RÉSUMÉ
Post-injury dysfunction of humoral immunity accounts for infections and poor outcomes in cardiovascular diseases. Among immunoglobulins (Ig), IgA, the most abundant mucosal antibody, is produced by plasma B cells in intestinal Peyer's patches (PP) and lamina propria. Here we show that patients with stroke and myocardial ischemia (MI) had strongly reduced IgA blood levels. This was phenocopied in experimental mouse models where decreased plasma and fecal IgA were accompanied by rapid loss of IgA-producing plasma cells in PP and lamina propria. Reduced plasma IgG was detectable in patients and experimental mice 3-10 d after injury. Stroke/MI triggered the release of neutrophil extracellular traps (NETs). Depletion of neutrophils, NET degradation or blockade of NET release inhibited the loss of IgA+ cells and circulating IgA in experimental stroke and MI and in patients with stroke. Our results unveil how tissue-injury-triggered systemic NET release disrupts physiological Ig secretion and how this can be inhibited in patients.
Sujet(s)
Pièges extracellulaires , Infarctus du myocarde , Granulocytes neutrophiles , Pièges extracellulaires/métabolisme , Pièges extracellulaires/immunologie , Humains , Animaux , Infarctus du myocarde/immunologie , Infarctus du myocarde/anatomopathologie , Infarctus du myocarde/métabolisme , Mâle , Granulocytes neutrophiles/immunologie , Granulocytes neutrophiles/métabolisme , Femelle , Modèles animaux de maladie humaine , Souris de lignée C57BL , Accident vasculaire cérébral/immunologie , Accident vasculaire cérébral/anatomopathologie , Accident vasculaire cérébral/métabolisme , Plaques de Peyer/immunologie , Plaques de Peyer/anatomopathologie , Plaques de Peyer/métabolisme , Immunoglobuline A/métabolisme , Immunoglobuline A/immunologie , Immunoglobuline A/sang , Sujet âgé , Adulte d'âge moyen , Immunoglobuline G/immunologie , Immunoglobuline G/métabolisme , Immunité humorale , Études cas-témoins , Souris , Plasmocytes/immunologie , Plasmocytes/métabolismeRÉSUMÉ
A T-cell-independent (TI) pathway activated by microbiota results in the generation of low-affinity homeostatic IgA with a critical role in intestinal homeostasis. Moderate aerobic exercise (MAE) provides a beneficial impact on intestinal immunity, but the action of MAE on TI-IgA generation under senescence conditions is unknown. This study aimed to determine the effects of long-term MAE on TI-IgA production in young (3 month old) BALB/c mice exercised until adulthood (6 months) or aging (24 months). Lamina propria (LP) from the small intestine was obtained to determine B cell and plasma cell sub-populations by flow cytometry and molecular factors related to class switch recombination [Thymic Stromal Lymphopoietin (TSLP), A Proliferation-Inducing Ligand (APRIL), B Cell Activating Factor (BAFF), inducible nitric oxide synthase (iNOS), and retinal dehydrogenase (RDH)] and the synthesis of IgA [α-chain, interleukin (IL)-6, IL-21, and Growth Factor-ß (TGF-ß)]; and epithelial cells evaluated IgA transitosis [polymeric immunoglobulin receptor (pIgR), tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), IL-4] by the RT-qPCR technique. The results were compared with data obtained from sedentary age-matched mice. Statistical analysis was computed with ANOVA, and p < 0.05 was considered to be a statistically significant difference. Under senescence conditions, MAE promoted the B cell and IgA+ B cells and APRIL, which may improve the intestinal response and ameliorate the inflammatory environment associated presumably with the downmodulation of pro-inflammatory mediators involved in the upmodulation of pIgR expression. Data suggested that MAE improved IgA and downmodulate the cytokine pro-inflammatory expression favoring homeostatic conditions in aging.
