Microbial colonization influences early B-lineage development in the gut lamina propria

The RAG1/RAG2 endonuclease ("RAG") initiates the V(D)J recombination reaction that assembles Ig heavy (IgH) and light (IgL) chain variable region exons from germline gene segments to generate primary antibody repertoires1. IgH V(D)J assembly occurs in progenitor (pro-) B cells followed by that of IgL in precursor (pre-) B cells. Expression of IgH μ and IgL (Igκ or Igλ) chains generates IgM, which is expressed on immature B cells as the B cell antigen-binding receptor ("BCR"). Rag expression can continue in immature B cells2, allowing continued Igκ V(D)J recombination that replaces the initial VκJκ exon with one that generates a new specificity3–5. This “receptor editing” process, which also can lead to Igλ V(D)J recombination and expression3,6,7, provides a mechanism whereby antigen-encounter at the Rag-expressing immature B cell stage helps shape pre-immune BCR repertoires. As the major site of post-natal B cell development, the bone marrow is the principal location of primary Ig repertoire diversification in mice. Here, we report that early B cell development also occurs within the mouse intestinal lamina propria (LP), where the associated V(D)J recombination/receptor editing processes modulate primary LP Ig repertoires. At weanling age in normally housed mice, the LP contains a population of Rag-expressing B lineage cells that harbor intermediates indicative of ongoing V(D)J recombination and which contain cells with pro-B, pre-B, and editing phenotypes. Consistent with LP-specific receptor editing, Rag-expressing LP B-lineage cells have similar VH repertoires, but significantly different Vκ repertoires, compared to those of Rag2-expressing BM counterparts. Moreover, colonization of germ-free mice leads to an increased ratio of Igλ-expressing versus Igκ-expressing B cells specifically in the LP. We conclude that B cell development occurs in the intestinal mucosa, where it is regulated by extra-cellular signals from commensal microbes that influence gut Ig repertoires

Immature B cells preferentially switch to IgE with increased direct Sμ to Sε recombination

Immunoglobulin heavy chain (IgH) class-switch recombination (CSR) replaces initially expressed Cμ (IgM) constant regions (C(H)) exons with downstream C(H) exons. Stimulation of B cells with anti-CD40 plus interleukin-4 induces CSR from Cμ to Cγ1 (IgG1) and Cε (IgE), the latter of which contributes to the pathogenesis of atopic diseases. Although Cε CSR can occur directly from Cμ, most mature peripheral B cells undergo CSR to Cε indirectly, namely from Cμ to Cγ1, and subsequently to Cε. Physiological mechanisms that influence CSR to Cγ1 versus Cε are incompletely understood. In this study, we report a role for B cell developmental maturity in IgE CSR. Based in part on a novel flow cytometric IgE CSR assay, we show that immature B cells preferentially switch to IgE versus IgG1 through a mechanism involving increased direct CSR from Cμ to Cε. Our findings suggest that IgE dysregulation in certain immunodeficiencies may be related to impaired B cell maturation

Chimeric Antigen Receptor T Cells for Multiple Myeloma: The Journey So Far-And the Road Ahead

ABSTRACT: Despite improvements in effective therapy, multiple myeloma remains incurable, and virtually all patients will face relapsed disease at some point after diagnosis. The prognosis for relapsed myeloma after developing resistance to anti-CD38 monoclonal antibodies, proteasome inhibitors, immunomodulatory agents, and autologous stem cell transplantation has been poor; however, the development of immune effector cell therapy with chimeric antigen receptor (CAR) T cells may dramatically improve the outlook for patients, although none of these therapies are approved for MM to date. Herein, we review the development and history of CAR T-cell therapy for multiple myeloma, mechanisms of resistance, and strategies to improve outcomes with CAR T therapy

A Case Report: Point-of-care Ultrasound in the Diagnosis of Post-Myocardial Infarction Ventricular Septal Rupture

Introduction: Ventricular septal rupture (VSR) is a rare complication of ST-elevation myocardial infarction (STEMI), typically discovered post-revascularization.Case report: We present the first case of VSR detected on point-of-care ultrasound (POCUS) in the emergency department immediately prior to emergent angiography, with management positively affected by this discovery. The VSR was quickly confirmed via right heart catheterization. Subsequently, hemodynamic stability was achieved using an intra-aortic balloon pump. A delayed surgical VSR repair, with concomitant coronary artery bypass grafting, was implemented for definitive management.Conclusion: This case highlights the utility of POCUS in a STEMI patient with a suspected mechanical complication

Identification and Prediction of Severe Hematologic Toxicity after CAR T-Cell Therapy Using Machine Learning-Based Time-Series Clustering

