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Lymphopenia is a unique manifestation of anti-MDA5 positive dermatomyositis with interstitial lung disease (MDA5 + DM-ILD). This study aimed to investigate the relationship between dynamic changes in peripheral lymphocytes and short-term prognosis in patients of MDA5 + DM-ILD. Two hundred sixty-three MDA5 + DM-ILD patients were divided into different groups according to lymphocyte count and death or survival within 1 month, then the differences in clinical features and outcomes were compared. Associations between lymphocytes and risk of death within 1 month were also investigated in different lymphocyte groups using Cox proportional hazard models. A generalized additive mixed model (GAMM) was established to analyze the dynamic changes of lymphocytes in the death 1-month group. Lymphocytes of the patients who died within 1 month were significantly lower than survivors by different lymphocyte grouping methods, and the total lymphocytes showed a gradually decreasing trend in non-survivors. And the difference between survivors and non-survivors was more obvious over time. The lowest tertile of baseline lymphocytes as a reference, the hazard ratios for death within 1 month in the highest tertile were 0.497 (95% CI 0.26-0.949, P for trend = 0.033) after adjustment for potential confounders. GAMM analysis found a mean daily decrease of lymphocytes (0.034 × 10^9/L) after admission in death 1-month patients. Low baseline lymphocytes and gradually declined lymphocytes are both associated with a high risk of death within 1 month. However dynamic changes in lymphocytes can better reflect the disease status and better predict the short-term prognosis than baseline lymphocytes in MDA5 + DM-ILD patients. Key points •Low baseline lymphocytes and gradually decreased trend along time correlated with poor short-term prognosis in MDA5 + DM-ILD patients. •Dynamic changes of lymphocytes can better reflect the disease status and better predict the 1-month prognosis than baseline lymphocytes in MDA5 + DM-ILD patients. •Generalized additive mixed model (GAMM) analysis found that in 1-month non-survivors, peripheral blood lymphocytes decreased by 0.034 × 10^9/L per day, while the lymphocytes in survivors gradually increased., (© 2024. The Author(s).)

Background: Herpes zoster (HZ) rarely results in subsequent death, but predictive biomarkers for mortality necessitate further elucidation., Objectives: To investigate immune dynamics prior to an HZ event, risk factors for HZ onset and immune status at initial HZ., Methods: This retrospective study extracted from patient records the absolute neutrophil and lymphocyte counts (ANC and ALC, respectively) at the initial HZ date of appearance and up to 30 days before HZ. A follow-up survey was completed within 180 days of onset of illness., Results: Patients with HZ showed a higher neutrophil-to-lymphocyte ratio (NLR) and lower ALC than patients in the control group at the initial date and had a poorer prognosis. In the pre-onset examination, the maximum and minimum ALC values were significantly lower in patients with HZ than in the control group, and the maximum ALC value in patients with HZ was lower than the minimum value in the control group. The lowest ALC was observed 7 days before the onset of HZ. An NLR of 4.53 or more and an ALC of 0.64 × 109 cells L-1 or less were predictive markers of HZ development within 30 days. Patients who died after HZ had a lower minimum ALC than those who survived longer., Conclusions: HZ develops in a state of immune reconstitution in patients with immunocompromised conditions, as part of 'unmasking' the immune reconstitution inflammatory syndrome. Lymphopenia prior to HZ onset is one of the most crucial factors in its pathogenesis and vital prognosis. Limitations of the study were small population size, varying age distribution, retrospective nature, and potential overestimation of pre-onset data., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Pathogenic variants in the transcription factor TP63 are associated with clinically overlapping syndromes including ectrodactyly-ectodermal dysplasia clefting (EEC) and ankyloblepharon-ectodermal defects-cleft lip/palate (AEC). T cell lymphopenia has rarely been described in individuals with TP63 variants and the cause of the T cell defect is unclear. Here, we present a case of a female infant born with TP63 -related syndrome and profound T cell lymphopenia, first uncovered through newborn screening. Flow cytometry analysis revealed low CD4+ naïve T cells and nearly absent CD8+ T cells with intact B and NK cell compartments. A de novo heterozygous pathogenic variant c.1040 G>A (C347Y) in exon 8 of TP63 was identified. An artificial thymic organoid system, to assess the intrinsic ability of the patient's hematopoietic cells to develop into T cells, was performed twice using separate peripheral blood samples. Ex vivo T cell differentiation was evident with the artificial organoid system, suggesting that a thymic stromal cell defect may be the cause of the T cell lymphopenia. Consistent with this, interrogation of publicly available data indicated that TP63 expression in the human thymus is restricted to thymic epithelial cells. Based on these data, congenital athymia was suspected and the patient received an allogenic cultured thymus tissue implant (CTTI). This is the first report of suspected congenital athymia and attempted treatment with CTTI associated with TP63 variant. At 9 months post-implant, peripheral lymphocyte analysis revealed measurable T cell receptor excision circles and presence of CD4+ recent thymic emigrants suggestive of early thymopoiesis. She will continue regular monitoring to ensure restoration of T cell immunity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Gall, Bosticardo, Ma, Chen, Amini, Pala, Delmonte, Wenger, Bamshad, Sleasman, Blessing, van Oers, Notarangelo and de la Morena.)

Objective: To analyze the lymphocyte subsets in individuals with Kabuki syndrome for better characterizing the immunological phenotype of this rare congenital disorder., Methods: We characterized the immunological profile including B-, T- and natural killer-cell subsets in a series (N = 18) of individuals with Kabuki syndrome., Results: All 18 individuals underwent genetic analysis: 15 had a variant in KMT2D and 3 a variant in KDM6A. Eleven of the 18 individuals (61%) had recurrent infections and 9 (50%) respiratory infections. Three (17%) had autoimmune diseases. On immunological analysis, 6 (33%) had CD4 T-cell lymphopenia, which was preferentially associated with the KMT2D truncating variant (5/9 individuals). Eight of 18 individuals (44%) had a humoral deficiency and eight (44%) had B lymphopenia. We found abnormal distributions of T-cell subsets, especially a frequent decrease in recent thymic emigrant CD4 + naive T-cell count in 13/16 individuals (81%)., Conclusion: The immunological features of Kabuki syndrome showed variable immune disorders with CD4 + T-cell deficiency in one third of cases, which had not been previously reported. In particular, we found a reduction in recent thymic emigrant naïve CD4 + T-cell count in 13 of 16 individuals, representing a novel finding that had not previously been reported., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The question whether interference with the ubiquitous splicing machinery can lead to cell-type specific perturbation of cellular function is addressed here by T cell specific ablation of the general U5 snRNP assembly factor CD2BP2/U5-52K. This protein defines the family of nuclear GYF domain containing proteins that are ubiquitously expressed in eukaryotes with essential functions ascribed to early embryogenesis and organ function. Abrogating CD2BP2/U5-52K in T cells, allows us to delineate the consequences of splicing machinery interferences for T cell development and function. Increased T cell lymphopenia and T cell death are observed upon depletion of CD2BP2/U5-52K. A substantial increase in exon skipping coincides with the observed defect in the proliferation/differentiation balance in the absence of CD2BP2/U5-52K. Prominently, skipping of exon 7 in Mdm4 is observed, coinciding with upregulation of pro-apoptotic gene expression profiles upon CD2BP2/U5-52K depletion. Furthermore, we observe enhanced sensitivity of naïve T cells compared to memory T cells to changes in CD2BP2/U5-52K levels, indicating that depletion of this general splicing factor leads to modulation of T cell homeostasis. Given the recent structural characterization of the U5 snRNP and the crosslinking mass spectrometry data given here, design of inhibitors of the U5 snRNP conceivably offers new ways to manipulate T cell function in settings of disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Bertazzon, Hurtado-Pico, Plaza-Sirvent, Schuster, Preußner, Kuropka, Liu, Kirsten, Schmitt, König, Álvaro-Benito, Abualrous, Albert, Kliche, Heyd, Schmitz and Freund.)

