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1.
Nat Immunol ; 25(8): 1422-1431, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38961274

ABSTRACT

The differentiation of naive and memory B cells into antibody-secreting cells (ASCs) is a key feature of adaptive immunity. The requirement for phosphoinositide 3-kinase-delta (PI3Kδ) to support B cell biology has been investigated intensively; however, specific functions of the related phosphoinositide 3-kinase-gamma (PI3Kγ) complex in B lineage cells have not. In the present study, we report that PI3Kγ promotes robust antibody responses induced by T cell-dependent antigens. The inborn error of immunity caused by human deficiency in PI3Kγ results in broad humoral defects, prompting our investigation of roles for this kinase in antibody responses. Using mouse immunization models, we found that PI3Kγ functions cell intrinsically within activated B cells in a kinase activity-dependent manner to transduce signals required for the transcriptional program supporting differentiation of ASCs. Furthermore, ASC fate choice coincides with upregulation of PIK3CG expression and is impaired in the context of PI3Kγ disruption in naive B cells on in vitro CD40-/cytokine-driven activation, in memory B cells on toll-like receptor activation, or in human tonsillar organoids. Taken together, our study uncovers a fundamental role for PI3Kγ in supporting humoral immunity by integrating signals instructing commitment to the ASC fate.


Subject(s)
Antibody Formation , B-Lymphocytes , Cell Differentiation , Class Ib Phosphatidylinositol 3-Kinase , Animals , Class Ib Phosphatidylinositol 3-Kinase/metabolism , Class Ib Phosphatidylinositol 3-Kinase/immunology , Mice , Cell Differentiation/immunology , Humans , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , Antibody Formation/immunology , Mice, Knockout , Antibody-Producing Cells/immunology , Lymphocyte Activation/immunology , Mice, Inbred C57BL , Signal Transduction/immunology , Memory B Cells/immunology , Memory B Cells/metabolism
2.
Immunity ; 54(5): 1083-1095.e7, 2021 05 11.
Article in English | MEDLINE | ID: mdl-33891889

ABSTRACT

Multisystem inflammatory syndrome in children (MIS-C) is a life-threatening post-infectious complication occurring unpredictably weeks after mild or asymptomatic SARS-CoV-2 infection. We profiled MIS-C, adult COVID-19, and healthy pediatric and adult individuals using single-cell RNA sequencing, flow cytometry, antigen receptor repertoire analysis, and unbiased serum proteomics, which collectively identified a signature in MIS-C patients that correlated with disease severity. Despite having no evidence of active infection, MIS-C patients had elevated S100A-family alarmins and decreased antigen presentation signatures, indicative of myeloid dysfunction. MIS-C patients showed elevated expression of cytotoxicity genes in NK and CD8+ T cells and expansion of specific IgG-expressing plasmablasts. Clinically severe MIS-C patients displayed skewed memory T cell TCR repertoires and autoimmunity characterized by endothelium-reactive IgG. The alarmin, cytotoxicity, TCR repertoire, and plasmablast signatures we defined have potential for application in the clinic to better diagnose and potentially predict disease severity early in the course of MIS-C.


Subject(s)
COVID-19/immunology , COVID-19/pathology , SARS-CoV-2/immunology , Systemic Inflammatory Response Syndrome/immunology , Systemic Inflammatory Response Syndrome/pathology , Adolescent , Alarmins/immunology , Autoantibodies/immunology , CD8-Positive T-Lymphocytes/immunology , Child , Child, Preschool , Cytotoxicity, Immunologic/genetics , Endothelium/immunology , Endothelium/pathology , Humans , Killer Cells, Natural/immunology , Myeloid Cells/immunology , Plasma Cells/immunology , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell/immunology , Severity of Illness Index
3.
Sci Immunol ; 8(83): eadh3455, 2023 05 12.
Article in English | MEDLINE | ID: mdl-37146127

