The giant cell arteritis (GCA) pathophysiology is complex and multifactorial, involving a predisposing genetic background, the role of immune aging and the activation of vascular dendritic cells by ...an unknown trigger. Once activated, dendritic cells recruit CD4 T cells and induce their activation, proliferation and polarization into Th1 and Th17, which produce interferon-gamma (IFN-γ) and interleukin-17 (IL-17), respectively. IFN-γ triggers the production of chemokines by vascular smooth muscle cells, which leads to the recruitment of additional CD4 and CD8 T cells and also monocytes that differentiate into macrophages. Recent data have shown that IL-17, IFN-γ and GM-CSF induce the differentiation of macrophage subpopulations, which play a role in the destruction of the arterial wall, in neoangiogenesis or intimal hyperplasia. Under the influence of different mediators, mainly endothelin-1 and PDGF, vascular smooth muscle cells migrate to the intima, proliferate and change their phenotype to become myofibroblasts that further proliferate and produce extracellular matrix proteins, increasing the vascular stenosis. In addition, several defects in the immune regulatory mechanisms probably contribute to chronic vascular inflammation in GCA: a defect in the PD-1/PD-L1 pathway, a quantitative and qualitative Treg deficiency, the implication of resident cells, the role of GM-CSF and IL-6, the implication of the NOTCH pathway and the role of mucosal-associated invariant T cells and tissue-resident memory T cells.
Polymyalgia rheumatica (PMR) is an inflammatory rheumatism of the shoulder and pelvic girdles. In 16 to 21% of cases, PMR is associated with giant cell arteritis (GCA) that can lead to severe ...vascular complications. Ruling out GCA in patients with PMR is currently a critical challenge for clinicians. Two GCA phenotypes can be distinguished: cranial GCA (C-GCA) and large vessel GCA (LV-GCA). C-GCA is usually suspected when cranial manifestations (temporal headaches, jaw claudication, scalp tenderness, or visual disturbances) occur. Isolated LV-GCA is more difficult to diagnose, due to the lack of specificity of clinical features which can be limited to constitutional symptoms and/or unexplained fever. Furthermore, many studies have demonstrated the existence-in varying proportions-of subclinical GCA in patients with apparently isolated PMR features. In PMR patients, the occurrence of clinical features of C-GCA (new onset temporal headaches, jaw claudication, or abnormality of temporal arteries) are highly predictive of C-GCA. Additionally, glucocorticoids' resistance occurring during follow-up of PMR patients, the occurrence of constitutional symptoms, or acute phase reactants elevation are suggestive of associated GCA. Research into the predictive biomarkers of GCA in PMR patients is critical for selecting PMR patients for whom imaging and/or temporal artery biopsy is necessary. To date, Angiopoietin-2 and MMP-3 are powerful for predicting GCA in PMR patients, but these results need to be confirmed in further cohorts. In this review, we discuss the diagnostic challenges of subclinical GCA in PMR patients and will review the predictive factors of GCA in PMR patients.
Background: No robust data assesses the risk of all-cause death and cardiovascular (CV) events in multiple myeloma (MM) patients. Patients and Methods: From 1 January to 31 December 2013, 3,381,472 ...adults were hospitalised (for any reason) in French hospitals. We identified 15,774 patients diagnosed with known MM at baseline. The outcome analysis (all-cause death, CV death, myocardial infarction (MI), ischaemic stroke, or hospitalization for bleedings) was performed with follow-ups starting at the time of the last event. For each MM patient, a propensity score-matched patient without MM was selected. Results: The mean follow-up in the propensity-score-matched population was 3.7 ± 2.3 years. Matched patients with MM had a higher risk of all-death (yearly rate 20.02 vs. 11.39%) than patients without MM. No difference was observed between the MM group and no-MM group for CV death (yearly rate 2.00 vs. 2.02%). The incidence rate of MI and stroke was lower in the MM group: 0.86 vs. 0.97%/y and 0.85 vs. 1.10%/y, respectively. In contrast, MM patients had a higher incidence rate of rehospitalization for major bleeding (3.61 vs. 2.24%/y) and intracranial bleeding (1.03 vs. 0.84%/y). Conclusions: From a large nationwide database, we demonstrated that MM patients do not have a higher risk of CV death or even a lower risk of both MI and ischaemic stroke. Conversely, MM patients had a higher risk of both major and intracranial bleedings, highlighting the key issue of thromboprophylaxis in these patients.
