Follicular B Cells Research Articles

Effect of POD24 on the prognosis of follicular and other indolent B-cell non-hodgkin lymphomas.

Indolent B-cell non-Hodgkin lymphomas(B-NHL) encompass a heterogeneous category of lymphomas characterized by a wide range of pathological subtypes. With the application of chemoimmunotherapy with rituximab (R-chemo), the prognosis of patients has improved considerably, with a 10-year survival rate of 60-80%. Despite these advancements, a significant number of patients still experience disease progression during or shortly after initial treatment. Those who progress within the first 24 months (POD24) continue to face a notably worse prognosis. This study aims to explore the significance of POD24 in predicting the prognosis of different subtypes of indolent B-cell NHL through a comprehensive literature review. The investigation extends to examining the existing prognostic assessment tools and evaluating the interrelationship between POD24 and these tools. By synthesizing relevant research findings, this study seeks to contribute to the current understanding of the role POD24 plays in prognostic evaluation and its potential implications in guiding clinical decision-making for patients with indolent B-cell NHL.

RNA sequencing and multiplexed immunohistochemistry reveal the factors for postoperative recurrence of stage IB-IIA cervical squamous cell carcinoma

BackgroundStage IB-IIA Cervical Squamous Cell Carcinoma (CSCC) presents diverse clinical outcomes, the mechanisms that cause recurrence in CC patients remain unclear. The goal of this study was to identify predictive biomarkers leading to tumor recurrence in IB-IIA CSCC after surgical treatment by comparing the transcriptional and immune landscape between the recurrence and non-recurrence group.MethodsWe performed mRNA sequencing and multiplexed immunohistochemistry (mIHC) analysis among stage IB-IIA patients with or without recurrence after surgical resection and were followed-up for a median of three years.ResultsIntegrated analysis indicates that the upregulated gene expression in zinc finger proteins, the activation of the PI3K/Akt pathway, and the low infiltration level of T follicular helper cells and B-cells may serve as potential recurrent biomarkers for CSCC. We also observed significant differences in the immune and genomic landscape between two groups.ConclusionsThese findings provide new insights into the relapse mechanisms of CSCC, which could potentially guide clinical exploration of drug targets.

IBCL-541 A Comprehensive Single-Cell Multi-Omic Analysis to Depict the Biological Heterogeneity of Follicular and Large B-Cell Lymphomas

IBCL-541 A Comprehensive Single-Cell Multi-Omic Analysis to Depict the Biological Heterogeneity of Follicular and Large B-Cell Lymphomas

A Comprehensive Single-Cell Multi-Omic Analysis to Depict the Biological Heterogeneity of Follicular and Large B-Cell Lymphomas

A Comprehensive Single-Cell Multi-Omic Analysis to Depict the Biological Heterogeneity of Follicular and Large B-Cell Lymphomas

A Comprehensive Single-Cell Multi-Omic Analysis to Depict the Biological Heterogeneity of Follicular and Large B-Cell Lymphomas

A Comprehensive Single-Cell Multi-Omic Analysis to Depict the Biological Heterogeneity of Follicular and Large B-Cell Lymphomas

Phase 2 open label, multicenter study evaluating CRG-022, a CD22-directed autologous CAR T-cell therapy, in patients (pts) with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) after CD19-directed CAR T-cell therapy.

