Bruce D. Mazer

Activation-induced deaminase (AID) drives antibody diversification through class-switch recombination and somatic hypermutation of the immunoglobulin (Ig) genes, but its off-target mutagenic activity contributes to B cell lymphoma^1,2,3,4,5. How AID selectively mutates Ig loci and a restricted set of other genes remains unknown. Transcription is required for AID activity, but most transcribed genes are not mutated^1,5,6,7, and AID occupies more loci than it mutates^7,8,9. Here we identify the super elongation complex histone readers MLLT1 and MLLT3 as determinants of selective AID activity. Combined loss of MLLT1 and MLLT3 abolishes all AID-dependent mutagenic processes, recapitulating AID deficiency. AID-mutated genomic regions in mouse and human B cells are precisely marked by high MLLT1 and MLLT3 occupancy (MLLT1/MLLT3^high). Transcriptional changes after deleting both readers are modest and cannot explain the AID activity loss. Mechanistically, MLLT1 and MLLT3 are dispensable for global AID chromatin tethering but locally enrich AID downstream from promoter regions. Both readers bind to AID and act redundantly, but MLLT1 has a dominant role in mice through its intrinsically disordered region, which promotes condensates that selectively concentrate AID. Fusing AID to MLLT1 or MLLT3 is sufficient to restore class-switch recombination and mutagenesis in Mllt1^−/−Mllt3^−/− cells. These findings reveal that local MLLT1/MLLT3^high-dependent enrichment licenses AID at a restricted subset of genomic regions by spatially confining and concentrating its activity, probably through condensate formation.

Background: Major peanut allergens are stable and resistant to denaturation under standard cooking conditions, contributing to allergenicity and low rates of developing natural tolerance in allergic individuals. We evaluated the effects of heat and pressure autoclaving on peanut proteins, IgE binding, and oral tolerability. Methods: Raw, roasted, and autoclaved peanut protein extracts were evaluated by Bradford assay, ELISA, and mass spectrometry‐proteomics to compare relative amounts of protein, specific IgE binding, and allergen fragmentation. To assess changes in clinical reactivity, we performed skin prick testing (SPT) in 41 subjects using standard and autoclaved peanut extracts. We also performed double‐blind oral food challenges (OFC) in 10 peanut‐allergic subjects with standard and autoclaved peanuts. Results: Autoclaving at 130°C, 2.4 atm, for 30 min significantly degraded allergens Ara h 1 and 2, and completely degraded Ara h 8. Mass spectrometry‐proteomics analysis of size‐filtered extracts (< 10 kDa) showed greater numbers and diversity of peptides from peanut proteins and allergens in autoclaved extracts. Autoclaving fragmented proteins into shorter peptides, against which sera from highly allergic patients exhibited a 74% reduction in IgE binding compared to raw peanuts. SPT demonstrated significant decreases in wheal diameters using autoclaved peanut extract (median [IQR] = 5 mm [2, 9]) compared to commercial extract (10 mm [6, 15]; p < 0.001). All OFC subjects tolerated the maximum cumulative autoclaved peanut dose (444 mg) versus standard peanut (median: 9 mg, range: [1, 44]). Conclusions: Autoclaving peanuts induces important chemical changes including fragmentation, leading to decreased peanut allergenicity and consequently increased tolerability. This has the potential for novel immunotherapeutic approaches with more favorable side effect profiles.

Myeloperoxidase (MPO) deficiency is a rare inherited neutrophil disorder associated with an increased risk of infections. We present a case of a male child with no underlying medical conditions who presented with a difficult-to-manage renal abscess, enterococcal urosepsis and an abnormal dihydro-rhodamine 123 test. On genetic evaluation, he was found to have a homozygous mutation in the MPO gene, leading to the diagnosis of MPO deficiency. This case highlights the clinical importance of MPO activity in the clearance of specific microorganisms. MPO deficiency should be considered in the differential diagnosis of paediatric patients with difficult-to-manage abscesses.

An early adolescent male with Shashi-Pena syndrome (SPS), characterised by a novel heterozygous pathogenic variant (p.Ser627Phefs*22) in the ASXL2 gene, presented with a spectrum of manifestations. These encompassed intellectual disability, severe scoliosis, unique facial dysmorphisms, congenital heart disease, recurrent infections and autoimmune cytopenia. Distinctively, this case revealed late-onset hypogammaglobulinaemia and autoimmune cytopenia, which had not been previously documented in SPS. To our knowledge, this is the first report clinically delineating immune system involvement in a patient with SPS, thereby accentuating the significance of evaluating for immunodeficiency in the presence of Additional Sex Combs-Like (ASXL) gene anomalies, particularly against a backdrop of recurrent infections and autoimmune presentations. The implications of this case encourage further investigation into the incidence and underlying mechanisms of immune dysregulation in ASXL-related syndromes, aiming to enrich the clinical understanding and enhance the therapeutic approaches for these complex conditions.

Objectives: The COVID-19 pandemic has highlighted the critical need for comprehensive preparedness strategies for future pandemics, particularly those caused by unknown pathogens, or Disease X. Study Design: Our systematic review examined current literature on COVID-19 risk factors, identifying significant gaps and inconsistencies in data reporting. Methods: A systematic literature search was conducted including all English language published retrospective and prospective observational studies which documented clinical outcomes of COVID-19 in adult patients, on Ovid MEDLINE(R) and Epub databases (December 2019 to March 2023). Results: The search yielded 440 articles of which 29 were included in the systematic review. We identified major risk factors for severe outcomes. However, inconsistencies in reporting comorbidities, age, disease control levels, medication use, vaccination status, and variant type, limited our analysis. In many publications, this information was not included. Additionally, variations in public attitudes, knowledge, and behaviours regarding COVID-19 vaccines further complicated resource distribution. We propose the CLARITY model to address these gaps by standardizing risk factor reporting, encompassing detailed comorbidity profiles, disease control metrics, age analyses, medication and vaccination data, and variant-specific information. Conclusions: Implementing the CLARITY model could improve preparedness and response strategies for Disease X, enabling healthcare professionals and systems to allocate resources more effectively and mitigate the impact of future pandemics. This review underscores the necessity for a coordinated global effort to enhance pandemic preparedness through improved data reporting and risk stratification. Funding: This study received financial support from Moderna Biopharma Canada Corporation. Trial Registration: PROSPERO Identifier CRD42023449647