Lymphoma Driver Mutations in the Pathogenic Evolution of an Iconic Human Autoantibody.

Pathogenic autoantibodies arise in many autoimmune diseases, but it is not understood how the cells making them evade immune checkpoints. Here, single-cell multi-omics analysis demonstrates a shared mechanism with lymphoid malignancy in the formation of public rheumatoid factor autoantibodies responsible for mixed cryoglobulinemic vasculitis. By combining single-cell DNA and RNA sequencing with serum antibody peptide sequencing and antibody synthesis, rare circulating B lymphocytes making pathogenic autoantibodies were found to comprise clonal trees accumulating mutations. Lymphoma driver mutations in genes regulating B cell proliferation and V(D)J mutation (CARD11, TNFAIP3, CCND3, ID3, BTG2, and KLHL6) were present in rogue B cells producing the pathogenic autoantibody. Antibody V(D)J mutations conferred pathogenicity by causing the antigen-bound autoantibodies to undergo phase transition to insoluble aggregates at lower temperatures. These results reveal a pre-neoplastic stage in human lymphomagenesis and a cascade of somatic mutations leading to an iconic pathogenic autoantibody.

Immunizations with diverse sarbecovirus receptor-binding domains elicit SARS-CoV-2 neutralizing antibodies against a conserved site of vulnerability.

Viral mutations are an emerging concern in reducing SARS-CoV-2 vaccination efficacy. Second-generation vaccines will need to elicit neutralizing antibodies against sites that are evolutionarily conserved across the sarbecovirus subgenus. Here, we immunized mice containing a human antibody repertoire with diverse sarbecovirus receptor-binding domains (RBDs) to identify antibodies targeting conserved sites of vulnerability. Antibodies with broad reactivity against diverse clade B RBDs targeting the conserved class 4 epitope, with recurring IGHV/IGKV pairs, were readily elicited but were non-neutralizing. However, rare class 4 antibodies binding this conserved RBD supersite showed potent neutralization of SARS-CoV-2 and all variants of concern. Structural analysis revealed that the neutralizing ability of cross-reactive antibodies was reserved only for those with an elongated CDRH3 that extends the antiparallel beta-sheet RBD core and orients the antibody light chain to obstruct ACE2-RBD interactions. These results identify a structurally defined pathway for vaccine strategies eliciting escape-resistant SARS-CoV-2 neutralizing antibodies.

The chemotactic receptor EBI2 regulates the homeostasis, localization and immunological function of splenic dendritic cells.

Spleen-resident dendritic cell (DC) populations occupy sentinel positions for the capture and presentation of blood-borne antigens. Here we found a difference in expression of the chemotactic receptor EBI2 (GPR183) on splenic DC subsets and that EBI2 regulated the positioning and homeostasis of DCs in the spleen. EBI2 and its main ligand, 7α,25-OHC, were required for the generation of the splenic CD4(+) DC subset and the localization of DCs in bridging channels. Absence of EBI2 from DCs resulted in defects in both the activation of CD4(+) T cells and the induction of antibody responses. Regulated expression of EBI2 on DC populations is therefore critical for the generation and correct positioning of splenic DCs and the initiation of immune responses.

Characterization of an HNA aptamer suggests a non-canonical G-quadruplex motif.

Nucleic acids not only form the basis of heredity, but are increasingly a source of novel nano-structures, -devices and drugs. This has spurred the development of chemically modified alternatives (xeno nucleic acids (XNAs)) comprising chemical configurations not found in nature to extend their chemical and functional scope. XNAs can be evolved into ligands (XNA aptamers) that bind their targets with high affinity and specificity. However, detailed investigations into structural and functional aspects of XNA aptamers have been limited. Here we describe a detailed structure-function analysis of LYS-S8-19, a 1',5'-anhydrohexitol nucleic acid (HNA) aptamer to hen egg-white lysozyme (HEL). Mapping of the aptamer interaction interface with its cognate HEL target antigen revealed interaction epitopes, affinities, kinetics and hot-spots of binding energy similar to protein ligands such as anti-HEL-nanobodies. Truncation analysis and molecular dynamics (MD) simulations suggest that the HNA aptamer core motif folds into a novel and not previously observed HNA tertiary structure, comprising non-canonical hT-hA-hT/hT-hT-hT triplet and hG4-quadruplex structures, consistent with its recognition by two different G4-specific antibodies.

