Epithelial-immune cell interplay in primary Sjogren syndrome salivary gland pathogenesis

In primary Sjogren syndrome (pSS), the function of the salivary glands is often considerably reduced. Multiple innate immune pathways are likely dysregulated in the salivary gland epithelium in pSS, including the nuclear factor-kappa B pathway, the inflammasome and interferon signalling. The ductal cells of the salivary gland in pSS are characteristically surrounded by a CD4(+) T cell-rich and B cell-rich infiltrate, implying a degree of communication between epithelial cells and immune cells. B cell infiltrates within the ducts can initiate the development of lymphoepithelial lesions, including basal ductal cell hyperplasia. Vice versa, the epithelium provides chronic activation signals to the glandular B cell fraction. This continuous stimulation might ultimately drive the development of mucosa-associated lymphoid tissue lymphoma. This Review discusses changes in the cells of the salivary gland epithelium in pSS (including acinar, ductal and progenitor cells), and the proposed interplay of these cells with environmental stimuli and the immune system. Current therapeutic options are insufficient to address both lymphocytic infiltration and salivary gland dysfunction. Successful rescue of salivary gland function in pSS will probably demand a multimodal therapeutic approach and an appreciation of the complicity of the salivary gland epithelium in the development of pSS. Salivary gland dysfunction is an important characteristic of primary Sjogren syndrome (pSS). In this Review, the authors discuss various epithelial abnormalities in pSS and the mechanisms by which epithelial cell-immune cell interactions contribute to disease development and progression

Tertiary Lymphoid Structures:Autoimmunity Goes Local

Tertiary lymphoid structures (TLS) are frequently observed in target organs of autoimmune diseases. TLS present features of secondary lymphoid organs such as segregated T and B cell zones, presence of follicular dendritic cell networks, high endothelial venules and specialized lymphoid fibroblasts and display the mechanisms to support local adaptive immune responses toward locally displayed antigens. TLS detection in the tissue is often associated with poor prognosis of disease, auto-antibody production and malignancy development. This review focuses on the contribution of TLS toward the persistence of the inflammatory drive, the survival of autoreactive lymphocyte clones and post-translational modifications, responsible for the pathogenicity of locally formed autoantibodies, during autoimmune disease development

Le consentement médical à l’ère de la médecine de précision

Le consentement libre et éclairé comme manifestation de l’adhésion à un acte thérapeutique en médecine est central dans la relation patient-médecin. Malgré d’importantes avancées, la médecine de précision fragilise la relation patient-médecin et ainsi la capacité du patient à consentir, du fait de la complexification de l’analyse des données disponibles et de l’intervention de nombreux médecins spécialistes dans la trajectoire des soins. Cet article propose d’interroger les conséquences de la médecine de précision sur la transmission et la nature de l’information, pour repenser la relation patient-médecin et les conditions de possibilité du consentement. Au-delà des impacts de la médecine de précision, nous pensons que le rôle du médecin s’apparente à celui d’un référent capable d’assurer la transmission et la cohérence des informations communiquées aux patients selon ses besoins en vue de restaurer sa compréhension de la maladie et des propositions thérapeutiques qui lui sont faites

Alterations of circulating lymphoid committed progenitor cellular metabolism after allogeneic stem cell transplantation in humans

peer reviewe

Regulatory T Cell Stability and Migration Are Dependent on mTOR

International audienceCD4+ Foxp3+ regulatory T cells (Treg) are essential to maintain immune tolerance, as their loss leads to a fatal autoimmune syndrome in mice and humans. Conflicting findings have been reported concerning their metabolism. Some reports found that Treg have low mechanistic target of rapamycin (mTOR) activity and would be less dependent on this kinase compared with conventional T cells, whereas other reports suggest quite the opposite. In this study, we revisited this question by using mice that have a specific deletion of mTOR in Treg. These mice spontaneously develop a severe and systemic inflammation. We show that mTOR expression by Treg is critical for their differentiation into effector Treg and their migration into nonlymphoid tissues. We also reveal that mTOR-deficient Treg have reduced stability. This loss of Foxp3 expression is associated with partial Foxp3 DNA remethylation, which may be due to an increased activity of the glutaminolysis pathway. Thus, our work shows that mTOR is crucial for Treg differentiation, migration, and identity and that drugs targeting this metabolism pathway will impact on their biology

SUV39H1 Ablation Enhances Long-term CAR T Function in Solid Tumors.