Sujet(s)
Vieillissement , Homéostasie , Immunoglobuline A , Souris de lignée BALB C , Conditionnement physique d'animal , Animaux , Immunoglobuline A/métabolisme , Immunoglobuline A/immunologie , Souris , Vieillissement/immunologie , Cytokines/métabolisme , Lymphocytes B/immunologie , Lymphocytes B/métabolisme , Facteur d'activation des lymphocytes B/métabolisme , Facteur d'activation des lymphocytes B/génétique , Muqueuse intestinale/métabolisme , Muqueuse intestinale/immunologie , Intestin grêle/immunologie , Intestin grêle/métabolisme , Mâle , Plasmocytes/immunologie , Plasmocytes/métabolisme , Membre-13 de la superfamille du facteur de nécrose tumorale/métabolisme , Membre-13 de la superfamille du facteur de nécrose tumorale/génétiqueRÉSUMÉ
The two primary types of non-puerperal mastitis (NPM) are granulomatous lobular mastitis (GLM) and plasma cell mastitis (PCM). Existing research indicates that immune inflammatory response is considered to be the core of the pathogenesis of GLM and PCM, and both innate and adaptive immune responses play an important role in the pathophysiology of PCM and GLM. However, the regulatory balance between various immune cells in these diseases is still unclear. Consequently, we present a comprehensive summary of the immune-related variables and recent advances in GLM and PCM.
Sujet(s)
Mastite , Humains , Femelle , Animaux , Mastite/immunologie , Immunité innée , Plasmocytes/immunologie , Mastite granulomateuse/immunologie , Immunité acquiseRÉSUMÉ
The IgG4-associated autoimmune hepatitis (IgG4-AIH) is a newly proposed disease entity characterised by the accumulation of the IgG4-expressing plasma cells in the liver. Its pathophysiology and clinical significance remain unclear and have poor evidence in the paediatric population. Thus, our study aims at comparing the group of paediatric patients with classical AIH and the IgG4-AIH. We carried out a retrospective analysis of 23 children (median age 8.5 years) diagnosed with AIH, who were compared according to the presence of IgG4-positive plasma cells in the liver biopsy. IgG4-AIH was defined if 10 or more IgG4 positive plasma cells/high-power field were found in the biopsy. The presence of the IgG4 component seems to be clinically insignificant. That is why, the conventional immunosuppressive protocol should be considered the standard treatment in the case of the IgG4-associated AIH.
Sujet(s)
Hépatite auto-immune , Immunoglobuline G , Humains , Hépatite auto-immune/immunologie , Hépatite auto-immune/anatomopathologie , Enfant , Femelle , Mâle , Études rétrospectives , Immunoglobuline G/immunologie , Enfant d'âge préscolaire , Adolescent , Plasmocytes/immunologie , Plasmocytes/anatomopathologie , Maladie associée aux immunoglobulines G4/immunologie , Maladie associée aux immunoglobulines G4/anatomopathologie , Maladie associée aux immunoglobulines G4/diagnostic , Nourrisson , Foie/anatomopathologie , Foie/immunologie , BiopsieRÉSUMÉ
BACKGROUND Fluid overload-associated large B-cell lymphoma (FO-LBCL) is a recently described malignant lymphoma that presents with serous effusions in the pleura, peritoneum, and/or pericardium but without an identifiable lymphoma mass. This report describes the case of an 80-year-old man who presented with a pleural effusion and describes the approach to diagnosis and management of FO-LBCL. CASE REPORT We present a case of an 80-year-old man who presented with right pleural effusion and shortness of breath at work. Initial radiological assessment suggested a pleural effusion on the right side, without an identifiable mass, given the patient's symptoms and imaging characteristics. Subsequently, he underwent a pleural fluid puncture and biopsy. Based on the initial pathological assessment, malignant lymphoma, a non-epithelial tumor, was considered likely, but differentiation from reactive proliferative cells was difficult, given the patient's symptoms and cytologic characteristics. Postoperatively, histopathological examination and immunohistochemistry confirmed a diagnosis of FO-LBCL. After 1 year of follow-up, the condition had progressed and the patient died due to recurrence. CONCLUSIONS This report has presented a case of FO-LBCL in an elderly man with pleural effusion and described how this rare and recently described lymphoma was diagnosed and managed.
