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Data on obstetric outcomes in patients with a history of immunoglobulin A vasculitis (IgA-V) are lacking. The aim of this study was to assess maternal, neonatal, and vasculitis outcomes during pregnancy. We conducted a French retrospective case–control study. Pregnancies of patients with a history of IgA-V (cases) were retrospectively studied and compared to pregnancies in women who developed IgA-V after their pregnancies and to pregnancies in healthy women (controls). Twenty-six pregnancies in patients with a history of IgA-V were included and compared to 15 pregnancies in women who later developed IgA-V and 52 pregnancies in healthy women. Both gestational hypertension and pre-eclampsia were more frequent in the case group than in the other groups (23% vs 0% vs 0%, p < 0.01; 12% vs 7% vs 0%, p = 0.04). Hypertensive disorder of pregnancy occurred more frequently in patients with pre-existing kidney disease (78% vs 12%, p < 0.01). Caesarean section was more often performed in the case group than in the other groups (27% vs 0% vs 10%, p = 0.04). No foetal loss or maternal deaths occurred. There were no differences in delivery term or birth weight. No vasculitis flares were observed during pregnancy. Women with a history of IgA-V appear to be at higher risk for gestational hypertension and pre-eclampsia, especially in cases with renal involvement; however, both mother and newborn outcomes appear to be favourable. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is an autoimmune disease whose pathophysiology remains incompletely understood, involving genetic and epigenetic factors. However, an increasing small subset of patients present with monogenic lupus, providing insight into the pathogenesis of the disease. This systematic review focuses on SLE associated with A20 haploinsufficiency (HA20), a monogenic disorder associated with tumor necrosis factor alpha-induced protein 3 gene (TNFAIP3) variants. Besides the mainly auto-inflammatory phenotypic expression of HA20 mimicking Behçet's disease spectrum, some of its clinical and biological manifestations are part of the spectrum of autoimmune diseases, including glomerulonephritis as well as the frequent presence of antinuclear antibodies, sometimes with anti-DNA specificity. Among all the 191 HA20 patients reported in the literature, we identified 16 patients (8.4 %) with a compatible diagnosis of SLE. When estimable, the SLICC 2012 and EULAR/ACR 2019 classification criteria were positive for 92.9 % of them. A majority had multi-system involvement, mainly cutaneous (81.3 %), musculoskeletal (56.3 %), and/or renal (56.3 %) manifestations. They also seemed to exhibit differences compared to other SLE patients: higher prevalence of fever, chronic cutaneous lupus erythematosus, oral and genital ulcers, neuropsychiatric manifestations, autoimmune cytopenia, and elevated biologic inflammatory markers. This review highlights the necessity of considering TNFAIP3 variants in SLE patients with early-onset disease, familial history, and/or specific clinical manifestations suggestive of autoinflammatory diseases. Recognizing HA20-SLE patients may improve our understanding of SLE pathogenesis and lead to better therapeutic strategies for these patients., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier B.V.)

Objectives: To identify factors associated with the progression of giant cell arteritis (GCA)-related or associated aortic dilations., Methods: In this retrospective study, 47 GCA patients with aortic dilation were longitudinally analyzed. Each patient underwent ≥2 imaging scans of the aorta during the follow-up. Three progression statuses of aortic dilations were distinguished: fast-progressive (FP) defined by a progression of the aortic diameter ≥5 mm/year or ≥1 cm/2 years, slow progressive (SP) by a progression of the aortic diameter >1 mm during the follow-up, and not progressive (NP) when aortic diameter remained stable., Results: Among the 47 patients with aortic dilation, the thoracic section was involved in 87 % of patients. Within a total follow-up of 89 [6-272] months, we identified 13 (28 %) patients with FP dilations, and 16 (34 %) and 18 (38 %) patients with SP and NP dilations, respectively. No differences regarding baseline characteristics, cardiovascular risk factors or treatments were observed among the 3 groups. However, FP patients more frequently showed atheromatous disease (p = 0.04), with a more frequent use of statins (p = 0.04) and antiplatelet agents (p = 0.02). Among the 27 (57 %) patients with aortitis, aortic dilation developed on an inflammatory segment in 23 (85 %). Among the FP patients who underwent aortic surgery with available histology (n = 3), all presented active vasculitis., Conclusion: This study suggests that aortic inflammation, as well as atheromatous disease, might participate in the fast progression of aortic dilation in GCA., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier B.V.)

Critically ill patients admitted to the intensive care unit (ICU) for SARS-CoV-2-induced acute respiratory distress syndrome (ARDS) are at increased risk of bacterial and fungal secondary pulmonary infections due to acquired immune dysfunction. Given that the activity of neutrophils has not been described in these patients, we aimed to investigate the function of neutrophils at ICU admission and on Day 7 (D7) post admission. Neutrophil maturation and several functional indicators were investigated. We detected a significant decrease in reactive oxygen species production at D7, but we did not observe any other significant alterations in neutrophil function. Furthermore, bronchoalveolar lavage obtained from patients displayed no inhibitory effect on the function of neutrophils from healthy donors. These findings indicate that patients admitted to the ICU for SARS-CoV-2-induced ARDS do not acquire neutrophil dysfunction within the first week of their stay, which suggests that nosocomial infections among these patients are not due to acquired neutrophil dysfunctions., (© 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.)