Background: LCP1 encodes L-plastin, an actin-bundling protein primarily expressed in hematopoietic cells. In mouse and fish models, LCP1 deficiency has been shown to result in hematologic and immune defects., Objective: This study aimed to determine the nature of a human inborn error of immunity resulting from a novel genetic variant of LCP1., Methods: We performed genetic, protein, and cellular analysis of PBMCs from a kindred with apparent autosomal dominant immune deficiency. We identified a candidate causal mutation in LCP1, which we evaluated by engineering the orthologous mutation in mice and Jurkat cells., Results: A splice-site variant in LCP1 segregated with lymphopenia, neutropenia, and thrombocytopenia. The splicing defect resulted in at least 2 aberrant transcripts, producing an in-frame deletion of 24 nucleotides, and a frameshift deletion of exon 8. Cellular analysis of the kindred revealed a proportionate reduction of T and B cells and a mild expansion of transitional B cells. Similarly, mice carrying the orthologous genetic variant exhibited the same in-frame aberrant transcript, reduced expression Lcp1 and gene dose-dependent leukopenia, mild thrombocytopenia, and lymphopenia, with a significant reduction of T-cell populations. Functional analysis revealed that LCP1 c740 - 1G>A confers a defect in platelet development and function with aberrant spreading on collagen. Immunologic analysis revealed defective actin organization in T cells, reduced migration of PBMCs from patients, splenocytes from mutant mice, and a mutant Jurkat cell line in response to CXCL12; impaired germinal center B-cell expansion after immunization; and reduced cytokinesis during T cell proliferation., Conclusions: We describe a unique human hematopoietic defect affecting neutrophils, lymphocytes, and platelets arising from partial LCP1 deficiency., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Autoimmune diseases often arise from conditions where the immune system is compromised. While lymphopenia-induced proliferation (LIP) is crucial for immune system development and maturation, it is also caused by environmental insults, such as infection, and becomes a risk factor for autoimmunity in adults. We used Dsg3H1 TCR transgenic mice, whose T cells are designed to recognize desmogrein-3, a skin antigen, to explore the impact of lymphopenia on post-thymic tolerance. Dsg3H1 mice are known to delete the most highly autoreactive T cells in the thymus, and develop only subtle immune-mediated pathology in the steady state. However, we found that transient lymphopenia induced by total body irradiation (TBI) or cyclophosphamide (CY) results in massive dermatitis in Dsg3H1 mice. The symptoms included expansion and development of self-reactive T cells, their differentiation into CD44high IL-17-producing helper T cells, and severe neutrophilic inflammation. Repopulation of FOXP3+ T regulatory cells after lymphopenia normally occurred, suggesting escape of skin-reactive conventional T cells from control by regulatory T cells. Furthermore, we found that a depletion of the intestinal microbiota by antibiotics prevents CY-induced dermatitis, indicating roles of the commensal intestinal microbiota in LIP and Th17 development in vivo. The current data suggested that post-thymic tolerance of Dsg3H1 mice is established on a fragile balance in the lymphoreplete immune environment and broken by the interplay between lymphopenia and intestinal microbiota. The dynamic phenotypes observed in Dsg3H1 mice prompt a re-evaluation of opportunistic lymphopenia together with the microbiota as pivotal environmental factors, impacting individuals with genetic predispositions for autoimmune diseases., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Japanese Society for Immunology.)

T lymphocytes play a primary role in the adaptive antiviral immunity. Both lymphocytosis and lymphopenia were found to be associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While lymphocytosis indicates an active anti-viral response, lymphopenia is a sign of poor prognosis. T-cells, in essence, rarely express ACE2 receptors, making the cause of cell depletion enigmatic. Moreover, emerging strains posed an immunological challenge, potentially alarming for the next pandemic. Herein, we review how possible indirect and direct key mechanisms could contribute to SARS-CoV-2-associated-lymphopenia. The fundamental mechanism is the inflammatory cytokine storm elicited by viral infection, which alters the host cell metabolism into a more acidic state. This "hyperlactic acidemia" together with the cytokine storm suppresses T-cell proliferation and triggers intrinsic/extrinsic apoptosis. SARS-CoV-2 infection also results in a shift from steady-state hematopoiesis to stress hematopoiesis. Even with low ACE2 expression, the presence of cholesterol-rich lipid rafts on activated T-cells may enhance viral entry and syncytia formation. Finally, direct viral infection of lymphocytes may indicate the participation of other receptors or auxiliary proteins on T-cells, that can work alone or in concert with other mechanisms. Therefore, we address the role of CD147-a novel route-for SARS-CoV-2 and its new variants. CD147 is not only expressed on T-cells, but it also interacts with other co-partners to orchestrate various biological processes. Given these features, CD147 is an appealing candidate for viral pathogenicity. Understanding the molecular and cellular mechanisms behind SARS-CoV-2-associated-lymphopenia will aid in the discovery of potential therapeutic targets to improve the resilience of our immune system against this rapidly evolving virus., (© 2024. The Author(s).)

Background: Common variable immunodeficiency (CVID) is considered the most symptomatic type of inborn errors of immunity in humans. Along with infectious complications, which have numerous consequences, noninfectious complications are a major challenge among CVID patients., Methods: All CVID patients registered in the national database were included in this retrospective cohort study. Patients were divided into 2 groups based on the presence of B-cell lymphopenia. Demographic characteristics, laboratory findings, noninfectious organ involvement, autoimmunity, and lymphoproliferative diseases were evaluated., Results: Among 387 enrolled patients, 66.4% were diagnosed with noninfectious complications and 33.6% with isolated infectious presentations. Enteropathy, autoimmunity, and lymphoproliferative disorders were reported in 35.1%, 24.3%, and 21.4% of patients, respectively. Some complications, including autoimmunity and hepatosplenomegaly, were reported to be significantly more frequent among patients with B-cell lymphopenia. As for organ involvement, the dermatologic, endocrine, and musculoskeletal systems were predominantly affected in CVID patients with B-cell lymphopenia. Among autoimmune manifestations, the frequency of rheumatologic, hematologic, and gastrointestinal autoimmunity was reported to be higher than that of other types of autoimmunity not associated with B cell-lymphopenia. Furthermore, hematological cancers, particularly lymphoma, were the most common type of malignancy. The mortality rate was 24.5%, and respiratory failure and malignancies were the most common causes of death, with no significant differences between the 2 groups., Conclusions: Considering that some of the noninfectious complications might be associated with B-cell lymphopenia, regular patient monitoring and follow-up with proper medication (in addition to immunoglobulin replacement therapy) are highly recommended to prevent sequelae and increase patient quality of life.

The transcription factor FOXN1 plays an established role in thymic epithelial development to mediate selection of maturing thymocytes. Patients with heterozygous loss-of-function FOXN1 variants are associated with T cell lymphopenia at birth and low TCR excision circles that can ultimately recover. Although CD4+ T cell reconstitution in these patients is not completely understood, a lower proportion of naive T cells in adults has suggested a role for homeostatic proliferation. In this study, we present an immunophenotyping study of fraternal twins with low TCR excision circles at birth. Targeted primary immunodeficiency testing revealed a heterozygous variant of uncertain significance in FOXN1 (c.1205del, p.Pro402Leufs*148). We present the immune phenotypes of these two patients, as well as their father who carries the same FOXN1 variant, to demonstrate an evolving immune environment over time. While FOXN1 haploinsufficiency may contribute to thymic defects and T cell lymphopenia, we characterized the transcriptional activity and DNA binding of the heterozygous FOXN1 variant in 293T cells and found the FOXN1 variant to have different effects across several target genes. These data suggest multiple mechanisms for similar FOXN1 variants pathogenicity that may be mutation specific. Increased understanding of how these variants drive transcriptional regulation to impact immune cell populations will guide the potential need for therapeutics, risk for infection or autoimmunity over time, and help inform clinical decisions for other variants that might arise., (Copyright © 2024 The Authors.)

Acute, transient lymphocytopenia, not clinically significant was observed in the CAPRISA 012B phase 1 clinical trial following administration of broadly neutralizing antibodies (bnAb)-CAP256V2LS alone or with VRC07-523LS. Lymphocytopenia was assigned upon a > 50% decline in absolute lymphocyte counts following bnAb administration. We posited that systemic immunoglobulins (Igs), and cytokine profiles of eight women who developed lymphocytopenia were different to the 12 women without lymphocytopenia. Plasma Ig subclasses (IgG)/isotypes (IgM/IgA), and 27 cytokines were measured at enrolment (prior to bnAbs) and at days 1, 7, 28, 56 post-bnAb administration. IgG subclasses, IgM and total lymphocyte counts were significantly lower prior to bnAbs in women with gradable lymphocytopenia than those without. Gradable lymphocytopenia compared to non-lymphocytopenia women had significantly higher MIP-1β from enrolment up to day 56. TNF-α was significantly lower in gradable lymphocytopenia compared to non-lymphocytopenia women for enrolment, days 7, 28 and 56 except for day 1. Within the gradable and within the non-lymphocytopenia women, from enrolment to day 1, significantly elevated IL-6, IL-8, IP-10, MCP-1, G-CSF and IL-1RA were found. Additionally, within the gradable lymphocytopenia women, 9 additional cytokines (TNF-α, MIP-1α, MIP-1β, RANTES, Basic FGF, eotaxin, IFN-γ, IL-17A and IL-4) were significantly elevated at day 1 post-bnAbs compared to enrolment. This sub study presents preliminary findings to support the monitoring of baseline immunological markers including lymphocyte counts for assessing the development of transient lymphocytopenia. In high-risk settings conducting clinical trials testing bnAbs for HIV prevention, understanding factors that could amplify rates of lymphocytopenia, even if transient, remain undefined., (© 2024. The Author(s).)

