EBV-driven immunity to epitope-specific autoimmunity in lupus.

BACKGROUND. Neurological Long COVID (n-LC) includes persistent cognitive and autonomic symptoms after SARS-CoV-2 infection. Prior studies of post-COVID conditions have described diverse humoral autoreactivity. It remains unclear whether n-LC is associated with a consistent CNS-directed humoral signature. METHODS. We performed a cross-cohort case-control analysis to detect autoantibodies in cerebrospinal fluid (CSF) and serum from n-LC participants. In the Yale COVID Mind Study cohort, CSF from n-LC participants and pre-pandemic and recovered controls was assessed using mouse brain immunofluorescence and proteome-wide phage immunoprecipitation sequencing (PhIP-Seq), followed by supervised modeling and orthogonal validation assays. In the Epidemiology, Immunology, and Clinical Characteristics of Emerging Infectious Diseases with Pandemic Potential (IDCRP EPICC) cohort, post-COVID sera collected prior to iPhone- or iPad-based cognitive screening were profiled by PhIP-Seq and compared between participants with and without cognitive impairment. RESULTS. CSF immunoreactivity on mouse brain tissue was observed in both n-LC and controls, with similar overall frequencies. PhIP-Seq identified sparse, patient-specific peptide reactivities to nuclear and neuronal proteins in CSF and serum. Supervised models provided limited discrimination between cases and controls. Candidate autoantigens had limited disease specificity on orthogonal testing. EPICC serum autoantibody profiling similarly failed to distinguish individuals with and without cognitive impairment. CONCLUSIONS. Across cohorts and compartments, n-LC was not associated with a shared CNS-directed autoantibody signature using the approaches employed. Observed heterogeneity may reflect biological diversity, although limited statistical power to detect a shared response cannot be excluded. FUNDING. Grants HU00012020067, HU00012120103, HU00011920111, R01NS125693, R01MH125737, and R01AI157488 from the Defense Health Program and NIH.

Treatment targeting progressive multiple sclerosis (MS) have limited efficacy, as central nervous system (CNS) resident B cells are resistant to peripheral B cell depletion by antiCD20 monoclonal antibodies. CD19 targeted chimeric antigen receptor (CAR)T cells offer the promise to deplete B cells more extensively in both the peripheral and CNS compartments. Two adult participants with treatment-refractory progressive MS were treated with 0.33e8 autologous anti CD19 CAR T cells (mivocabtagene autoleucel, miv-cel) intravenously after a preconditioning regimen. Participant 1 (50's year old female, EDSS 6) had no cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS). Participant 2 (60's year old female, EDSS 4.5) had grade 1 CRS and no ICANS. Expansion of CAR T cells in the cerebrospinal fluid (CSF) at Day 14 was noted in both participants, remarkably with sustained disappearance of disease-associated oligoclonal band (OCB) or normalization of IgG index despite peripheral naive B cell reconstitution. MRI and clinical outcomes showed sustained stability at Week 48. Serologic studies showed a decline in anti-Epstein Barr Virus seropositivity. Single cell myeloid and proteomic signatures showed a decline in proinflammatory profiles. In the 2 subjects with progressive MS reported here, low dose anti CD19 CAR T cell therapy (miv-cel) was safe, penetrated the CSF effectively, reduced intrathecal humoral activity, modulated peripheral immune tone, and appeared to stabilize EDSS scores. Overall, these results support the continued investigation of CAR T cell therapy in MS.

Coccidioidomycosis is a fungal infection of rising public health concern, with coccidioidal meningitis (CM) representing its most devastating manifestation. Diagnosis of CM remains challenging due to the limited sensitivity and technical demands of conventional cerebrospinal fluid (CSF) serology testing. To comprehensively characterize the humoral immune response across the full spectrum of coccidioidal disease, we designed and deployed a proteome-wide Coccidioides phage immunoprecipitation sequencing (PhIP-Seq) library tiling both C. immitis and C. posadasii proteomes. We profiled antibody reactivity in sera from 323 participants spanning six clinically defined disease severity categories, as well as CSF and matched serum from participants with confirmed CM (n=108) and Coccidioides -negative other neurologic disease (OND) controls (n=163). Serum profiling revealed a potential narrowing of the antigenic repertoire as disease severity increased, with subclinical participants mounting the broadest response (55 peptides from 55 proteins) compared to 3-7 peptides in symptomatic categories. Two proteins, spherule outer wall glycoprotein (SOWgp) and a previously uncharacterized Proline-rich Immunodominant Antigen (PIA1), emerged as immunodominant across disease categories. Enriched antigens were disproportionately proline-rich and repetitive, a structural feature associated with immunodominance in other pathogens. CSF profiling revealed a compartment-specific antibody signature in CM, with 94% of CSF-enriched seroreactive peptides absent from matched sera. To orthogonally validate these findings, we developed a five-antigen Luminex assay using SOWgp- and PIA1-derived peptides, achieving 100% sensitivity and 100% specificity in both a discovery cohort (CM n=20, OND n=20) and an independent, blinded validation cohort (34 CM and 36 OND CSF samples. These findings expand the repertoire of Coccidioides serological responses associated with disease severity and demonstrate that proteome-wide antibody discovery can be translated into a targeted, high-performance diagnostic platform.