Bird breeder's disease: a rare diagnosis in young children

Bird breeder's lung disease is the most common form of hypersensitivity pneumonitis and is a rare entity in young children. We report three cases of children under 7 years of age in whom this diagnosis was confirmed early in the course of the disease. Three children aged 4.4 to 6.5 years presented with dry cough lasting for more than 1 month, dyspnoea, variable loss of appetite, weight loss, fatigue, fever and mild signs of respiratory distress. Chest X-ray films and CT scans showed a bilateral micronodular infiltrate. All three patients had strongly suggestive bronchoalveolar lavage fluid findings with lymphocytosis; two had elevated cell counts and decreased CD4/CD8 ratios. Lung biopsy confirmed the diagnosis in all children. Contact with allergens was identified in all children: two had spent holidays close to a farm in the previous month and one was living next to a pigeon house. In all children, avian precipitins were positive. The symptoms rapidly resolved after allergen avoidance and treatment with oral prednisone. Corticoid treatment was given between 11 and 15 weeks. One child relapsed and required long-term low-dose corticotherapy for 1 year. Lung function tests were normal in all three patients, 3.9 to 5.7 years after diagnosis. Conclusion:Bird breeder's lung disease is a rare entity but should be considered in young children presenting long lasting cough. While rapid allergen exclusion and start of treatment can avoid the evolution into irreversible lung fibrosis, clinical and biological evolution should be monitored carefully even after stopping corticoid treatment because of the possibility of relaps

Lack of Adipocytes Alters Hematopoiesis in Lipodystrophic Mice.

Adult hematopoiesis takes place in the perivascular zone of the bone cavity, where endothelial cells, mesenchymal stromal/stem cells and their derivatives such as osteoblasts are key components of bone marrow (BM) niches. Defining the contribution of BM adipocytes to the hematopoietic stem cell niche remains controversial. While an excess of medullar adiposity is generally considered deleterious for hematopoiesis, an active role for adipocytes in shaping the niche has also been proposed. We thus investigated the consequences of total adipocyte deletion, including in the BM niche, on adult hematopoiesis using mice carrying a constitutive deletion of the gene coding for the nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ). We show that Pparg <sup>Δ/Δ</sup> lipodystrophic mice exhibit severe extramedullary hematopoiesis (EMH), which we found to be non-cell autonomous, as it is reproduced when wild-type donor BM cells are transferred into Pparg <sup>Δ/Δ</sup> recipients. This phenotype is not due to a specific alteration linked to Pparg deletion, such as chronic inflammation, since it is also found in AZIP <sup>tg/+</sup> mice, another lipodystrophic mouse model with normal PPARγ expression, that display only very moderate levels of inflammation. In both models, the lack of adipocytes alters subpopulations of both myeloid and lymphoid cells. The CXCL12/CXCR4 axis in the BM is also dysregulated in an adipocyte deprived environment supporting the hypothesis that adipocytes are required for normal hematopoietic stem cell mobilization or retention. Altogether, these data suggest an important role for adipocytes, and possibly for the molecular interactions they provide within the BM, in maintaining the appropriate microenvironment for hematopoietic homeostasis

Intestinal lamina propria fibroblasts - phenotype and function for IgA+ plasma cells