The T cell population size is stringently controlled before, during, and after immune responses, as improper cell death regulation can result in autoimmunity and immunodeficiency. RIPK1 is an important regulator of peripheral T cell survival and homeostasis. However, whether different peripheral T cell subsets show a differential requirement for RIPK1 and which programmed cell death pathway they engage in vivo remains unclear. In this study, we demonstrate that conditional ablation of Ripk1 in conventional T cells (Ripk1 ΔCD4 ) causes peripheral T cell lymphopenia, as witnessed by a profound loss of naive CD4 + , naive CD8 + , and FoxP3 + regulatory T cells. Interestingly, peripheral naive CD8 + T cells in Ripk1 ΔCD4 mice appear to undergo a selective pressure to retain RIPK1 expression following activation. Mixed bone marrow chimeras revealed a competitive survival disadvantage for naive, effector, and memory T cells lacking RIPK1. Additionally, tamoxifen-induced deletion of RIPK1 in CD4-expressing cells in adult life confirmed the importance of RIPK1 in post-thymic survival of CD4 + T cells. Ripk1 K45A mice showed no change in peripheral T cell subsets, demonstrating that the T cell lymphopenia was due to the scaffold function of RIPK1 rather than to its kinase activity. Enhanced numbers of Ripk1 ΔCD4 naive T cells expressed the proliferation marker Ki-67 + despite the peripheral lymphopenia and single-cell RNA sequencing revealed T cell-specific transcriptomic alterations that were reverted by additional caspase-8 deficiency. Furthermore, Ripk1 ΔCD4 Casp8  ΔCD4 and Ripk1 ΔCD4 Tnfr1 -/- double-knockout mice rescued the peripheral T cell lymphopenia, revealing that RIPK1-deficient naive CD4 + and CD8 + cells and FoxP3 + regulatory T cells specifically die from TNF- and caspase-8-mediated apoptosis in vivo. Altogether, our findings emphasize the essential role of RIPK1 as a scaffold in maintaining the peripheral T cell compartment and preventing TNFR1-induced apoptosis., (© 2024. The Author(s).)

Because one-third of patients deteriorate after their admission to the emergency department, assessing the prognosis of COVID-19 patients is of great importance. However, to date, only lymphopenia and the partial pressure of oxygen/fraction of inspired oxygen (PaO2/FiO2) ratio have been reported as partly predictive of COVID-19-related further deterioration, and their association has not been evaluated. We asked whether other key biomarkers of SARS-CoV-2 immunologic defects-increase in circulating immature granulocytes, loss of monocyte HLA-DR (mHLA-DR) expression, and monocyte differentiation blockade-could also predict further COVID-19 deterioration. A series of 284 consecutive COVID-19 patients, with the sole inclusion criterion of being an adult, were prospectively enrolled at emergency department admission (day 0) of 2 different hospitals: 1 for the exploratory cohort (180 patients) and 1 for the confirmatory cohort (104 patients). Deterioration was assessed over the next 7 days. Neither increased immature granulocyte levels nor monocyte differentiation blockade predicted patient worsening. Among more than 30 clinical, biological, and radiological parameters, the value of decreased P/F ratio and lymphopenia for prediction of further COVID-19 deterioration was strongly confirmed, and the loss of mHLA-DR was the only additional independent marker. Combined together in a simple OxyLymphoMono score, the 3 variables perfectly predicted patients who did not worsen and correctly predicted worsening in 59% of cases. By highlighting lymphocyte and monocyte defects as preceding COVID-19 deterioration, these results point on early immunosuppression in COVID-19 deterioration. Combining P/F ratio, lymphopenia, and loss of mHLA-DR together in a simple and robust score could offer a pragmatic method for COVID-19 patient stratification., Competing Interests: Conflict of interest statement. None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Leukocyte Biology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Objective: To compare the extent of cytopenias and systemic immune inflammation index of hospitalised coronavirus disease-2019 patients during the first and second/third waves of the pandemic., Methods: The retrospective, cross-sectional study was conducted in October 2021 at Fatima Memorial Hospital, Lahore, Pakistan, and comprised data of hospitalised coronavirus disease-2019 patients regardless of age and gender from May 2020 to June 2021. Data was segregated into first wave that lasted from May to July 2020, second wave that lasted from early November to mid-December 2020, and third wave that ranged from mid-March to June 2021. For comparison purposes, the data of first wave was in group A, while data of second and third waves was pooled into group B. Age, gender, comorbidities, requirement of ventilator support and outcome of the patients was noted. Inflammatory markers were compared on the basis of complete blood count and systemic immune-inflammation index data. Data was analysed using SPSS 25., Results: Of the 202 patients, 90(44.5%) were in group A and 112(55.4%) were in group B. There were 108(53.5%) males and 94(46.5%) females. The median age in males was 58 years (interquartile range: 21 years) and it was 56 years (interquartile range: 21 years) in females. Neutrophilia (p<0.001), leukocytosis (p<0.001) and lymphocytopenia (p<0.001) had direct association with increased systemic immune-inflammation. Raised systemic immune-inflammation also had an association with increased requirement of ventilator support (p=0.2) and increased mortality (p=0.001). There were more females, more critical patients, more patients with anaemia, leukopenia, lymphocytopenia and thrombocytopenia in group B compared to group A (p<0.05). Need for ventilator support and mortality were also higher in group B compared to group A (p<0.05)., Conclusion: All the indicators analysed were worse during the second and third waves of coronavirus disease-2019 compared to the first wave of the pandemic.

Introduction: COVID-19 patients can develop autoantibodies against a variety of secreted and membrane proteins, including some expressed on lymphocytes. However, it is unclear what proportion of patients might develop anti-lymphocyte antibodies (ALAb) and what functional relevance they might have., Methods: We evaluated the presence and lytic function of ALAb in the sera of a cohort of 85 COVID-19 patients (68 unvaccinated and 17 vaccinated) assigned to mild (N=63), or moderate/severe disease (N=22) groups. Thirty-seven patients were followed-up after recovery. We also analyzed in vivo complement deposition on COVID-19 patients' lymphocytes and examined its correlation with lymphocyte numbers during acute disease., Results: Compared with healthy donors (HD), patients had an increased prevalence of IgM ALAb, which was significantly higher in moderate/severe disease patients and persisted after recovery. Sera from IgM ALAb+ patients exhibited complement-dependent cytotoxicity (CDC) against HD lymphocytes. Complement protein C3b deposition on patients' CD4 T cells was inversely correlated with CD4 T cell numbers. This correlation was stronger in moderate/severe disease patients., Discussion: IgM ALAb and complement activation against lymphocytes may contribute to the acute lymphopenia observed in COVID-19 patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Pérez-Díez, Liu, Calderon, Bennett, Lisco, Kellog, Galindo, Memoli, Rocco, Epling, Laidlaw, Sneller, Manion, Wortmann, Poon, Kumar and Sereti.)