Genetic and structural basis of the human anti-α-galactosyl antibody response.

Humans lack the capacity to produce the Galα1-3Galß1-4GlcNAc (α-gal) glycan, and produce anti-α-gal antibodies upon exposure to the carbohydrate on a diverse set of immunogens, including commensal gut bacteria, malaria parasites, cetuximab, and tick proteins. Here we use X-ray crystallographic analysis of antibodies from α-gal knockout mice and humans in complex with the glycan to reveal a common binding motif, centered on a germline-encoded tryptophan residue at Kabat position 33 (W33) of the complementarity-determining region of the variable heavy chain (CDRH1). Immunoglobulin sequencing of anti-α-gal B cells in healthy humans and tick-induced mammalian meat anaphylaxis patients revealed preferential use of heavy chain germline IGHV3-7, encoding W33, among an otherwise highly polyclonal antibody response. Antigen binding was critically dependent on the presence of the germline-encoded W33 residue for all of the analyzed antibodies; moreover, introduction of the W33 motif into naive IGHV3-23 antibody phage libraries enabled the rapid selection of α-gal binders. Our results outline structural and genetic factors that shape the human anti-α-galactosyl antibody response, and provide a framework for future therapeutics development.

Heritability of cognitive and emotion processing during functional MRI in a twin sample.

Despite compelling evidence that brain structure is heritable, the evidence for the heritability of task-evoked brain function is less robust. Findings from previous studies are inconsistent possibly reflecting small samples and methodological variations. In a large national twin sample, we systematically evaluated heritability of task-evoked brain activity derived from functional magnetic resonance imaging. We used established standardised tasks to engage brain regions involved in cognitive and emotional functions. Heritability was evaluated across a conscious and nonconscious Facial Expressions of Emotion Task (FEET), selective attention Oddball Task, N-back task of working memory maintenance, and a Go-NoGo cognitive control task in a sample of Australian adult twins (N ranged from 136 to 226 participants depending on the task and pairs). Two methods for quantifying associations of heritability and brain activity were utilised; a multivariate independent component analysis (ICA) approach and a univariate brain region-of-interest (ROI) approach. Using ICA, we observed that a significant proportion of task-evoked brain activity was heritable, with estimates ranging from 23% to 26% for activity elicited by nonconscious facial emotion stimuli, 27% to 34% for N-back working memory maintenance and sustained attention, and 32% to 33% for selective attention in the Oddball task. Using the ROI approach, we found that activity of regions specifically implicated in emotion processing and selective attention showed significant heritability for three ROIs, including estimates of 33%-34% for the left and right amygdala in the nonconscious processing of sad faces and 29% in the medial superior prefrontal cortex for the Oddball task. Although both approaches show similar levels of heritability for the Nonconscious Faces and Oddball tasks, ICA results displayed a more extensive network of heritable brain function, including additional regions beyond the ROI analysis. Furthermore, multivariate twin modelling of both ICA networks and ROI activation suggested a mix of common genetic and unique environmental factors that contribute to the associations between networks/regions. Together, the results indicate a complex relationship between genetic factors and environmental interactions that ultimately give rise to neural activation underlying cognition and emotion.

Change in Cerebrospinal Fluid Tau Microtubule Binding Region Detects Symptom Onset, Cognitive Decline, Tangles, and Atrophy in Dominantly Inherited Alzheimer's Disease.

OBJECTIVE: Identifying cerebrospinal fluid measures of the microtubule binding region of tau (MTBR-tau) species that reflect tau aggregation could provide fluid biomarkers that track Alzheimer's disease related neurofibrillary tau pathological changes. We examined the cerebrospinal fluid (CSF) MTBR-tau species in dominantly inherited Alzheimer's disease (DIAD) mutation carriers to assess the association with Alzheimer's disease (AD) biomarkers and clinical symptoms. METHODS: Cross-sectional and longitudinal CSF from 229 DIAD mutation carriers and 130 mutation non-carriers had sequential characterization of N-terminal/mid-domain phosphorylated tau (p-tau) followed by MTBR-tau species and tau positron emission tomography (tau PET), other soluble tau and amyloid biomarkers, comprehensive clinical and cognitive assessments, and brain magnetic resonance imaging of atrophy. RESULTS: CSF MTBR-tau species located within the putative "border" region and one species corresponding to the "core" region of aggregates in neurofibrillary tangles (NFTs) increased during the presymptomatic stage and decreased during the symptomatic stage. The "border" MTBR-tau species were associated with amyloid pathology and CSF p-tau; whereas the "core" MTBR-tau species were associated stronger with tau PET and CSF measures of neurodegeneration. The ratio of the border to the core species provided a continuous measure of increasing amounts that tracked clinical progression and NFTs. INTERPRETATION: Changes in CSF soluble MTBR-tau species preceded the onset of dementia, tau tangle increase, and atrophy in DIAD. The ratio of 4R-specific MTBR-tau (border) to the NFT (core) MTBR-tau species corresponds to the pathology of NFTs in DIAD and change with disease progression. The dynamics between different MTBR-tau species in the CSF may serve as a marker of tau-related disease progression and target engagement of anti-tau therapeutics. ANN NEUROL 2023;93:1158-1172.

