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Gastroenterology Jun 2024Nonresponsive celiac disease (CeD) is relatively common. It is generally attributed to persistent gluten exposure and resolves after correction of diet errors. However,... (Review)
Review
Nonresponsive celiac disease (CeD) is relatively common. It is generally attributed to persistent gluten exposure and resolves after correction of diet errors. However, other complications of CeD and disorders clinically mimicking CeD need to be excluded. Novel therapies are being evaluated to facilitate mucosal recovery, which might benefit patients with nonresponsive CeD. Refractory CeD (RCeD) is rare and is divided into 2 types. The etiology of type I RCeD is unclear. A switch to gluten-independent autoimmunity is suspected in some patients. In contrast, type II RCeD represents a low-grade intraepithelial lymphoma. Type I RCeD remains a diagnosis of exclusion, requiring ruling out gluten intake and other nonmalignant causes of villous atrophy. Diagnosis of type II RCeD relies on the demonstration of a clonal population of neoplastic intraepithelial lymphocytes with an atypical immunophenotype. Type I RCeD and type II RCeD generally respond to open-capsule budesonide, but the latter has a dismal prognosis due to severe malnutrition and frequent progression to enteropathy-associated T-cell lymphoma; more efficient therapy is needed.
Topics: Celiac Disease; Humans; Diet, Gluten-Free; Intestinal Mucosa; Glutens; Treatment Outcome; Budesonide
PubMed: 38556189
DOI: 10.1053/j.gastro.2024.02.048 -
The Journal of Pathology Aug 2023Epithelioid sarcoma is a rare and aggressive mesenchymal tumour, the genetic hallmark of which is the loss of expression of SMARCB1, a key member of the SWItch/Sucrose...
Epithelioid sarcoma is a rare and aggressive mesenchymal tumour, the genetic hallmark of which is the loss of expression of SMARCB1, a key member of the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodelling complex. Hampered by its rarity, epithelioid sarcoma has received little research attention and therapeutic options for this disease remain limited. SMARCB1-deficient tumours also include malignant rhabdoid tumour, atypical teratoid and rhabdoid tumour, epithelioid malignant peripheral nerve sheath tumour, and poorly differentiated chordoma. Histologically, it can be challenging to distinguish epithelioid sarcoma from malignant rhabdoid tumour and other SMARCB1-deficient tumours, whereas methylation profiling shows that they represent distinct entities and facilitates their classification. Methylation studies on SMARCB1-deficient tumours, although not including epithelioid sarcomas, reported methylation subgroups which resulted in new clinical stratification and therapeutic approaches. In addition, emerging evidence indicates that immunotherapy, including immune checkpoint inhibitors, represents a promising therapeutic strategy for SMARCB1-deficient tumours. Here, we show that some epithelioid sarcomas share methylation patterns of malignant rhabdoid tumours indicating that this could help to distinguish these entities and guide treatment. Using gene expression data, we also showed that the immune environment of epithelioid sarcoma is characterised by a predominance of CD8 lymphocytes and M2 macrophages. These findings have potential implications for the management of patients with epithelioid sarcoma. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Topics: Humans; DNA-Binding Proteins; Chromosomal Proteins, Non-Histone; Rhabdoid Tumor; Immunohistochemistry; SMARCB1 Protein; Sarcoma
PubMed: 37316954
DOI: 10.1002/path.6135 -
Virchows Archiv : An International... Sep 2023Session 3 of the lymphoma workshop of the XXI joint meeting of the European Association for Haematopathology and the Society for Hematopathology took place in Florence,... (Review)
Review
Session 3 of the lymphoma workshop of the XXI joint meeting of the European Association for Haematopathology and the Society for Hematopathology took place in Florence, Italy, on September 22, 2022. The topics of this session were splenic and nodal marginal zone lymphomas, transformation in marginal zone lymphomas, and pediatric nodal marginal zone lymphomas and their differential diagnosis as well as related entities. Forty-two cases in these categories were submitted to the workshop, including splenic lymphomas (marginal zone and diffuse red pulp lymphomas), transformed marginal zone lymphomas (splenic and nodal), nodal marginal zone lymphomas with increased TFH-cells, and pediatric nodal marginal zone lymphomas. The case review highlighted some of the principal problems in the diagnosis of marginal zone lymphomas, including the difficulties in the distinction between splenic marginal zone lymphoma, splenic diffuse red pulp lymphoma, and hairy cell leukemia variant/splenic B-cell lymphoma with prominent nucleoli which requires integration of clinical features, immunophenotype, and morphology in blood, bone marrow, and spleen; cases of marginal zone lymphoma with markedly increased TFH-cells, simulating a T-cell lymphoma, where molecular studies (clonality and mutation detection) can help to establish the final diagnosis; the criteria for transformation of marginal zone lymphomas, which are still unclear and might require the integration of morphological and molecular data; the concept of an overlapping spectrum between pediatric nodal marginal zone lymphoma and pediatric-type follicular lymphoma; and the distinction between pediatric nodal marginal zone lymphoma and "atypical" marginal zone hyperplasia, where molecular studies are mandatory to correctly classify cases.