TPS7085 Background: Autologous (auto) CD19-directed CAR T-cell therapy can induce long-term remissions for pts with R/R LBCL but approximately 60% will experience disease progression resulting in poor outcomes (Neelapu, 2023; Zurko, 2023). CRG-022 is a novel CAR T-cell product targeting CD22, a common B-cell antigen widely expressed in LBCL. Key features of CRG-022 include a fully human scFv derived from the m971 monoclonal antibody and 4-1BB/CD3z intracellular signaling domains (Singh, 2021). This CD22 CAR construct was developed at the National Cancer Institute and was investigated in phase (ph) 1 studies of pediatric/young adult pts with R/R CD22+ malignancies (Shah, 2020; NCT02315612) and at Stanford University in adults with R/R LBCL (Baird, 2021; NCT04088890) primarily in pts who received prior CD19-directed CAR-T therapy. The Stanford ph 1b study reported an overall response rate (ORR) and complete response rates of 66% and 52%, respectively in 29 pts treated at the recommended Phase 2 dose (RP2D) of 1x106 CAR+ T cells/kg (Frank, 2023). After a median follow-up of 27.3 months, the median overall survival had not been reached at the RP2D (Su, 2023). At the RP2D, no grade >3 cytokine release syndrome (CRS), immune-effector cell associated neurotoxicity syndrome (ICANS), or immune effector cell associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) occurred; two pts (7%) developed grade 2 IEC-HS (Su, 2023; Srinagesh, 2023). Based on these notable results, this potentially pivotal ph 2 trial has been initiated. Methods: This Phase 2 study will evaluate the safety/efficacy of CRG-022 at 1x106 CAR+ T cells/kg in pts with R/R LBCL whose disease has progressed after CD19-directed CAR T-cell therapy. The primary endpoint is ORR according to Lugano response criteria (Cheson, 2014) by blinded independent review. Adverse events (AEs) are graded per CTCAE v5 except with CRS, ICANS, and IEC-HS graded per ASTCT guidelines. Pts with diffuse large B-cell lymphoma (DLBCL), high grade B-cell lymphoma, DLBCL transformed from follicular or marginal zone lymphoma, follicular large B-cell lymphoma (FLBL)/FL Grade 3B, and primary mediastinal B-cell lymphoma are eligible. Other eligibility criteria include adequate hematologic and organ function, and no prior allogeneic stem cell transplant. Pts with prior treatment to both a CD19-directed auto CAR-T and a bispecific T-cell engaging antibody are also eligible within a separate cohort. Lymphodepletion with fludarabine 30 mg/m2/day and cyclophosphamide 500 mg/m2/day for 3 days will be administered ahead of a single infusion of CRG-022. The study is designed to enroll approximately 123 pts. Study enrollment commenced in the US in August 2023, with 9 pt infused as of 08 JAN 2024. Clinical trial information: NCT05972720 .

Chemokine receptor 7 contributes to T- and B-cell filtering in ageing bladder, cystitis and bladder cancer

BackgroundResearch has suggested significant correlations among ageing, immune microenvironment, inflammation and tumours. However, the relationships among ageing, immune microenvironment, cystitis and bladder urothelial carcinoma (BLCA) in the bladder have rarely been reported.MethodsBladder single-cell and transcriptomic data from young and old mice were used for immune landscape analysis. Transcriptome, single-cell and The Cancer Genome Atlas Program datasets of BLCA and interstitial cystitis/bladder pain syndrome (IC/BPS) were used to analyse immune cell infiltration and molecular expression. Bladder tissues from mice, IC/BPS and BLCA were collected to validate the results.ResultsEight types of immune cells (macrophages, B-cells, dendritic cells, T-cells, monocytes, natural killer cells, γδ T-cells and ILC2) were identified in the bladder of mice. Aged mice bladder tissues had a significantly higher number of T-cells, γδ T-cells, ILC2 and B-cells than those in the young group (P < 0.05). Three types of T-cells (NK T-cells, γδ T-cells and naïve T-cells) and three types of B-cells (follicular B-cells, plasma and memory B-cells) were identified in aged mice bladder. Chemokine receptor 7 (CCR7) is highly expressed in aged bladder, IC/BPS and BLCA (P < 0.05). CCR7 is likely to be involved in T- and B-cell infiltration in aged bladder, IC/BPS and BLCA. Interestingly, the high CCR7 expression on BLCA cell membranes was a prognostic protective factor.ConclusionsIn this study, we characterised the expression profiles of immune cells in bladder tissues of aged and young mice and demonstrated that CCR7-mediated T- and B-cell filtration contributes to the development of bladder ageing, IC/BPS and BLCA.