Objectives: To assess the frequency and characteristics of severe relapse in patients with giant cell arteritis (GCA) in a real-life setting., Methods: In a monocentric database of 530 patients, we retrospectively analysed patients who experienced at least one relapse and distinguished severe from nonsevere relapses. Severe relapse was defined by the occurrence of an ischaemic event (ophthalmologic, neurologic, digestive, limb ischaemia), the occurrence of an aortic complication (i.e. new or worsening of aortic dilation, aortic dissection), or new or worsening of vascular stenosis., Results: From the cohort of 530 patients, 242 (45.7%) patients experienced relapse at least once, including 13 (2.5% of the cohort) who experienced severe relapse. Among the 464 recorded relapses, 14 (3% of all relapses) were severe. Severe relapse corresponded to the following vascular events: a peripheral limb ischaemia in 6 patients, a visual event in 3 patients (including 2 acute anterior ischaemic anterior neuropathies), an aortic complication in 3 patients, a mesenteric ischaemia in one patient and an ischaemic stroke in one patient.When compared with the 229 patients who experienced nonsevere relapses, severe relapse patients were younger at diagnosis (p= 0.02), more frequently showed limb claudication at baseline (p< 0.0001) and fewer GCA-related cranial signs (p< 0.0001). At diagnosis, more large-vessel vasculitis on imaging (82% vs 36%, p= 0.002) were observed in patients with severe relapse. The death rate did not differ between patients with severe and nonsevere relapses., Conclusion: In a real-life setting, relapse affects nearly half of GCA patients, but severe relapse is rare., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: To determine how therapeutic strategies for giant cell arteritis (GCA), especially glucocorticoid (GC) management, evolved between 2014 and 2020. Patients and Methods: Consecutive GCA patients followed for at least 24 months in a single tertiary center were enrolled and separated into two groups: those diagnosed from 2014 to 2017 and those diagnosed from 2018 to 2020. GC doses (mg/kg/day) were analyzed at onset, at Month 3 (M3) and, if continued, at M6, M12, M18 and M24. Physicians' practices were also individually analyzed. Results: Among the 180 patients included, 96 (53%) were diagnosed in 2014-2017 and 84 (47%) in 2018-2020. All patients received GC at diagnosis without a difference in the initial dose between the two groups ( p = 0.07). At M3, the daily dose was lower in patients treated after 2017 ( p = 0.002). In patients who still received GC at M6 ( p = 0.0008), M12 ( p = 0.01) and M24 ( p = 0.02), the daily GC dose was still lower in patients treated after 2017. The proportion of patients who definitively discontinued GC use before M18 (42% versus 21%, p = 0.003) was higher in those treated after 2017. The rates of immunosuppressant use were not different between the two time periods (31% versus 38%, p = 0.34), but tocilizumab replaced methotrexate. Significant differences were observed among practitioners regarding the GC doses at M6 ( p = 0.04) and M12 ( p = 0.04), the total GC duration ( p = 0.02) and the ability to stop GC before M18 ( p = 0.007). Conclusions: This real-life study showed a global change in GC management over time for GCA patients, with important variability among physicians' practices.

Macrophages play a central role in tissue homeostasis and host defense. However, the properties of human macrophages in non-diseased tissues remain poorly understood. Here, we characterized human tonsil macrophages and identified three subsets with distinct phenotype, transcriptome, life cycle, and function. CD36hi macrophages were related to monocytes, while CD36lo macrophages showed features of embryonic origin and CD36int macrophages had a mixed profile. scRNA-seq on non-human primate tonsils showed that monocyte recruitment did not pre-exist an immune challenge. Functionally, CD36hi macrophages were specialized for stimulating T follicular helper cells, by producing Activin A. Combining reconstruction of ligand-receptor interactions and functional assays, we identified stromal cell-derived TNF-α as an inducer of Activin A secretion. However, only CD36hi macrophages were primed for Activin A expression, via the activity of IRF1. Our results provide insight into the heterogeneity of human lymphoid organ macrophages and show that tonsil CD36hi macrophage specialization is the result of both intrinsic features and interaction with stromal cells., (© 2023 Alaoui et al.)