Background: Multisystem inflammatory syndrome in children (MIS-C) represents a hyperinflammatory state that can result in multi-organ dysfunction and death. Myeloid-derived suppressor cells (MDSC) are an immunosuppressive cell population that expands under inflammatory conditions and suppresses T cell function. We hypothesized that MDSC would be increased in children with MIS-C and that MDSC expansion would be associated with T cell lymphopenia., Methods: We conducted a prospective, observational study. Initial blood samples were collected within 48 h of admission. Age-matched healthy controls underwent sampling once. MDSC and T cell populations were identified by flow cytometric methods., Results: We enrolled 22 children with MIS-C (12 ICU, 10 ward) and 21 healthy controls (HC). Children with MIS-C demonstrated significantly higher MDSC compared to HC, and MDSC expansion persisted for >3 weeks in the ICU group. Children with MIS-C admitted to the ICU demonstrated significantly lower absolute numbers of T cells and natural killer cells. There were no significant associations between MDSC and cardiac dysfunction, duration of hospitalization, or vasoactive inotrope score., Conclusions: Our study suggests that children critically ill with MIS-C have expansion of MDSC and associated decreased T cell and NK cell populations. Our results did not demonstrate associations between MDSC and clinical outcomes., Impact: Multisystem inflammatory syndrome in children (MIS-C) is a dysregulated immune response occurring several weeks after SARS-CoV-2 infection that can result in multi-organ dysfunction and death. Children severely ill with MIS-C demonstrated increased myeloid-derived suppressor cells and decreased absolute numbers of CD4+ and CD8 + T cells and NK cells compared to healthy controls. There was no significant association between MDSC numbers and clinical outcomes; including cardiac dysfunction, length of stay, or requirement of vasoactive support, in children with MIS-C., (© 2023. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Background: One hallmark of sepsis is the reduced number of lymphocytes, termed lymphopenia, that occurs from decreased lymphocyte proliferation or increased cell death contributing to immune suppression. Histone modification enzymes regulate immunity by their epigenetic and non-epigenetic functions; however, the role of these enzymes in lymphopenia remains elusive., Methods: We used molecular biological approaches to investigate the high expression and function of a chromatin modulator protein arginine N-methyltransferase 4 (PRMT4)/coactivator-associated arginine methyltransferase 1 in human samples from septic patients and cellular and animal septic models., Results: We identified that PRMT4 is elevated systemically in septic patients and experimental sepsis. Gram-negative bacteria and their derived endotoxin lipopolysaccharide (LPS) increased PRMT4 in B and T lymphocytes and THP-1 monocytes. Single-cell RNA sequencing results indicate an increase of PRMT4 gene expression in activated T lymphocytes. Augmented PRMT4 is crucial for inducing lymphocyte apoptosis but not monocyte THP-1 cells. Ectopic expression of PRMT4 protein caused substantial lymphocyte death via caspase 3-mediated cell death signalling, and knockout of PRMT4 abolished LPS-mediated lymphocyte death. PRMT4 inhibition with a small molecule compound attenuated lymphocyte death in complementary models of sepsis., Conclusions: These findings demonstrate a previously uncharacterised role of a key chromatin modulator in lymphocyte survival that may shed light on devising therapeutic modalities to lessen the severity of septic immunosuppression., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The coronavirus disease 2019 (COVID-19) is a highly transmissible disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that poses a major threat to global public health. Although COVID-19 primarily affects the respiratory system, causing severe pneumonia and acute respiratory distress syndrome in severe cases, it can also result in multiple extrapulmonary complications. The pathogenesis of extrapulmonary damage in patients with COVID-19 is probably multifactorial, involving both the direct effects of SARS-CoV-2 and the indirect mechanisms associated with the host inflammatory response. Recognition of features and pathogenesis of extrapulmonary complications has clinical implications for identifying disease progression and designing therapeutic strategies. This review provides an overview of the extrapulmonary complications of COVID-19 from immunological and pathophysiologic perspectives and focuses on the pathogenesis and potential therapeutic targets for the management of COVID-19., (© 2022. The Author(s).)

Immune response dysregulation plays a key role in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogenesis. In this study, we evaluated immune and endothelial blood cell profiles of patients with coronavirus disease 2019 (COVID-19) to determine critical differences between those with mild, moderate, or severe COVID-19 using spectral flow cytometry. We examined a suite of immune phenotypes, including monocytes, T cells, NK cells, B cells, endothelial cells, and neutrophils, alongside surface and intracellular markers of activation. Our results showed progressive lymphopenia and depletion of T cell subsets (CD3 + , CD4 + , and CD8 + ) in patients with severe disease and a significant increase in the CD56 + CD14 + Ki67 + IFN-γ + monocyte population in patients with moderate and severe COVID-19 that has not been previously described. Enhanced circulating endothelial cells (CD45 - CD31 + CD34 + CD146 + ), circulating endothelial progenitors (CD45 - CD31 + CD34 +/- CD146 - ), and neutrophils (CD11b + CD66b + ) were coevaluated for COVID-19 severity. Spearman correlation analysis demonstrated the synergism among age, obesity, and hypertension with upregulated CD56 + monocytes, endothelial cells, and decreased T cells that lead to severe outcomes of SARS-CoV-2 infection. Circulating monocytes and endothelial cells may represent important cellular markers for monitoring postacute sequelae and impacts of SARS-CoV-2 infection during convalescence and for their role in immune host defense in high-risk adults after vaccination., (Copyright © 2022 by The American Association of Immunologists, Inc.)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection results in rapid T lymphocytopenia and functional impairment of T cells. The underlying mechanism, however, remains incompletely understood. In this study, we focused on characterizing the phenotype and kinetics of T-cell subsets with mitochondrial dysfunction (MD) by multicolor flow cytometry and investigating the association between MD and T-cell functionality. While 73.9% of study subjects displayed clinical lymphocytopenia upon hospital admission, a significant reduction of CD4 or CD8 T-cell frequency was found in all asymptomatic, symptomatic, and convalescent cases. CD4 and CD8 T cells with increased MD were found in both asymptomatic and symptomatic patients within the first week of symptom onset. Lower proportion of memory CD8 T cell with MD was found in severe patients than in mild ones at the stage of disease progression. Critically, the frequency of T cells with MD in symptomatic patients was preferentially associated with CD4 T-cell loss and CD8 T-cell hyperactivation, respectively. Patients bearing effector memory CD4 and CD8 T cells with the phenotype of high MD exhibited poorer T-cell responses upon either phorbol 12-myristate-13-acetate (PMA)/ionomycin or SARS-CoV-2 peptide stimulation than those with low MD. Our findings demonstrated an MD-associated mechanism underlying SARS-CoV-2-induced T lymphocytopenia and functional impairment during the acute phase of infection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Mo, To, Zhou, Liu, Cao, Huang, Du, Lim, Yim, Luk, Chan, Chik, Lau, Tsang, Tam, Hung, Yuen and Chen.)

Background: Both lymphopenia and thyroid dysfunction are commonly observed among COVID-19 patients. Whether thyroid function independently correlates with lymphocyte counts (LYM) remains to be elucidated., Methods: We included consecutive adults without known thyroid disorder admitted to Queen Mary Hospital for COVID-19 from July 2020 to April 2021 who had thyroid-stimulating hormone (TSH), free thyroxine (fT4), free triiodothyronine (fT3) and LYM measured on admission., Results: A total of 541 patients were included. Median LYM was 1.22 x 10 9 /L, with 36.0% of the cohort lymphopenic. 83 patients (15.4%) had abnormal thyroid function tests (TFTs), mostly non-thyroidal illness syndrome (NTIS). Patients with lymphopenia had lower TSH, fT4 and fT3 levels than those without. Multivariable stepwise linear regression analysis revealed that both TSH (standardized beta 0.160, p<0.001) and fT3 (standardized beta 0.094, p=0.023), but not fT4, remained independently correlated with LYM, in addition to age, SARS-CoV-2 viral load, C-reactive protein levels, coagulation profile, sodium levels and more severe clinical presentations. Among the 40 patients who had reassessment of TFTs and LYM after discharge, at a median of 9 days from admission, there were significant increases in TSH (p=0.031), fT3 (p<0.001) and LYM (p<0.001). Furthermore, patients who had both lymphopenia and NTIS were more likely to deteriorate compared to those who only had either one alone, and those without lymphopenia or NTIS (p for trend <0.001)., Conclusion: TSH and fT3 levels showed independent positive correlations with LYM among COVID-19 patients, supporting the interaction between the hypothalamic-pituitary-thyroid axis and immune system in COVID-19., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lui, Lee, Chow, Lee, Tam, Pang, Ho, Cheung, Fong, Law, To, Lam, Tan, Woo, Hung and Lam.)

Pathogenic variants of PLCG2 encoding phospholipase C gamma 2 (PLCγ2) were first reported in 2012 and their clinical manifestations vary widely. PLCG2-associated antibody deficiency and immune dysregulation (PLAID) and autoinflammation and PLCγ2-associated antibody deficiency and immune dysregulation (APLAID) are representative examples of PLCG2 pathogenic variants. In this report, we describe a 17-year-old male with recurrent blistering skin lesions, B-cell lymphopenia, and asthma. Distinct from the patients in previous reports, this patient had the heterozygous de novo c.2119T > C missense variant (NM&#95;002661.4) resulting in a serine to proline amino acid substitution (p.Ser707Pro). The variant located to the PLCγ2 C-terminal Src homology 2 (cSH2) domain, which is a critical site for the restriction of intrinsic enzyme activity. This variant could be classified as "likely pathogenic" according to American College of Medical Genetics and Genomics guidelines. Laboratory results showed a reduction in circulating B cells without a decrease of serum IgG and IgA. Our findings expand the variety of clinical phenotypes for PLCG2 missense variants., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Background: Pediatric endogenous Cushing syndrome (eCs) is mainly caused by pituitary corticotropin-producing adenomas, and most glucocorticoid-dependent effects progressively regress upon tumor removal. eCs reproduces long-term, high-dose glucocorticoid therapy, representing a clean, natural, and unbiased model in which to study glucocorticoid bona fide effects on immunity., Objective: We performed extensive immunologic studies in otherwise healthy pediatric patients with eCs before and 6 to 13 months after tumor resection, as well as in in vitro glucocorticoid-treated control cells., Methods: Flow cytometry, immunoblotting, enzyme-linked immunosorbent assay, real-time quantitative PCR, and RNA-Seq techniques were used to characterize patients' and in vitro glucocorticoid treated cells., Results: Reduced thymic output, decreased naive T cells, diminished proliferation, and increased T-cell apoptosis were detected before surgery; all these defects eventually normalized after tumor removal in patients. In vitro studies also showed increased T-cell apoptosis, with correspondingly diminished NF-κB signaling and IL-21 levels. In this setting, IL-21 addition upregulated antiapoptotic BCL2 expression and rescued T-cell apoptosis in a PI3K pathway-dependent manner. Similar and reproducible findings were confirmed in eCs patient cells as well., Conclusions: We identified decreased thymic output and lymphocyte proliferation, together with increased apoptosis, as the underlying causes to T-cell lymphopenia in eCs patients. IL-21 was decreased in both natural and in vitro long-term, high-dose glucocorticoid environments, and in vitro addition of IL-21 counteracted the proapoptotic effects of glucocorticoid therapy. Thus, our results suggest that administration of IL-21 in patients receiving long-term, high-dose glucocorticoid therapy may contribute to ameliorate lymphopenia and the complications associated to it., (Published by Elsevier Inc.)