Neighborhood social composition and refugee mental health - quasi-experimental evidence of associations from a Danish population register study.

BACKGROUND: Refugees are at an elevated risk of some mental disorders with studies highlighting the contributing role of post-migration factors. Studies of migrant groups show neighborhood social composition, such as ethnic density, to be important. This is the first longitudinal study to examine this question for refugees and uses a novel quasi-experimental design. METHODS: We followed a cohort of 44 033 refugees from being first assigned housing under the Danish dispersal policy, operating from 1986 to 1998, until 2019. This comprised, in effect, a natural experiment whereby the influence of assigned neighborhood could be determined independently of endogenous factors. We examined three aspects of neighborhood social composition: proportion of co-nationals, refugees, and first-generation migrants; and subsequent incidence of different mental disorders. RESULTS: Refugees assigned to neighborhoods with fewer co-nationals (lowest v. highest quartile) were more likely to receive a subsequent diagnosis of non-affective psychosis, incident rate ratio (IRR) 1.25 (95% confidence interval (CI) 1.06-1.48), and post-traumatic stress disorder (PTSD), IRR 1.21 (95% CI I.05-1.39). A comparable but smaller effect was observed for mood disorders but none observed for stress disorders overall. Neighborhood proportion of refugees was less clearly associated with subsequent mental disorders other than non-affective psychosis, IRR 1.24 (95% CI 1.03-1.50). We found no statistically significant associations with proportion of migrants. CONCLUSIONS: For refugees, living in a neighborhood with a lower proportion of co-nationals is related to subsequent increased risk of diagnosed mental disorders particularly non-affective psychosis and PTSD.

Interventions targeting social determinants of mental disorders and the Sustainable Development Goals: a systematic review of reviews.

Globally, mental disorders account for almost 20% of disease burden and there is growing evidence that mental disorders are socially determined. Tackling the United Nations Sustainable Development Goals (UN SDGs), which address social determinants of mental disorders, may be an effective way to reduce the global burden of mental disorders. We conducted a systematic review of reviews to examine the evidence base for interventions that map onto the UN SDGs and seek to improve mental health through targeting known social determinants of mental disorders. We included 101 reviews in the final review, covering demographic, economic, environmental events, neighborhood, and sociocultural domains. This review presents interventions with the strongest evidence base for the prevention of mental disorders and highlights synergies where addressing the UN SDGs can be beneficial for mental health.

FAS Inactivation Releases Unconventional Germinal Center B Cells that Escape Antigen Control and Drive IgE and Autoantibody Production.

The mechanistic links between genetic variation and autoantibody production in autoimmune disease remain obscure. Autoimmune lymphoproliferative syndrome (ALPS) is caused by inactivating mutations in FAS or FASL, with autoantibodies thought to arise through failure of FAS-mediated removal of self-reactive germinal center (GC) B cells. Here we show that FAS is in fact not required for this process. Instead, FAS inactivation led to accumulation of a population of unconventional GC B cells that underwent somatic hypermutation, survived despite losing antigen reactivity, and differentiated into a large population of plasma cells that included autoantibody-secreting clones. IgE(+) plasma cell numbers, in particular, increased after FAS inactivation and a major cohort of ALPS-affected patients were found to have hyper-IgE. We propose that these previously unidentified cells, designated "rogue GC B cells," are a major driver of autoantibody production and provide a mechanistic explanation for the linked production of IgE and autoantibodies in autoimmune disease.