Sca-1+ cardiac fibroblasts promote development of heart failure

The causative effect of GM-CSF produced by cardiac fibroblasts to development of heart failure has not been shown. We identified the pathological GM-CSF-producing cardiac fibroblast subset and the specific deletion of IL-17A signaling to these cells attenuated cardiac inflammation and heart failure. We describe here the CD45−CD31−CD29+mEFSK4+PDGFRα+Sca-1+periostin+ (Sca-1+) cardiac fibroblast subset as the main GM-CSF producer in both experimental autoimmune myocarditis and myocardial infarction mouse models. Specific ablation of IL-17A signaling to Sca-1+periostin+ cardiac fibroblasts (PostnCreIl17rafl/fl) protected mice from post-infarct heart failure and death. Moreover, PostnCreIl17rafl/fl mice had significantly fewer GM-CSF-producing Sca-1+ cardiac fibrob-lasts and inflammatory Ly6Chi monocytes in the heart. Sca-1+ cardiac fibroblasts were not only potent GM-CSF producers, but also exhibited plasticity and switched their cytokine production profiles depending on local microenvironments. Moreover, we also found GMCSF-positive cardiac fibroblasts in cardiac biopsy samples from heart failure patients of myocarditis or ischemic origin. Thus, this is the first identification of a pathological GMCSF-producing cardiac fibroblast subset in human and mice hearts with myocarditis and ischemic cardiomyopathy. Sca-1+ cardiac fibroblasts direct the type of immune cells infiltrating the heart during cardiac inflammation and drive the development of heart failure

Non-cytotoxic Cardiac Innate Lymphoid Cells Are a Resident and Quiescent Type 2-Commited Population

Innate lymphoid cells (ILC) are a subset of leukocytes with lymphoid properties that lack antigen specific receptors. They can be stimulated by and exert their effect via specific cytokine axes, whereas Natural Killers (NK) cells are the only known cytotoxic member of this family. ILCs are considered key in linking the innate and adaptive response in physiologic and pathologic environments. In this study, we investigated the properties of non-cytotoxic cardiac ILCs in physiologic, inflammatory, and ischemic conditions. We found that in healthy humans and mice, non-cytotoxic cardiac ILCs are predominantly a type 2-committed population with progenitor-like features, such as an absence of type-specific immunophenotype, intermediate GATA3 expression, and capacity to transiently express Pro-myelocytic Leukemia Zinc Finger protein (PLZF) upon activation. During myocarditis and ischemia, in both human and mice, cardiac ILCs differentiated into conventional ILC2s. We found that cardiac ILCs lack IL-25 receptor and cannot become inflammatory ILC2s. We found a strong correlation between IL-33 production in the heart and the ability of cardiac ILCs to become conventional ILC2s. The main producer of IL-33 was a subset of CD29+Sca-1+ cardiac fibroblasts. ILC2 expansion and fibroblast-derived IL-33 production were significantly increased in the heart in mouse models of infarction and myocarditis. Despite its progenitor-like status in healthy hearts, cardiac ILCs were unable to become ILC1 or ILC3 in vivo and in vitro. Using adoptive transfer and parabiosis, we demonstrated that the heart, unlike other organs such as lung, cannot be infiltrated by circulating ILCs in adulthood even during cardiac inflammation or ischemia. Thus, the ILC2s present during inflammatory conditions are derived from the heart-resident and quiescent steady-state population. Non-cytotoxic cardiac ILCs are a resident population of ILC2-commited cells, with undifferentiated progenitor-like features in steady-state conditions and an ability to expand and develop pro-inflammatory type 2 features during inflammation or ischemia

Inmunología y homeóstasis: conceptos actuales y perspectivas.