ABSTRACT

Rare immune-mediated cardiac tissue inflammation can occur after vaccination, including after SARS-CoV-2 mRNA vaccines. However, the underlying immune cellular and molecular mechanisms driving this pathology remain poorly understood. Here, we investigated a cohort of patients who developed myocarditis and/or pericarditis with elevated troponin, B-type natriuretic peptide, and C-reactive protein levels as well as cardiac imaging abnormalities shortly after SARS-CoV-2 mRNA vaccination. Contrary to early hypotheses, patients did not demonstrate features of hypersensitivity myocarditis, nor did they have exaggerated SARS-CoV-2-specific or neutralizing antibody responses consistent with a hyperimmune humoral mechanism. We additionally found no evidence of cardiac-targeted autoantibodies. Instead, unbiased systematic immune serum profiling revealed elevations in circulating interleukins (IL-1ß, IL-1RA, and IL-15), chemokines (CCL4, CXCL1, and CXCL10), and matrix metalloproteases (MMP1, MMP8, MMP9, and TIMP1). Subsequent deep immune profiling using single-cell RNA and repertoire sequencing of peripheral blood mononuclear cells during acute disease revealed expansion of activated CXCR3+ cytotoxic T cells and NK cells, both phenotypically resembling cytokine-driven killer cells. In addition, patients displayed signatures of inflammatory and profibrotic CCR2+ CD163+ monocytes, coupled with elevated serum-soluble CD163, that may be linked to the late gadolinium enhancement on cardiac MRI, which can persist for months after vaccination. Together, our results demonstrate up-regulation in inflammatory cytokines and corresponding lymphocytes with tissue-damaging capabilities, suggesting a cytokine-dependent pathology, which may further be accompanied by myeloid cell-associated cardiac fibrosis. These findings likely rule out some previously proposed mechanisms of mRNA vaccine--associated myopericarditis and point to new ones with relevance to vaccine development and clinical care.


Subject(s)
Antineoplastic Agents , COVID-19 , Myocarditis , Humans , Myocarditis/etiology , SARS-CoV-2 , Leukocytes, Mononuclear , COVID-19 Vaccines/adverse effects , Contrast Media , COVID-19/prevention & control , Gadolinium , Killer Cells, Natural , Cytokines
4.
Artif Intell Med ; 128: 102300, 2022 06.
Article in English | MEDLINE | ID: mdl-35534144

ABSTRACT

Indian healthcare is fast growing and with significant chunk of it being in small, fragmented, informal sector; Artificial Intelligence (AI) is pegged as a magical tool for a better healthcare system. There is an inclination to merely mimic the US approach in the on-going policy making and legislative exercises, which can have serious fallouts for Indian healthcare. India needs a different approach to suite her unique requirements. In this regard, each of the five stages in AI development lifecycle has been analyzed in the light of current on-ground realities. These boil down to three fold challenges of how to increase adoption of digital health, prevent data silos and create maximum value from data. Availability of quality data for value addition without barriers and restrictions is the common denominator for leveraging the full potential of AI. This requires liberal policies enabling secondary use of data in developing countries with rapidly growing healthcare sector akin to India. This has to be carefully balanced with data privacy and security. Restrictive healthcare data policies and laws can slow down adoption of digitization, perpetuate status-quo, be biased towards the incumbent players, cause Industry stagnation and thus will do more harm than good. It is therefore the data policies that will make or break AI in Indian healthcare.


Subject(s)
Artificial Intelligence , Delivery of Health Care , India
5.
Curr Opin Immunol ; 73: 50-57, 2021 12.
Article in English | MEDLINE | ID: mdl-34695727

ABSTRACT

Monogenic immune disorders provide unprecedented insights into the consequences of disrupting single genes in humans, thereby informing our understanding of fundamental immune function and disease. Genomics has accelerated monogenic disease discovery while also revealing the complexity of human disease, where several factors beyond the genome can govern pathogenesis. At this juncture, the optimal path forward will focus on maximizing basic and translational immunology insights from these disorders. This pursuit will be most direct and impactful if human disease gene discovery is paired with mechanistic studies employing integrative omics and mouse modeling to leverage their unique strengths.