Objectives: To assess the indications, efficiency and tolerance profiles of methotrexate (MTX) in patients with giant cell arteritis (GCA) in a real-life setting., Methods: From a monocentric database of >500 GCA patients, we retrospectively selected 49 patients who received MTX between 2010 and 2020. Cumulative glucocorticoid (GC) doses, the number of relapses and GC-related adverse events were recorded before, during and after MTX. We separately analyzed the 3 main indications of MTX, i.e., disease relapse, GC-sparing strategy, and GCA presentation., Results: With a median follow-up of 84 [10-255] months, 25 (51%) and 18/41 (44%) patients relapsed during MTX treatment and after its discontinuation, respectively. Among the 40 patients who relapsed before MTX, 26 (65%) experienced a new relapse after MTX introduction. Once MTX was introduced, 24 (49%) patients were able to discontinue GC after 20.5 [7-64] months. No significant difference in cumulative GC doses were noted before and after MTX introduction with a total GC dose of 14.7 [1.05-69.4] grams. At the last follow-up, MTX was discontinued in 41 patients, including 13 (32%) due to clinicobiological remission, 12 (30%) due to treatment failure and 15 (36%) due to side effects., Conclusion: Our real-life study showed a modest beneficial effect of MTX on relapse in patients with GCA. However, we did not observe any GC-sparing effect in this study. Other studies are needed to assess the GC-sparing effect in patients in whom GC management is adapted from recent recommendations., Competing Interests: Declarations of Competing Interest None., (Copyright © 2023. Published by Elsevier Inc.)

Objectives: To analyze whether beta-blockers (BBs), in addition to conventional care, can decrease the risk of aortic dilation in giant-cell arteritis (GCA)-related aortitis., Methods: We conducted in a single medical center retrospective study including 65 consecutive patients with GCA-related aortitis who all underwent aortic morphology control during follow-up. The impact of previous cardiovascular (CV) risk factors and/or events on BB prescription and on the risk for new aortic dilation was analyzed using a weighted (8-point maximum) score between 0 (i.e., 0/8 CV risk factors and events) and 1 (i.e., 8/8)., Results: Among the 65 patients with GCA-related aortitis, 15 (23%) were taking BBs before GCA diagnosis and continued them thereafter. The vascular score was significantly higher in patients who received BBs (0.25 [0.125-0.625] vs. 0.125 [0-0.625] in patients without BBs, p < 0.0001). The median follow-up was 91 [25-163] months in GCA patients taking BBs and 61 [14-248] months in patients not taking BBs (p = 0.13). None of the patients taking BBs developed a new aortic dilation, whereas 15 (15/50; 30%) patients not taking BBs did (p = 0.01), as detected at a median time of 38 [6-120] months after the first imaging. Rates of other CV events during follow-up did not differ between the groups (p = 1)., Conclusions: This study is the first to suggest that BBs in addition to conventional care in patients with GCA-related aortitis may help to prevent the risk of aortic dilation during follow-up. Larger-sized studies are required to confirm these results., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Nanofat grafting (NG) is a simple and cost-effective method of lipoaspirates with inter-syringe passages, to produce stromal vascular fraction (SVF) and isolate adipose-derived stem cells (ASCs). This represents a tremendous interest in the future clinical needs of tissue engineering. In this study, we optimized the NG technique to increase the yield of ASC extractions. Methods: We analyzed three groups of SVF obtained by 20, 30, and 40 inter-syringe passages. The control group was an SVF obtained by enzymatic digestion with Celase. We studied their cell composition by flow cytometry, observed their architecture by confocal microscopy, and observed immunomodulatory properties of the ASCs from each of the SVFs by measuring inflammatory markers of macrophages obtained by an ASC monocyte co-culture. Results: We have established the first cell mapping of the stromal vascular fraction of adipose tissue. The results showed that SVF obtained by 20 inter-syringe passages contains more statistically significant total cells, more cells expressing the ASC phenotype, more endothelial cells, and produces more CFU-F than the SVF obtained by 30 and 40 passages and by enzymatic digestion. Confocal microscopy showed the presence of residual adipocytes in SVF obtained by inter-syringe passages but not by enzymatic digestion. The functional study indicates an orientation toward a more anti-inflammatory profile and homogenization of their immunomodulatory properties. Conclusion: This study places mechanically dissociated SVF in the center of approaches to easily extract ASCs and a wide variety and number of other progenitor cells, immediately available in a clinical setting to provide both the amount and quality of cells required for decellularized tissues., 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 Girard, Dulong, Duisit, Mocquard, Le Gallou, Chaput, Lupon, Watier, Varin, Tarte and Bertheuil.)