Naturally occurring polymorphisms reveal the cis-regulatory sites and transcription factors controlling follicular and marginal zone B cells

Abstract The splenic B cell compartment consists of follicular (FoB) and marginal zone (MZB) B cells. In contrast to FoB, MZB exist in a poised state and rapidly respond to blood-borne pathogens in the absence of T cell help, predominately generating a rapid wave of short-lived plasma cells. These differences in responses are driven by differential genetic and epigenetic priming of each subset. MZB epigenetic programming are enriched for bHLH, POU, Rel and RUNT motifs, whereas FoB are enriched for IRF and KLF motifs. MZB also exhibit increased expression of genes associated with Notch signaling, Myc, and mTORC1 pathways. However, it is unclear how sequence specific transcription factors directly and indirectly regulate distinct states in MZB and FoB that underpin B cell activation, differentiation, and acquisition of effector functions. To address this, we generated an F1 hybrid model which utilizes naturally occurring polymorphism present in the wild-derived mouse line Spret/EiJ compared to the reference strain C57BL/6. The monoallelic polymorphisms present in this F1 generation allows us to use the allelic imbalance to dissect how alterations in genetic features impact TF binding, epigenetic architecture, and ultimately resulting gene expression programs. MZB and FoB were sorted from naive (Spret x B6) F1’s and subject to RNA and ATAC-seq. This study aims to define the cis-regulatory mechanisms responsible for the epigenetic and transcriptional differences of FoB and MZB cells.

CAR19 monitoring by peripheral blood immunophenotyping reveals histology-specific expansion and toxicity

AbstractChimeric antigen receptor (CAR) T cells directed against CD19 (CAR19) are a revolutionary treatment for B-cell lymphomas (BCLs). CAR19 cell expansion is necessary for CAR19 function but is also associated with toxicity. To define the impact of CAR19 expansion on patient outcomes, we prospectively followed a cohort of 236 patients treated with CAR19 (brexucabtagene autoleucel or axicabtagene ciloleucel) for mantle cell lymphoma (MCL), follicular lymphoma, and large BCL (LBCL) over the course of 5 years and obtained CAR19 expansion data using peripheral blood immunophenotyping for 188 of these patients. CAR19 expansion was higher in patients with MCL than other lymphoma histologic subtypes. Notably, patients with MCL had increased toxicity and required fourfold higher cumulative steroid doses than patients with LBCL. CAR19 expansion was associated with the development of cytokine release syndrome, immune effector cell–associated neurotoxicity syndrome, and the requirement for granulocyte colony-stimulating factor 14 days after infusion. Younger patients and those with elevated lactate dehydrogenase (LDH) had significantly higher CAR19 expansion. In general, no association between CAR19 expansion and LBCL treatment response was observed. However, when controlling for tumor burden, we found that lower CAR19 expansion in conjunction with low LDH was associated with improved outcomes in LBCL. In sum, this study finds CAR19 expansion principally associates with CAR-related toxicity. Additionally, CAR19 expansion as measured by peripheral blood immunophenotyping may be dispensable to favorable outcomes in LBCL.

Notch2 controls developmental fate choices between germinal center and marginal zone B cells upon immunization

Sustained Notch2 signals induce trans-differentiation of Follicular B (FoB) cells into Marginal Zone B (MZB) cells in mice, but the physiology underlying this differentiation pathway is still elusive. Here, we demonstrate that most B cells receive a basal Notch signal, which is intensified in pre-MZB and MZB cells. Ablation or constitutive activation of Notch2 upon T-cell-dependent immunization reveals an interplay between antigen-induced activation and Notch2 signaling, in which FoB cells that turn off Notch2 signaling enter germinal centers (GC), while high Notch2 signaling leads to generation of MZB cells or to initiation of plasmablast differentiation. Notch2 signaling is dispensable for GC dynamics but appears to be re-induced in some centrocytes to govern expansion of IgG1+ GCB cells. Mathematical modelling suggests that antigen-activated FoB cells make a Notch2 dependent binary fate-decision to differentiate into either GCB or MZB cells. This bifurcation might serve as a mechanism to archive antigen-specific clones into functionally and spatially diverse B cell states to generate robust antibody and memory responses.

