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Journal of Clinical Immunology Apr 2022Anti-interferon (IFN)-γ autoantibodies (anti-IFN-γ Abs) is an emerging adult-onset immunodeficiency syndrome. Immune dysfunction in this distinct disorder remains to...
PURPOSE
Anti-interferon (IFN)-γ autoantibodies (anti-IFN-γ Abs) is an emerging adult-onset immunodeficiency syndrome. Immune dysfunction in this distinct disorder remains to be clarified.
METHODS
We prospectively collected blood samples of 20 patients with anti-IFN-γ Abs and 40 healthy normal subjects. The percentages of lymphocyte subpopulations, most relevant to T, B, and NK cells, and the percentages of stimulated lymphocytes with cytokine production were assessed using eight-color flow cytometry. The results were adjusted to age and absolute lymphocyte counts.
RESULTS
Most (85%) patients presented nontuberculous mycobacterial infection. Skin lesions were predominantly manifested by neutrophilic dermatoses. The involved lymph nodes had granulomatous inflammation, except 22.2% showing atypical lymphoid hyperplasia without granuloma formation. The percentages of CD4 + T cells and nonactivated subpopulations (recent thymic emigrants and naïve subtypes) decreased significantly with increased expression of activation markers and polarization to differentiated cells. The percentage of NK cells increased, but that of two major NK subpopulations, CD161 + CD56 and CD161 + CD56 + CD16 + subsets, decreased. Increased CD161, CD161 + CD56 - CD16 + , and CD57 + NK cell subsets coupled with the decreased expression of NKp30 and NKp46 indicate reconfiguration of the NK cell population and acquisition of adaptive features. Intracellular cytokine production of the lymphocyte subpopulations was significantly low in the patients compared with the control group.
CONCLUSION
We conclude that the immune system in patients with anti-IFN-γ Abs could be exhausted in T cells and be adaptive in NK cells, contributing to the distinct clinicopathologic features.
Topics: Autoantibodies; CD56 Antigen; Flow Cytometry; Humans; Immunologic Deficiency Syndromes; Interferon-gamma; Killer Cells, Natural; Phenotype
PubMed: 35089479
DOI: 10.1007/s10875-022-01210-y -
Frontiers in Immunology 2022Long-term protective immunity to infectious disease depends on cell-mediated and humoral immune responses. Induction of a strong humoral response relies on efficient B... (Review)
Review
Long-term protective immunity to infectious disease depends on cell-mediated and humoral immune responses. Induction of a strong humoral response relies on efficient B cell activation and differentiation to long-lived plasma cells and memory B cells. For many viral or bacterial infections, a single encounter is sufficient to induce such responses. In malaria, the induction of long-term immunity can take years of pathogen exposure to develop, if it occurs at all. This repeated pathogen exposure and suboptimal immune response coincide with the expansion of a subset of B cells, often termed atypical memory B cells. This subset is present at low levels in healthy individuals as well but it is observed to expand in an inflammatory context during acute and chronic infection, autoimmune diseases or certain immunodeficiencies. Therefore, it has been proposed that this subset is exhausted, dysfunctional, or potentially autoreactive, but its actual role has remained elusive. Recent reports have provided new information regarding both heterogeneity and expansion of these cells, in addition to indications on their potential role during normal immune responses to infection or vaccination. These new insights encourage us to rethink how and why they are generated and better understand their role in our complex immune system. In this review, we will focus on recent advances in our understanding of these enigmatic cells and highlight the remaining gaps that need to be filled.
Topics: Autoimmune Diseases; B-Lymphocytes; Cell Differentiation; Humans; Immunologic Memory; Inflammation
PubMed: 35812395
DOI: 10.3389/fimmu.2022.908034 -
Pathology, Research and Practice Sep 2020
Topics: Betacoronavirus; COVID-19; Coronavirus Infections; Humans; Lymphocytes; Pandemics; Pneumonia, Viral; SARS-CoV-2; Severe Acute Respiratory Syndrome
PubMed: 32825937
DOI: 10.1016/j.prp.2020.153063 -
Laboratory Medicine Sep 2021Platelet and erythrocyte agglutination is known to happen in vitro due to EDTA or temperature-induced cold antibodies. Leukocyte agglutination is far less common, and...