Sujet(s)
Lymphome B diffus à grandes cellules , Humains , Mâle , Sujet âgé de 80 ans ou plus , Lymphome B diffus à grandes cellules/anatomopathologie , Lymphome B diffus à grandes cellules/complications , Lymphome B diffus à grandes cellules/diagnostic , Plasmocytes/anatomopathologie , Épanchement pleural malin/étiologie , Issue fatale , Épanchement pleural/étiologieRÉSUMÉ
OBJECTIVE: To investigate the correlation between morphological typing and monoclonality of bone marrow plasma cells, and explore the diagnostic value of plasma cell morphological typing for high-risk smoldering multiple myeloma(HR-SMM). METHODS: The correlation between the morphological characteristics and the monoclonality of bone marrow plasma cells was analyzed in 84 patients with HR-SMM who treated in our hospital. The consistency of morphologically abnormal bone marrow plasma cells with serum free light chain (sFLC) ratio, next-generation sequencing (NGS) detection results, and its correlation with monoclonal plasma cells detected by flow cytometry (FCM) were further verified. The immunoglobulin types and levels of non-involved immunoglobulins in serum of the patients were detected, and the distribution of plasma cell clusters in patients with different disease was observed. RESULTS: The mean percentage of mature plasma cells were decreased successively in the order of reactive plasmacytosis (RP) group, monoclonal gammopathy of undetermined significance (MGUS) group, smoldering multiple myeloma (SMM) group, HR-SMM group and multiple myeloma (MM) group; while the mean percentage of immature, primitive, reticular and flaming plasma cells were increased successively in the order of RP group, MGUS group, SMM group, and HR-SMM group, and the difference between any two groups was statistically significant (P < 0.05).The average proportion of abnormal plasma cells in the bone marrow of HR-SMM patients was 96.2% of the total plasma cells. The proportion of abnormal plasma cells were in good agreement with the sFLC ratio and the results of NGS detection in HR-SMM patients (kappa=0.879 and kappa=0.891, both >0.75)ï¼and showed good correlation with the monoclonal plasma cells with immunophenotype of CD45-/CD38+/CD138+/CD56+/CD19-( γ=0.825). The levels of non-involved immunoglobulin in IgG, IgA and IgM type HR-SMM patients were all decreased by more than 25% compared with the normal reference range, and the differences were statistically significant (P < 0.05). There was no significant difference in the distribution ratio of plasma cell clusters among different disease groups (P >0.05). CONCLUSION: In HR-SMM patients, the immature, primitive, reticular and flaming plasma cells in bone marrow are considered as abnormal plasma cells, and they are correlated with monoclonal plasma cells. The proportion of abnormal plasma cells in total plasma cells of bone marrow and the reduction extent of non-involved immunoglobulin level in patients have certain reference value for the diagnosis of HR-SMM.
Sujet(s)
Myélome multiple , Plasmocytes , Humains , Myélome multiple/anatomopathologie , Myélome multiple indolent/diagnostic , Moelle osseuse/anatomopathologie , Cellules de la moelle osseuse , Cytométrie en flux , FumerSujet(s)
Maladie associée aux immunoglobulines G4 , Plasmocytes , Humains , Plasmocytes/anatomopathologie , Plasmocytes/immunologie , Maladie associée aux immunoglobulines G4/complications , Maladie associée aux immunoglobulines G4/anatomopathologie , Maladie associée aux immunoglobulines G4/diagnostic , Mâle , Maladies de la peau/anatomopathologie , Maladies de la peau/immunologie , Femelle , Adulte d'âge moyen , Sujet âgéRÉSUMÉ
Tertiary lymphoid structures (TLSs) are associated with enhanced immunity in tumors. However, their formation and functions in colorectal cancer liver metastasis (CRLM) remain unclear. Here, we reveal that intra- and peri-tumor mature TLSs (TLS+) are associated with improved clinical outcomes than TLS- tumors. Using single-cell-RNA-sequencing and spatial-enhanced-resolution-omics-sequencing (Stereo-seq), we reveal that TLS+ tumors are enriched with IgG+ plasma cells (PCs), while TLS- tumors are characterized with IgA+ PCs. By generating TLS-associated PC-derived monoclonal antibodies in vitro, we show that TLS-PCs secrete tumor-targeting antibodies. As the proof-of-concept, we demonstrate the anti-tumor activities of TLS-PC-mAb6 antibody in humanized mouse model of colorectal cancer. We identify a fibroblast lineage secreting CCL19 that facilitates lymphocyte trafficking to TLSs. CCL19 treatment promotes TLS neogenesis and prevents tumor growth in mice. Our data uncover the central role of CCL19+ fibroblasts in TLS formation, which in turn generates therapeutic antibodies to restrict CRLM.