Severe hematologic toxicity is a significant complication associated with CAR T-cell therapy, leading to infections, transfusion dependency, and mortality. Using data from >400 CAR T-cell patients (pts), we hypothesized a time-series clustering-based approach could: i) automate the identification of pts with impaired absolute neutrophil count (ANC) recovery, ii) enable the identification of factors associated with ANC recovery, and iii) assess predictive models of hematologic toxicity after CAR T-cell therapy. Adults who received their first infusion of CAR T cells for hematologic malignancies with commercial or investigational products at our center (2013-2023) were included. ANC trajectories were clustered using non-supervised longitudinal k-means based on Euclidean distances. Sensitivity and specificity were computed based on the Youden criteria. 403 pts were included. The most common disease types were aggressive NHL (n = 161; 40%), indolent NHL (n = 82; 20%), ALL (n = 74; 18%), and MM/PCL (n = 44; 11%). The most common CAR T-cell products were investigational CD19 or CD20 CAR T-cell products (n = 174; 43%), axi-cel (n = 101; 25%), and liso-cel (n = 46; 11%). The longitudinal ANC data clustered into 4 distinct trajectories: 1) very good recovery (high nadir followed by rapid recovery), n = 294 (73%); 2) good recovery (low nadir followed by rapid recovery), n = 87 (22%); 3) poor recovery (low nadir followed by intermittent recovery), n = 13 (3%); 4) very poor recovery (aplastic phenotype), n = 9 (2%) (Figure 1). Pts with poor/very poor ANC recovery had significantly shorter overall survival than those with good/very good recovery (median 3 vs. 19 months, p < 0.001; Figure 2). 100-day mortality in pts with in very good/good vs. poor/very poor recovery was 62% vs. 11%, respectively (p < 0.001). In univariate logistic regression, predictors of poor/very poor recovery included disease type and inflammatory biomarkers (Table 1). Next, we assessed the ability of the CAR-HEMATOTOX score (high vs. low risk; Rejeski, Blood 2021) to predict poor/very poor ANC recovery. Due to missing data, day +0 rather than pre-lymphodepletion (LD) values were used for CRP and ferritin. The specificity and sensitivity of the CAR-HEMATOTOX were 31% and 100%, respectively. A logistic regression model using restricted cubic splines and including pre-LD ANC, peak CRP, and peak ferritin showed high discrimination (C-index: 0.91) with 74% specificity and 95% sensitivity. We introduce an automated and scalable framework that successfully identifies pts with the most severe hematologic toxicity after CAR T-cell therapy, and specifically those displaying an “aplastic” trajectory. We identified key factors associated with poor ANC recovery. A new model including peak inflammatory biomarkers showed improved performance compared to the CAR-HEMATOTOX score

Patients recently treated for B-lymphoid malignancies show increased risk of severe COVID-19: a CCC19 registry analysisImpact of B-cell malignancy therapy on COVID-19 outcomes

Patients with B-lymphoid malignancies have been consistently identified as a population at high risk of severe COVID-19. Whether this is exclusively due to cancer-related deficits in humoral and cellular immunity, or whether risk of severe COVID-19 is increased by anticancer therapy, is uncertain. Using data derived from the COVID-19 and Cancer Consortium (CCC19), we show that patients treated for B-lymphoid malignancies have an increased risk of severe COVID-19 compared with control populations of patients with non-B-lymphoid malignancies. Among patients with B-lymphoid malignancies, those who received anticancer therapy within 12 months of COVID-19 diagnosis experienced increased COVID-19 severity compared with patients with non-recently treated B-lymphoid malignancies, after adjustment for cancer status and several other prognostic factors. Our findings suggest that patients recently treated for a B-lymphoid malignancy are at uniquely high risk for severe COVID-19.SignificanceOur study suggests that recent therapy for a B-lymphoid malignancy is an independent risk factor for COVID-19 severity. These findings provide rationale to develop mitigation strategies targeted at the uniquely high-risk population of patients with recently treated B-lymphoid malignancies. This article is highlighted in the In This Issue feature, p. 171

Patients recently treated for B-lymphoid malignancies show increased risk of severe COVID-19: a CCC19 registry analysis

Patients with B-lymphoid malignancies have been consistently identified as a population at high risk of severe COVID-19. Whether this is exclusively due to cancer-related deficits in humoral and cellular immunity, or whether risk of severe COVID-19 is increased by anti-cancer therapy, is uncertain. Using data derived from the COVID-19 and Cancer Consortium (CCC19), we show that patients treated for B-lymphoid malignancies have an increased risk of severe COVID-19 compared to control populations of patients with non-B-lymphoid hematologic malignancies. Among patients with B-lymphoid malignancies, those who received anti-cancer therapy within 12 months of COVID-19 diagnosis experienced increased COVID-19 severity compared to patients with B-lymphoid malignancies off therapy, after adjustment for cancer status and several other prognostic factors. Our findings suggest that patients recently treated for a B-lymphoid malignancy are at uniquely high risk for severe COVID-19