Platelet and erythrocyte agglutination is known to happen in vitro due to EDTA or temperature-induced cold antibodies. Leukocyte agglutination is far less common, and its etiology is not always known. The 2 cases presented herein are of low-grade B-cell lymphomas consistent with splenic marginal-zone lymphoma that presented with lymphocyte agglutination. In Case A, the lymphocyte aggregates were not resolved by warming the sample or by non-EDTA anticoagulation. In Case B, the lymphocyte aggregates were largely resolved by warming the specimen at 37°C for 15 minutes. The 2 cases presented herein further show that the etiology of lymphocyte aggregation can have multiple causes, even within the same disease process.
Topics: Agglutination; Blood Platelets; Humans; Lymphocytes; Lymphoma, B-Cell
PubMed: 33900388
DOI: 10.1093/labmed/lmab010 -
Surgical Pathology Clinics Jun 2023Coronavirus disease 2019 is caused by severe acute respiratory syndrome coronavirus 2 and is associated with pronounced hematopathologic findings. Peripheral blood... (Review)
Review
Coronavirus disease 2019 is caused by severe acute respiratory syndrome coronavirus 2 and is associated with pronounced hematopathologic findings. Peripheral blood features are heterogeneous and very often include neutrophilia, lymphopenia, myeloid left shift, abnormally segmented neutrophils, atypical lymphocytes/plasmacytoid lymphocytes, and atypical monocytes. Bone marrow biopsies and aspirates are often notable for histiocytosis and hemophagocytosis, whereas secondary lymphoid organs may exhibit lymphocyte depletion, pronounced plasmacytoid infiltrates, and hemophagocytosis. These changes are reflective of profound innate and adaptive immune dysregulation, and ongoing research efforts continue to identify clinically applicable biomarkers of disease severity and outcome.
Topics: Humans; COVID-19; SARS-CoV-2; Lymphopenia
PubMed: 37149356
DOI: 10.1016/j.path.2023.01.007 -
Current Opinion in HIV and AIDS Sep 2021HIV-1 elite controllers encompass small populations of people infected with HIV-1 who can spontaneously control plasma viral loads below the limit of detection, in the... (Review)
Review
PURPOSE OF REVIEW
HIV-1 elite controllers encompass small populations of people infected with HIV-1 who can spontaneously control plasma viral loads below the limit of detection, in the absence of antiretroviral treatment. Antiviral immune responses are likely to contribute to such an impressive HIV-1 disease outcome. In this review, we discuss recent novel findings regarding antiviral innate and adaptive immune responses in elite controllers.
RECENT FINDINGS
Elite controllers maintain a pool of infected cells in which intact HIV-1 proviruses are more frequently integrated into noncoding regions of the host genome, likely conferring a state of deep latency. This atypical viral reservoir configuration is best explained by potent antiviral immune responses that can successfully eliminate virally infected cells in which proviruses are integrated into permissive chromatin. However, identifying the specific type and nature of this immune selection pressure represents a formidable challenge. Recent studies continue to support the role of HIV-1-specific CD8+ T cells as the main driver of elite immune control of HIV-1, however, increasing evidence suggests that their role is complemented by a fine-tuned interplay with innate immune cell subsets. Therefore, the combination of different immune effector mechanisms may shape antiviral immunity in elite controllers.
SUMMARY
Understanding the complex immune mechanisms responsible for natural, drug-free HIV-1 control represents a premier avenue to find and develop interventions for a cure of HIV-1 infection. Future single-cell assays designed to uncover the full genetic, epigenetic, transcriptional and functional complexity of antiviral immune responses in elite controllers may allow us to define correlates of antiviral immune protection in greater detail.
