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Frontiers in Immunology 2022CD11c T-bet atypical B cells (ABCs) have been identified in the context of vaccination, acute and chronic infections and autoimmune disease. However, the origins and... (Review)
Review
CD11c T-bet atypical B cells (ABCs) have been identified in the context of vaccination, acute and chronic infections and autoimmune disease. However, the origins and functions of ABCs remain elusive. A major obstacle in the study of ABCs, and human MBCs more generally, has been the use of different phenotypic markers in different contexts to identify what appear to be phenotypically similar cells. Advances in single-cell RNA sequencing (scRNA-seq) technology have allowed researchers to accurately identify ABCs in different immune contexts such as diseases and tissues. Notably, recent studies utilizing single cell techniques have demonstrated ABCs are a highly conserved memory B cell lineage. This analysis has also revealed that ABCs are more abundant in ostensibly healthy donors than previously thought. Nonetheless, the normal function of these cells remains elusive. In this review, we will focus on scRNA-seq studies to discuss recent advances in our understanding about the development and functions of ABCs.
Topics: Autoimmune Diseases; B-Lymphocytes; CD11c Antigen; Humans; Lymphocyte Count; Single-Cell Analysis
PubMed: 36072594
DOI: 10.3389/fimmu.2022.979060 -
The Journal of Allergy and Clinical... Jan 2023Forkhead box protein 3 (FOXP3) is the master transcription factor in CD4CD25CD127 regulatory T (Treg) cells. Mutations in FOXP3 result in IPEX (immune dysregulation,...
BACKGROUND
Forkhead box protein 3 (FOXP3) is the master transcription factor in CD4CD25CD127 regulatory T (Treg) cells. Mutations in FOXP3 result in IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome. Clinical presentation of IPEX syndrome is broader than initially described, challenging the understanding of the disease, its evolution, and treatment choice.
OBJECTIVE
We sought to study the type and extent of immunologic abnormalities that remain ill-defined in IPEX, across genetic and clinical heterogeneity.
METHODS
We performed Treg-cell-specific epigenetic quantification and immunologic characterization of severe "typical" (n = 6) and "atypical" or asymptomatic (n = 9) patients with IPEX.
RESULTS
Increased number of cells with Treg-cell-Specific Demethylated Region demethylation in FOXP3 is a consistent feature in patients with IPEX, with (1) highest values in those with typical IPEX, (2) increased values in subjects with pathogenic FOXP3 but still no symptoms, and (3) gradual increase over the course of disease progression. Large-scale profiling using Luminex identified plasma inflammatory signature of macrophage activation and T2 polarization, with cytokines previously not associated with IPEX pathology, including CCL22, CCL17, CCL15, and IL-13, and the inflammatory markers TNF-α, IL-1A, IL-8, sFasL, and CXCL9. Similarly, both Treg-cell and Teff compartments, studied by Mass Cytometry by Time-Of-Flight, were skewed toward the T2 compartment, especially in typical IPEX.
CONCLUSIONS
Elevated TSDR-demethylated cells, combined with elevation of plasmatic and cellular markers of a polarized type 2 inflammatory immune response, extends our understanding of IPEX diagnosis and heterogeneity.
Topics: Humans; Forkhead Transcription Factors; Genetic Diseases, X-Linked; Polyendocrinopathies, Autoimmune; T-Lymphocytes, Regulatory; Mutation; Epigenesis, Genetic
PubMed: 36152823
DOI: 10.1016/j.jaci.2022.09.013 -
Romanian Journal of Internal Medicine =... 2016Mycosis fungoides is the most common primary T-cell lymphoma of skin. The disease has a protean clinical and histological presentation in its early patch and plaque... (Review)
Review
Mycosis fungoides is the most common primary T-cell lymphoma of skin. The disease has a protean clinical and histological presentation in its early patch and plaque stages, when distinction from mimicking inflammatory dermatoses is difficult. Since no single criterion is specific enough, a reliable diagnosis in early stages requires integration of clinical, histopathological and molecular findings. In skin biopsies, the most helpful histologic features are the detection of atypical lymphocytes in the epidermis with minimal epidermal changes, basal alignment of lymphocytes along dermal-epidermal junction and formation of Pautrier microabscesses. An aberrant immunophenotype of T cells and molecular detection of a clonal T-cell population are factors that could allow a more specific diagnosis. This work recapitulates and discusses these features from a practical perspective.
Topics: Biopsy; Dermis; Epidermis; Humans; Immunophenotyping; Lymphocytes; Mycosis Fungoides; Skin Neoplasms; T-Lymphocytes
PubMed: 27141565
DOI: 10.1515/rjim-2016-0001 -
Italian Journal of Pediatrics Apr 2023Clinical manifestations of Epstein-Barr virus (EBV) infection are diverse. This study aimed to explore the immune response in EBV-related diseases and the correlation...
BACKGROUND
Clinical manifestations of Epstein-Barr virus (EBV) infection are diverse. This study aimed to explore the immune response in EBV-related diseases and the correlation between immune cells and adenosine deaminase (ADA) levels.