In the presence of temporal arteritis, clinicians often refer to the diagnosis of giant cell arteritis (GCA). However, differential diagnoses should also be evoked because other types of vascular ...diseases, vasculitis or not, may affect the temporal artery. Among vasculitis, Anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis is probably the most common, and typically affects the peri-adventitial small vessel of the temporal artery and sometimes mimics giant cell arteritis, however, other symptoms are frequently associated and more specific of ANCA-associated vasculitis prompt a search for ANCA. The Immunoglobulin G4-related disease (IgG4-RD) can cause temporal arteritis as well. Some infections can also affect the temporal artery, primarily an infection caused by the varicella-zoster virus (VZV), which has an arterial tropism that may play a role in triggering giant cell arteritis. Drugs, mainly checkpoint inhibitors that are used to treat cancer, can also trigger giant cell arteritis. Furthermore, the temporal artery can be affected by diseases other than vasculitis such as atherosclerosis, calcyphilaxis, aneurysm, or arteriovenous fistula. In this review, these different diseases affecting the temporal artery are described.
Recently developed cell-based therapies have shown potential for graft-versus-host disease (GvHD) mitigation. Our team previously developed a protocol to generate human monocyte-derived suppressor ...Cells (HuMoSC), a subpopulation of CD33+ suppressor cells of monocytic origin. CD33+HuMoSC successfully reduced xenoGvHD severity in NOD/SCID/IL-2Rγc
(NSG) mice. While CD33+ HuMoSC culture supernatant inhibits T cell activation and proliferation, the recovery of CD33+ HuMoSC immunosuppressive cells and the subsequent production of their supernatant is limited. An attractive solution would be to use both the CD33+ and the large number of CD14+ cells derived from our protocol. Here, we assessed the immunoregulatory properties of the CD14+HuMoSC supernatant and demonstrated that it inhibited both CD4 and CD8 T cell proliferation and decreased CD8 cytotoxicity.
, injection of CD14+HuMoSC supernatant reduced xenoGvHD in NSG mice. Furthermore, CD14+HuMoSC supernatant maintained its immunoregulatory properties in an inflammatory environment. Proteomic and multiplex analyses revealed the presence of immunosuppressive proteins such as GPNMB, galectin-3 and IL-1R(A) Finally, CD14+HuMoSC supernatant can be produced using good manufacturing practices and be used as complement to current immunosuppressive drugs. CD14+HuMoSC supernatant is thus a promising therapy for preventing GvHD. .
Immunosuppressive cell-based therapy is a recent strategy for controlling Graft-versus-Host Disease (GvHD). Such cells ought to maintain their suppressive function in inflammatory conditions and in ...the presence of immunosuppressive agents currently used in allogeneic hematopoietic cell transplantation (allo-HCT). Moreover, these therapies should not diminish the benefits of allo-HCT, the Graft-versus-Leukemia (GvL) effect. We have previously reported on a novel subset of human monocyte-derived suppressor cells (HuMoSC) as a prospective approach for controlling GvHD.Objective
The objective of this study was to explore the therapeutic relevance of the HuMoSC in clinical conditions.
Immune regulatory functions of HuMoSC were assessed in inflammatory conditions and in the presence of immunosuppressants. The therapeutic efficiency of the association of HuMoSC with immunosuppressants was evaluated in an experimental model of GvHD induced by human PBMC in NOD/SCID/IL2-Rγ
c
−/−
(NSG) mice.
Interestingly, the inhibitory functions of HuMoSC against T lymphocytes and their ability to polarize Treg are preserved, in vitro, in inflammatory environments and are not affected by immunosuppressive agents. In vivo, the association of HuMoSC-based treatment with an immunosuppressive drug showed a synergistic effect for controlling GvHD. Furthermore, HuMoSC control GvHD while preserving GvL effect in a xeno-GvHD conditioned mouse model with cell neoplasm (CAL-1). HuMoSC are generated according to good manufacturing practices (GMP) and we demonstrated that these cells tolerate long-term preservation with unaltered phenotype and function.Conclusion
HuMoSC-based therapy represents a promising approach for controlling GvHD and could be quickly implemented in clinical practice.