Sujet(s)
Chimiokine CCL19 , Tumeurs colorectales , Immunoglobuline G , Tumeurs du foie , Structures lymphoïdes tertiaires , Tumeurs colorectales/anatomopathologie , Tumeurs colorectales/immunologie , Tumeurs colorectales/métabolisme , Animaux , Structures lymphoïdes tertiaires/immunologie , Structures lymphoïdes tertiaires/anatomopathologie , Humains , Tumeurs du foie/immunologie , Tumeurs du foie/secondaire , Tumeurs du foie/anatomopathologie , Tumeurs du foie/métabolisme , Souris , Immunoglobuline G/immunologie , Chimiokine CCL19/métabolisme , Chimiokine CCL19/génétique , Fibroblastes/métabolisme , Fibroblastes/immunologie , Anticorps monoclonaux/pharmacologie , Plasmocytes/immunologie , Plasmocytes/métabolisme , Femelle , Lignée cellulaire tumoraleRÉSUMÉ
Antibody-producing plasma cells fuel humoral immune responses. They also contribute to autoimmune diseases such as systemic lupus erythematosus or IgA nephropathy. Interleukin-6 and the tumor necrosis factor (TNF) family ligands BAFF (B cell-activating factor) and APRIL (a proliferation-inducing ligand) participate in plasma cell survival. BAFF binds to three receptors, BAFFR (BAFF receptor), TACI (transmembrane activator and CAML interactor), and BCMA (B cell maturation antigen), while APRIL binds to TACI, BCMA, and proteoglycans. However, which ligand-receptor pair(s) are required to maintain plasma cells in different body locations remains unknown. Here, by combining mouse genetic and pharmacological approaches, we found that plasma cells required BCMA and/or TACI but not BAFFR. BCMA responded exclusively to APRIL, while TACI responded to both BAFF and APRIL, identifying three self-sufficient ligand-receptor pairs for plasma cell maintenance: BAFF-TACI, APRIL-TACI, and APRIL-BCMA. Together, these actors accounted for 90% of circulating antibodies. In BAFF-ko mice, the reduction of plasma cells upon APRIL inhibition indicated that APRIL could function in the absence of BAFF-APRIL heteromers. No evidence was found that in the absence of BCMA and TACI, binding of APRIL to proteoglycans would help maintain plasma cells. IL-6, alone or together with BAFF and APRIL, supported mainly splenic plasmablasts and plasma cells and contributed to circulating IgG but not IgA levels. In conclusion, survival factors for plasma cells can vary with body location and with the antibody isotype that plasma cells produce. To efficiently target plasma cells, in particular IgA-producing ones, dual inhibition of BAFF and APRIL is required.
Sujet(s)
Facteur d'activation des lymphocytes B , Récepteur du BAFF , Antigène de maturation des cellules B , Interleukine-6 , Protéine TACI , Membre-13 de la superfamille du facteur de nécrose tumorale , Animaux , Facteur d'activation des lymphocytes B/immunologie , Facteur d'activation des lymphocytes B/métabolisme , Facteur d'activation des lymphocytes B/génétique , Membre-13 de la superfamille du facteur de nécrose tumorale/métabolisme , Membre-13 de la superfamille du facteur de nécrose tumorale/immunologie , Membre-13 de la superfamille du facteur de nécrose tumorale/génétique , Antigène de maturation des cellules B/immunologie , Antigène de maturation des cellules B/métabolisme , Protéine TACI/métabolisme , Protéine TACI/génétique , Protéine TACI/immunologie , Interleukine-6/métabolisme , Interleukine-6/immunologie , Souris , Récepteur du BAFF/métabolisme , Récepteur du BAFF/immunologie , Récepteur du BAFF/génétique , Plasmocytes/immunologie , Plasmocytes/métabolisme , Souris knockout , Cellules productrices d'anticorps/immunologie , Cellules productrices d'anticorps/métabolisme , Souris de lignée C57BLRÉSUMÉ
