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Journal of Immunology (Baltimore, Md. :... Nov 2020Use of the atypical antipsychotic clozapine is associated with life-threatening agranulocytosis. The delayed onset and the association with HLA variants are...
Use of the atypical antipsychotic clozapine is associated with life-threatening agranulocytosis. The delayed onset and the association with HLA variants are characteristic of an immunological mechanism. The objective of this study was to generate clozapine-specific T cell clones (TCC) and characterize pathways of T cell activation and cross-reactivity with clozapine metabolites and olanzapine. TCC were established and characterized by culturing PBMCs from healthy donors and patients with a history of clozapine-induced agranulocytosis. Modeling was used to explore the drug-HLA binding interaction. Global TCC protein changes were profiled by mass spectrometry. Six well-growing clozapine-responsive CD4 and CD8 TCC were used for experiments; activation of TCC required APC, with clozapine interacting directly at therapeutic concentrations with several HLA-DR molecules. TCC were also activated with -desmethylclozapine and olanzapine at supratherapeutic concentrations. Marked changes in TCC protein expression profiles were observed when clozapine treatment was compared with olanzapine and the medium control. Docking of the compounds into the HLA-DRB1*15:01 and HLA-DRB1*04:01 binding clefts revealed that clozapine and olanzapine bind in a similar conformation to the P4-P6 peptide binding pockets, whereas clozapine oxide, which did not activate the TCC, bound in a different conformation. TCC secreted Th1, Th2, and Th22 cytokines and effector molecules and expressed TCR Vβ 5.1, 16, 20, and 22 as well as chemokine receptors CXCR3, CCR6, CCR4, and CCR9. Collectively, these data show that clozapine interacts at therapeutic concentrations with HLA-DR molecules and activates human CD4 T cells. Olanzapine only activates TCC at supratherapeutic concentrations.
Topics: Adult; Clone Cells; Clozapine; Cross Reactions; Cytokines; Female; HLA-DR Antigens; Humans; Lymphocyte Activation; Male; Middle Aged; T-Lymphocytes
PubMed: 32989092
DOI: 10.4049/jimmunol.2000646 -
Clinical Rheumatology Feb 2020Leptin is the forerunner of the adipokine superfamily and plays a key role in regulating energy expenditure and neuroendocrine function. Researches into leptin put... (Review)
Review
Leptin is the forerunner of the adipokine superfamily and plays a key role in regulating energy expenditure and neuroendocrine function. Researches into leptin put emphasize not only on the metabolic role but also its immunoregulatory effect on immune response through immunocyte activation and cytokine secretion. Leptin acts on receptors that are widespread throughout the body and that are expressed across many tissue types. As a consequence, the abnormal expression of leptin has been found to correlate with a number of diseases, including cancers, autoimmune diseases, and cardiovascular diseases. The significance of leptin in the development of autoimmune diseases is becoming increasingly prominent. Systemic lupus erythematosus (SLE) is a severe atypical autoimmune disease that causes damage to multiple organ systems. It is characterised by the following: impaired clearance of apoptotic cells, loss of tolerance to self-antigens, aberrant activation of T cells and B cells, and chronic inflammation. The heightened immunocyte response in SLE means that these physiological systems are particularly vulnerable to regulation by leptin in addition to being of great significance to the research field. Our current review provides insight into the regulatory roles that leptin plays on immune effector cells in SLE.
Topics: B-Lymphocytes; Cytokines; Humans; Inflammation; Leptin; Lupus Erythematosus, Systemic; Macrophages; Neutrophils; T-Lymphocytes, Regulatory; Th17 Cells
PubMed: 31707542
DOI: 10.1007/s10067-019-04831-8 -
Nature Communications Oct 2022Interleukin-9 (IL-9)-producing CD4 T helper cells (Th9) have been implicated in allergy/asthma and anti-tumor immunity, yet molecular insights on their differentiation...