Topics: CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; HIV Infections; HIV-1; Humans; Proviruses; Viral Load
PubMed: 34270465
DOI: 10.1097/COH.0000000000000693 -
Virchows Archiv : An International... Jan 2023Hodgkin lymphoma was the first of the lymphomas to be recognized as a specific disease entity. However, recent studies have highlighted the heterogeneity of the diseases... (Review)
Review
Hodgkin lymphoma was the first of the lymphomas to be recognized as a specific disease entity. However, recent studies have highlighted the heterogeneity of the diseases associated with this eponym warranting clarification and refinement of diagnostic terminology. While classic Hodgkin lymphoma (CHL) remains an essentially unchanged diagnostic entity in the 2022 International Consensus Classification of Mature Lymphoid Neoplasms (2022 ICC), nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is now renamed nodular lymphocyte predominant B cell lymphoma (NLPBL) in recognition of the distinct pathologic, biologic, and clinical differences. Fan patterns A, B, and C (sharing the presence of evident follicular structures, and retention of a B cell rich background) will be combined in "typical" or grade 1, while the other "variant" patterns, D, E, and F, are considered grade 2. T-cell/histiocyte-rich large B cell lymphoma (THRBCL) is considered part of the "variant" NLPHL continuum.The entity previously known as "B cell lymphoma, unclassifiable (BCLU), with features intermediate between diffuse large B cell lymphoma (DLBCL) and CHL" has been renamed "mediastinal gray zone lymphoma" (MGZL) in recognition of the importance of the thymic niche in the biology of this tumor. The diagnostic criteria for MGZL have been refined and require both a high tumor cell density and a strongly preserved B cell program.This article will describe updates on CHL, NLPBL, and MGZL in the recently published 2022 ICC and provide some useful differential diagnostic clues in cases with atypical morphology or immunophenotype.
Topics: Humans; Hodgkin Disease; Diagnosis, Differential; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Follicular; B-Lymphocytes; Mediastinal Neoplasms
PubMed: 36274093
DOI: 10.1007/s00428-022-03427-z -
Science Translational Medicine Jan 2023Natural killer (NK) cells likely play an important role in immunity to malaria, but the effect of repeated malaria on NK cell responses remains unclear. Here, we...
Natural killer (NK) cells likely play an important role in immunity to malaria, but the effect of repeated malaria on NK cell responses remains unclear. Here, we comprehensively profiled the NK cell response in a cohort of 264 Ugandan children. Repeated malaria exposure was associated with expansion of an atypical, CD56 population of NK cells that differed transcriptionally, epigenetically, and phenotypically from CD56 NK cells, including decreased expression of PLZF and the Fc receptor γ-chain, increased histone methylation, and increased protein expression of LAG-3, KIR, and LILRB1. CD56 NK cells were highly functional and displayed greater antibody-dependent cellular cytotoxicity than CD56 NK cells. Higher frequencies of CD56 NK cells were associated with protection against symptomatic malaria and high parasite densities. After marked reductions in malaria transmission, frequencies of these cells rapidly declined, suggesting that continuous exposure to is required to maintain this modified, adaptive-like NK cell subset.
Topics: Child; Humans; CD56 Antigen; Killer Cells, Natural; Plasmodium falciparum; Receptors, Fc; Malaria
PubMed: 36696483
DOI: 10.1126/scitranslmed.add9012 -
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 -
Immunological Reviews Nov 2019T cells exposed to persistent antigen in the inflammatory environment of chronic infections often show progressive loss of effector functions, high expression of... (Review)
Review
T cells exposed to persistent antigen in the inflammatory environment of chronic infections often show progressive loss of effector functions, high expression of inhibitory receptors and distinct transcriptional programs. T cells in this functional state are termed "exhausted" and T cell exhaustion is associated with inefficient control of infections. A remarkably similar scenario has been described for B cells during chronic infections in humans, including malaria, in which case a subpopulation of atypical memory B cells (MBCs) greatly expands and these MBCs show attenuation of B cell receptor signaling, loss of the B cell effector functions of antibody and cytokine production, high expression of inhibitory receptors and distinct transcriptional profiles. The expansion of these MBCs is also associated with inefficient control of infections. Despite the similarities with exhausted T cells we speculate that at least in malaria, atypical MBCs may not be exhausted but rather may be functional, possibly even beneficial. Our recent results suggest that we simply may not have known how to ask an atypical MBC to function. Thus, exhaustion may not be in the human B cell's vocabulary, at least not in malaria.
Topics: Animals; Antigens, Protozoan; B-Lymphocytes; Humans; Immunologic Memory; Malaria; Receptors, Antigen, B-Cell; Signal Transduction; T-Lymphocytes
PubMed: 31553065
DOI: 10.1111/imr.12809