Bispecific antibodies are an important tool for the management and treatment of acute leukemias. As a next step toward clinical translation of engineered plasma cells, we describe approaches for secretion of bispecific antibodies by human plasma cells. We show that human plasma cells expressing either fragment crystallizable domain-deficient anti-CD19 × anti-CD3 (blinatumomab) or anti-CD33 × anti-CD3 bispecific antibodies mediate T cell activation and direct T cell killing of B acute lymphoblastic leukemia or acute myeloid leukemia cell lines in vitro. We demonstrate that knockout of the self-expressed antigen, CD19, boosts anti-CD19-bispecific secretion by plasma cells and prevents self-targeting. Plasma cells secreting anti-CD19-bispecific antibodies elicited in vivo control of acute lymphoblastic leukemia patient-derived xenografts in immunodeficient mice co-engrafted with autologous T cells. In these studies, we found that leukemic control elicited by engineered plasma cells was similar to CD19-targeted chimeric antigen receptor-expressing T cells. Finally, the steady-state concentration of anti-CD19 bispecifics in serum 1 month after cell delivery and tumor eradication was comparable with that observed in patients treated with a steady-state infusion of blinatumomab. These findings support further development of ePCs for use as a durable delivery system for the treatment of acute leukemias, and potentially other cancers.
Sujet(s)
Anticorps bispécifiques , Antigènes CD19 , Plasmocytes , Tests d'activité antitumorale sur modèle de xénogreffe , Humains , Anticorps bispécifiques/pharmacologie , Animaux , Souris , Antigènes CD19/immunologie , Antigènes CD19/génétique , Antigènes CD19/métabolisme , Plasmocytes/métabolisme , Plasmocytes/immunologie , Lignée cellulaire tumorale , Lymphocytes T/immunologie , Lymphocytes T/métabolisme , Antigènes CD3/immunologie , Antigènes CD3/métabolisme , Antigènes CD3/génétique , Activation des lymphocytes/immunologie , Cytotoxicité immunologiqueRÉSUMÉ
Hematopoietic and stromal cells within the bone marrow (BM) provide membrane-bound and/or soluble factors that are vital for the survival of plasma cells (PCs). Recent reports in murine BM demonstrated the dynamic formation and dispersion of PC clusters. To date, PC clustering in normal human BM has yet to be thoroughly examined. The goal of this study was to determine whether PC clusters are present in human BM and whether clustering changes as a function of age. Quantification of PCs and clustering in BM sections across six different age groups revealed that fewer PCs and PC clusters were observed in the youngest and oldest age groups. PC clustering increased with age until the sixth decade and then began to decrease. A positive correlation between the number of PCs and PC clusters was observed across all age groups. PC clusters were typically heterogeneous for immunoglobulin heavy- and light-chain expression. Taken together, these data demonstrate that PC clusters are present in human BM and that PC clustering increases until middle adulthood and then begins to diminish. These results suggest the spatial distribution of BM PC-supportive stromal cells changes with age.
Sujet(s)
Vieillissement , Plasmocytes , Humains , Adulte , Adulte d'âge moyen , Plasmocytes/cytologie , Plasmocytes/métabolisme , Sujet âgé , Mâle , Femelle , Jeune adulte , Sujet âgé de 80 ans ou plus , Adolescent , Moelle osseuse/métabolisme , Enfant , Enfant d'âge préscolaireSujet(s)
Leucémie aigüe myéloïde , Gammapathie monoclonale de signification indéterminée , Mutation , Protéines nucléaires , Nucléophosmine , Plasmocytes , Humains , Leucémie aigüe myéloïde/génétique , Leucémie aigüe myéloïde/anatomopathologie , Protéines nucléaires/génétique , Gammapathie monoclonale de signification indéterminée/génétique , Gammapathie monoclonale de signification indéterminée/anatomopathologie , Gammapathie monoclonale de signification indéterminée/complications , Plasmocytes/anatomopathologie , Plasmocytes/métabolisme , Mâle , Corps d'inclusion/anatomopathologie , Femelle , Adulte d'âge moyenRÉSUMÉ
Generation of a stable long-lived plasma cell (LLPC) population is the sine qua non of durable antibody responses after vaccination or infection. We studied 20 individuals with a prior coronavirus disease 2019 infection and characterized the antibody response using bone marrow aspiration and plasma samples. We noted deficient generation of spike-specific LLPCs in the bone marrow after severe acute respiratory syndrome coronavirus 2 infection. Furthermore, while the regression model explained 98% of the observed variance in anti-tetanus immunoglobulin G levels based on LLPC enzyme-linked immunospot assay, we were unable to fit the same model with anti-spike antibodies, again pointing to the lack of LLPC contribution to circulating anti-spike antibodies.