Due to the continuous pressure of an extremely diverse and numerous microbiota in the gut lumen, the majority of immune cells of the body reside in the intestinal mucosa regulating the complex and delicate balance between effective immunological control of the microbiota and pathogens, the tolerance towards food antigens and commensals, and the preservation of tissue homeostasis. Among the various immune cells populating the mucosa, plasma cells (PC) are responsible for the production of the major antibody isotype secreted, namely IgA, which is crucial for preventing the entry of the microbiota into the body and for preventing tissue inflammation. In fact, IgA deficiency in mice and humans leads to an altered microbiota composition, or dysbiosis, and higher susceptibility to certain types of infections, highlighting the need for a constantly high IgA production by PC in healthy mammals. The sustained IgA production is maintained by the continuous development of new IgA+ PC, their migration into the intestinal lamina propria (LP), and the maintenance of IgA+ PC in this site allowing IgA secretion and transport into the gut lumen. Regarding their survival, PC are known to be particularly prone to die when extracted from their tissue and their survival is thought to be regulated by extracellular stimuli existing in limiting amounts and provided by a specialized microenvironment, called survival niche. Currently, the cell types and factors defining and regulating this niche for IgA+ PC are poorly defined. Therefore, the aim of this thesis was to explore the nature of this particularly important PC niche. In this study, we show that intestinal collagen1α1+ podoplanin+ fibroblasts (iFB) form a dense and organized network throughout the LP making extensive physical contacts with all immune cells including IgA+ PC and constituting the main source of known PC survival factors including baff and cxcl12, besides being one of the april sources. I have established a new in vitro culture system mimicking the complex LP microenvironment where IgA+ PC reside in order to define the cells and factors that are critical for PC homeostasis. I observed that purified iFB as well as macrophages (M) are the LP cell types most efficient at promoting IgA+ PC survival and IgA production. Interestingly, they achieve PC survival in a synergistic and cell contact- dependent fashion. When screening for membrane-bound factors using inhibitors in our coculture system, I identified the surface protein CD44 as positive regulator of PC survival and IgA secretion. Using CD44-deficient cells CD44 was found to be important on the niche cells and even more on IgA+ PC. Finally, investigation of the CD44-deficient mouse phenotype revealed that IgA+ PC are selectively reduced in number within the LP which correlated with an even greater defect in the levels of fecal IgA in comparison with wildtype mice, while IgA+ PC development in inductive sites, such as Peyer’s patches and mesenteric lymph nodes, seemed normal. Altogether, this study characterized the iFB network both histologically and functionally with a new level of detail and revealed that these cells are a major structural and functional component of the IgA+ PC niche allowing PC maintenance in a CD44-dependent fashion and in synergy with myeloid cells. These findings improve our understanding of how intestinal homeostasis and microbiome control is achieved and regulated, and should be of relevance for the development of oral vaccines that typically aim to induce a potent IgA response at mucosal surfaces. -- Due à la pression constante du microbiome, une communauté impressionnante de cellules immunitaires colonise la muqueuse intestinale, régulant ainsi le délicat équilibre entre un contrôle immunitaire efficace du microbiome et une préservation de l’intégrité des tissus. Parmi les différents types cellulaires participant à l’homéostasie de l’intestin, les cellules plasma (PC) sont responsables de la production massive d’IgA qui régule directement la flore intestinale et participe à la défense contre les pathogènes entériques. En effet, une déficience dans la sécrétion d’IgA conduit à une altération de la composition du microbiome, appelée dysbiose, et une prédisposition à développer certaines infections entériques. La production soutenue d’IgA est maintenue grâce à la génération continue de nouvelles PC, leur migration dans la muqueuse intestinale et la survie de ces PC une fois dans leur site effecteur. Concernant leur survie, les PC sont connues pour être particulièrement sensibles à la mort cellulaire, ce qui implique qu’elles ont constamment besoin de stimulus, appelés facteurs de survie, provenant de leur environnement. Les cellules qui fournissent les facteurs de survie aux PC sont localisées dans des endroits restreints et spécialisés à cette fonction. On peut les trouver dans la moelle osseuse, la medulla des ganglions lymphatiques, et potentiellement l’intestin. Actuellement, les facteurs et les types cellulaires responsables de la survie des PC qui sécrètent les IgA dans l’intestin ne sont pas clairement identifiés. Dans ce travail, je montre que les fibroblastes intestinaux (iFB), qui expriment le collagen11 et la podoplanin, forment une structure complexe à travers toute la lamina propria et contactent physiquement les cellules immunitaires, les PC compris. Je montre que les iFB sont une source importante d’ARN messagers de plusieurs facteurs de survie connus pour PC, comme baff et cxcl12, et participent aussi à la production de april. Dans des expériences de coculture, la survie des PC était améliorée quand elles étaient placées en coculture avec des iFB ou des macrophages (M). Lorsque les iFB et les M étaient associés, un effet synergétique a été mesuré sur la survie et la fonction des PC. De manière intéressante, l’effet des iFB/ M sur la survie des PC est dépendant du contact entre les PC et les iFB/ M et est en grande partie aboli après neutralisation de la protéine transmembranaire CD44. L’implication de CD44 dans ce processus a ensuite été confirmée en utilisant des PC isolées de souris déficientes pour CD44 (ou CD44KO). En effet, les PC CD44KO étaient plus sensibles à la mort cellulaire in vitro que les PC normales. De plus, j’ai pu montrer que les iFB/ M isolés de souris CD44KO avaient un effet sur la survie des PC réduit par rapport aux iFB/ M normaux. Finalement, l’investigation des souris déficientes pour CD44 a révélé que le nombre de PC était significativement réduit dans la muqueuse intestinale, alors que le développement des PC dans les sites inducteurs, tels que les plaques de Peyer ou les ganglions lymphatiques mésentériques, semblait normal. Cette étude met en lumière la structure tridimensionnelle que forment les iFB in vivo et révèle le nouveau rôle des iFB et des M dans la maintenance de la population de PC dans l’intestin ainsi que le rôle important de CD44 dans ce processus

Bird breeder's disease: a rare diagnosis in young children

Bird breeder's lung disease is the most common form of hypersensitivity pneumonitis and is a rare entity in young children. We report three cases of children under 7 years of age in whom this diagnosis was confirmed early in the course of the disease. Three children aged 4.4 to 6.5 years presented with dry cough lasting for more than 1 month, dyspnoea, variable loss of appetite, weight loss, fatigue, fever and mild signs of respiratory distress. Chest X-ray films and CT scans showed a bilateral micronodular infiltrate. All three patients had strongly suggestive bronchoalveolar lavage fluid findings with lymphocytosis; two had elevated cell counts and decreased CD4/CD8 ratios. Lung biopsy confirmed the diagnosis in all children. Contact with allergens was identified in all children: two had spent holidays close to a farm in the previous month and one was living next to a pigeon house. In all children, avian precipitins were positive. The symptoms rapidly resolved after allergen avoidance and treatment with oral prednisone. Corticoid treatment was given between 11 and 15 weeks. One child relapsed and required long-term low-dose corticotherapy for 1 year. Lung function tests were normal in all three patients, 3.9 to 5.7 years after diagnosis