Clinical pathological characteristics analysis of ocular adnexal follicular lymphoma

Objective: To investigate the clinical pathological characteristics of ocular adnexal follicular lymphoma (OAFL). Methods: A retrospective case series study was conducted. Clinical data of 10 OAFL patients diagnosed at Tianjin Eye Hospital from January 1990 to May 2022 were collected. The study analyzed general patient information, medical history, site of involvement, imaging, histopathology, and molecular detection. Among them, 7 cases underwent Epstein-Barr virus-encoded small RNA (EBER) and B-cell lymphoma protein 2 (BCL-2)/immunoglobulin heavy chain gene (IgH) translocation gene detection. Treatment and prognosis of patients were followed up. Results: All 10 patients (10 eyes) had unilateral involvement, including 5 males and 5 females, with an age range of 58 (43, 68) years. Clinical manifestations included eyelid swelling, pink conjunctival thickening, painless slow-growing masses in the lacrimal gland area, extraconal muscle cone, conjunctiva, lacrimal sac, or a combination of lacrimal sac and conjunctiva. Among them, 8 cases were primary, and 2 cases were secondary. According to the Ann Arbor staging, 8 cases were stage Ⅰ-Ⅱ E, and 2 cases were stage Ⅲ E. Histopathological grading revealed 6 cases of grade 1-2 and 3 cases of grade 3A. One case showed grade 3B in the lacrimal sac area and grade 1-2 in the conjunctiva. The predominant subtype was follicular in 4 cases, diffuse in 3 cases, and mixed in 2 cases. One case had a mixed subtype involving the lacrimal sac and conjunctiva. All patients expressed positivity for leukocyte differentiation antigens (CD) 20, CD21, and CD23. Nine cases were positive for CD10, with 1 case showing partial CD10 positivity. All patients were positive for B-cell lymphoma protein 6 (BCL-6), and 9 cases were positive for BCL-2. Specific markers CyclinD1 and Multiple Myeloma Oncogene Protein 1 (MUM-1) were negatively expressed in all cases. The Ki-67 proliferation index ranged from 10% to 90%. Molecular detection was performed in 7 patients, with none showing positive EBER in situ hybridization. However, 5 cases exhibited BCL2/IgH gene fusion. Among 7 patients with follow-up data, the median follow-up time was 17 (6, 34) months. Four patients achieved complete remission, 2 had partial remission, and 1 patient died due to lung infection. Conclusions: OAFL is a tumor originating from follicular center B-cells, characterized by positive expression of BCL-2, CD10, and BCL-6. It can involve the lacrimal gland, extraconal muscles, lacrimal sac, and conjunctiva. Patients generally have a favorable prognosis.

Modeling the crosstalk between malignant B cells and their microenvironment in B-cell lymphomas: challenges and opportunities.

B-cell lymphomas are a group of heterogeneous neoplasms resulting from the clonal expansion of mature B cells arrested at various stages of differentiation. Specifically, two lymphoma subtypes arise from germinal centers (GCs), namely follicular lymphoma (FL) and GC B-cell diffuse large B-cell lymphoma (GCB-DLBCL). In addition to recent advances in describing the genetic landscape of FL and GCB-DLBCL, tumor microenvironment (TME) has progressively emerged as a central determinant of early lymphomagenesis, subclonal evolution, and late progression/transformation. The lymphoma-supportive niche integrates a dynamic and coordinated network of immune and stromal cells defining microarchitecture and mechanical constraints and regulating tumor cell migration, survival, proliferation, and immune escape. Several questions are still unsolved regarding the interplay between lymphoma B cells and their TME, including the mechanisms supporting these bidirectional interactions, the impact of the kinetic and spatial heterogeneity of the tumor niche on B-cell heterogeneity, and how individual genetic alterations can trigger both B-cell intrinsic and B-cell extrinsic signals driving the reprogramming of non-malignant cells. Finally, it is not clear whether these interactions might promote resistance to treatment or, conversely, offer valuable therapeutic opportunities. A major challenge in addressing these questions is the lack of relevant models integrating tumor cells with specific genetic hits, non-malignant cells with adequate functional properties and organization, extracellular matrix, and biomechanical forces. We propose here an overview of the 3D in vitro models, xenograft approaches, and genetically-engineered mouse models recently developed to study GC B-cell lymphomas with a specific focus on the pros and cons of each strategy in understanding B-cell lymphomagenesis and evaluating new therapeutic strategies.