Topics: Humans; Child; Lymphoma, B-Cell, Marginal Zone; Lymphoma, Follicular; Leukemia, Lymphocytic, Chronic, B-Cell; Spleen; Bone Marrow; Hyperplasia; Splenic Neoplasms
PubMed: 37656249
DOI: 10.1007/s00428-023-03633-3 -
The Journal of Allergy and Clinical... Sep 2023CD11cTbet B cells are enriched in autoimmunity and chronic infections and also expand on immune challenge in healthy individuals. CD11cTbet B cells remain an enigmatic...
BACKGROUND
CD11cTbet B cells are enriched in autoimmunity and chronic infections and also expand on immune challenge in healthy individuals. CD11cTbet B cells remain an enigmatic B-cell population because of their intrinsic heterogeneity.
OBJECTIVES
We investigated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigen-specific development and differentiation properties of 3 separate CD11c B-cell subsets-age-associated B cells (ABCs), double-negative 2 (DN2) B cells, and activated naive B cells-and compared them to their canonical CD11c counterparts.
METHODS
Dynamics of the response of the 3 CD11c B-cell subsets were assessed at SARS-CoV-2 vaccination in healthy donors by spectral flow cytometry. Distinct CD11c B-cell subsets were functionally characterized by optimized in vitro cultures.
RESULTS
In contrast to a durable expansion of antigen-specific CD11c memory B cells over time, both ABCs and DN2 cells were strongly expanded shortly after second vaccination and subsequently contracted. Functional characterization of antibody-secreting cell differentiation dynamics revealed that CD11cTbet B cells were primed for antibody-secreting cell differentiation compared to relevant canonical CD11c counterparts.
CONCLUSION
Overall, CD11cTbet B cells encompass heterogeneous subpopulations, of which primarily ABCs as well as DN2 B cells respond early to immune challenge and display a pre-antibody-secreting cell phenotype.
Topics: Humans; B-Lymphocyte Subsets; COVID-19 Vaccines; COVID-19; SARS-CoV-2; Cell Differentiation
PubMed: 36858158
DOI: 10.1016/j.jaci.2023.02.020 -
Nature Communications Nov 2023The efficacy of the B cell-targeting drug rituximab (RTX) in childhood idiopathic nephrotic syndrome (INS) suggests that B cells may be implicated in...
The efficacy of the B cell-targeting drug rituximab (RTX) in childhood idiopathic nephrotic syndrome (INS) suggests that B cells may be implicated in disease pathogenesis. However, B cell characterization in children with INS remains limited. Here, using single-cell RNA sequencing, we demonstrate that a B cell transcriptional program poised for effector functions represents the major immune perturbation in blood samples from children with active INS. This transcriptional profile was associated with an extrafollicular B cell response marked by the expansion of atypical B cells (atBCs), marginal zone-like B cells, and antibody-secreting cells (ASCs). Flow cytometry of blood from 13 children with active INS and 24 healthy donors confirmed the presence of an extrafollicular B cell response denoted by the expansion of proliferating RTX-sensitive extrafollicular (CXCR5) CD21 T-bet CD11c atBCs and short-lived T-bet ASCs in INS. Together, our study provides evidence for an extrafollicular origin for humoral immunity in active INS.
Topics: Child; Humans; Nephrotic Syndrome; B-Lymphocytes; Rituximab
PubMed: 37996443
DOI: 10.1038/s41467-023-43504-8 -
Frontiers in Bioscience (Landmark... Nov 2023Chimeric antigen receptor (CAR) T-cell therapy carries the risk of inducing severe and life-threatening toxicities such as cytokine release syndrome (CRS),...