Failure of adoptive T-cell therapies in patients with cancer is linked to limited T-cell expansion and persistence, even in memory-prone 41BB-(BBz)-based chimeric antigen receptor (CAR) T cells. We show here that BBz-CAR T-cell stem/memory differentiation and persistence can be enhanced through epigenetic manipulation of the histone 3 lysine 9 trimethylation (H3K9me3) pathway. Inactivation of the H3K9 trimethyltransferase SUV39H1 enhances BBz-CAR T cell long-term persistence, protecting mice against tumor relapses and rechallenges in lung and disseminated solid tumor models up to several months after CAR T-cell infusion. Single-cell transcriptomic (single-cell RNA sequencing) and chromatin opening (single-cell assay for transposase accessible chromatin) analyses of tumor-infiltrating CAR T cells show early reprogramming into self-renewing, stemlike populations with decreased expression of dysfunction genes in all T-cell subpopulations. Therefore, epigenetic manipulation of H3K9 methylation by SUV39H1 optimizes the long-term functional persistence of BBz-CAR T cells, limiting relapses, and providing protection against tumor rechallenges. Limited CAR T-cell expansion and persistence hinders therapeutic responses in solid cancer patients. We show that targeting SUV39H1 histone methyltransferase enhances 41BB-based CAR T-cell long-term protection against tumor relapses and rechallenges by increasing stemness/memory differentiation. This opens a safe path to enhancing adoptive cell therapies for solid tumors. See related article by Jain et al., p. 142. This article is featured in Selected Articles from This Issue, p. 5

Pozitivno in negativno

Immune recovery after profound lymphopenia is a major challenge in many clinical situations, such as allogeneic hematopoietic stem cell transplantation (allo-HSCT). Recovery depends, in a first step, on hematopoietic lymphoid progenitors production in the bone marrow (BM). In this study, we characterized CD34+Lin-CD10+ lymphoid progenitors in the peripheral blood of allo-HSCT patients. Our data demonstrate a strong recovery of this population 3 months after transplantation. This rebound was abolished in patients who developed acute graft-versus-host disease (aGVHD). A similar recovery profile was found for both CD24+ and CD24- progenitor subpopulations. CD34+lin-CD10+CD24- lymphoid progenitors sorted from allo-HSCT patients preserved their T cell potentiel according to in vitro T-cell differentiation assay and the expression profile of 22 genes involved in T-cell differentiation and homing. CD34+lin-CD10+CD24- cells from patients without aGVHD had reduced CXCR4 gene expression, consistent with an enhanced egress from the BM. CCR7 gene expression was reduced in patients after allo-HSCT, as were its ligands CCL21 and CCL19. This reduction was particularly marked in patients with aGVHD, suggesting a possible impact on thymic homing. Thus, the data presented here identify this population as an important early step in T cell reconstitution in humans and so, an important target when seeking to enhance immune reconstitution

Lymphoid progenitors are detected in peripheral blood after allo-HSCT and are increased in the absence of aGVHD.

<p>(A) Naïve T-cell and B-cell immune recovery was measured by CD4⁺CD45RA⁺CD62L⁺ and CD19⁺CD27⁻ staining and flow cytometry analysis and thymic output was determined by quantitative PCR for sjTREC in 79 patients with (closed circles) and without (open circles) aGVHD from time pre-HSCT to M12 (12 Months post-HSCT). (B) Mononuclear cells from cord blood (CB) and peripheral blood were stained with a combination of lineage (Lin) markers and anti-CD34, anti-CD10, and anti-CD24 antibodies. Percentage of CD34⁺lin⁻CD10⁺ progenitors/CD34⁺Lin⁻ cells in CB, peripheral blood from HD and HSCT patients 3 months post-graft. (C) Percentage of CD34⁺lin⁻CD10⁺ progenitors/CD34⁺Lin⁻ cells for HSCT patients with grade 0-I (Gr 0-I) or II-IV (Gr II-IV) aGVHD. (D) Percentage of CD34⁺Lin⁻CD10⁺CD24⁻/CD34⁺Lin⁻ and of CD34⁺Lin⁻CD10⁺CD24⁺/CD34⁺Lin⁻ in Gr 0-I <i>vs</i>. Gr II-IV patients and <i>vs.</i> HD. (E) Absolute numbers of CD34⁺Lin⁻CD10⁺CD24⁻ and CD34⁺lin⁻CD10⁺CD24⁺ in HSCT patients at months 3 (M3) and 6 (M6). (F) Correlation between absolute numbers of CD34⁺Lin⁻CD10⁺CD24⁻ and the number of CD34⁺ cells in the graft, normalized by recipient weight. Correlation is positive in the absence of aGVHD, but not with severe aGVHD (<i>Spearman test</i>). (G) Correlation between absolute numbers of CD34⁺Lin⁻CD10⁺CD24⁺ B progenitors at month 3 and the number of naïve B cells at month 6. (<i>Spearman test).**p<0.01, *p<0.05, NS: Not Significant (Mann-Whitney)</i>.</p