The systemic processes involved in the manifestation of life-threatening COVID-19 and in disease recovery are still incompletely understood, despite investigations focusing on the dysregulation of immune responses after SARS-CoV-2 infection. To define hallmarks of severe COVID-19 in acute disease (n = 58) and in disease recovery in convalescent patients (n = 28) from Hannover Medical School, we used flow cytometry and proteomics data with unsupervised clustering analyses. In our observational study, we combined analyses of immune cells and cytokine/chemokine networks with endothelial activation and injury. ICU patients displayed an altered immune signature with prolonged lymphopenia but the expansion of granulocytes and plasmablasts along with activated and terminally differentiated T and NK cells and high levels of SARS-CoV-2-specific antibodies. The core signature of seven plasma proteins revealed a highly inflammatory microenvironment in addition to endothelial injury in severe COVID-19. Changes within this signature were associated with either disease progression or recovery. In summary, our data suggest that besides a strong inflammatory response, severe COVID-19 is driven by endothelial activation and barrier disruption, whereby recovery depends on the regeneration of the endothelial integrity., (© 2021. The Author(s).)

Background: Protein-losing enteropathy (PLE) is a severe complication of the Fontan circulation. There is increasing discussion about whether lymphatic dysregulation is involved as pathomechanism of PLE. This investigation focuses on the interplay between alteration of lymphatic cells and immunologic pathway alterations., Methods: Micro-ribonucleic acid (miRNA) expression profiling was performed in 49 patients ( n  = 10 Fontan patients with PLE, n  = 30 Fontan patients without PLE, and n  = 9 patients with dextro-transposition of the great arteries (dTGA). miRNA pathway analysis was performed to identify significantly enriched pathways. To determine lymphocyte populations and subtypes multiparameter flow cytometry was used., Results: miRNAs pathway analysis of Fontan patients with PLE revealed 20 significantly changed networks of which four of the ten largest were associated with immunologic processes. This finding is supported by significant T cell deficiency with decreased CD4+ count ( p  = 0.0002), altered CD4 +/CD8+ ratio, and significantly modified CD4+ ( p  < 0.0001) and CD8+ ( p  = 0.0002) T cell differentiation toward effector and terminal differentiated T cells in Fontan patients with PLE. Analyses of CD4+ T cell subsets demonstrated significantly increased frequencies of CD4+ CD25+ CD127- regulatory T cells (Treg) in Fontan patients with PLE ( p  = 0.0011)., Conclusion: PLE in Fontan patients is associated with severe lymphopenia, T cell deficiency, significant alterations of T cell differentiation, and increased Treg frequency reflecting an immune status of chronic inflammation and shortened protection against pathogens and autoimmunity. These cellular alterations seemed to be dysregulated by several miRNA controlled immunological pathways., Competing Interests: The authors have no conflicts of interest to declare., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Chimeric antigen receptor (CAR) T cells are a new class of anti-cancer therapy that involves manipulating autologous or allogeneic T cells to express a CAR directed against a membrane antigen. In Europe, tisagenlecleucel (Kymriah™) has marketing authorization for the treatment of relapsed / refractory acute lymphoblastic leukemia (ALL) in children and young adults, in addition to the treatment of relapsed/refractory diffuse large B-cell lymphoma (DLBCL); the marketing authorization for axicabtagene ciloleucel (Yescarta™) is for the treatment of relapsed / refractory high-grade B-cell lymphoma and for the treatment of primary mediastinal B-cell lymphoma. Both cell products are genetically modified autologous T cells directed against CD19. These recommendations, drawn up by a working group of the Francophone Society of Bone Marrow transplantation and cellular Therapy (SFGM-TC) relate to the management of patients and the supply chain: medium-term complications, in particular cytopenias and B-cell aplasia, nursing and psychological supportive care. In another work, we will address long-term monitoring, post-marketing authorization pharmacovigilance and issues relating to JACIE and regulatory authorities. These recommendations are not prescriptive; their aim is to provide guidelines for the use of this new therapeutic approach. The purpose of this workshop is to outline the organizational aspects of this new therapeutic approach., (Copyright © 2021 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Coronavirus disease 2019 (COVID-19) is a highly infectious viral disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Laboratory findings from a significant number of patients with COVID-19 indicate the occurrence of leukocytopenia, specifically lymphocytopenia. Moreover, infected patients can experience contrasting outcomes depending on lymphocytopenia status. Patients with resolved lymphocytopenia are more likely to recover, whereas critically ill patients with signs of unresolved lymphocytopenia develop severe complications, sometimes culminating in death. Why immunodepression manifests in patients with COVID-19 remains unclear. Therefore, the evaluation of clinical symptoms and laboratory findings from infected patients is critical for understanding the disease course and its consequences. In this review, we take a logical approach to unravel the reasons for immunodepression in patients with COVID-19. Following the footprints of the virus within host tissues, from entry to exit, we extrapolate the mechanisms underlying the phenomenon of immunodepression.

The coronavirus disease 19 (COVID-19) caused by the novel coronavirus known as SARS-CoV-2 has caused a global public health crisis. As of 7 January 2021, 87,640,402 confirmed cases and 1,891,692 mortalities have been reported worldwide. Studies focusing on the epidemiological and clinical characteristics of COVID-19 patients have suggested a dysregulated immune response characterized by lymphopenia and cytokine storm in these patients. The exaggerated immune response induced by the cytokine storm causes septic shock, acute respiratory distress syndrome (ARDS), and/or multiple organs failure, which increases the fatality rate of patients with SARS-CoV-2 infection. Herein, we review the recent research progress on epidemiology, clinical features, and system pathology in COVID-19. Moreover, we summarized the recent therapeutic strategies, which are either approved, under clinical trial, and/or under investigation by the local or global health authorities. We assume that treatments should focus on the use of antiviral drugs in combination with immunomodulators as well as treatment of the underlying comorbidities.

Foot-and-mouth disease (FMD) is characterized by a pronounced lymphopenia that is associated with immune suppression. However, the mechanisms leading to lymphopenia remain unclear. In this study, the number of total CD4 + , CD8 + T cells, B cells, and NK cells in the peripheral blood were dramatically reduced in C57BL/6 mice infected with foot-and-mouth disease virus (FMDV) serotype O, and it was noted that mice with severe clinical symptoms had expressively lower lymphocyte counts than mice with mild or without clinical symptoms, indicating that lymphopenia was associated with disease severity. A further analysis revealed that lymphocyte apoptosis and trafficking occurred after FMDV infection. In addition, coinhibitory molecules were upregulated in the expression of CD4 + and CD8 + T cells from FMDV-infected mice, including CTLA-4, LAG-3, 2B4, and TIGIT. Interestingly, the elevated IL-10 in the serum was correlated with the appearance of lymphopenia during FMDV infection but not IL-6, IL-2, IL-17, IL-18, IL-1β, TNF-α, IFN-α/β, TGF-β, and CXCL1. Knocking out IL-10 (IL-10 -/- ) mice or blocking IL-10/IL-10R signaling in vivo was able to prevent lymphopenia via downregulating apoptosis, trafficking, and the coinhibitory expression of lymphocytes in the peripheral blood, which contribute to enhance the survival of mice infected with FMDV. Our findings support that blocking IL-10/IL-10R signaling may represent a novel therapeutic approach for FMD.