BACKGROUND
Chimeric antigen receptor (CAR) T-cell therapy carries the risk of inducing severe and life-threatening toxicities such as cytokine release syndrome (CRS), neurotoxicity, and infection. Although CRS and infections have similar symptoms, their treatment strategies differ, and early diagnosis is very important. For CRS and infections, the fastest detection time currently takes more than 24 h, so a quick and simple method to identify a fever after CAR T-cell infusion is urgently needed.
METHODS
We enrolled 27 patients with recurrent fever treated with different types of CAR T-cells, including cluster of differentiation (CD) 7, CD19, CD22, and CD19-CD22 bicistronic CAR T-cells, and evaluated the infection events occurring in these patients. We detailed the morphology of CAR T-cells in peripheral blood smears (PBS) and reported the infection events, CAR transgene copy number, and inflammatory indicators within the first month after treatment.
RESULTS
Similar morphological characteristics were observed in the PBS of different CAR T-cells, namely, enlarged cell bodies, deep outside and shallow inside basophilic blue cytoplasm, and natural killer (NK) cell-like purplish red granules. There were ten infections in nine of the twenty-seven patients (33%). The percentage of atypical lymphocytes in PBS was significantly associated with CAR transgene copy number and absolute lymphocyte count in all patients. The atypical lymphocyte percentage was significantly higher in the non-infection group.
CONCLUSIONS
In conclusion, the unique morphology of CAR T-cells in PBS can be used to evaluate CAR T-cell kinetics and provide reliable evidence for the rapid early identification of fever after CAR T-cell infusion.
CLINICAL TRIAL REGISTRATIONS
ChiCTR-OPN-16008526; ChiCTR-OPN-16009847; ChiCTR2000038641; NCT05618041; NCT05388695.
Topics: Humans; Receptors, Chimeric Antigen; Immunotherapy, Adoptive; Cytokine Release Syndrome; Killer Cells, Natural; Antigens, CD19
PubMed: 38062808
DOI: 10.31083/j.fbl2811299 -
Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome in childhood: a narrative review.Frontiers in Medicine 2023Despite being rare, the Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome is a serious, possibly fatal condition that may affect both adults and... (Review)
Review
Despite being rare, the Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome is a serious, possibly fatal condition that may affect both adults and children who may be also burdened by delayed sequelae. It is an adverse drug reaction characterized by widespread skin involvement, fever, lymphadenopathy, visceral involvement, and laboratory abnormalities (eosinophilia, mononucleosis-like atypical lymphocytes). It is more frequently triggered by anticonvulsants, sulphonamides, or antibiotics, the latter being responsible for up to 30% of pediatric cases. The disease typically develops 2-8 weeks after exposure to the culprit medication, with fever and widespread skin eruption; mild viral prodromes are possible. Unfortunately, diagnosis is challenging due to the absence of a reliable test; however, a score by the European Registry of Severe Cutaneous Adverse Reactions (RegiSCAR) allows to classify suspect patients into no, possible, probable, or definite DRESS cases. Moreover, rapid-onset DRESS syndrome has been described in recent years. It affects children more often than adults and differs from the most common form because it appears ≤15 days vs. >15 days after starting the drug, it is usually triggered by antibiotics or iodinated contrast media rather than by anticonvulsants and has a higher presence of lymphadenopathy. Differential diagnosis between rapid-onset antibiotic-driven DRESS syndrome, viral exanthems, or other drug eruptions may be challenging, but it is mandatory to define it as early as possible to start adequate treatment and monitor possible complications. The present review reports the latest evidence about the diagnosis and treatment of pediatric DRESS syndrome.
PubMed: 37575981
DOI: 10.3389/fmed.2023.1108345 -
Frontiers in Immunology 2023B cell activating factor (BAFF) has an important role in normal B cell development. The aberrant expression of BAFF is related with the autoimmune diseases development...