La inmunología es un campo que no solo ha tenido un crecimiento enorme en cuanto a su comprensión intrínseca y práctica clínica, sino además en el descubrimiento de su influencia en otros sistemas del organismo de los cuales parecía estar aislada. Es de importancia vital el hecho de que dicha interacción del sistema inmunológico con otros no ocurre solo durante una noxa externa, sino también durante la homeostasis fisiológica. Se ha descubierto que el sistema inmunológico, mas allá de su función de defensa, funge un rol esencial en la regulación de múltiples funciones biológicas, incluyendo la integridad de las mucosas, la hemodinámica e incluso el metabolismo, entre muchos otros. La independencia de los sistemas y sub-sistemas ha de ser revisada, pues una comprensión integradora es requerida. Modificaciones importantes han de ser implementadas en nuestros sistemas educativos a fin de lograr una enseñanza adecuada de los conceptos ubicuos de la inmunología. En esta revisión/artículo de opinión serán discutidos los conceptos modernosno-clásicos de la inmunología, con énfasis especial en: infiltración y residencia, microentorno (microenvironment), interacción con células no leucocitarias (estroma/parénquima), funciones no canónicas del sistema inmunológico y leucocitos reguladores. Esta revisión contiene además opiniones e hipótesis de las cuales como autor me hago enteramente responsable. Más que una revisión fáctica puntual, este artículo pretende dibujar la visión holística del sistema inmunológico en la homeostasis fisiológica basado en los conceptos y evidencias más modernas.Immunology and Homeostasis: Current Concepts and PerspectivesImmunology is a field that has grown enormously in terms of its intrinsic understanding and clinical practice. It has been also remarkable the discovery of its influence in other systems of the organism, of which it seemed to be isolated. It is key to point out that interaction of the immune system with others does not occur only during an external insult, but also during physiological homeostasis. It has been discovered that the immune system, beyond its anti-microbial function, plays a critical role in the regulation of many biological functions; including mucosal integrity, hemodynamics and even metabolism, amongst others. The independence of systems and sub-systems has to be revised, since an integrative understanding is required. Important modifications have to be implemented in our educational systems in order to achieve an appropriated teaching method of the ubiquitous concepts of immunology. In this review/opinion article, the modern non-classical concepts of immunology will be discussed, with special emphasis on: infiltration and residence, microenvironment, interaction with non-leukocyte cells (stroma/parenchyma), non-canonical functions of the immune system and leukocytes regulators. This review also contains opinions and hypothesesof which as author I am entirely responsible. Finally, more than a specific revision, this article aims to draw the holistic view of the immune system in physiological homeostasis, considering the most modern concepts and evidence

Non-inherited maternal antigens, pregnancy, and allotolerance

Non-inherited maternal antigens (NIMA) are those protein products derived from polymorphic genes that the mothers express but not the offspring. During normal human pregnancy, a bidirectional regulation occurs in such a way that the maternal immune system tolerates the inherited paternal antigens (IPA) expressed by the fetus and the developing fetal immune system tolerates NIMA. The process by which the described bidirectional regulation is developed is related to microchimerism, due to the bidirectional traffic of cells allowed by the decidua-trophoblast interface. An extensive body of knowledge from the transplantation and pregnancy physiology fields suggests a role for microchimerism and NIMA exposure in the development of NIMA-specific alloresponse regulation, which may include transforming growth factor β (TGF-β) as well as interleukin (IL)-10 and IL-35, producing peripheral T regulatory lymphocytes. The induction of this NIMA-specific allotolerance is called the "NIMA effect." Some experimental data suggest the existence of a "split tolerance" phenomenon associated with NIMA effect, in which regulation of NIMA-specific indirect pathway is induced without tolerogenic impact on the direct pathway. In this review, the most relevant literature about the immunological phenomena underlying the NIMA effect is discussed, including the most recent proposals about the role played by antigen-acquisition and the semi-direct pathway of allorecognition

Characteristics and Outcomes of Pulmonary Angioplasty With or Without Stenting for Sarcoidosis-Associated Pulmonary Hypertension: Systematic Review and Individual Participant Data Meta-Analysis

Background: Pulmonary angioplasty has been performed in patients with sarcoidosis-associated pulmonary hypertension (SAPH) but most evidence comes from case reports and small case series. Overall outcomes remain unclear. We conducted an individual participant data (IPD) meta-analysis of baseline, procedural, and outcome data of pulmonary angioplasty in patients with SAPH. Methods: We performed searches and systematically reviewed references from PubMed, Embase, Cochrane, ClinicalTrials.gov, and grey literature. We included IPD of patients who underwent pulmonary angioplasty for SAPH. Those without definitive diagnosis of sarcoidosis or with other causes of pulmonary vascular stenosis or compression were excluded. Results: Of 1293 screened references, 7 were included. IPD was obtained for 17 patients (median age 60 (55-65) years; 82.4% female); most of whom were Scadding stages III or IV and had NYHA FC III or IV. All patients with documented changes in 6-minute-walk distance (6MWD) had a significant improvement that ranged from 12.6 to 102.4% (P < 0.01). There were no deaths during a median follow-up of 6 (3-18) months. Conclusions: Pulmonary angioplasty with or without stenting of focal stenosis or compressions of pulmonary vessels may lead to significant improvement in 6MWD in patients with SAPH. However, this study had a small sample and some methodological limitations, such as analysis mostly of case reports and series. Randomized controlled clinical trials and/or large multicenter registry studies are needed to provide higher evidence in this topic