Niet-genezende huidletsels van de borst

Non-healing skin lesions in the right mammary region Although almost all dermatological conditions are visible, some patients wait a long time to consult a dermatologist. Nevertheless, an early diagnosis is important for the treatment and prognosis in case of cutaneous cancers. A 39-year-old man with skin lesions on his right chest, present for 3 years and slowly growing over time, consulted the dermatologist. The anatomopathological examination showed a diffuse-type primary cutaneous follicular B-cell non-Hodgkin lymphoma. Staging revealed a primary cutaneous lymphoma. After deliberation in a multidisciplinary oncologic consultation, radiotherapy was started. Cutaneous lymphomas are often difficult to diagnose because of their non-specific and variable clinical presentation. Skin biopsies should be performed when patients present with atypical cutaneous lesions. In case of cutaneous B-cell lymphomas, early diagnosis is important to detect and treat an underlying systemic or aggressive B-cell lymphoma. A multidisciplinary management team including dermatologists, pathologists, hematologists and radiation oncologists is necessary.

Abstract P3079: Integrating Existing Cardiac Single-cell RNA Sequencing Datasets To Uncover The Role Of B-cells In Heart Disease

Introduction: The role of B-cells in human heart failure remains unclear. To address this knowledge gap, we analyzed publicly available datasets of scRNAseq and snRNAseq from patients with various forms of cardiomyopathy. Methods and Results: We used two public datasets including single cells or single nuclei RNAseq data collected from the myocardium of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), dilated cardiomyopathy (DCM), idiopathic cardiac diseases (ICD), or healthy controls. The first dataset comprised 30 healthy controls and 22 non-ischemic DCM; the second contained 18 controls and 61 with DCM, ARVC, or ICD. Data were normalized and scaled, a UMAP plot was generated, and cells were classified using ScType. B-cells were merged into a single matrix, and the final dataset contained 1100 cells from 32 healthy controls, 59 DCM, and 8 ARVC patients. Four different B-cell clusters were identified. The top 100 biomarkers from each cluster were used to identify B-cell subtypes. Cluster 1 was identified as transitional splenic B-cells; Cluster 2 as plasma cells; Cluster 3 as follicular splenic B-cells; Cluster 4, present only in DCM, as immature B cells. Ingenuity Pathway Analysis (IPA) of the genes enriched in each cluster highlighted that different B cell clusters displayed distinct biological activity, ranging from phagosome formation to B cell receptor signaling and cytokine production. Differentially expressed gene analysis comparing healthy controls to DCM and ARVC showed both similar and disease-specific gene expression patterns in the various B cell clusters. For instance, cluster 2 showed upregulation of oxidative phosphorylation in both DCM and ARVC. On the other hand, DCM cluster 2 showed downregulation of CD40 signaling, while in ARVC the same cluster showed downregulation of IL-6 signaling (Z score &gt;2, p&lt;0.05). Discussion: Our findings suggest that human heart failure is associated with perturbations in B cell gene expression, with both shared and disease-specific features. This data supports the notion that B cells likely play a role in human cardiomyopathy. Further, this data suggests that B-cells play distinct roles in disparate forms of cardiac disease.

Revision Tracheotomy Complicated by History of Follicular B-Cell Lymphoma.

This case report presents a 65-year-old woman with multiple complications during a revision tracheotomy including subcutaneous emphysema and a pneumothorax. Management of her airway was complicated by a history of recurrent follicular B-cell lymphoma associated with extensive cervical lymphadenopathy. We detail the importance of heightened clinical awareness and the use of intraoperative safety adjuncts when performing revision tracheostomies.

CD4+ T-cell-dependent differentiation of CD23+ follicular B cells contributes to the pulmonary pathology in a primary Sjögren's syndrome mouse model.

Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease that affects the function of exocrine glands, such as the lacrimal and the salivary glands. Extraglandular lesions and malignant lymphoma also occur during the progressive stage of pSS. We have, herein, focused on the pulmonary lesions of pSS and have aimed clarifying their pathophysiological mechanism by comparing the glandular with the extraglandular lesions observed in a mouse model of pSS. The histopathological analysis of lung tissues obtained from NFS/sld mice that have undergone neonatal thymectomy was performed. Moreover, in vivo and in vitro experiments were conducted along with immunological analyses in order to characterize the unique phenotypes of the pulmonary lesions identified in these pSS model mice. Inflammatory lesions with a bronchus-associated lymphoid tissue-like structure were identified in the lungs of pSS model mice. In addition, relative to salivary gland lesions, pulmonary lesions showed increased CD23+ follicular B (FB) cells. In vitro and pulmonary B cells were more readily driven to CD23+ FB cell phenotype than salivary gland B cells in pSS model mice. Furthermore, the CD23+ FB cell differentiation was found to be enhanced in a CD4+ T-cell-dependent manner under a Th2-type condition in the lungs of herein examined pSS model mice. A Th2-type response in the pSS lung may promote the progression of autoimmune lesions through an enhanced abnormal differentiation of B cells.

Divergent evolution of metachronous follicular lymphoma and extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue from a common precursor.

The translocation t(14;18)(q32:q21)/IGH::BCL2 occurs at the pre-B stage of B-cell development in the bone marrow and is insufficient for malignant transformation, although it leads to the formation of in situ follicular B-cell neoplasia (ISFN). Despite that, the translocation is the genetic hallmark of follicular lymphoma (FL), it occurs infrequently in metachronous/synchronous lymphomas, including extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (EMZL), mantle cell lymphoma, and Hodgkin's lymphoma. In each of these scenarios, the two lymphomas often appear to be clonally related by analyses of IGH::BCL2 and/or rearranged IG genes. However, it remains largely unknown whether one lymphoma originates from the other or they develop independently. We studied five cases of metachronous EMZL and FL. In four cases, the two lymphomas were clonally related, as shown by identical IGH::BCL2 and/or rearranged IG genes or shared mutations. There were common and unique mutations between the paired EMZL and FL, indicating that they developed independently from a common premalignant cell population, harbouring IGH::BCL2 in three cases. Furthermore, case 1 presented with three metachronous FLs, and all of them originated from a common precursor cell population via divergent evolution. Our findings highlight the multi-malignant potential of IGH::BCL2-positive B-cells. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Quantifying the impact of PFOA Exposure on B cell development and antibody production.

Per- and polyfluoroalkyl substances (PFAS) are synthetic chemicals; the vast majority are environmentally and biologically persistent, and some have demonstrated toxicity, including cancer, effects on metabolism, endocrine disruption, and immune dysfunction. Suppression of T-cell dependent antibody responses (TDAR) has been observed in numerous studies of PFAS but mechanisms remain elusive. Evidence from our work suggests that B cells and how they use energy are impacted by PFAS exposure. We hypothesize that a well-studied and immunotoxic PFAS, perfluorooctanoic acid (PFOA), alters B cell subclasses and markers of their metabolism. Adult male and female C57BL/6 mice were given PFOA (0 or 7.5 mg/kg) via gavage for 15 days, a duration and dose sufficient to suppress the TDAR. After dosing and immunization of subgroups, spleens were prepared to quantify B cell subsets. Flow cytometric analysis revealed decreased numbers of plasmablasts, follicular, naïve, and overall B cell subclasses in female PFOA-exposed groups. Male PFOA-exposed groups had a significant increase in follicular B cells and other subsets had decreases, including in the overall number of B cells. Twenty-four hours after naïve B cell isolation and ex vivo activation, metabolic measurements revealed a five-fold increase in metabolic markers in response to stimulation in PFOA-exposed groups compared to controls. These findings suggest that B cell development and survival may be hindered by PFOA exposure, but that activation of the remaining B cells was not. Based on these findings, PFOA mediated suppression of the primary IgM antibody response results changes to specific subsets of B cells.