Objective: To assess patients' self-reported glucocorticoid (GC)-related adverse events (AEs) in a GCA population., Methods: A questionnaire was sent to the 100 patients most recently diagnosed with GCA in a tertiary centre. This questionnaire included open- and close-ended questions on the disease and GC effects. Eight primary AE areas were analysed: cardiovascular, metabolic, muscle, cognitive and psychologic, bone, cutaneous and hairiness, infective and visual complications. Including derivative subitems from preceding areas, a total of 18 GC-related AEs were analysed separately and according to GC duration., Results: Ninety patients were analysed and 89 (99%) reported at least one GC-related AE [median 6 (range 1-11)]. Cognitive and psychological changes, primarily insomnia (72%), affected 90% of patients. Cutaneous changes and muscle loss affected 70% of patients, with frequent impairment of physical autonomy (P = 0.007) associated with this event. Metabolic issues, especially weight gain (40%) and diabetes mellitus (20%), affected 49% of patients. Conversely, vision troubles and bone fractures were mentioned by 42% and 9% of patients, respectively, and more frequently in patients who received GCs for >18 months (P = 0.01 and P = 0.007, respectively). Cardiovascular changes and infections affected 30% and 26% of patients, respectively., Conclusion: This real-life study of GC tolerance assessed using a self-evaluation provides pragmatic and updated data reminding us that GC tolerance remains more noteworthy than ever. This study suggests carefully monitoring GC-related AEs during follow-up and encourages GC-sparing strategies in some patients., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: To describe the impact of cumulative glucocorticoid (GC) doses on related adverse events (AEs) in giant cell arteritis (GCA) in a real-life setting., Methods: The medical charts of the last 139 consecutive GCA patients followed in a tertiary centre were retrospectively analysed. The cumulative GC doses were calculated, and the main GC-related AEs were collected during the follow-up., Results: After a median follow-up duration of 35.6 (2-111) months, the median cumulative GC dose in the 139 patients was 9184 (1770-24,640) mg, and 131 patients (94%) presented at least one GC-related AE. Infections (63%) were the most frequently reported GC-related AE, followed by metabolic events (63%), including weight gain in 51% of them. Cardiovascular and neuropsychiatric events occurred in 51% and 47% of patients, respectively. Osteoporotic fractures, muscular involvement, digestive events, geriatric deterioration, skin fragility, ophthalmologic complications and hypokalaemia were reported in <35% of patients. Cardiovascular events ( p = 0.01), osteoporotic fractures ( p = 0.004), cataract occurrence ( p = 0.03), weight gain ( p = 0.04) and infections ( p = 0.01) were significantly associated with GC cumulative doses > 9 g. Longer GC durations were associated with cataract occurrence ( p = 0.01), weight gain ( p = 0.03) and all-grade infections ( p = 0.048), especially herpes zoster occurrence ( p = 0.003). Neuropsychiatric and metabolic events appeared within the first months after GC introduction, whereas herpes zoster recurred, and most cardiovascular AEs emerged after 1 year. Geriatric events, especially osteoporotic fractures, occurred 2 years after GC introduction., Conclusion: This study highlights how frequent GC-related AEs are and the impact of prolonged GC and cumulative doses.

Absolute count of circulating monocytes has been proposed as an independent prognostic factor in diffuse large B-cell lymphoma (DLBCL). However, monocyte nomenclature includes various subsets with pro-, anti-inflammatory, or suppressive functions, and their clinical relevance in DLBCL has been poorly explored. Herein, we broadly assessed circulating monocyte heterogeneity in 91 DLBCL patients. Classical- (cMO, CD14 pos CD16 neg ) and intermediate- (iMO, CD14 pos CD16 pos ) monocytes accumulated in DLBCL peripheral blood and exhibited an inflammatory phenotype. On the opposite, nonclassical monocytes (ncMOSlan pos , CD14 low CD16 pos Slan neg and ncMOSlan neg , CD14 low CD16 pos , Slan neg ) were decreased in peripheral blood. Tumor-conditioned monocytes presented similarities with ncMO phenotype from DLBCL and were prone to migrate in response to CCL5 and CXCL12, and presented similarities with DLBCL-infiltrated myeloid cells, as defined by mass cytometry. Finally, we demonstrated the adverse value of an accumulation of nonclassical monocytes in 2 independent cohorts of DLBCL., 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 Le Gallou, Lhomme, Irish, Mingam, Pangault, Monvoisin, Ferrant, Azzaoui, Rossille, Bouabdallah, Damaj, Cartron, Godmer, Le Gouill, Casasnovas, Molina, Houot, Lamy, Tarte, Fest and Roussel.)

Little is known about the impact of giant cell arteritis (GCA) and its treatment on patient-reported physical, mental, and psychic quality of life (QoL). In this monocentric study, a questionnaire was sent to the 100 last patients diagnosed with GCA and followed-up in a single tertiary center. Their physical, mental and psychic status were self-assessed via close-ended questions, the 12-item short form survey (SF-12) and the 15-item geriatric depression scale (GDS). We aimed to identify parameters that were significantly associated with moderate-to-severe disability in both physical and mental domains. Ninety patients were analyzable. Moderate to severe physical disability was found in 41 (46%) patients. In multivariate analysis, walking difficulties (OR, 95% CI 8.42 [2.98-26.82], p <0.0001), muscle mass and strength reduction (OR, 95% CI 4.38 [1.37-16.31], p = 0.01) and age >80 (OR, 95% CI 4.21 [1.44-13.61], p = 0.008) were independent findings associated with moderate to severe physical disability. Moderate to severe mental disability was found in 30 (33%) patients. In multivariate analysis, depressive mood (OR, 95% CI 11.05 [3.78-37.11], p < 0.0001), felt adverse events attributable to glucocorticoids (OR, 95% CI 10.54 [1.65-213.1], p = 0.01) and use of immune-suppressants (OR, 95% CI 3.50 [1.14-11.87], p = 0.03) were independent findings associated with moderate to severe mental disability. There was a statistically significant negative correlation between GDS and the physical and/or mental disability scores (GDS and PCS-12: r = -0.33, p = 0.0013; GDS and MCS-12: r = -0.36, p = 0.0005). In conclusion, this study identified via a self-assessment of patients with GCA some medical and modifiable findings that significantly affect their physical and mental quality of life. A better knowledge of these factors may help improve the care of GCA 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 © 2021 de Boysson, Barakat, Dumont, Boutemy, Martin Silva, Maigné, Nguyen, Lavergne, Castan, Gallou, Sultan, Deshayes and Aouba.)