Interleukin-9 (IL-9)-producing CD4 T helper cells (Th9) have been implicated in allergy/asthma and anti-tumor immunity, yet molecular insights on their differentiation from activated T cells, driven by IL-4 and transforming growth factor-beta (TGF-β), is still lacking. Here we show opposing functions of two transcription factors, D-binding protein (DBP) and E2F8, in controlling Th9 differentiation. Specifically, TGF-β and IL-4 signaling induces phosphorylation of the serine 213 site in the linker region of the Smad3 (pSmad3L-Ser) via phosphorylated p38, which is necessary and sufficient for Il9 gene transcription. We identify DBP and E2F8 as an activator and repressor, respectively, for Il9 transcription by pSmad3L-Ser. Notably, Th9 cells with siRNA-mediated knockdown for Dbp or E2f8 promote and suppress tumor growth, respectively, in mouse tumor models. Importantly, DBP and E2F8 also exhibit opposing functions in regulating human TH9 differentiation in vitro. Thus, our data uncover a molecular mechanism of Smad3 linker region-mediated, opposing functions of DBP and E2F8 in Th9 differentiation.
Topics: Animals; Humans; Mice; Cell Differentiation; Interleukin-4; Interleukin-9; Repressor Proteins; RNA, Small Interfering; Serine; T-Lymphocytes, Helper-Inducer; Transforming Growth Factor beta; Transforming Growth Factors
PubMed: 36241625
DOI: 10.1038/s41467-022-33733-8 -
European Journal of Immunology Oct 2022Rituximab (RTX), a chimeric monoclonal antibody targeting CD20-positive cells, is a valuable treatment option for malignant and benign immune-related disorders. The... (Review)
Review
Rituximab (RTX), a chimeric monoclonal antibody targeting CD20-positive cells, is a valuable treatment option for malignant and benign immune-related disorders. The rationale of targeting the CD20 antigen relies on depletion of both healthy and autoreactive/malignant CD20-espressing cells, but normal B-cell reconstitution is expected within months after treatment. Nevertheless, a number of recent studies have documented prolonged B-cell deficiency associated with new-onset hypogammaglobulinemia in patients receiving RTX. Awareness of post-RTX hypogammaglobulinemia has become wider among clinicians, with a growing number of reports about the increased incidence, especially in children. Although these patients were previously regarded as affected by secondary/iatrogenic immunodeficiency, atypical clinical and immunological manifestations (e.g., severe or opportunistic infections; prolonged B-cell aplasia) raise concerns of delayed manifestations of genetic immunological disorders that have been unveiled by B-cell perturbation. As more patients with undiagnosed primary immune deficiency receiving RTX have been identified, it remains the challenge in discerning those that might display a higher risk of persistent RTX-associated hypogammaglobulinemia and need a tailored immunology follow-up. In this review, we summarize the principal evidence regarding post-RTX hypogammaglobulinemia and provide a guideline for identifying patients at higher risk of RTX-associated hypogammaglobulinemia that could harbor an inborn error of immunity.
Topics: Agammaglobulinemia; Antigens, CD20; B-Lymphocytes; Child; Humans; Immune System Diseases; Rituximab
PubMed: 35892275
DOI: 10.1002/eji.202149667 -
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 -
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 -
Poultry Science Aug 2021A description of standard and atypical heterophils, lymphocytes, and 2 types of giant cells found in the circulation of 17 wk commercial ducks (N = 24) in apparent...