Characterizing A Novel Variant in ABCB1 in a Family with Activated PI3K Delta Syndrome-like Presentation

IntroductionActivated PI3K delta syndrome (APDS) is a rare inborn error of immunity (IEI) due to a heterozygous gain-of-function mutation in the PIK3CD or PIK3R1 genes. APDS patients have high variability in clinical manifestations including recurrent sinopulmonary infections, lymphoproliferation, and susceptibility to CMV and/or EBV viremia. APDS is characterized by a block in B-cell development to follicular stage. Therefore, increase in transitional compartment is almost exclusively seen in untreated APDS patients. We describe a family that present with APDS-like clinical and laboratory findings, while harboring a novel variant in ATP binding cassette subfamily B member 1 (ABCB1), which is involved in adenosine salvage and mTORC1 pathways. MethodsRetrospective chart review was performed for clinical and laboratory data. Extensive immune phenotyping was obtained. Genetic evaluation included targeted immune panel and whole exome sequencing. Mitotracker-green detection by flow cytometry was used to determine progression to follicular B cell stage. Case PresentationIndex case is a 14-year-old female with a complex presentation of infectious and non-infectious complications notable for lifelong hypogammaglobulinemia with poor vaccine response, multiple intubations for upper respiratory illnesses, bronchiectasis, and short stature. Patient had 3 other siblings who also had similar presentation with varied severity, including features of short stature, recurrent infections, alopecia universalis and immune dysregulation. Three siblings required immunoglobulin replacement therapy. Extensive immune-phenotyping revealed significant expansion of CD24hiCD38hi transitional and CD19hiCD21lo B-cells, with decrease in follicular and memory B-cell compartment in all. Although clinical and lab findings prompted APDS diagnosis, repeated targeted genetic panel testing did not show variants in PIK3CD or PIK3R1. Consequent whole exome sequencing revealed a candidate variant in ABCB1 p.Ala1187Thr that was shared among all. Interestingly, surface expression of ABCB1 was significantly elevated in patients compared to healthy controls. Initial functional testing showed disruption in mitochondrial efflux, further supporting the block from transitional to follicular stage. Discussion/ConclusionsDetermining diagnostic approaches in APDS-like disorders liked to ABCB1 variant is challenging, especially when pathogenesis is yet to be determined. Although further functional testing of ABCB1 and its potential role in PI3K signaling is needed, ABCB1 gene may play an important role in APDS pathology.

Follicular Lymphoma in the 5th Edition of the WHO-Classification of Haematolymphoid Neoplasms-Updated Classification and New Biological Data.

The conceptual description of Follicular lymphoma (FL) in the 5th edition of the World Health Organization (WHO) classification of haematolymphoid tumors (WHO-HAEM5) has undergone significant revision. The vast majority of FL (85%) with a follicular growth pattern are composed of centrocytes and centroblasts, harbor the t(14;18)(q32;q21) translocation and are now termed classic FL (cFL). They are set apart from three related subtypes, FL with predominantly follicular growth pattern, FL with unusual cytological features (uFL) and follicular large B-cell lymphoma (FLBCL). In contrast to the revised 4th edition of the WHO classification of haematolymphoid tumors (WHO-HAEM4R), grading of cFL is no longer mandatory. FL with a predominantly diffuse growth pattern had been previously recognized in WHO-HAEM4R. It frequently occurs as a large tumor in the inguinal region and is associated with CD23 expression. An absence of the IGH::BCL2 fusion and frequent STAT6 mutations along with 1p36 deletion or TNFRSF14 mutation is typical. The newly introduced subtype of uFL includes two subsets that significantly diverge from cFL: one with "blastoid" and one with "large centrocyte" variant cytological features. uFL more frequently displays variant immunophenotypic and genotypic features. FLBCL is largely identical to WHO-HAEM4R FL grade 3B and renaming was done for reasons of consistency throughout the classification. In-situ follicular B-cell neoplasm, pediatric-type FL, duodenal-type FL and primary cutaneous follicle center lymphoma are categorized as discrete entities. In addition, novel findings concerning underlying biological mechanisms in the pathogenesis of early and systemic follicular lymphoma will be presented.