{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T13:50:42Z","timestamp":1774533042068,"version":"3.50.1"},"reference-count":48,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2023,6,9]],"date-time":"2023-06-09T00:00:00Z","timestamp":1686268800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pathogens"],"abstract":"<jats:p>Tuberculosis (TB) remains a public health problem worldwide and is one of the deadliest infectious diseases, only after the current COVID-19 pandemic. Despite significant advances in the TB field, there needs to be more immune response comprehension; for instance, the role played by humoral immunity is still controversial. This study aimed to identify the frequency and function of B1 and immature\/transitional B cells in patients with active and latent TB (ATB and LTB, respectively). Here we show that LTB patients have an increased frequency of CD5+ B cells and decreased CD10+ B cells. Furthermore, LTB patients stimulated with mycobacteria\u2019s antigens increase the frequency of IFN-\u03b3-producing B cells, whereas cells from ATB do not respond. Moreover, under the mycobacterial protein stimulus, LTB promotes a pro-inflammatory environment characterized by a high level of IFN-\u03b3 but also can produce IL-10. Regarding the ATB group, they cannot produce IFN-\u03b3, and mycobacterial lipids and proteins stimulate only the IL-10 production. Finally, our data showed that in ATB, but not in LTB, B cell subsets correlate with clinical and laboratory parameters, suggesting that these CD5+ and CD10+ B cell subpopulations have the potential to be biomarkers to differentiate between LTB and ATB. In conclusion, LTB has increased CD5+ B cells, and these cells can maintain a rich microenvironment of IFN-\u03b3, IL-10, and IL-4. In contrast, ATB only maintains an anti-inflammatory environment when stimulated with mycobacterial proteins or lipids.<\/jats:p>","DOI":"10.3390\/pathogens12060818","type":"journal-article","created":{"date-parts":[[2023,6,9]],"date-time":"2023-06-09T09:54:32Z","timestamp":1686304472000},"page":"818","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Latent Tuberculosis Patients Have an Increased Frequency of IFN-\u03b3-Producing CD5+ B Cells, Which Respond Efficiently to Mycobacterial Proteins"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4707-718X","authenticated-orcid":false,"given":"Julio","family":"Flores-Gonzalez","sequence":"first","affiliation":[{"name":"Laboratory of Integrative Immunology, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas, Mexico City 14080, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2004-7570","authenticated-orcid":false,"given":"Lucero A.","family":"Ram\u00f3n-Luing","sequence":"additional","affiliation":[{"name":"Laboratory of Integrative Immunology, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas, Mexico City 14080, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jesus","family":"Romero-Tendilla","sequence":"additional","affiliation":[{"name":"Laboratory of Integrative Immunology, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas, Mexico City 14080, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexia","family":"Urb\u00e1n-Solano","sequence":"additional","affiliation":[{"name":"Laboratory of Integrative Immunology, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas, Mexico City 14080, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alfredo","family":"Cruz-Lagunas","sequence":"additional","affiliation":[{"name":"Laboratory of Immunobiology and Genetic, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas, Mexico City 14080, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2334-0361","authenticated-orcid":false,"given":"Leslie","family":"Chavez-Galan","sequence":"additional","affiliation":[{"name":"Laboratory of Integrative Immunology, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas, Mexico City 14080, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,9]]},"reference":[{"key":"ref_1","unstructured":"Forum of International Respiratory Societies, and European Respiratory Society (2017). The Global Impact of Respiratory Disease, Forum of International Respiratory Societies."