On the nature of the pulmonary alveolar lining and the origin of the alveolar phagocyte

1. The alveoli possess an epithelial lining.2. This epithelium is composed of flat nucleated cells. The existence of the non -nucleated cells has not been demonstrated.3. In addition to the purely epithelial cells, certain cuboidal cells, "septal cells," are found which have been demonstrated to have a phagocytic function and to stain specifically with Hortega's silver carbonate. These are part of the reticuloendothelial system and give rise by mitosis to the free alveolar phagocytes

Cellular and vascular responses to foreign particles

Thesis (M.A.)--Boston UniversityPreliminary observations were made on the reactions of the cellular and vascular elements of the retrolingual membrane of the frog's tongue to stimulation by certain foreign particles. The technique of Pratt and Reid (1930) was used in preparing the membrane. Microscopic drops of irritants, croton oil and turpentine, and a non-irritant, cedar oil, were applied from a micropipette, using the Emerson micro-manipulator, to the different experimental membranes. Non-irritating substances, neutral red, trypan blue, and India ink were injected into the abdominal cavity of frogs in successive experiments. Responses to each of the substances were compared with the condition in the normal membrane. The ciliated epithelium responded to all stimulation except the neutral red. Vacuoles of trypan blue were found in these cells. There vrere many carbon granules in the membranes of frogs treated with India ink. Both the cedar oil and croton oil were lifted from the membrane by the ciliated epithelial cells, with cilia beating. There was no evidence of phagocytosis of the cedar oil, but pink vacuoles appeared in the ciliated cells of the croton oil preparation. When croton oil with Sudan III was placed on the membranes of frogs previously injected with trypan blue, epithelial cells with active cilia and large blue vacuoles removed the drop from the surface and phagocytized some of the oil. Phagocytosis of the dye did not incapacitate these cells for further ingestion of foreign particles. Other substances should be used experimentally to determine the extent of the power of phagocytosis by the epithelial cells of the retrolingual membrane of the frog. Histiocytes phagocytized neutral red and India ink. Their only response to irritants was migration toward the substance. Leucocytes phagocytized India ink. They responded to irritants by migrating from the blood stream into the tissues, but showed no evidence of phagocytizing the irritant. Further study should be made in regard to the materials phagocytized by each one of these cells. There were no vascular changes in the membranes when non-irritating substances were used. Irritating substances stimulated blood vessels changes which followed the basic pattern of inflammation. A greater number of capillaries opened at the site of irritation; dilation of the small blood vessels occurred; the permeability of the endothelium was increased, as demonstrated by stasis and the migration of leucocytes from the blood vessels

Immune surveillance of the lung by migrating tissue-monocytes

International audienceMonocytes are phagocytic effector cells in the blood and precursors of resident and inflammatory tissue macrophages. The aim of the current study was to analyse and compare their contribution to innate immune surveillance of the lung in the steady state with macrophage and dendritic cells (DC). ECFP and EGFP transgenic reporters based upon Csf1r and Cx3cr1 distinguish monocytes from resident mononuclear phagocytes. We used these transgenes to study the migratory properties of monocytes and macrophages by functional imaging on explanted lungs. Migratory monocytes were found to be either patrolling within large vessels of the lung or locating at the interface between lung capillaries and alveoli. This spatial organisation gives to monocytes the property to capture fluorescent particles derived from both vascular and airway routes. We conclude that monocytes participate in steady-state surveillance of the lung, in a way that is complementary to resident macrophages and DC, without differentiating into macrophages