Background: Lymphopenia is a key feature for adult patients with coronavirus disease 2019 (COVID-19), although it is rarely observed in children. The underlying mechanism remains unclear., Methods: Immunohistochemical and flow cytometric analyses were used to compare the apoptotic rate of T cells from COVID-19 adults and children and apoptotic responses of adult and child T cells to COVID-19 pooled plasma. Biological properties of caspases and reactive oxygen species were assessed in T cells treated by COVID-19 pooled plasma., Results: Mitochondria apoptosis of peripheral T cells were identified in COVID-19 adult patient samples but not in the children. Furthermore, increased tumor necrosis factor-α and interleukin-6 in COVID-19 plasma induced mitochondria apoptosis and caused deoxyribonucleic acid damage by elevating reactive oxygen species levels of the adult T cells. However, the child T cells showed tolerance to mitochondrial apoptosis due to mitochondria autophagy. Activation of autophagy could decrease apoptotic sensitivity of the adult T cells to plasma from COVID-19 patients., Conclusions: Our results indicated that the mitochondrial apoptosis pathway was activated in T cells of COVID-19 adult patients specifically, which may shed light on the pathophysiological difference between adults and children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 )., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Neutralizing antibody (nAb) response is generated following infection or immunization and plays an important role in the protection against a broad of viral infections. The role of nAb during clinical progression of coronavirus disease 2019 (COVID-19) remains little known., Methods: 123 COVID-19 patients during hospitalization in Tongji Hospital were involved in this retrospective study. The patients were grouped based on the severity and outcome. The nAb responses of 194 serum samples were collected from these patients within an investigation period of 60 days after the onset of symptoms and detected by a pseudotyped virus neutralization assay. The detail data about onset time, disease severity and laboratory biomarkers, treatment, and clinical outcome of these participants were obtained from electronic medical records. The relationship of longitudinal nAb changes with each clinical data was further assessed., Results: The nAb response in COVID-19 patients evidently experienced three consecutive stages, namely, rising, stationary, and declining periods. Patients with different severity and outcome showed differential dynamics of the nAb response over the course of disease. During the stationary phase (from 20 to 40 days after symptoms onset), all patients evolved nAb responses. In particular, high levels of nAb were elicited in severe and critical patients and older patients (≥60 years old). More importantly, critical but deceased COVID-19 patients showed high levels of several proinflammation cytokines, such as IL-2R, IL-8, and IL-6, and anti-inflammatory cytokine IL-10 in vivo, which resulted in lymphopenia, multiple organ failure, and the rapidly decreased nAb response., Conclusion: Our results indicate that nAb plays a crucial role in preventing the progression and deterioration of COVID-19, which has important implications for improving clinical management and developing effective interventions., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Qing Lei et al.)

Hypomorphic RAG1 or RAG2 mutations cause primary immunodeficiencies and can lead to autoimmunity, but the underlying mechanisms are elusive. We report here a patient carrying a c.116+2T>G homozygous splice site mutation in the first intron of RAG1, which led to aberrant splicing and greatly reduced RAG1 protein expression. B cell development was blocked at both the pro-B to pre-B transition and the pre-B to immature B cell differentiation step. The patient B cells had reduced B cell receptor repertoire diversity and decreased complementarity determining region 3 lengths. Despite B cell lymphopenia, the patient had abundant plasma cells in the BM and produced large quantities of IgM and IgG Abs, including autoantibodies. The proportion of naive B cells was reduced while the frequency of IgD-CD27- double-negative (DN) B cells, which quickly differentiated into Ab-secreting plasma cells upon stimulation, was greatly increased. Immune phenotype analysis of 52 patients with primary immunodeficiency revealed a strong association of the increased proportion of DN B and memory B cells with decreased number and proportion of naive B cells. These results suggest that the lymphopenic environment triggered naive B cell differentiation into DN B and memory B cells, leading to increased Ab production.

Most persons living with HIV (PLWH) experience a significant restoration of their immunity associated with successful inhibition of viral replication after antiretroviral therapy (ART) initiation. Nevertheless, with the robust quantitative and qualitative restoration of CD4 + T-lymphocytes, a fraction of patients co-infected with tuberculosis develop immune reconstitution inflammatory syndrome (TB-IRIS), a dysregulated inflammatory response that can be associated with significant tissue damage. Several studies underscored the role of adaptive immune cells in IRIS pathogenesis, but to what degree T lymphocyte activation contributes to TB-IRIS development remains largely elusive. Here, we sought to dissect the phenotypic landscape of T lymphocyte activation in PLWH coinfected with TB inititating ART, focusing on characterization of the profiles linked to development of TB-IRIS. We confirmed previous observations demonstrating that TB-IRIS individuals display pronounced CD4 + lymphopenia prior to ART initiation. Additionally, we found an ART-induced increase in T lymphocyte activation, proliferation and cytotoxicity among TB-IRIS patients. Importantly, we demonstrate that TB-IRIS subjects display higher frequencies of cytotoxic CD8 + T lymphocytes which is not affected by ART. Moreover, These patients exhibit higher levels of activated (HLA-DR + ) and profilerative (Ki-67 + ) CD4 + T cells after ART commencenment than their Non-IRIS counterparts. Our network analysis reveal significant negative correlations between Total CD4 + T cells counts and the frequencies of Cytotoxic CD8 + T cells in our study population which could suggest the existance of compensatory mechanisms for Mtb-infected cells elimination in the face of severe CD4 + T cell lymphopenia. We also investigated the correlation between T lymphocyte activation profiles and the abundance of several inflammatory molecules in plasma. We applied unsupervised machine learning techniques to predict and diagnose TB-IRIS before and during ART. Our analyses suggest that CD4 + T cell activation markers are good TB-IRIS predictors, whereas the combination of CD4 + and CD8 + T cells markers are better at diagnosing TB-IRIS patients during IRIS events Overall, our findings contribute to a more refined understanding of immunological mechanisms in TB-IRIS pathogenesis that may assist in new diagnostic tools and more targeted patient management., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Tibúrcio, Barreto-Duarte, Naredren, Queiroz, Anbalagan, Nayak, Ravichandran, Subramani, Antonelli, Satagopan, Anbalagan, Porter, Sher, Swaminathan, Sereti and Andrade.)

The abscopal effect has been mentioned since 1953. The increase in knowledge about the immune system and the development of immunotherapies support its potential therapeutic interest. While it is accepted that radiotherapy induces an immune response, demonstrating its systemic impact is not easy. The preclinical basis is solid but its clinical validation pending. Radiotherapy rarely induces tumor reduction at a distance from the beams, probably due to its immunosuppressive effect. This is why a synergy between radiotherapy and systemic treatments targeting these immunosuppressive mechanisms was observed. Several parameters can modulate the induction of the abscopal effect. Among these, the fractionation of the dose seems to be determining with currently a pre-eminence of hypofractionated stereotaxis. On the other hand, even if the choice of more immunogenic targets (liver, lung) should be favoured, the optimal number of lesions to be irradiated remains to be defined as well as the minimum volume allowing sufficient release of tumor antigens. The impact of radiation-induced lymphopenia on radiotherapy/immunotherapy efficacy needs to be assessed more precisely, as does the effect of radiotherapy techniques on them. Finally, the choice of immunotherapy(ies) and the combination regimen with radiotherapy remain under discussion. A sequential scheme appears to provide less toxicities but the concomitant would lead to a better response. The study of these different parameters should allow us to deliver optimized radiotherapy/immunotherapy(ies) combinations to our metastatic patients in order to benefit as many people as possible from this abscopal effect., (Copyright © 2021 Société française de radiothérapie oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.)

Aims: Coronavirus disease 2019 (COVID-19) is a novel viral infection threatening worldwide health as currently there exists no effective treatment strategy and vaccination programs are not publicly available yet. T lymphocytes play an important role in antiviral defenses. However, T cell frequency and functionality may be affected during the disease., Material and Methods: Total blood samples were collected from patients with mild and severe COVID-19, and the total lymphocyte number, as well as CD4+ and CD8 + T cells were assessed using flowcytometry. Besides, the expression of exhausted T cell markers was evaluated. The levels of proinflammatory cytokines were also investigated in the serum of all patients using enzyme-linked immunesorbent assay (ELISA). Finally, the obtained results were analyzed along with laboratory serological reports., Results: COVID-19 patients showed lymphopenia and reduced CD4+ and CD8 + T cells, as well as high percentage of PD-1 expression by T cells, especially in severe cases. Serum secretion of TNF-α, IL-1β, and IL-2 receptor (IL-2R) were remarkably increased in patients with severe symptoms, as compared with healthy controls. Moreover, high levels of triglyceride (TG) and low density lipoprotein cholesterol (LDL-C), were correlated with the severity of the disease., Conclusion: Reduced number and function of T cells were observed in COVID-19 patients, especially in severe patients. Meanwhile, the secretion of proinflammatory cytokines was increased as the disease developed. High level of serum IL-2R was also considered as a sign of lymphopenia. Additionally, hypercholesterolemia and hyperlipidemia could be important prognostic factors in determining the severity of the infection., (Copyright © 2021. Published by Elsevier Ltd.)