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1016\/S2213-2600(20)30105-3","article-title":"Prevalence and Attributable Health Burden of Chronic Respiratory Diseases, 1990\u20132017: A Systematic Analysis for the Global Burden of Disease Study 2017","volume":"8","author":"Soriano","year":"2020","journal-title":"Lancet Respir. Med."},{"key":"ref_3","unstructured":"World Health Organization (2022). Global Tuberculosis Report 2022, World Health Organization."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1642","DOI":"10.1016\/S0140-6736(19)30308-3","article-title":"Tuberculosis","volume":"393","author":"Furin","year":"2019","journal-title":"Lancet"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Houben, R.M.G.J., and Dodd, P.J. (2016). The Global Burden of Latent Tuberculosis Infection: A Re-Estimation Using Mathematical Modelling. PLoS Med., 13.","DOI":"10.1371\/journal.pmed.1002152"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"163","DOI":"10.3389\/fcimb.2020.00163","article-title":"Infection of Monocytes from Tuberculosis Patients with Two Virulent Clinical Isolates of Mycobacterium tuberculosis Induces Alterations in Myeloid Effector Functions","volume":"10","author":"Lavalett","year":"2020","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"640168","DOI":"10.3389\/fimmu.2021.640168","article-title":"B-Cells and Antibodies as Contributors to Effector Immune Responses in Tuberculosis","volume":"12","author":"Rijnink","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/j.tube.2016.08.001","article-title":"Antibodies and Tuberculosis","volume":"101","author":"Jacobs","year":"2016","journal-title":"Tuberculosis"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"S225","DOI":"10.1093\/cid\/civ614","article-title":"B in TB: B Cells as Mediators of Clinically Relevant Immune Responses in Tuberculosis","volume":"61","author":"Rao","year":"2015","journal-title":"Clin. Infect. Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1016\/j.cmi.2019.11.003","article-title":"An IFN-\u03b3 and TNF-\u03b1 Dual Release Fluorospot Assay for Diagnosing Active Tuberculosis","volume":"26","author":"Kim","year":"2020","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"727300","DOI":"10.3389\/fimmu.2021.727300","article-title":"High Dimensional Immune Profiling Reveals Different Response Patterns in Active and Latent Tuberculosis Following Stimulation with Mycobacterial Glycolipids","volume":"12","author":"Silva","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1164\/rccm.201707-1475OC","article-title":"B Cells Producing Type I IFN Modulate Macrophage Polarization in Tuberculosis","volume":"197","author":"Sakwa","year":"2018","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4768","DOI":"10.1038\/s41467-019-12824-z","article-title":"B-1a Cells Acquire Their Unique Characteristics by Bypassing the Pre-BCR Selection Stage","volume":"10","author":"Wong","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.cellimm.2012.01.007","article-title":"CD19+CD1d+CD5+ B Cell Frequencies Are Increased in Patients with Tuberculosis and Suppress Th17 Responses","volume":"274","author":"Zhang","year":"2012","journal-title":"Cell. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1016\/j.immuni.2008.03.017","article-title":"A Regulatory B Cell Subset with a Unique CD1dhiCD5+ Phenotype Controls T Cell-Dependent Inflammatory Responses","volume":"28","author":"Yanaba","year":"2008","journal-title":"Immunity"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4390","DOI":"10.1182\/blood-2004-11-4284","article-title":"Identification and Characterization of Circulating Human Transitional B Cells","volume":"105","author":"Sims","year":"2005","journal-title":"Blood"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2262","DOI":"10.1073\/pnas.0511094103","article-title":"Appearance of Immature\/Transitional B Cells in HIV-Infected Individuals with Advanced Disease: Correlation with Increased IL-7","volume":"103","author":"Malaspina","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"86","DOI":"10.30978\/TB2021-2-86","article-title":"WHO Consolidated Guidelines on Tuberculosis. Module 1: Prevention. Tuberculosis Preventive Treatment","volume":"2","author":"Organizat","year":"2021","journal-title":"Tuberc. Lung Dis. HIV Infect."