Linking innate and adaptive immunity to streptococcus pneumoniae

Streptococcus pneumoniae (the pneumococcus) most commonly colonizes the human nasopharyngeal mucosa without causing any symptoms. However, this organism has the potential to spread to normally sterile sites and cause pneumonia, meningitis or sepsis; diseases which are characterized by excessive inflammation. Despite the large burden of pneumococcal disease, relatively little is known about the mechanisms behind development of natural immunity to the pneumococcus. The purpose of this thesis was to study the role of human dendritic cells (DCs) in linking innate and adaptive immune responses to pneumococci. The immunological events in which DC-mediated T helper (Th) cell responses are generated were also investigated, as well as possible ways to modulate these responses. As a first part of this work, a novel role of the pneumococcal toxin pneumolysin in the evasion of DC-mediated immunosurveillance was described. Pneumolysin inhibited DC maturation, production of inflammatory cytokines and inflammasome activation, and induced caspase-dependent apoptosis of infected cells. Interestingly, murine DCs differed in their response to pneumolysin, emphasizing the need to study human responses to this human-specific pathogen In the second part of this work, we demonstrated that pneumococcus-infected monocytes and DCs efficiently promote the production of inflammatory Th1 and Th17 cytokines from autologous co-cultured memory cells. Live pneumococci and pneumococcal peptidoglycan triggered activation of DCs, which in turn induced the generation of Th cytokines via cell-to-cell contact and soluble components. Our work further revealed that the inflammatory response could be modulated with exogenous substances, such as recombinant cytokines, and cytokine- and receptor-blocking antibodies. Moreover, exposure of DCs to vitamin D skewed the response from an inflammatory Th1/Th17 phenotype towards a regulatory T cell phenotype. In the last part of this work, we focused on patients with primary immunodeficiencies (PIDs), suffering from frequent respiratory tract infections. The mechanisms behind the infectious susceptibility among these patients remain elusive and we hypothesized that it may be due to defects in the production of antimicrobial peptides (AMPs) in the nasal mucosa. We found that two patient groups, namely common variable immunodeficiency (CVID) and Hyper-IgE syndrome (HIES), had a dysregulated AMP response to bacteria in the upper respiratory tract. In addition, cells from these patients exhibited an impaired Th17 cytokine response. In order to improve management of patients with pneumococcal infections there is a need to elucidate the role of DC-mediated cytokine responses in the delicate balance between protective immunity and immunopathology. An increased understanding of these processes is also essential for the development of pneumococcal vaccines, designed to elicit cell-mediated immunity. The work presented in this thesis contributes to our understanding of the dynamic interplay between pneumococci and host cells, and provides the opportunity to explore the potential role of vitamin D in limiting the inflammatory response in pneumococcal disease

Consequences of cystic fibrosis transmembrane regulator mutations on inflammatory cells

Recent studies in cystic fibrosis (CF) transmembrane regulator (CFTR) mutations and function have shed light on its involvement in disease progression. The extent of cell and tissue distribution of CFTR facilitates systemic dysfunction of ion transport in patients carrying a mutation in CFTR, however, its incidences as cofounding risk factor to develop other diseases is not well studied. In this review we differentiate the dysfunctions driven by CFTR mutations in cell of the immune system and their role in CF progression and examine the types of medical treatments available to patients up to date.Fil: Grumelli, Sandra. Universidad Católica de Córdoba; ArgentinaFil: Islan, German Abel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigación y Desarrollo en Fermentaciones Industriales. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Centro de Investigación y Desarrollo en Fermentaciones Industriales; ArgentinaFil: Castro, Guillermo Raul. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigación y Desarrollo en Fermentaciones Industriales. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Centro de Investigación y Desarrollo en Fermentaciones Industriales; Argentin

Alveolar macrophages develop from fetal monocytes that differentiate into long-lived cells in the first week of life via GM-CSF

Tissue-resident macrophages can develop from circulating adult monocytes or from primitive yolk sac-derived macrophages. The precise ontogeny of alveolar macrophages (AMFs) is unknown. By performing BrdU labeling and parabiosis experiments in adult mice, we found that circulating monocytes contributed minimally to the steady-state AMF pool. Mature AMFs were undetectable before birth and only fully colonized the alveolar space by 3 d after birth. Before birth, F4/80(hi)CD11b(lo) primitive macrophages and Ly6C(hi)CD11b(hi) fetal monocytes sequentially colonized the developing lung around E12.5 and E16.5, respectively. The first signs of AMF differentiation appeared around the saccular stage of lung development (E18.5). Adoptive transfer identified fetal monocytes, and not primitive macrophages, as the main precursors of AMFs. Fetal monocytes transferred to the lung of neonatal mice acquired an AMF phenotype via defined developmental stages over the course of one week, and persisted for at least three months. Early AMF commitment from fetal monocytes was absent in GM-CSF-deficient mice, whereas short-term perinatal intrapulmonary GM-CSF therapy rescued AMF development for weeks, although the resulting AMFs displayed an immature phenotype. This demonstrates that tissue-resident macrophages can also develop from fetal monocytes that adopt a stable phenotype shortly after birth in response to instructive cytokines, and then self-maintain throughout life