Objectives: To describe, in a real-life setting, the direct causes of death in a cohort of consecutive patients with GCA., Methods: We retrospectively analysed the deaths that occurred in a cohort of 470 consecutive GCA patients from a centre of expertise between January 2000 and December 2019. Among the 120 patients who died, we retrieved data from the medical files of 101 patients., Results: Cardiovascular events were the dominant cause of death (n = 41, 41%) followed by infections (n = 22, 22%), geriatric situations (i.e. falls or senile deterioration; n = 17, 17%) and cancers (n = 15, 15%). Patients in each of these four groups were compared with the other deceased patients pooled together. Patients who died from cardiovascular events were more frequently male (46 vs 27%; P = 0.04) with a past history of coronary artery disease (29 vs 8%; P = 0.006). Patients who died from infections mostly had ongoing glucocorticoid treatment (82 vs 53%; P = 0.02) with higher cumulative doses (13 994 vs 9150 mg; P = 0.03). Patients who died from geriatric causes more frequently had osteoporosis (56 vs 17%; P = 0.0009) and had mostly discontinued glucocorticoid treatment (76 vs 33%; P = 0.001). The predictive factors of death in multivariate analysis were a history of coronary disease [hazard ratio (HR) 2.39; 95% CI 1.27, 4.21; P = 0.008], strokes at GCA diagnosis (HR 2.54; 95% CI 1.05, 5.24; P = 0.04), any infection during follow-up (HR 1.93; 95% CI 1.24, 2.98; P = 0.004) and fever at GCA diagnosis (HR 1.99; 95% CI 1.16, 3.28; P = 0.01)., Conclusion: Our study provides real-life insight on the cause-specific mortality in GCA patients., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: Pyoderma gangrenosum (PG) is a rare, mainly dermatological condition, whose unusual and little-known lung involvement presents a diagnostic and therapeutic challenge., Case Report: A 66-year-old man, followed for 6 years for an IgA monoclonal gammopathy of undetermined significance and an initially cutaneous corticosteroid-dependent PG, received a pneumonectomy for a mass suspected of neoplasia, that turns out to be a PG pulmonary localisation. During successive pneumopathies, sometimes dyspneic and excavated, several hypotheses are discussed. Various infectious and immunological explorations, and various antibacterial/fungal or immunosuppressive therapies are conducted, to finally conclude to pulmonary and/or cutaneous recurrences of PG. The outcome at 14 months seems finally favourable with tofacitinib., Conclusion: The recognition of cutaneous involvement of PG, which is essential for the diagnosis of its lung involvement, is probably the mirror of its evolution under treatment. Only multidisciplinary confrontation of reported cases will allow the elaboration of diagnostic and therapeutic recommendations., (Copyright © 2021 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.)

Acute respiratory distress syndrome (ARDS) is the main complication of coronavirus disease 2019 (COVID-19), requiring admission to the intensive care unit (ICU). Despite extensive immune profiling of COVID-19 patients, to what extent COVID-19-associated ARDS differs from other causes of ARDS remains unknown. To address this question, here, we build 3 cohorts of patients categorized in COVID-19 - ARDS + , COVID-19 + ARDS + , and COVID-19 + ARDS - , and compare, by high-dimensional mass cytometry, their immune landscape. A cell signature associating S100A9/calprotectin-producing CD169 + monocytes, plasmablasts, and Th1 cells is found in COVID-19 + ARDS + , unlike COVID-19 - ARDS + patients. Moreover, this signature is essentially shared with COVID-19 + ARDS - patients, suggesting that severe COVID-19 patients, whether or not they experience ARDS, display similar immune profiles. We show an increase in CD14 + HLA-DR low and CD14 low CD16 + monocytes correlating to the occurrence of adverse events during the ICU stay. We demonstrate that COVID-19-associated ARDS displays a specific immune profile and may benefit from personalized therapy in addition to standard ARDS management., Competing Interests: J. Ferrant, F.R., S.L.G., J.D., M. Lesouhaitier, M.G., N.B., C.V., M. Latour, I.B., M. Cornic, A.V., C.M., B.S., S.L., S.P., J. Feuillard, R.J., T.D., and M. Cogné declare no competing interests. M.R., S.C., V.K.T., J.M.T., and K.T. are the inventors of a patent, EP 20305642.9, “A method for early detection of propensity to severe clinical manifestations methods” submitted June 11, 2020 under University Hospital of Rennes and Scailyte AG names., (© 2021 The Authors.)