Sujet(s)
Anticorps antiviraux , Moelle osseuse , COVID-19 , Plasmocytes , SARS-CoV-2 , Glycoprotéine de spicule des coronavirus , Humains , COVID-19/immunologie , Plasmocytes/immunologie , Glycoprotéine de spicule des coronavirus/immunologie , Anticorps antiviraux/sang , SARS-CoV-2/immunologie , Mâle , Adulte d'âge moyen , Femelle , Moelle osseuse/virologie , Adulte , Immunoglobuline G/sang , Sujet âgéRÉSUMÉ
Nasal vaccination elicits a humoral immune response that provides protection from airborne pathogens1, yet the origins and specific immune niches of antigen-specific IgA-secreting cells in the upper airways are unclear2. Here we define nasal glandular acinar structures and the turbinates as immunological niches that recruit IgA-secreting plasma cells from the nasal-associated lymphoid tissues (NALTs)3. Using intact organ imaging, we demonstrate that nasal vaccination induces B cell expansion in the subepithelial dome of the NALT, followed by invasion into commensal-bacteria-driven chronic germinal centres in a T cell-dependent manner. Initiation of the germinal centre response in the NALT requires pre-expansion of antigen-specific T cells, which interact with cognate B cells in interfollicular regions. NALT ablation and blockade of PSGL-1, which mediates interactions with endothelial cell selectins, demonstrated that NALT-derived IgA-expressing B cells home to the turbinate region through the circulation, where they are positioned primarily around glandular acinar structures. CCL28 expression was increased in the turbinates in response to vaccination and promoted homing of IgA+ B cells to this site. Thus, in response to nasal vaccination, the glandular acini and turbinates provide immunological niches that host NALT-derived IgA-secreting cells. These cellular events could be manipulated in vaccine design or in the treatment of upper airway allergic responses.
Sujet(s)
Immunoglobuline A , Tissu lymphoïde , Muqueuse nasale , Plasmocytes , Lymphocytes T , Cornets , Animaux , Femelle , Mâle , Souris , Bactéries/immunologie , Mouvement cellulaire , Chimiokines CC/immunologie , Chimiokines CC/métabolisme , Centre germinatif/immunologie , Centre germinatif/cytologie , Immunoglobuline A/immunologie , Immunoglobuline A/métabolisme , Tissu lymphoïde/immunologie , Tissu lymphoïde/cytologie , Souris de lignée C57BL , Muqueuse nasale/cytologie , Muqueuse nasale/immunologie , Plasmocytes/immunologie , Plasmocytes/cytologie , Plasmocytes/métabolisme , Lymphocytes T/immunologie , Lymphocytes T/cytologie , Lymphocytes T/métabolisme , Cornets/cytologie , Cornets/immunologie , Vaccination , Administration par voie nasale , Vaccins/immunologie , SymbioseRÉSUMÉ
The upper airway is an important site of infection, but immune memory in the human upper airway is poorly understood, with implications for COVID-19 and many other human diseases1-4. Here we demonstrate that nasal and nasopharyngeal swabs can be used to obtain insights into these challenging problems, and define distinct immune cell populations, including antigen-specific memory B cells and T cells, in two adjacent anatomical sites in the upper airway. Upper airway immune cell populations seemed stable over time in healthy adults undergoing monthly swabs for more than 1 year, and prominent tissue resident memory T (TRM) cell and B (BRM) cell populations were defined. Unexpectedly, germinal centre cells were identified consistently in many nasopharyngeal swabs. In subjects with SARS-CoV-2 breakthrough infections, local virus-specific BRM cells, plasma cells and germinal centre B cells were identified, with evidence of local priming and an enrichment of IgA+ memory B cells in upper airway compartments compared with blood. Local plasma cell populations were identified with transcriptional profiles of longevity. Local virus-specific memory CD4+ TRM cells and CD8+ TRM cells were identified, with diverse additional virus-specific T cells. Age-dependent upper airway immunological shifts were observed. These findings provide new understanding of immune memory at a principal mucosal barrier tissue in humans.