METHODS
This study was conducted at the Children's Hospital of Soochow University. In total, 104 patients with EBV-associated respiratory tract infection (EBV-RTI), 32 patients with atypical EBV infection, 54 patients with EBV-associated infectious mononucleosis (IM1, with normal alanine aminotransferase [ALT] levels), 50 patients with EBV-IM2 (with elevated ALT levels), 50 patients with acute respiratory infection (AURI, with other pathogens), and 30 healthy controls were enrolled in this study. Indicators of ADA, immunoglobulins (Igs), and lymphocyte subsets were analyzed for EBV-related diseases.
RESULTS
Differences in the white blood cell, lymphocyte counts, ADA levels, IgA, IgG and IgM titers, percentage of CD3, CD3CD4, CD3CD8, CD16CD56, CD3CD19, and CD19CD23 lymphocytes, and CD4/CD8 ratio between EBV-related disease groups were all statistically significant (P < 0.01). ADA levels in the EBV-related disease groups were significantly higher than those in the control group (P < 0.01). The lymphocyte count, ADA levels, IgA and IgG titers, and percentage of CD3 and CD3CD8 + lymphocytes in the atypical EBV infection, EBV-IM1, and EBV-IM2 groups were significantly higher than those in the EBV-RTI, AUTI, and control groups (P < 0.01), whereas the percentage of CD3CD4, CD3CD19, and CD19CD23 lymphocytes and CD4/CD8 ratio showed the opposite trend. ADA levels were consistent with and closely related to the viral load and cellular and humoral immunity in EBV-related diseases.
CONCLUSIONS
ADA levels, humoral immunity, and cellular immunity were diverse in EBV-related diseases, and ADA was closely related to Igs and lymphocyte subsets.
Topics: Child; Humans; Herpesvirus 4, Human; Epstein-Barr Virus Infections; Adenosine Deaminase; Lymphocyte Subsets; Lymphocyte Count; Antigens, CD19; Immunoglobulin A; Immunoglobulin G
PubMed: 37095577
DOI: 10.1186/s13052-023-01457-0 -
ELife Jun 2023Affinity matured self-reactive antibodies are found in autoimmune diseases like systemic lupus erythematous. Here, we used fate-mapping reporter mice and single-cell...
Affinity matured self-reactive antibodies are found in autoimmune diseases like systemic lupus erythematous. Here, we used fate-mapping reporter mice and single-cell transcriptomics coupled to antibody repertoire analysis to characterize the post-germinal center (GC) B cell compartment in a new mouse model of autoimmunity. Antibody-secreting cells (ASCs) and memory B cells (MemBs) from spontaneous GCs grouped into multiple subclusters. ASCs matured into two terminal clusters, with distinct secretion, antibody repertoire and metabolic profiles. MemBs contained FCRL5+ and CD23+ subsets, with different in vivo localization in the spleen. GC-derived FCRL5+ MemBs share transcriptomic and repertoire properties with atypical B cells found in aging and infection and localize to the marginal zone, suggesting a similar contribution to recall responses. While transcriptomically diverse, ASC and MemB subsets maintained an underlying clonal redundancy. Therefore, self-reactive clones could escape subset-targeting therapy by perpetuation of self-reactivity in distinct subsets.
Topics: Mice; Animals; B-Lymphocytes; Germinal Center; Autoimmunity; Autoimmune Diseases; Autoantibodies
PubMed: 37341394
DOI: 10.7554/eLife.81012 -
Cells Mar 2022Mycosis fungoides (MF) is the most common subtype of cutaneous T-cell lymphoma. Early-stage disease is characterized by superficial infiltrates of small- to medium-sized...
Mycosis fungoides (MF) is the most common subtype of cutaneous T-cell lymphoma. Early-stage disease is characterized by superficial infiltrates of small- to medium-sized atypical epidermotropic T lymphocytes that are clonal related. Nevertheless, the percentage of atypical T cells is low with many admixed reactive immune cells. Despite earlier studies, the composition and spatial characteristics of the cutaneous lymphocytic infiltrate has been incompletely characterized. Here, we applied mass cytometry to profile the immune system in skin biopsies of patients with early-stage MF and in normal skin from healthy individuals. Single-cell suspensions were prepared and labeled with a 43-antibody panel, and data were acquired on a Helios mass cytometer. Unbiased hierarchical clustering of the data identified the major immune lineages and heterogeneity therein. This revealed patient-unique cell clusters in both the CD4 and myeloid cell compartments but also phenotypically distinct cell clusters that were shared by most patients. To characterize the immune compartment in the tissue context, we developed a 36-antibody panel and performed imaging mass cytometry on MF skin tissue. This visualized the structure of MF skin and the distribution of CD4 T cells, regulatory T cells, CD8 T cells, malignant T cells, and various myeloid cell subsets. We observed clusters of CD4 T cells and multiple types of dendritic cells (DCs) identified through differential expression of CD11c, CD1a, and CD1c in the dermis. These results indicated substantial heterogeneity in the composition of the local immune infiltrate but suggest a prominent role for clustered CD4-DC interactions in disease pathogenesis. Probably, the local inhibition of such interactions may constitute an efficient treatment modality.