A description of standard and atypical heterophils, lymphocytes, and 2 types of giant cells found in the circulation of 17 wk commercial ducks (N = 24) in apparent good health is the subject. Heterophils were sorted as either "classic" (HC) having red rod-shaped cytoplasmic granules, "typical" (HT) having weakly stained granules providing a reticular cytoplasmic appearance, or rarely as "variant" types (HV) having orange spherical granules. Atypical HT's and HC's were in 14 of 24 (58%) of the ducks. Small lymphocytes (Ls), reactive lymphocytes and plasmacytes (Lm) were routinely found. Giant cells, also present, were placed with Lm or monocytes (Mn) depending on cytology. Two counts of 200 leukocytes gave the total white count (TWBC) and 2 heterophil/lymphocyte ratios. H/L 1 = (HT + HC +HV) / Ls; and H/L 2 = (HT + HC + HV) / (Ls + Lm). The results showed that TWBC were normal (~ 23,000 /μL) but both H/L ratios were highly variable. HT were differentiated from HC on nuclear and cytoplasmic criteria. Many HT and HC exhibited signs of deterioration. Some giant cells likely represented developmental stages. Multiple nucleoli were evident in others suggesting polyploidy. The more common lymphoid giants were usually round whereas monocyte types were irregular. Mn types were actively phagocytic often consuming thrombocytes or rarely erythrocytes (RBC). Giant cells of either type were in 13 of 24 (54%) of the duck hemograms. Conidiospores were detected in the blood smears of 4 ducks and bacteria in 2 with 1 duck having both. As all ducks were in apparent good health the blood born microorganisms likely represented low grade infections. Presumably the atypical cells were a response to the presence of toxins of bacterial and fungal origin. The presence of atypical heterophils and lymphocytes complicates interpretation of H/L ratios traditionally used to establish stress. As atypical cells can be found in the context of normal TWBC or nonstress H/L values cytological observations attain additional importance. Moreover, giant cells may be useful indicators of infection even without direct microscopic observation or isolation of the offending organisms.
Topics: Animals; Blood Cell Count; Chickens; Ducks; Leukocytes; Plasma Cells
PubMed: 34225201
DOI: 10.1016/j.psj.2021.101248 -
Cell Metabolism Dec 2023The malate shuttle is known to maintain the balance of NAD/NADH between the cytosol and mitochondria. However, in T cells, it primarily detoxifies ammonia (via...
The malate shuttle is known to maintain the balance of NAD/NADH between the cytosol and mitochondria. However, in T cells, it primarily detoxifies ammonia (via GOT1-mediated production of 2-KG in an atypical reaction) and provides longevity to chronic-infection-induced T cells against ammonia-induced cell death.
Topics: Malates; Ammonia; T-Lymphocytes; Oxidation-Reduction; Mitochondria; Cytosol; NAD; Aspartic Acid; Malate Dehydrogenase
PubMed: 38056428
DOI: 10.1016/j.cmet.2023.11.005 -
Frontiers in Immunology 2022A series of rheumatoid arthritis (RA) studies established a PD-1CXCR5CD4 T-cell subset that was coined peripheral helper T (Tph) cells. CXCL13 production is a key... (Review)
Review
A series of rheumatoid arthritis (RA) studies established a PD-1CXCR5CD4 T-cell subset that was coined peripheral helper T (Tph) cells. CXCL13 production is a key feature of Tph cells and may contribute to the formation of tertiary lymphoid structures (TLS) in inflamed tissues. In addition, Tph cells provide help to B cells as efficiently as follicular helper T (Tfh) cells, and these features would implicate Tph cells in the pathogenesis of RA. Subsequent studies have revealed that Tph cells are involved in various human diseases such as autoimmune diseases, infectious diseases, and cancers. Although the analysis of human immunity has various limitations, accumulating evidence demonstrated the expansion of B cells with low somatic hypermutation and a link between TLS and immune functions in these diseases. We discuss about the emerging roles of the Tph cell and its relevant immune responses in peripheral tissues including B-cell expansion with atypical features.
Topics: Arthritis, Rheumatoid; B-Lymphocytes; Humans; Receptors, CXCR5; T-Lymphocyte Subsets; T-Lymphocytes, Helper-Inducer
PubMed: 35880181
DOI: 10.3389/fimmu.2022.946786 -
International Journal of Laboratory... Feb 2022
Topics: COVID-19; Humans; Lymphocytes; Pleural Effusion; Pneumonia; SARS-CoV-2
PubMed: 34146462
DOI: 10.1111/ijlh.13630