Subject(s)
Immune System Diseases/genetics , Animals , Disease Models, Animal , Genetic Testing , Genomics , Humans , Mice , Proteomics , Translational Research, Biomedical
6.
medRxiv ; 2021 Apr 03.
Article in English | MEDLINE | ID: mdl-33300011

ABSTRACT

Multisystem inflammatory syndrome in children (MIS-C) is a life-threatening post-infectious complication occurring unpredictably weeks after mild or asymptomatic SARS-CoV2 infection in otherwise healthy children. Here, we define immune abnormalities in MIS-C compared to adult COVID-19 and pediatric/adult healthy controls using single-cell RNA sequencing, antigen receptor repertoire analysis, unbiased serum proteomics, and in vitro assays. Despite no evidence of active infection, we uncover elevated S100A-family alarmins in myeloid cells and marked enrichment of serum proteins that map to myeloid cells and pathways including cytokines, complement/coagulation, and fluid shear stress in MIS-C patients. Moreover, NK and CD8 T cell cytotoxicity genes are elevated, and plasmablasts harboring IgG1 and IgG3 are expanded. Consistently, we detect elevated binding of serum IgG from severe MIS-C patients to activated human cardiac microvascular endothelial cells in culture. Thus, we define immunopathology features of MIS-C with implications for predicting and managing this SARS-CoV2-induced critical illness in children.

7.
Trends Microbiol ; 28(12): 956-958, 2020 12.
Article in English | MEDLINE | ID: mdl-33190685

ABSTRACT

Following emergence of the coronavirus disease 2019 (COVID-19) pandemic, a surge in the life-threatening illness now termed 'multisystem inflammatory syndrome in children' (MIS-C) has raised questions about the unique effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in children and adolescents. Two important new studies by Consiglio et al. and Gruber et al. have begun to shine light on the immune drivers of this enigmatic disease.


Subject(s)
Coronavirus Infections , Coronavirus , Pandemics , Pneumonia, Viral , Severe Acute Respiratory Syndrome , Adolescent , Betacoronavirus , COVID-19 , Child , Coronavirus Infections/epidemiology , Humans , SARS-CoV-2 , Systemic Inflammatory Response Syndrome
8.
Cancer Discov ; 8(8): 1026-1043, 2018 08.
Article in English | MEDLINE | ID: mdl-29907586

ABSTRACT

Regulatory T cells (Treg) are critical for maintaining self-tolerance and immune homeostasis, but their suppressive function can impede effective antitumor immune responses. FOXP3 is a transcription factor expressed in Tregs that is required for their function. However, the pathways and microenvironmental cues governing FOXP3 expression and Treg function are not completely understood. Herein, we report that YAP, a coactivator of the Hippo pathway, is highly expressed in Tregs and bolsters FOXP3 expression and Treg function in vitro and in vivo. This potentiation stemmed from YAP-dependent upregulation of activin signaling, which amplifies TGFß/SMAD activation in Tregs. YAP deficiency resulted in dysfunctional Tregs unable to suppress antitumor immunity or promote tumor growth in mice. Chemical YAP antagonism and knockout or blockade of the YAP-regulated activin receptor similarly improved antitumor immunity. Thus, we identify YAP as an unexpected amplifier of a Treg-reinforcing pathway with significant potential as an anticancer immunotherapeutic target.Significance: Tregs suppress antitumor immunity, and pathways supporting their function can be novel immunotherapy targets. Here, the selective expression of YAP by Tregs, its importance for their function, and its unexpected enhancement of pro-Treg Activin/SMAD signaling are reported, as are validations of potential cancer-fighting antagonists of YAP and its regulatory targets. Cancer Discov; 8(8); 1026-43. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 899.


Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolism , Forkhead Transcription Factors/metabolism , Neoplasms, Experimental/pathology , Phosphoproteins/genetics , Phosphoproteins/metabolism , T-Lymphocytes, Regulatory/immunology , Activins/metabolism , Adult , Animals , Cell Line, Tumor , Female , Gene Expression Regulation, Neoplastic , Humans , Male , Mice , Mice, Knockout , Middle Aged , Neoplasms, Experimental/genetics , Neoplasms, Experimental/immunology , Neoplasms, Experimental/metabolism , Signal Transduction , Transcription Factors , Tumor Microenvironment , Up-Regulation , YAP-Signaling Proteins
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