Topics: CD8-Positive T-Lymphocytes; Humans; Lymphoma, T-Cell, Cutaneous; Mycosis Fungoides; Skin; Skin Neoplasms
PubMed: 35406628
DOI: 10.3390/cells11071062 -
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 -
Croatian Medical Journal Jun 2016To assess the diagnostic value of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in lung cancer (LC). We compared the ratios between healthy...
AIM
To assess the diagnostic value of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in lung cancer (LC). We compared the ratios between healthy participants and all LC patients, as well patients with different pathohistological LC subtypes.
METHODS
We retrieved the data on neutrophil, lymphocyte, and platelet levels in 449 patients with different pathohistological LC subtypes (non-small cell LC, small-cell LC, atypical or metastatic LC, neuroendocrine, and sarcomatoid carcinoma) and 47 healthy controls. NLR and PLR were calculated by dividing the absolute number of neutrophils or platelets with the absolute number of lymphocytes.
RESULTS
There were significant differences in both NLR and PLR (P<0.001) between all LC patients and the control group, but there were no differences between patients with different LC subtypes. Reciever operating characteristics analysis for NLR showed the optimal cut-off value of 2.71, with a sensitivity of 77.05% and specificity of 87.23%. The optimal cut-off value for PLR was 182.31, with a sensitivity of 51.09% and specificity of 91.49%.
CONCLUSION
The results showed that the NLR and PLR may have added value in the early diagnosis of LC, but further research is needed to confirm these results.
Topics: Blood Platelets; Female; Humans; Lung Neoplasms; Lymphocytes; Male; Middle Aged; Neutrophils; Prognosis; ROC Curve; Retrospective Studies; Sensitivity and Specificity
PubMed: 27374830
DOI: 10.3325/cmj.2016.57.287 -
Immunological Reviews Mar 2012From the very early days of nuclear factor-κB (NF-κB) research, it was recognized that different protein kinase C (PKC) isoforms might be involved in the activation of... (Review)
Review
From the very early days of nuclear factor-κB (NF-κB) research, it was recognized that different protein kinase C (PKC) isoforms might be involved in the activation of NF-κB. Pharmacological tools and pseudosubstrate inhibitors suggested that these kinases play a role in this important inflammatory and survival pathway; however, it was the analysis of several genetic mouse knockout models that revealed the complexity and interrelations between the different components of the PB1 network in several cellular functions, including T-cell biology, bone homeostasis, inflammation associated with the metabolic syndrome, and cancer. These studies unveiled, for example, the critical role of PKCζ as a positive regulator of NF-κB through the regulation of RelA but also its inflammatory suppressor activities through the regulation of the interleukin-4 signaling cascade. This observation is of relevance in T cells, where p62, PKCζ, PKCλ/ι, and NBR1 establish a mesh of interactions that culminate in the regulation of T-cell effector responses through the modulation of T-cell polarity. Many questions remain to be answered, not just from the point of view of the implication for NF-κB activation but also with regard to the in vivo interplay between these pathways in pathophysiological processes like obesity and cancer.
Topics: Adipocytes; Animals; Humans; Inflammation; Isoenzymes; Lymphocyte Activation; NF-kappa B; Protein Kinase C; Receptors, Proteinase-Activated; Signal Transduction; T-Lymphocytes
PubMed: 22435553
DOI: 10.1111/j.1600-065X.2012.01093.x -
Immunologic Research Aug 2014Emerging respiratory coronaviruses such as the severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) pose... (Review)
Review
Emerging respiratory coronaviruses such as the severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) pose potential biological threats to humans. SARS and MERS are manifested as severe atypical pneumonia associated with high morbidity and mortality in humans. The majority of studies carried out in SARS-CoV-infected humans and animals attribute a dysregulated/exuberant innate response as a leading contributor to SARS-CoV-mediated pathology. A decade after the 2002-2003 SARS epidemic, we do not have any approved preventive or therapeutic agents available in case of re-emergence of SARS-CoV or other related viruses. A strong neutralizing antibody response generated against the spike (S) glycoprotein of SARS-CoV is completely protective in the susceptible host. However, neutralizing antibody titers and the memory B cell response are short lived in SARS-recovered patients and the antibody will target primary homologous strain. Interestingly, the acute phase of SARS in humans is associated with a severe reduction in the number of T cells in the blood. Surprisingly, only a limited number of studies have explored the role of the T cell-mediated adaptive immune response in respiratory coronavirus pathogenesis. In this review, we discuss the role of anti-virus CD4 and CD8 T cells during respiratory coronavirus infections with a special emphasis on emerging coronaviruses.
Topics: Animals; B-Lymphocytes; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Humans; Immunity, Cellular; Immunologic Memory; Middle East Respiratory Syndrome Coronavirus; Portraits as Topic; Severe acute respiratory syndrome-related coronavirus; Severe Acute Respiratory Syndrome; Time Factors
PubMed: 24845462
DOI: 10.1007/s12026-014-8534-z