Sujet(s)
Mémoire immunologique , Cellules B mémoire , Cellules T mémoire , Muqueuse nasale , Partie nasale du pharynx , SARS-CoV-2 , Adulte , Humains , Lymphocytes T CD4+/immunologie , Lymphocytes T CD4+/cytologie , Lymphocytes T CD8+/immunologie , Lymphocytes T CD8+/cytologie , COVID-19/immunologie , COVID-19/virologie , Centre germinatif/immunologie , Centre germinatif/cytologie , Immunoglobuline A/immunologie , Mémoire immunologique/immunologie , Cellules B mémoire/immunologie , Cellules T mémoire/immunologie , Muqueuse nasale/immunologie , Muqueuse nasale/virologie , Partie nasale du pharynx/virologie , Partie nasale du pharynx/immunologie , Plasmocytes/immunologie , Plasmocytes/cytologie , SARS-CoV-2/immunologieRÉSUMÉ
Plasma cells correspond to the last stage of B cell differentiation and are professional antibody-secreting cells. While most persist for only few days, some may survive for weeks to years in dedicated survival niches. The determination of plasma cell survival rate seems to rely both on intrinsic and extrinsic factors. Although often opposed, the deterministic and environmental models for plasma cell longevity are certainly overlapping. Understanding the contribution and the regulation of these different factors is paramount to develop better vaccines but also to target malignant plasma cells. Here, we review recent literature highlighting new findings pertaining to plasma cell survival rate, intrinsic regulation of plasma cell persistence and function, as well as the plasma cell/niche dialogue. Moreover, the now well-recognised heterogeneity observed among plasma cells is also discussed.
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Survie cellulaire , Plasmocytes , Humains , Plasmocytes/immunologie , Plasmocytes/cytologie , Animaux , Survie cellulaire/immunologie , Différenciation cellulaire/immunologieRÉSUMÉ
Memory B cells (MBCs) differentiate into plasma cells (PCs) or germinal centers (GCs) upon antigen recall. How this decision is programmed is not understood. We found that the relative strength between two antagonistic transcription factors, B lymphocyte-induced maturation protein 1 (BLIMP1) and BTB domain and CNC homolog 2 (BACH2), progressively increases in favor of BLIMP1 in antigen-responding B cells through the course of primary responses. MBC subsets that preferentially produce secondary GCs expressed comparatively higher BACH2 but lower BLIMP1 than those predisposed for PC development. Skewing the BLIMP1-BACH2 balance in otherwise fate-predisposed MBC subsets could switch their fate preferences. Underlying the changing BLIMP1-over-BACH2 balance, we observed progressively increased accessibilities at chromatin loci that are specifically opened in PCs, particularly those that contain interferon-sensitive response elements (ISREs) and are controlled by interferon regulatory factor 4 (IRF4). IRF4 is upregulated by B cell receptor, CD40 or innate receptor signaling and it induces graded levels of PC-specifying epigenetic imprints according to the strength of stimulation. By analyzing history-stamped GC B cells, we found progressively increased chromatin accessibilities at PC-specific, IRF4-controlled gene loci over time. Therefore, the cumulative stimulation history of B cells is epigenetically recorded in an IRF4-dependent manner, determines the relative strength between BLIMP1 and BACH2 in individual MBCs and dictates their probabilities to develop into GCs or PCs upon restimulation.
