Inhibitory receptors expressed by T cells mediate tolerance to tumor antigens, with coexpression of these receptors exacerbating this dysfunctional state. Using the VectraR automated multiparametric ...immunofluorescence technique, we quantified intratumoral CD8
T cells coexpressing the inhibitory receptors PD-1 and Tim-3 from patients with renal cell carcinoma (RCC). A second validation cohort measured the same parameters by cytometry. The percentage of tumor-infiltrating CD8
T cells coexpressing PD-1 and Tim-3 correlated with an aggressive phenotype and a larger tumor size at diagnosis. Coexpression of PD-1 and Tim-3 above the median conferred a higher risk of relapse and a poorer 36-month overall survival. Notably, other CD8
T-cell subsets did not exert a similar effect on overall survival. Moreover, only the PD-1
Tim-3
subset of CD8
T cells exhibited impaired function after stimulation. Our findings establish intratumoral Tim-3
PD1
CD8
T cells as critical mediators of an aggressive phenotype in RCC. Use of the Vectra tool may be useful to identify similarly critical prognostic and predictive biomarkers in other tumor types and their response to immunotherapy.
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Macrophages are the immune cells that accumulate the most in the majority of established tumors and this accumulation is associated with a poor prognosis. Tumor-associated macrophages (TAMs) produce ...inflammatory cytokines and growth factors that promote tumor expansion and metastasis. TAMs have recently emerged as targets of choice to restore an efficient antitumor response and to limit tumor growth. Many molecules targeting TAMs are actually evaluated in clinical trials, alone or in combination. While these molecules induce tumor regression and stimulate cytotoxic responses in mouse models of tumor development, results from early clinical trials are less impressive. In this review, we list the biological differences between human and mouse macrophages that help explain the different efficacy of antitumor strategies targeting TAMs between human and animal studies. Differences in the impact of survival and polarization factors and in the cytokines produced and markers expressed as well as the limitations of extrapolations based on in vitro models of TAM-like generation should be considered in order to improve the design and efficacy of antitumor drugs targeting TAMs.
Pentraxins are soluble innate immunity receptors involved in sensing danger molecules. They are classified as short (CRP, SAP) and long pentraxin subfamilies, including the prototypic long pentraxin ...PTX3. Pentraxins act mainly as bridging molecules favoring the clearance of microbes and dead cells. They are also involved in many other biological processes, such as regulation of complement activation, inflammation and tissue homeostasis. Autoantibodies directed against pentraxins have been reported in various autoimmune diseases, especially in systemic lupus erythematosus and ANCA-associated vasculitis. In this review, we review the main biological characteristics and functions of pentraxins and summarize data concerning autoantibodies directed against pentraxins in the context of autoimmune diseases and discuss their potential pathological role.
Chronic silica exposure can lead to silicosis, complicated or not by autoimmune diseases (AID). The pathophysiology of silica-induced AID remains not fully understood, especially immune mechanisms ...that may develop in patients without yet established silicosis. We conducted a prospective clinical study to analyze the impact of crystalline silica (CS) on T cell phenotype and regulatory T cells (Tregs) frequency, as well as on auto-antibodies development in non-silicotic workers exposed to CS.
Workers with moderate to high exposure level to CS and aged between 30 and 60 years-old were considered for inclusion. Peripheral blood mononuclear cells were analyzed by flow cytometry. Auto-antibodies were screened in serum by immunofluorescence. Blood from 42 and 45 healthy subjects (HC) was used as control for T cell phenotype and serum analyses, respectively.
Among the 63 included workers exposed to CS, 55 had full data available and were analyzed. Ten were exposed to CS for <5 years, 18 for 5-10 years and 27 for more than 10 years. The frequency of Tregs (CD4
CD25
CD127
FoxP3
) was significantly lower in CS exposed workers as compared to HC. We found an increased expression of the activation marker HLA-DR on T cells (CD3
, CD4
, and CD8
) of CS exposed workers as compared to HC. Tregs to activated T cells ratio was also lower in exposed subjects. In the latter, HLA-DR expression level and Tregs frequency were significantly associated with CS exposure duration. Serum autoantibody detection was significantly higher in CS exposed workers as compared to HC. Especially, among workers exposed more than 10 years, antinuclear antibodies and ANCA were detected in 44 and 22% among them, as compared to 5 and 2.5% in HC, respectively.
This work shows that CS exposure is associated with a decrease of Tregs frequency, an increase of T cell activation status, and a tolerance breakdown against auto-antigens. These results show that alterations of the T cell compartment can be detected early over the course of CS exposure, preceding silicosis development or AID onset.
Electrophoresis-derived techniques for anti-SSA/Ro60 KDa (anti-SSA) antibodies detection have been progressively replaced by methods using non-native antigens. We aimed to compare the patients' ...phenotypes and the occurrence of extraglandular manifestations in primary Sjögren's syndrome according to the method used to detect anti-SSA antibodies. Sera from patients with a diagnosis of pSS according to ACR/EULAR 2016 criteria between 2008 and 2017 were tested for anti-SSA antibodies using methods with non-native antigens (magnetic bead multiplex assay; line immunoassays) and one with native antigens (counterimmunoelectrophoresis (CIE)). The population was split into three groups according to anti-SSA antibodies status: absence (SSA-), presence in any method except for CIE (SSA+CIE-), and presence in CIE (SSA+CIE+). The patients in the SSA+CIE+ group (
= 70, 42.7%) were ten years younger and presented more immunological activity compared with both the SSA- (
= 80, 48.8%) and SSA+CIE- groups (
= 14, 8.5%). The SSA- and SSA+CIE- groups were poorly distinct. The presence of anti-SSA antibodies solely in CIE was significantly associated with the occurrence of extraglandular manifestations of pSS (HR = 4.45 (2.35-8.42)). Contrary to CIE, methods using non-native antigens to detect anti-SSA antibodies were unable to predict the occurrence of systemic expression of pSS.
Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease of the central nervous system resulting from the reactivation of the John Cunningham virus (JCV). PML occurs almost ...exclusively during profound immune suppression but it can also be observed in immunocompromised subjects as part of an inflammatory immune reconstitution syndrome (IRIS) in patients receiving antiviral therapy. We report a case of PML in a 61‐year‐old patient with acute myeloid leukemia who had developed after discontinuation of durvalumab (anti‐PD‐L1) therapy initiated after multiple treatments. Results suggest that PML may result from two nonexclusive mechanisms: (i) an inhibition of the protective response of JCV‐specific T cells as a consequence of the blockade of the PD1‐PDL1 pathway, associated with a lack of compensatory expression of other inhibitory receptors by T cells and (ii) a neuroinflammatory response (PML‐IRIS) that may have contributed to virus reactivation.
While vitamin B12 (B12) deficiency is considered as the hallmark of pernicious anemia (PA), iron deficiency (ID) is also prevalent. Indeed, this auto immune gastritis is responsible for parietal cell ...atrophy and increase in gastric pH, leading to impaired iron absorption. We compared PA patients’ features according to their iron status at PA diagnosis, and we assessed the iron status recovery after oral or intravenous iron supplementation.
We prospectively included patients presenting with a newly diagnosed PA in a tertiary referral hospital between November 2018 and October 2020. Iron status was assessed at PA diagnosis then regularly during a standardized follow-up. In case of ID, the decision of treatment with oral and/or intravenous iron supplementation was left to the clinician convenience.
We included 28 patients with newly diagnosed PA. ID was observed in 21/28 (75.0%) patients: from the PA diagnosis in 13 patients, or during the follow-up in 8 patients. Iron deficient PA patients had higher plasma B12 (p = 0.04) and lower homocysteine levels (p = 0.04). Also, ID was independently associated with the ‘APCA (anti-parietal cell antibodies) alone’ immunological status (absence of anti-intrinsic factor antibodies) after adjustment for age, gender and B12 level (aOR 12.1 1.1–141.8, p = 0.04). High level of APCA was associated with lower ferritin level. After 3 months of supplementation, 3/11 PA patients normalized the iron status with oral iron supplementation, versus 7/8 with intravenous iron supplementation (p = 0.02).
The high frequency of iron deficiency in PA highlights the interest of regular assessment of iron status in this condition. ID was associated with a profile including APCA alone and less pronounced B12 deficiency. Intravenous iron supplementation seemed to be more efficient than an oral supplementation in these preliminary data.
No antibody response in acral cutaneous manifestations associated with COVID‐19? Mahieu, R.; Tillard, L.; Le Guillou‐Guillemette, H. ...
JEADV. Journal of the European Academy of Dermatology and Venereology/Journal of the European Academy of Dermatology and Venereology,
October 2020, Volume:
34, Issue:
10
Journal Article
Peer reviewed
Open access
Skins symptoms during COVID‐19 have been recently described but their relation to SARS‐CoV‐2 is unclear while results for real‐time reverse transcriptase polymerase chain reaction (rRT‐PCR) testing ...were variable. Recalcati et al. reported 14 cases of patients with skin symptoms consistent with previous described COVID‐19 lesions but all the patients were tested negative. They asked for a serology to validate the hypothesis that these lesions are related to COVID‐19.
Abstract
Background and Aims
Antineutrophil-cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) with kidney involvement (AAV-GN) frequently evolves to end-stage kidney disease (ESKD) despite ...aggressive immunosuppressive treatment. Several risk scores have been used to assess renal prognosis. We aimed to determine whether kidney function and markers of AAV-GN activity after 6 months could improve the prediction of ESKD.
Method
This retrospective and observational study included adult patients with AAV-GN recruited from 6 French nephrology centers (including from the Maine-Anjou AAV registry). The primary outcome was kidney survival. Analyses were conducted in the whole population and in a sub-population that did not develop ESKD early in the course of the disease.
Results
241 patients were included in the whole cohort, with a median follow-up of 59 months. At diagnosis, Berden classification and Renal Risk Score (RRS) were not found better than kidney function (eGFR) alone, at predicting ESKD (C-index = 0.70, 0.79, 0.82, respectively). At 6 months, 20 patients reached ESKD. In the sub-population of 221 patients, 6 months eGFR outperformed Berden classification and RRS (C-index = 0.88, 0.62, 0.69, respectively) to predict ESKD. RRS performed better when it was updated with the eGFR at 6 months instead of the baseline eGFR. While 6-months proteinuria was associated with ESKD and improved ESKD prediction, hematuria and serological remission did not.
Conclusion
This work suggests the interest of the reassessment of the renal prognosis 6 months after AAV-GN diagnosis. Kidney function at this time remains the most reliable for predicting renal outcome. To improve the long-term prediction of ESKD, there may be a place for repeated kidney biopsy following induction treatment, in order to obtain a precise evaluation of disease activity, discuss the immunosuppressive treatment strategy and improve prognosis scores.
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