Emerging evidence has unveiled the secondary infection as one of the mortal causes of post-SARS-CoV-2 infection, but the factors related to secondary bacterial or fungi infection remains largely unexplored. We here systematically investigated the factors that might contribute to secondary infection. By clinical examination index analysis of patients, combined with the integrative analysis with RNA-seq analysis in the peripheral blood mononuclear cell isolated shortly from initial infection, this study showed that the antibiotic catabolic process and myeloid cell homeostasis were activated while the T-cell response were relatively repressed in those with the risk of secondary infection. Further monitoring analysis of immune cell and liver injury analysis showed that the risk of secondary infection was accompanied by severe lymphocytopenia at the intermediate and late stages and liver injury at the early stages of SARS-CoV-2. Moreover, the metagenomics analysis of bronchoalveolar lavage fluid and the microbial culture analysis, to some extent, showed that the severe pneumonia-related bacteria have already existed in the initial infection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Guo, Gao, Gao, Zhang, Jin, Fan, Wang, Li, Chen and Zhu.)

Adoptive cell therapy (ACT) using chimeric antigen receptor (CAR) T cells holds impressive clinical outcomes especially in patients who are refractory to other kinds of therapy. However, many challenges hinder its clinical applications. For example, patients who undergo chemotherapy usually have an insufficient number of autologous T cells due to lymphopenia. Long-term ex vivo expansion can result in T cell exhaustion, which reduces the effector function. There is also a batch-to-batch variation during the manufacturing process, making it difficult to standardize and validate the cell products. In addition, the process is labor-intensive and costly. Generation of universal off-the-shelf CAR T cells, which can be broadly given to any patient, prepared in advance and ready to use, would be ideal and more cost-effective. Human induced pluripotent stem cells (iPSCs) provide a renewable source of cells that can be genetically engineered and differentiated into immune cells with enhanced anti-tumor cytotoxicity. This review describes basic knowledge of T cell biology, applications in ACT, the use of iPSCs as a new source of T cells and current differentiation strategies used to generate T cells as well as recent advances in genome engineering to produce next-generation off-the-shelf T cells with improved effector functions. We also discuss challenges in the field and future perspectives toward the final universal off-the-shelf immunotherapeutic products., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Netsrithong and Wattanapanitch.)

Sterile alpha motif (SAM) and Src homology-3 (SH3) domain-containing 3 (SASH3), also called SH3-containing lymphocyte protein (SLY1), is a putative adaptor protein that is postulated to play an important role in the organization of signaling complexes and propagation of signal transduction cascades in lymphocytes. The SASH3 gene is located on the X-chromosome. Here, we identified 3 novel SASH3 deleterious variants in 4 unrelated male patients with a history of combined immunodeficiency and immune dysregulation that manifested as recurrent sinopulmonary, cutaneous, and mucosal infections and refractory autoimmune cytopenias. Patients exhibited CD4+ T-cell lymphopenia, decreased T-cell proliferation, cell cycle progression, and increased T-cell apoptosis in response to mitogens. In vitro T-cell differentiation of CD34+ cells and molecular signatures of rearrangements at the T-cell receptor α (TRA) locus were indicative of impaired thymocyte survival. These patients also manifested neutropenia and B-cell and natural killer (NK)-cell lymphopenia. Lentivirus-mediated transfer of the SASH3 complementary DNA-corrected protein expression, in vitro proliferation, and signaling in SASH3-deficient Jurkat and patient-derived T cells. These findings define a new type of X-linked combined immunodeficiency in humans that recapitulates many of the abnormalities reported in mice with Sly1-/- and Sly1Δ/Δ mutations, highlighting an important role of SASH3 in human lymphocyte function and survival., (© 2021 by The American Society of Hematology.)

The Coronavirus Disease 2019 (COVID-19) is caused by the betacoronavirus Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) virus that can mediate asymptomatic or fatal infections characterized by pneumonia, acute respiratory distress syndrome (ARDS), and multi-organ failure. Several studies have highlighted the importance of B and T lymphocytes, given that neutralizing antibodies and T cell responses are required for an effective immunity. In addition, other reports have described myeloid cells such as macrophages and monocytes play a major role in the immunity against SARS-CoV-2 as well as dysregulated pro-inflammatory signature that characterizes severe COVID-19. During COVID-19, neutrophils have been defined as a heterogeneous group of cells, functionally linked to severe inflammation and thrombosis triggered by degranulation and NETosis, but also to suppressive phenotypes. The physiological role of suppressive neutrophils during COVID-19 and their implications in severe disease have been poorly studied and is not well understood. Here, we discuss the current evidence regarding the role of neutrophils with suppressive properties such as granulocytic myeloid-derived suppressor cells (G-MDSCs) and their possible role in suppressing CD4+ and CD8+ T lymphocytes expansion and giving rise to lymphopenia in severe COVID-19 infection., Competing Interests: I have read the journal’s policy and have the following conflicts. J.S.L. discloses a paid consultantship with Janssen Pharmaceuticals, Inc. that is unrelated to the work presented in this manuscript. We have no other relevant conflicts of interest to disclose.

Adenosine is a potent modulator that has a tremendous effect on the immune system. Adenosine affects T cell activity, and is necessary in maintaining the T helper/regulatory T cell (T reg ) ratio. Adenosine signalling is also involved in activating neutrophils and the formation of neutrophil extracellular traps (NETs), which has been linked to autoimmune disorders. Therefore, adenosine, through its receptors, is extremely important in maintaining homeostasis and involved in the development of autoimmune diseases. In this study, we aim to evaluate the role of adenosine A 1 and A 2A receptors in involvement of autoimmune diseases. We studied adenosine regulation by NETosis in vitro, and used two murine models of autoimmune diseases: type I diabetes mellitus (T1DM) induced by low-dose streptozotocin and pristane-induced systemic lupus erythematosus (SLE). We have found that A 1 R enhances and A 2A R suppresses NETosis. In addition, in both models, A 1 R-knock-out (KO) mice were predisposed to the development of autoimmunity. In the SLE model in wild-type (WT) mice we observed a decline of A 1 R mRNA levels 6 h after pristane injection that was parallel to lymphocyte reduction. Following pristane, 43% of A 1 R-KO mice suffered from lupus-like disease while WT mice remained without any sign of disease at 36 weeks. In WT mice, at 10 days A 2A R mRNA levels were significantly higher compared to A1R-KO mice. Similar to SLE, in the T1DM model the presence of A 1 R and A 2A R was protective. Our data suggest that, in autoimmune diseases, the acute elimination of lymphocytes and reduction of DNA release due to NETosis depends upon A 1 R desensitization and long-term suppression of A 2A R., (© 2021 British Society for Immunology.)

In this study, laboratorial parameters of hospitalized novel coronavirus (COVID-19) patients, who were complicated with severe pneumonia, were compared with the findings of cytokine storm developing in macrophage activation syndrome (MAS)/secondary hemophagocytic lymphohistiocytosis (sHLH). Severe pneumonia occurred as a result of cytokine storm in some patients who needed intensive care unit (ICU), and it is aimed to determine the precursive parameters in this situation. Also in this study, the aim is to identify laboratory criteria that predict worsening disease and ICU intensification, as well as the development of cytokine storm. This article comprises a retrospective cohort study of patients admitted to a single institution with COVID-19 pneumonia. This study includes 150 confirmed COVID-19 patients with severe pneumonia. When they were considered as severe pneumonia patients, the clinic and laboratory parameters of this group are compared with H-score criteria. Patients are divided into two subgroups; patients with worsened symptoms who were transferred into tertiary ICU, and patients with stable symptoms followed in the clinic. For the patients with confirmed COVID-19 infection, after they become complicated with severe pneumonia, lymphocytopenia (55.3%), anemia (12.0%), thrombocytopenia (19.3%), hyperferritinemia (72.5%), hyperfibrinogenemia (63.7%) and elevated lactate dehydrogenase (LDH) (90.8%), aspartate aminotransaminase (AST) (31.3%), alanine aminotransaminase (ALT) (20.7%) are detected. There were no significant changes in other parameters. Blood parameters between the pre-ICU period and the ICU period (in which their situation had been worsened and acute respiratory distress syndrome [ARDS] was developed) were also compared. In the latter group lymphocyte levels were found significantly reduced (p = 0.01), and LDH, highly sensitive troponin (hs-troponin), procalcitonin, and triglyceride levels were significantly increased (p < 0.05). In addition, there was no change in hemoglobin, leukocyte, platelet, ferritin, and liver function test levels, including patients who developed ARDS, similar to the cytokine storm developed in MAS/sHLH. COVID-19 pneumonia has similar findings as hyperinflammatory syndromes but does not seem to have typical features as in cytokine storm developed in MAS/sHLH. In the severe patient group who has started to develop ARDS signs, a decrease in lymphocyte level in addition to the elevated LDH, hs-troponin, procalcitonin, and triglyceride levels can be a predictor in progression to ICU admission and could help in the planning of anti-cytokine therapy., (© 2021 Wiley Periodicals LLC.)