Dendritic cells (DCs), essential for the initiation and regulation of adaptive immune responses, have been used as anticancer vaccines. DCs may also directly trigger tumor cell death. In the current ...study, we have investigated the tumoricidal and immunostimulatory activities of mouse bone marrow-derived DCs. Our results indicate that these cells acquire killing capabilities toward tumor cells only when activated with LPS or Pam3Cys-SK4. Using different transgenic mouse models including inducible NO synthase or GP91 knockout mice, we have further established that LPS- or Pam3Cys-SK4-activated DC killing activity involves peroxynitrites. Importantly, after killing of cancer cells, DCs are capable of engulfing dead tumor cell fragments and of presenting tumor Ags to specific T lymphocytes. Thus, upon specific stimulation, mouse bone marrow-derived DCs can directly kill tumor cells through a novel peroxynitrite-dependent mechanism and participate at virtually all levels of antitumor immune responses, which reinforces their interest in immunotherapy.
Overexpression of the tyrosine kinase receptor, ErbB2/HER2/Neu, occurs in 25–30% of invasive breast cancer (BC) with poor patient prognosis. Due to confounding factors, inconsistencies still remain ...regarding the protective effects of n-3 polyunsaturated fatty acids (PUFAs) on BC. We therefore evaluated whether fat-1 transgenic mice, endogenously synthesizing n-3 PUFAs from n-6 PUFAs, were protected against BC development, and we then aimed to study in vivo a mechanism potentially involved in such protection. E0771 BC cells were implanted into fat-1 and wild-type (WT) mice. After tumorigenesis examination, we analyzed the expression of proteins involved in the HER2 signaling pathway and lipidomic analyses were performed in tumor tissues and plasma. Our results showed that tumors totally disappeared by day 15 in fat-1 mice but continued to grow in WT mice. This prevention can be related in part to significant repression of the HER2/β-catenin signaling pathway and formation of significant levels of n-3 PUFA-derived bioactive mediators (particularly 15-hydroxyeicosapentaenoic acid, 17-hydroxydocosahexaenoic acid, and prostaglandin E3) in the tumors of fat-1 mice compared with WT mice. All together these data demonstrate an anti-BC effect of n-3 PUFAs through, at least in part, HER2 signaling pathway downregulation, and highlight the importance of gene-diet interactions in BC.
Anti-glomerular basement membrane (GBM) antibodies are pathogenic antibodies first detected in renal-limited anti-GBM disease and in Goodpasture disease, the latter characterized by rapidly ...progressive crescentic glomerulonephritis combined with intra-alveolar hemorrhage. Studies have suggested that anti-GBM antibody positivity may be of interest in lupus nephritis (LN). Moreover, severe anti-GBM vasculitis cases in patients with systemic lupus erythematosus (SLE) have been described in the literature, but few studies have assessed the incidence of anti-GBM antibodies in SLE patients.
The main study objective was to determine if positive anti-GBM antibodies were present in the serum of SLE patients with or without proliferative renal damage and compared to a healthy control group.
This retrospective study was performed on SLE patients' sera from a Franco-German European biobank, developed between 2011 and 2014, from 17 hospital centers in the Haut-Rhin region. Patients were selected according to their renal involvement, and matched by age and gender. The serum from healthy voluntary blood donors was also tested. Anti-GBM were screened by fluorescence enzyme immunoassay (FEIA), and then by indirect immunofluorescence (IIF) in case of low reactivity detection (titer >6 U/ml).
The cohort was composed of 100 SLE patients with proliferative LN (27% with class III, 67% with class IV, and 6% with class V), compared to 100 SLE patients without LN and 100 controls. Patients were mostly Caucasian and met the ACR 1997 criteria and/or the SLICC 2012 criteria. Among the 300 tested sera, no significant levels of anti-GBM antibodies were detected (>10 U/ml) by the automated technique, three sera were found "ambivalent" (>7 U/ml): one in the SLE with LN group and two in the SLE without LN group. Subsequent IIF assays did not detect anti-GBM antibodies.
Anti-GBM antibodies were not detected in the serum of Caucasian patients with SLE, even in case of renal involvement, a situation favoring the antigenic exposure of glomerular basement membranes. Our results reaffirm the central role of anti-GBM antibodies as a specific diagnostic biomarker for Goodpasture vasculitis and therefore confirm that anti-GBM antibody must not be carried out in patients with SLE (with or without LN) in the absence of disease-suggestive symptoms.
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