Distinguishing chronic lymphoproliferative disorders of NK cells (CLPD-NK) from reactive NK-cell expansion is challenging. We assessed the value of killer immunoglobulin-like receptor(KIR) phenotyping and targeted high-throughput sequencing in a cohort of 114 consecutive patients with NK cell proliferation, retrospectively assigned to a CLPD-NK group (n = 46) and a reactive NK group (n = 68). We then developed an NK-cell clonality score combining flow cytometry and molecular profiling with a positive predictive value of 93%. STAT3 and TET2 mutations were respectively identified in 27% and 34% of the patients with CLPD-NK, constituting a new diagnostic hallmark for this disease. TET2-mutated CLPD-NK preferentially exhibited a CD16low phenotype, more frequently displayed a lower platelet count, and was associated with other hematologic malignancies such as myelodysplasia. To explore the mutational clonal hierarchy of CLPD-NK, we performed whole-exome sequencing of sorted, myeloid, T, and NK cells and found that TET2 mutations were shared by myeloid and NK cells in 3 of 4 cases. Thus, we hypothesized that TET2 alterations occur in early hematopoietic progenitors which could explain a potential link between CLPD-NK and myeloid malignancies. Finally, we analyzed the transcriptome by RNA sequencing of 7 CLPD-NK and evidenced 2 groups of patients. The first group displayed STAT3 mutations or SOCS3 methylation and overexpressed STAT3 target genes. The second group, including 2 TET2-mutated cases, significantly underexpressed genes known to be downregulated in angioimmunoblastic T-cell lymphoma. Our results provide new insights into the pathogenesis of NK-cell proliferative disorders and, potentially, new therapeutic opportunities., (© 2021 by The American Society of Hematology.)

Multiple sclerosis (MS) is an immune-driven demyelinating disease of the central nervous system. Immune cell features are particularly promising as predictive biomarkers due to their central role in the pathogenesis but also as drug targets, even if nowadays, they have no impact in clinical practice. Recently, high-resolution approaches, such as mass cytometry (CyTOF), helped to better understand the diversity and functions of the immune system. In this study, we performed an exploratory analysis of blood immune response profiles in healthy controls and MS patients sampled at their first neurological relapse, using two large CyTOF panels including 62 markers exploring myeloid and lymphoid cells. An increased abundance of both a T-bet-expressing B cell subset and a CD206 + classical monocyte subset was detected in the blood of early MS patients. Moreover, T-bet-expressing B cells tended to be enriched in aggressive MS patients. This study provides new insights into understanding the pathophysiology of MS and the identification of immunological biomarkers. Further studies will be required to validate these results and to determine the exact role of the identified clusters in neuroinflammation., 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 Couloume, Ferrant, Le Gallou, Mandon, Jean, Bescher, Zephir, Edan, Thouvenot, Ruet, Debouverie, Tarte, Amé, Roussel and Michel.)

In diffuse large B-cell lymphoma (DLBCL), tumor-infiltrating T lymphocytes (TILs) are involved in therapeutic responses. However, tumor-specific TILs can be dysfunctional, with impaired effector functions. Various mechanisms are involved in this exhaustion, and the increased expression of programmed cell death receptor 1 (PD1) and TIM3 on dysfunctional cells suggests their involvement. However, conflicting data have been published regarding their expression or coexpression in DLBCL. We evaluated the presence and phenotype of CD4+ and CD8+ TILs in freshly collected tumor tissues in DLBCL and compared the results with those in follicular lymphoma, classical Hodgkin lymphoma, and nonmalignant reactive lymphadenopathy. We found that TILs expressing both PD1 and TIM3 were expanded in DLBCL, particularly in the activated B cell-like subgroup. Isolated PD1+TIM3+ TILs exhibited a transcriptomic signature related to T-cell exhaustion associated with a reduction in cytokine production, both compromising the antitumor immune response. However, these cells expressed high levels of cytotoxic molecules. In line with this, stimulated PD1+TIM3+ TILs from DLBCL patients exhibited reduced proliferation and impaired secretion of interferon-γ, but these functions were restored by the blockade of PD1 or TIM3. In summary, the PD1+TIM3+ TIL population is expanded and exhausted in DLBCL but can be reinvigorated with appropriate therapies., (© 2021 by The American Society of Hematology.)