Sujet(s)
Facteurs de transcription à motif basique et à glissière à leucines , Différenciation cellulaire , Épigenèse génétique , Centre germinatif , Mémoire immunologique , Facteurs de régulation d'interféron , Cellules B mémoire , Plasmocytes , Facteur-1 liant le domaine de régulation positive I , Facteur-1 liant le domaine de régulation positive I/métabolisme , Facteur-1 liant le domaine de régulation positive I/génétique , Animaux , Facteurs de régulation d'interféron/métabolisme , Facteurs de régulation d'interféron/génétique , Souris , Facteurs de transcription à motif basique et à glissière à leucines/métabolisme , Facteurs de transcription à motif basique et à glissière à leucines/génétique , Cellules B mémoire/immunologie , Cellules B mémoire/métabolisme , Plasmocytes/immunologie , Plasmocytes/métabolisme , Centre germinatif/immunologie , Centre germinatif/métabolisme , Souris de lignée C57BL , Transduction du signal , Activation des lymphocytes/génétiqueRÉSUMÉ
Teleost IgM+ B cells can phagocytose, like mammalian B1 cells, and secrete Ag-specific IgM, like mammalian B2 cells. Therefore, teleost IgM+ B cells may have the functions of both mammalian B1 and B2 cells. To support this view, we initially found that grass carp (Ctenopharyngodon idella) IgM+ plasma cells (PCs) exhibit robust phagocytic ability, akin to IgM+ naive B cells. Subsequently, we sorted grass carp IgM+ PCs into two subpopulations: nonphagocytic (Pha-IgM+ PCs) and phagocytic IgM+ PCs (Pha+IgM+ PCs), both of which demonstrated the capacity to secrete natural IgM with LPS and peptidoglycan binding capacity. Remarkably, following immunization of grass carp with an Ag, we observed that both Pha-IgM+ PCs and Pha+IgM+ PCs could secrete Ag-specific IgM. Furthermore, in vitro concatenated phagocytosis experiments in which Pha-IgM+ PCs from an initial phagocytosis experiment were sorted and exposed again to beads confirmed that these cells also have phagocytic capabilities, thereby suggesting that all teleost IgM+ B cells have phagocytic potential. Additionally, we found that grass carp IgM+ PCs display classical phenotypic features of macrophages, providing support for the hypothesis that vertebrate B cells evolved from ancient phagocytes. These findings together reveal that teleost B cells are a primitive B cell type with functions reminiscent of both mammalian B1 and B2 cells, providing insights into the origin and evolution of B cells in vertebrates.
Sujet(s)
Lymphocytes B , Carpes (poisson) , Immunoglobuline M , Phagocytose , Plasmocytes , Animaux , Carpes (poisson)/immunologie , Immunoglobuline M/immunologie , Phagocytose/immunologie , Plasmocytes/immunologie , Lymphocytes B/immunologie , Phagocytes/immunologie , Évolution biologiqueRÉSUMÉ
OBJECTIVES: Patients diagnosed with primary sclerosing cholangitis (PSC) but with characteristics of immunoglobulin G4 (IgG4)-associated cholangitis (IAC) have been described. IAC often presents with biliary IgG4-positive plasma cell (IgG4+ PC) infiltration and responds to corticosteroids. In PSC, the frequencies or implications of biliary IgG4+ PC are unknown. We aimed to characterize the phenomenon of biliary IgG4+ PC in patients with an established PSC diagnosis. METHODS: Bile duct biopsies from 191 surveillance or therapeutic endoscopic retrograde cholangiography of 58 PSC patients were retrospectively analyzed for IgG4+ PC infiltration. Patients with ≥10 IgG4+ PC per high-power field (HPF) were identified and characterized by clinical parameters, including serum IgG4 and cholangiographic presentations. RESULTS: Altogether 39.7% of the PSC patients showed ≥10 IgG4+ PC/HPF in bile duct biopsies. Patients with biliary IgG4+ PC infiltration were significantly younger at diagnosis of PSC (P = 0.023). There was no association between biliary IgG4+ PC infiltration and transplant-free survival (P = 0.618). Patients with IgG4+ PC infiltration in bile duct biopsies showed significantly higher baseline (P = 0.002) and maximum (P = 0.001) serum IgG4 compared to those without. Biliary IgG4+ PC infiltration was associated with high-grade bile duct strictures (P = 0.05). IgG4-positive plasma cell infiltrations were found multifocally in 72.7% of this subgroup of PSC patients. CONCLUSIONS: IgG4+ PC ≥10/HPF can be found abundantly in bile duct biopsies in PSC. Histological findings correlated with serum IgG4, age, and high-grade bile duct strictures. IgG4+ PC was located multifocally, hinting at a systemic biliary phenotype.