Etude de la nature moléculaire et des rôles de l'entrée constitutive de calcium dans le cancer du pancreas.

International audienc

Pivotal role of Ccr1 in murine lupus nephritis

Systemic Lupus Erythematosus is a chronic, inflammatory autoimmune disease that affects multiple organs including the kidney. Mononuclear cell infiltration in both glomerular and tubulointerstitial compartments characterizes human and experimental lupus nephritis and is associated with a progressive loss of renal function. Molecular recruitment mechanisms into chronically inflamed kidneys have not been fully characterized especially in the lupus-prone New Zealand Black/New Zealand White (NZB/W) mouse model. By combining pharmacologic and functional approaches, we uncover a previously unappreciated role for the chemokine receptor Ccr1 in renal infiltration of myeloid and T cells in nephritis NZB/W mice. We revealed a functional expression of Ccr1 on peripheral T cells, macrophages and neutrophils from NZB/W mice. Acute treatment of nephritis NZB/W mice with the orally available Ccr1 antagonist BL5923 reduced kidney recruitment of myeloid and T cells, while sparing B cells. Late onset BL5923-based treatment delayed proteinuria and death in nephritis mice. This is likely related to the beneficial effect of Ccr1 blockade on interstitial infiltration of T cells and macrophages as well as on tubulointerstitial and glomerular injuries. In contrast, systemic and renal humoral autoimmunity was unaffected in BL5923-treated mice. Altogether, these findings highlight a pivotal role for Ccr1 in recruiting T and myeloid cells to inflamed kidneys of NZB/W mice and that such activity contributes to the progression of renal injury

DataSheet_1_Deciphering the maturation of tertiary lymphoid structures in cancer and inflammatory diseases of the digestive tract using imaging mass cytometry.pdf

Persistent inflammation can promote the development of tertiary lymphoid structures (TLS) within tissues resembling secondary lymphoid organs (SLO) such as lymph nodes (LN). The composition of TLS across different organs and diseases could be of pathophysiological and medical interest. In this work, we compared TLS to SLO in cancers of the digestive tract and in inflammatory bowel diseases. Colorectal and gastric tissues with different inflammatory diseases and cancers from the department of pathology of CHU Brest were analyzed based on 39 markers using imaging mass cytometry (IMC). Unsupervised and supervised clustering analyses of IMC images were used to compare SLO and TLS. Unsupervised analyses tended to group TLS per patient but not per disease. Supervised analyses of IMC images revealed that LN had a more organized structure than TLS and non-encapsulated SLO Peyer’s patches. TLS followed a maturation spectrum with close correlations between germinal center (GC) markers’ evolution. The correlations between organizational and functional markers made relevant the previously proposed TLS division into three stages: lymphoid-aggregates (LA) (CD20+CD21-CD23-) had neither organization nor GC functionality, non-GC TLS (CD20+CD21+CD23-) were organized but lacked GC’s functionality and GC-like TLS (CD20+CD21+CD23+) had GC’s organization and functionality. This architectural and functional maturation grading of TLS pointed to differences across diseases. TLS architectural and functional maturation grading is accessible with few markers allowing future diagnostic, prognostic, and predictive studies on the value of TLS grading, quantification and location within pathological tissues in cancers and inflammatory diseases.</p

Memory CD4+ T-Cell Lymphocytic Angiopathy in Fatal Forms of COVID-19 Pulmonary Infection

International audienceThe immunopathological pulmonary mechanisms leading to Coronavirus Disease (COVID-19)-related death in adults remain poorly understood. Bronchoalveolar lavage (BAL) and peripheral blood sampling were performed in 74 steroid and non-steroid-treated intensive care unit (ICU) patients (23–75 years; 44 survivors). Peripheral effector SARS-CoV-2-specific T cells were detected in 34/58 cases, mainly directed against the S1 portion of the spike protein. The BAL lymphocytosis consisted of T cells, while the mean CD4/CD8 ratio was 1.80 in non-steroid- treated patients and 1.14 in steroid-treated patients. Moreover, strong BAL SARS-CoV-2 specific T-cell responses were detected in 4/4 surviving and 3/3 non-surviving patients. Serum IFN-γ and IL-6 levels were decreased in steroid-treated patients when compared to non-steroid treated patients. In the lung samples from 3 (1 non-ICU and 2 ICU) additional deceased cases, a lymphocytic memory CD4 T-cell angiopathy colocalizing with SARS-CoV-2 was also observed. Taken together, these data show that disease severity occurs despite strong antiviral CD4 T cell-specific responses migrating to the lung, which could suggest a pathogenic role for perivascular memory CD4 T cells upon fatal COVID-19 pneumonia

Dysregulated Lymphoid Cell Populations in Mouse Models of Systemic Lupus Erythematosus.

International audienceBiases in the distribution and phenotype of T, B, and antigen-presenting cell populations are strongly connected to mechanisms of disease development in mouse models of systemic lupus erythematosus (SLE). Here, we describe longitudinal changes in lymphoid and antigen-presenting cell subsets in bone marrow, blood and spleen from two lupus-prone strains (MRL/lpr and B6.Sle1.Sle2.Sle3 tri-congenic mice), and how they integrate in our present understanding of the pathogenesis of the disease. In particular, we focus on (autoreactive) T cell activation patterns in lupus-prone mice. Break of T cell tolerance to chromatin constituents (histone peptides) is key to the development of the disease and is related to T cell intrinsic defects, contributed by genetic susceptibility factors and by extrinsic amplificatory mechanisms, in particular over-stimulation by antigen-presenting cells. We also describe shifts in B cell sub-populations, going from skewed immature B cell populations as an indication of disturbed central and peripheral tolerance checkpoints, to enriched long-lived plasma cells, which are key to persistent autoantibody production in the disease. B cell activation mechanisms in SLE are both T cell-dependent (break of tolerance and production of specific autoantibodies) and -independent (polyclonal B cell activation, production of autoantibodies by long-lived plasma cells). By providing a comprehensive evaluation of B and T cell surface markers in two major mouse models of SLE and a description of their changes before and after disease onset, this review illustrates how the study of lymphoid cell phenotype delivers key information regarding pathogenic pathways and supplies tools to assess the beneficial effects of novel therapeutic interventions