Purpose: The SARS-CoV-2 infection can lead to a severe acute respiratory distress syndrome (ARDS) with prolonged mechanical ventilation and high mortality rate. Interestingly, COVID-19-associated ARDS share biological and clinical features with sepsis-associated immunosuppression since lymphopenia and acquired infections associated with late mortality are frequently encountered. Mechanisms responsible for COVID-19-associated lymphopenia need to be explored since they could be responsible for delayed virus clearance and increased mortality rate among intensive care unit (ICU) patients., Methods: A series of 26 clinically annotated COVID-19 patients were analyzed by thorough phenotypic and functional investigations at days 0, 4, and 7 after ICU admission., Results: We revealed that, in the absence of any difference in demographic parameters nor medical history between the two groups, ARDS patients presented with an increased number of myeloid-derived suppressor cells (MDSC) and a decreased number of CD8 pos effector memory cell compared to patients hospitalized for COVID-19 moderate pneumonia. Interestingly, COVID-19-related MDSC expansion was directly correlated to lymphopenia and enhanced arginase activity. Lastly, T cell proliferative capacity in vitro was significantly reduced among COVID-19 patients and could be restored through arginine supplementation., Conclusions: The present study reports a critical role for MDSC in COVID-19-associated ARDS. Our findings open the possibility of arginine supplementation as an adjuvant therapy for these ICU patients, aiming to reduce immunosuppression and help virus clearance, thereby decreasing the duration of mechanical ventilation, nosocomial infection acquisition, and mortality.

The monocyte/macrophage lineage has been shown to be involved in the promotion of a protumoral tumor microenvironment and resistance to treatment in B cell lymphomas. However, it is still poorly described at the single cell level, and tissue samples are not easily accessible. Thus, a detailed analysis of the circulating myeloid cell compartment in the different B lymphomas is needed to better understand the mechanisms of resistance to treatment and identify at risk patients. In this Perspective, we review current knowledge on the phenotypic and functional description of the circulating monocytic lineage in B cell lymphomas and provide first insights into the heterogeneity of these cell populations in health and lymphoma, using mass cytometry. Indeed, the monocytic compartment is a continuum more than distinct subpopulations, as demonstrated by our high-resolution approach, explaining the sometimes confusing and contradictory conclusions on the prognostic impact of the different populations, including monocytes and monocytic myeloid derived suppressor cells (M-MDSC). By identifying S100A9 high monocytic cells as a potential biomarker in diffuse large B cell lymphoma (DLBCL) in this proof-of-concept preliminary study including a limited number of samples, we underline the potential of circulating myeloid regulatory cells as diagnostic and prognostic biomarkers in B-cell lymphomas., 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 Ferrant, Lhomme, Le Gallou, Irish and Roussel.)

Myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) are heterogeneous cells that share myeloid markers and are not easily distinguishable in human tumors due to their lack of specific markers. These cells are a major player in the tumor microenvironment and are involved in the prognosis and physiopathology of various tumors. Here is presented a scheme to decipher these cells by mass cytometry.

To what extent immune responses against the gut flora are compartmentalized within mucosal tissues in homeostatic conditions remains a much-debated issue. We describe here, based on an inducible AID fate-mapping mouse model, that systemic memory B cell subsets, including mainly IgM + B cells in spleen, together with IgA + plasma cells in spleen and bone marrow, are generated in mice in the absence of deliberate immunization. While the IgA component appears dependent on the gut flora, IgM memory B cells are still generated in germ-free mice, albeit to a reduced extent. Clonal relationships and renewal kinetics after anti-CD20 treatment reveal that this long-lasting splenic population is mainly sustained by output of B cell clones persisting in mucosal germinal centers. IgM-secreting hybridomas established from splenic IgM memory B cells showed reactivity against various bacterial isolates and endogenous retroviruses. Ongoing activation of B cells in gut-associated lymphoid tissues thus generates a diversified systemic compartment showing long-lasting clonal persistence and protective capacity against systemic bacterial infections., (© 2018 Le Gallou et al.)

Previous data have suggested that B-cell-depletion therapy may induce the settlement of autoreactive long-lived plasma cells (LLPCs) in the spleen of patients with autoimmune cytopenia. To investigate this process, we used the AID-CreERT2-EYFP mouse model to follow plasma cells (PCs) engaged in an immune response. Multiplex polymerase chain reaction at the single-cell level revealed that only a small fraction of splenic PCs had a long-lived signature, whereas PCs present after anti-CD20 antibody treatment appeared more mature, similar to bone marrow PCs. This observation suggested that, in addition to a process of selection, a maturation induced on B-cell depletion drove PCs toward a long-lived program. We showed that B-cell activating factor (BAFF) and CD4 + T cells play a major role in the PC survival niche, because combining anti-CD20 with anti-BAFF or anti-CD4 antibody greatly reduce the number of splenic PCs. Similar results were obtained in the lupus-prone NZB/W model. These different contributions of soluble and cellular components of the PC niche in the spleen demonstrate that the LLPC expression profile is not cell intrinsic but largely depends on signals provided by the splenic microenvironment, implying that interfering with these components at the time of B-cell depletion might improve the response rate in autoimmune cytopenia., (© 2018 by The American Society of Hematology.)