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2473","DOI":"10.1093\/bioinformatics\/btw191","article-title":"FlowAI: Automatic and Interactive Anomaly Discerning Tools for Flow Cytometry Data","volume":"32","author":"Monaco","year":"2016","journal-title":"Bioinformatics"},{"key":"ref_20","first-page":"PA2432","article-title":"Pulmonary Hypertension in Pulmonary Tuberculosis\u2014A Prognostic Indicator","volume":"50","author":"Tiwari","year":"2017","journal-title":"Eur. Respir. Soc. J."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1016472","DOI":"10.3389\/fimmu.2022.1016472","article-title":"High Levels of PF4, VEGF-A, and Classical Monocytes Correlate with the Platelets Count and Inflammation during Active Tuberculosis","volume":"13","year":"2022","journal-title":"Front. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.3389\/fimmu.2020.01081","article-title":"Innate Immune Sensing by Cells of the Adaptive Immune System","volume":"11","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"747799","DOI":"10.3389\/fimmu.2022.747799","article-title":"Macrophage: A Cell with Many Faces and Functions in Tuberculosis","volume":"13","author":"Ahmad","year":"2022","journal-title":"Front. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1016\/j.cell.2020.09.062","article-title":"M. tuberculosis Reprograms Hematopoietic Stem Cells to Limit Myelopoiesis and Impair Trained Immunity","volume":"183","author":"Khan","year":"2020","journal-title":"Cell"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"La Manna, M.P., Shekarkar-Azgomi, M., Badami, G.D., Tamburini, B., Dieli, C., Di Carlo, P., Fasciana, T., Marcian\u00f2, V., Lo Sasso, B., and Giglio, R.V. (2022). Impact of Mycobacterium tuberculosis Infection on Human B Cell Compartment and Antibody Responses. Cells, 11.","DOI":"10.3390\/cells11182906"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Joosten, S.A., van Meijgaarden, K.E., del Nonno, F., Baiocchini, A., Petrone, L., Vanini, V., Smits, H.H., Palmieri, F., Goletti, D., and Ottenhoff, T.H.M. (2016). Patients with Tuberculosis Have a Dysfunctional Circulating B-Cell Compartment, Which Normalizes Following Successful Treatment. PLoS Pathog., 12.","DOI":"10.1371\/journal.ppat.1005687"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1186\/s10020-021-00320-4","article-title":"Anti-Tuberculosis Chemotherapy Alters TNFR2 Expression on CD4+ Lymphocytes in Both Drug-Sensitive and -Resistant Tuberculosis: However, Only Drug-Resistant Tuberculosis Maintains a pro-Inflammatory Profile after a Long Time","volume":"27","year":"2021","journal-title":"Mol. Med."},{"key":"ref_28","first-page":"6654220","article-title":"Leukocytes from Patients with Drug-Sensitive and Multidrug-Resistant Tuberculosis Exhibit Distinctive Profiles of Chemokine Receptor Expression and Migration Capacity","volume":"2021","author":"Herrera","year":"2021","journal-title":"J. Immunol. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1111\/j.1440-1843.2005.00711.x","article-title":"Levels of Tumour Necrosis Factor-Alpha and IL-1alpha in Newly Diagnosed and Multidrug Resistant Tuberculosis","volume":"10","author":"Cagatay","year":"2005","journal-title":"Respirology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1007\/s10238-013-0258-1","article-title":"Alterations in the Peripheral Blood B Cell Subpopulations of Multidrug-Resistant Tuberculosis Patients","volume":"14","author":"Abreu","year":"2014","journal-title":"Clin. Exp. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"JCD.S2822","DOI":"10.4137\/JCD.S2822","article-title":"Interferon-\u03b3 Regulates the Death of M. tuberculosis-Infected Macrophages","volume":"3","author":"Lee","year":"2010","journal-title":"J. Cell Death"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1038\/s42003-022-04265-0","article-title":"Mycobacterium tuberculosis Senses Host Interferon-\u03b3 via the Membrane Protein MmpL10","volume":"5","author":"Ahmed","year":"2022","journal-title":"Commun. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1016\/j.jiph.2019.03.001","article-title":"Increased CD5+ B-Cells Are Associated with Autoimmune Phenomena in Lepromatous Leprosy Patients","volume":"12","author":"Kotb","year":"2019","journal-title":"J. Infect. Public Health"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.1128\/CVI.00058-11","article-title":"Induction of B Cell Responses upon Experimental Infection of Neonatal Calves with Mycobacterium Avium Subsp. Paratuberculosis","volume":"18","author":"Stabel","year":"2011","journal-title":"Clin. Vaccine Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Stabel, J.R., Bannantine, J.P., and Humphrey, S. (2022). B Cell Phenotypes and Maturation States in Cows Naturally Infected with Mycobacterium Avium Subsp. Paratuberculosis. PLoS ONE, 17.","DOI":"10.1371\/journal.pone.0278313"},{"key":"ref_36","first-page":"282","article-title":"Protective Roles of Natural IgM Antibodies","volume":"3","author":"Vas","year":"2012","journal-title":"Front. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1111\/imm.12909","article-title":"Both B-1a and B-1b Cells Exposed to Mycobacterium tuberculosis Lipids Differentiate into IgM Antibody-Secreting Cells","volume":"154","author":"Savage","year":"2018","journal-title":"Immunology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"856906","DOI":"10.3389\/fimmu.2022.856906","article-title":"Defining Discriminatory Antibody Fingerprints in Active and Latent Tuberculosis","volume":"13","author":"Nziza","year":"2022","journal-title":"Front. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1111\/1348-0421.12674","article-title":"Serum Antibody Profiles in Individuals with Latent Mycobacterium tuberculosis Infection","volume":"63","author":"Maekura","year":"2019","journal-title":"Microbiol. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1016\/j.immuni.2016.04.003","article-title":"CD5 Binds to Interleukin-6 and Induces a Feed-Forward Loop with the Transcription Factor STAT3 in B Cells to Promote Cancer","volume":"44","author":"Zhang","year":"2016","journal-title":"Immunity"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1477","DOI":"10.1016\/j.imbio.2013.05.003","article-title":"Retinoic Acid and \u03b1-Galactosylceramide Regulate the Expression of Costimulatory Receptors and Transcription Factors Responsible for B Cell Activation and Differentiation","volume":"218","author":"Chen","year":"2013","journal-title":"Immunobiology"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"5982","DOI":"10.4049\/jimmunol.0801859","article-title":"Novel Human Transitional B Cell Populations Revealed by B Cell Depletion Therapy","volume":"182","author":"Palanichamy","year":"2009","journal-title":"J. Immunol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"264","DOI":"10.7555\/JBR.29.20150035","article-title":"Translating Transitions\u2014How to Decipher Peripheral Human B Celldevelopment","volume":"29","author":"Mats","year":"2015","journal-title":"J. Biomed. Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"745483","DOI":"10.1155\/2012\/745483","article-title":"Role of TNF-Alpha, IFN-Gamma, and IL-10 in the Development of Pulmonary Tuberculosis","volume":"2012","author":"Cavalcanti","year":"2012","journal-title":"Pulm. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1038\/cr.2013.155","article-title":"Identification of IFN-\u03b3-Producing Innate B Cells","volume":"24","author":"Bao","year":"2014","journal-title":"Cell Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1046\/j.1365-2249.2003.02121.x","article-title":"T Lymphocyte Phenotypic Profile in Lung Segments Affected by Cavitary and Non-Cavitary Tuberculosis","volume":"132","author":"Mazzarella","year":"2003","journal-title":"Clin. Exp. Immunol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2037","DOI":"10.18632\/oncotarget.12184","article-title":"Successful TB Treatment Induces B-Cells Expressing FASL and IL5RA MRNA","volume":"8","author":"Wagman","year":"2017","journal-title":"Oncotarget"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"851940","DOI":"10.3389\/fphar.2022.851940","article-title":"Interleukins 4 and 13 in Asthma: Key Pathophysiologic Cytokines and Druggable Molecular Targets","volume":"13","author":"Pelaia","year":"2022","journal-title":"Front. Pharmacol."}],"container-title":["Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-0817\/12\/6\/818\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:51:48Z","timestamp":1760125908000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-0817\/12\/6\/818"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,9]]},"references-count":48,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2023,6]]}},"alternative-id":["pathogens12060818"],"URL":"https:\/\/doi.org\/10.3390\/pathogens12060818","relation":{},"ISSN":["2076-0817"],"issn-type":[{"value":"2076-0817","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,9]]}}}