Severe coronavirus disease 2019 (COVID-19) has been associated with T cell lymphopenia, but no causal effect of T cell deficiency on disease severity has been established. To investigate the specific role of T cells in recovery from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, we studied rhesus macaques that were depleted of either CD4 + , CD8 + , or both T cell subsets prior to infection. Peak virus loads were similar in all groups, but the resolution of virus in the T cell-depleted animals was slightly delayed compared to that in controls. The T cell-depleted groups developed virus-neutralizing antibody responses and class switched to IgG. When reinfected 6 weeks later, the T cell-depleted animals showed anamnestic immune responses characterized by rapid induction of high-titer virus-neutralizing antibodies, faster control of virus loads, and reduced clinical signs. These results indicate that while T cells play a role in the recovery of rhesus macaques from acute SARS-CoV-2 infections, their depletion does not induce severe disease, and T cells do not account for the natural resistance of rhesus macaques to severe COVID-19. Neither primed CD4 + nor CD8 + T cells appeared critical for immunoglobulin class switching, the development of immunological memory, or protection from a second infection. IMPORTANCE Patients with severe COVID-19 often have decreased numbers of T cells, a cell type important in fighting most viral infections. However, it is not known whether the loss of T cells contributes to severe COVID-19 or is a consequence of it. We studied rhesus macaques, which develop only mild COVID-19, similar to most humans. Experimental depletion of T cells slightly prolonged their clearance of virus, but there was no increase in disease severity. Furthermore, they were able to develop protection from a second infection and produced antibodies capable of neutralizing the virus. They also developed immunological memory, which allows a much stronger and more rapid response upon a second infection. These results suggest that T cells are not critical for recovery from acute SARS-CoV-2 infections in this model and point toward B cell responses and antibodies as the essential mediators of protection from re-exposure.

Background: Mucosal-associated invariant T (MAIT) cells constitute a subset of unconventional, MR1-restricted T cells involved in antimicrobial responses as well as inflammatory, allergic, and autoimmune diseases. Chronic infection and inflammatory disorders as well as immunodeficiencies are often associated with decline and/or dysfunction of MAIT cells., Methods: We investigated the MAIT cells in patients with idiopathic CD4+ lymphocytopenia (ICL), a syndrome characterized by consistently low CD4 T-cell counts (<300 cell/µL) in the absence of HIV infection or other known immunodeficiency, and by susceptibility to certain opportunistic infections., Results: The numbers, phenotype, and function of MAIT cells in peripheral blood were preserved in ICL patients compared to healthy controls. Administration of interleukin-7 (IL-7) to ICL patients expanded the CD8+ MAIT-cell subset, with maintained responsiveness and effector functions after IL-7 treatment., Conclusions: ICL patients maintain normal levels and function of MAIT cells, preserving some antibacterial responses despite the deficiency in CD4+ T cells., Clinical Trials Registration: NCT00867269., (Published by Oxford University Press for the Infectious Diseases Society of America 2020.)

Adoptive cell therapy (ACT) using tumor-reactive T cells is a promising form of immunotherapy to specifically target cancer. However, the survival and functional maintenance of adoptively transferred T cells remains a challenge, ultimately limiting their efficacy. Here, we evaluated the use of recombinant IL7-Fc in ACT. In a lymphopenic murine melanoma model, IL7-Fc treatment led to the enhanced inhibition of tumor growth with an increased number of adoptively transferred CD8 + T cells in tumor tissue and tumor-draining lymph nodes. Additionally, IL7-Fc further enhanced anti-tumor responses that were induced by recombinant human IL2 in the same mouse model. In contrast, in an immunocompetent murine melanoma model, IL7-Fc dampened the anti-tumor immunity. Further, IL7-Fc decreased the proliferation of adoptively transferred and immune-activated tumor-reactive CD8 + T cells in immunocompetent mice by inducing the massive expansion of endogenous T cells, thereby limiting the space for adoptively transferred T cells. Our data suggest that IL7-Fc is principally beneficial for enhancing the efficacy of tumor-reactive T-cells in lymphopenic conditions for the ACT.

A whole-genome CRISPR/Cas9 screen identified ATP2A2, the gene encoding the Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) 2 protein, as being important for V(D)J recombination. SERCAs are ER transmembrane proteins that pump Ca2+ from the cytosol into the ER lumen to maintain the ER Ca2+ reservoir and regulate cytosolic Ca2+-dependent processes. In preB cells, loss of SERCA2 leads to reduced V(D)J recombination kinetics due to diminished RAG-mediated DNA cleavage. SERCA2 deficiency in B cells leads to increased expression of SERCA3, and combined loss of SERCA2 and SERCA3 results in decreased ER Ca2+ levels, increased cytosolic Ca2+ levels, reduction in RAG1 and RAG2 gene expression, and a profound block in V(D)J recombination. Mice with B cells deficient in SERCA2 and humans with Darier disease, caused by heterozygous ATP2A2 mutations, have reduced numbers of mature B cells. We conclude that SERCA proteins modulate intracellular Ca2+ levels to regulate RAG1 and RAG2 gene expression and V(D)J recombination and that defects in SERCA functions cause lymphopenia., Competing Interests: Disclosures: The authors declare no competing interests exist., (© 2021 Chen et al.)

Objectives: The patients with hematological malignancies are a vulnerable group to COVID-19, due to the immunodeficiency resulting from the underlying disease and oncological treatment that significantly impair cellular and humoral immunity. Here we report on a beneficial impact of a passive immunotherapy with convalescent plasma to treat a prolonged, active COVID-19 infection in a patient with a history of nasopharyngeal diffuse large B-cell lymphoma treated with the therapy inducing substantial impairment of particularly humoral arm of immune system. The specific aim was to quantify SARS-CoV2 neutralizing antibodies in a patient plasma during the course of therapy., Materials and Methods: Besides the standard of care treatment and monitoring, neutralizing antibody titers in patient's serum samples, calibrated according to the First WHO International Standard for anti-SARS-CoV-2 immunoglobulin (human), were quantified in a time-dependent manner. During the immunotherapy period peripheral blood flow cytometry immunophenotyping was conducted to characterize lymphocyte subpopulations., Results: The waves of clinical improvements and worsening coincided with transfused neutralizing antibodies rises and drops in the patient's systemic circulation, proving their contribution in controlling the disease progress. Besides the patient's lack of own humoral immune system, immunophenotyping analysis revealed also the reduced level of helper T-lymphocytes and immune exhaustion of monocytes., Conclusion: Therapeutic approach based on convalescent plasma transfusion transformed a prolonged, active COVID-19 infection into a manageable chronic disease., (Copyright © 2021 Société française de transfusion sanguine (SFTS). Published by Elsevier Masson SAS. All rights reserved.)

Lymphopenia is a frequent hematological manifestation, associated with a severe course of COVID-19, with an insufficiently understood pathogenesis. We present molecular genetic immunohistochemical, and electron microscopic data on SARS-CoV-2 dissemination and viral load (VL) in lungs, mediastinum lymph nodes, and the spleen of 36 patients who died from COVID-19. Lymphopenia <1 × 10 9 /L was observed in 23 of 36 (63.8%) patients. In 12 of 36 cases (33%) SARS-CoV-2 was found in lung tissues only with a median VL of 239 copies (range 18-1952) SARS-CoV-2 cDNA per 100 copies of ABL1. Histomorphological changes corresponding to bronchopneumonia and the proliferative phase of DAD were observed in these cases. SARS-CoV-2 dissemination into the lungs, lymph nodes, and spleen was detected in 23 of 36 patients (58.4%) and was associated with the exudative phase of DAD in most of these cases. The median VL in the lungs was 12,116 copies (range 810-250281), lymph nodes-832 copies (range 96-11586), and spleen-71.5 copies (range 0-2899). SARS-CoV-2 in all cases belonged to the 19A strain. A immunohistochemical study revealed SARS-CoV-2 proteins in pneumocytes, alveolar macrophages, and bronchiolar epithelial cells in lung tissue, sinus histiocytes of lymph nodes, as well as cells of the Billroth pulp cords and spleen capsule. SARS-CoV-2 particles were detected by transmission electron microscopy in the cytoplasm of the endothelial cell, macrophages, and lymphocytes. The infection of lymphocytes with SARS-CoV-2 that we discovered for the first time may indicate a possible link between lymphopenia and SARS-CoV-2-mediated cytotoxic effect.