The monocyte phagocyte system (MPS) includes numerous monocyte, macrophage, and dendritic cell (DC) populations that are heterogeneous, both phenotypically and functionally. In this study, we sought to characterize those diverse MPS phenotypes with mass cytometry (CyTOF). To identify a deep phenotype of monocytes, macrophages, and DCs, a panel was designed to measure 38 identity, activation, and polarization markers, including CD14, CD16, HLA-DR, CD163, CD206, CD33, CD36, CD32, CD64, CD13, CD11b, CD11c, CD86, and CD274. MPS diversity was characterized for 1) circulating monocytes from healthy donors, 2) monocyte-derived macrophages further polarized in vitro (i.e., M-CSF, GM-CSF, IL-4, IL-10, IFN-γ, or LPS long-term stimulations), 3) monocyte-derived DCs, and 4) myeloid-derived suppressor cells (MDSCs), generated in vitro from bone marrow and/or peripheral blood. Known monocyte subsets were detected in peripheral blood to validate the panel and analysis pipeline. Then, using various culture conditions and stimuli before CyTOF analysis, we constructed a multidimensional framework for the MPS compartment, which was registered against historical M1 or M2 macrophages, monocyte subsets, and DCs. Notably, MDSCs generated in vitro from bone marrow expressed more S100A9 than when generated from peripheral blood. Finally, to test the approach in vivo, peripheral blood from patients with melanoma ( n = 5) was characterized and observed to be enriched for MDSCs with a phenotype of CD14 + HLA-DR low S100A9 high (3% of PBMCs in healthy donors, 15.5% in patients with melanoma, P < 0.02). In summary, mass cytometry comprehensively characterized phenotypes of human monocyte, MDSC, macrophage, and DC subpopulations in both in vitro models and patients., (© Society for Leukocyte Biology.)

Expression of activation-induced cytidine deaminase (AID) is the hallmark of B cells engaged in an immune response in germinal centers. We designed an inducible fate-mapping reporter mouse in which AID-expressing B cells could be timely and irreversibly marked, by knockin at the Aicda locus of a tamoxifen-inducible Cre recombinase. This mouse model allows notably for the long-term follow-up of memory B cells and plasma cells engaged in an immune response. We describe here a protocol to generate hybridomas from small memory subsets that can be easily traced and identified in this mouse line through Cre-activated fluorescent reporters.

Primary warm autoimmune hemolytic anemia (wAIHA) is a rare autoimmune disease in which red blood cells are eliminated by IgG autoantibodies. We analyzed the antibody-secreting cells in the spleen and the peripheral blood of wAIHA patients in various contexts of treatment. Plasmablasts were observed in peripheral blood of newly diagnosed wAIHA patients and, accordingly, active germinal center reactions were present in the spleen of patients receiving short-term corticosteroid therapy. Long-term corticosteroid regimens markedly reduced this response while splenic plasma cells were able to persist, a fraction of them secreting anti-red blood cell IgG in vitro. In wAIHA patients treated by rituximab and who underwent splenectomy because of treatment failure, plasma cells were still present in the spleen, some of them being autoreactive. By using a set of diagnostic genes that allowed us to assess the plasma cell maturation stage, we observed that these cells displayed a long-lived program, differing from the one of plasma cells from healthy donors or from wAIHA patients with various immunosuppressant treatments, and more similar to the one of normal long-lived bone-marrow plasma cells. Interestingly, an increased level of B-cell activating factor (BAFF) was observed in the supernatant of spleen cell cultures from such rituximab-treated wAIHA patients. These results suggest, in line with our previous report on primary immune thrombocytopenia, that the B-cell depletion induced by rituximab promoted a suitable environment for the maturation and survival of auto-immune long-lived plasma cells in the spleen., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

B cell memory has long been considered the attribute of the sole IgG-positive B cell subset. Since a few years, and due to new B-cell subset identification procedures, increasing heterogeneity has been identified among the memory B cell pool. IgM-positive cells and germinal center-independent subsets are recent additions to the field. This review describes the diversity of memory B cells, as well as controversial issues on their relative contribution to the recall response. The impact of a protracted germinal center response to the specific mobilization of IgM memory B cells is proposed., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Primary immune thrombocytopenia (ITP) is a disorder caused by autoantibody-mediated platelet destruction and decreased platelet production. Rituximab, a B cell-depleting agent, has become the first-line treatment for ITP; however, patients with refractory disease usually require splenectomy. We identified antibody-secreting cells as the major splenic B cell population that is resistant to rituximab. The phenotype, antibody specificity, and gene expression profile of these cells were characterized and compared to those of antibody-secreting cells from untreated ITP spleens and from healthy tissues. Antiplatelet-specific plasma cells (PC) were detected in the spleens of patients with ITP up to 6 months after rituximab treatment, and the PC population displayed a long-lived program similar to the one of bone marrow PC, thus explaining for most of these patients the absence of response to rituximab and the response to splenectomy. When analyzed by multiplex PCR at the single-cell level, normal splenic PC showed a markedly different gene expression profile, with an intermediate signature, including genes characteristic of both long-lived PC and proliferating plasmablasts. Surprisingly, long-lived PC were not detected in untreated ITP spleens. These results suggest that the milieu generated by B cell depletion promotes the differentiation and settlement of long-lived PC in the spleen.