INTRODUCTION
B cell activating factor (BAFF) has an important role in normal B cell development. The aberrant expression of BAFF is related with the autoimmune diseases development like Systemic Lupus Erythematosus (SLE) for promoting self-reactive B cells survival. BAFF functions are exerted through its receptors BAFF-R (BR3), transmembrane activator calcium modulator and cyclophilin ligand interactor (TACI) and B cell maturation antigen (BCMA) that are reported to have differential expression on B cells in SLE. Recently, atypical B cells that express CD11c have been associated with SLE because they are prone to develop into antibody-secreting cells, however the relationship with BAFF remains unclear. This study aims to analyze the BAFF system expression on CXCR5 CD11c atypical B cell subsets double negative 2 (DN2), activated naïve (aNAV), switched memory (SWM) and unswitched memory (USM) B cells.
METHODS
Forty-five SLE patients and 15 healthy subjects (HS) were included. Flow cytometry was used to evaluate the expression of the receptors in the B cell subpopulations. Enzyme-linked immunosorbent assay (ELISA) was performed to quantify the soluble levels of BAFF (sBAFF) and IL-21.
RESULTS
We found increased frequency of CXCR5 CD11c atypical B cell subpopulations DN2, aNAV, SWM and USM B cells in SLE patients compared to HS. SLE patients had increased expression of membrane BAFF (mBAFF) and BCMA receptor in classic B cell subsets (DN, NAV, SWM and USM). Also, the CXCR5 CD11c DN1, resting naïve (rNAV), SWM and USM B cell subsets showed higher mBAFF expression in SLE. CXCR5 CD11c atypical B cell subpopulations DN2, SWM and USM B cells showed strong correlations with the expression of BAFF receptors. The atypical B cells DN2 in SLE showed significant decreased expression of TACI, which correlated with higher IL-21 levels. Also, lower expression of TACI in atypical B cell DN2 was associated with high disease activity.
DISCUSSION
These results suggest a participation of the BAFF system in CXCR5 CD11c atypical B cell subsets in SLE patients. Decreased TACI expression on atypical B cells DN2 correlated with high disease activity in SLE patients supporting the immunoregulatory role of TACI in autoimmunity.
Topics: Humans; Memory B Cells; B-Cell Activating Factor; B-Cell Maturation Antigen; B-Lymphocytes; Lupus Erythematosus, Systemic; Autoimmune Diseases
PubMed: 37675114
DOI: 10.3389/fimmu.2023.1235937 -
International Journal of Molecular... Feb 2024Endometriosis (E) and adenomyosis (A) are associated with a wide spectrum of symptoms and may present various histopathological transformations, such as the presence of...
UNLABELLED
Endometriosis (E) and adenomyosis (A) are associated with a wide spectrum of symptoms and may present various histopathological transformations, such as the presence of hyperplasia, atypia, and malignant transformation occurring under the influence of local inflammatory, vascular and hormonal factors and by the alteration of tumor suppressor proteins and the inhibition of cell apoptosis, with an increased degree of lesion proliferation.
MATERIAL AND METHODS
This retrospective study included 243 patients from whom tissue with E/A or normal control uterine tissue was harvested and stained by histochemical and classical immunohistochemical staining. We assessed the symptomatology of the patients, the structure of the ectopic epithelium and the presence of neovascularization, hormone receptors, inflammatory cells and oncoproteins involved in lesion development. Atypical areas were analyzed using multiple immunolabeling techniques.
RESULTS
The cytokeratin (CK) CK7+/CK20- expression profile was present in E foci and differentiated them from digestive metastases. The neovascularization marker cluster of differentiation (CD) 34+ was increased, especially in areas with malignant transformation of E or A foci. T:CD3+ lymphocytes, B:CD20+ lymphocytes, CD68+ macrophages and tryptase+ mast cells were abundant, especially in cases associated with malignant transformation, being markers of the proinflammatory microenvironment. In addition, we found a significantly increased cell division index (Ki67+), with transformation and inactivation of tumor suppressor genes p53, B-cell lymphoma 2 (BCL-2) and Phosphatase and tensin homolog (PTEN) in areas with E/A-transformed malignancy.
CONCLUSIONS
Proinflammatory/vascular/hormonal changes trigger E/A progression and the onset of cellular atypia and malignant transformation, exacerbating symptoms, especially local pain and vaginal bleeding. These triggers may represent future therapeutic targets.
Topics: Female; Humans; Endometriosis; Retrospective Studies; Adenomyosis; Epithelium; Tumor Suppressor Protein p53
PubMed: 38339066
DOI: 10.3390/ijms25031789