Hyperglycemia leads to corneal DC infiltration, and obesity aggravates this immune response. The direct contact between DCs and the SNP can be assumed to be a trigger of nerve fiber damage and thus a contributing factor to polyneuropathy in diabetic corneas.
Caloric restriction (CR) is a well-described dietary intervention that delays the onset of aging-associated biochemical and physiological changes, thereby extending the life span of rodents. The influence of CR on metabolism, strength, and morphology of bone has been controversially discussed in literature. Thus, the present study evaluated whether lifelong CR versus short-term late-onset dietary intervention differentially affects the development of senile osteoporosis in C57BL/6 mice. Two different dietary regimens with 40% food restriction were performed: lifelong CR starting in 4-week-old mice was maintained for 4, 20, or 74 weeks. In contrast, short-term late-onset CR lasting a period of 12 weeks was commenced at 48 or 68 weeks of age. Control mice were fed ad libitum (AL). Bone specimens were assessed using microcomputed tomography (mCT, femur and lumbar vertebral body) and biomechanical testing (femur). Adverse effects of CR, including reduced cortical bone mineral density (Ct.BMD) and thickness (Ct.Th), were detected to some extent in senile mice (68þ12w) but in particular in cortical bone of young growing mice (4þ4w), associated with reduced femoral failure force (F). However, we observed a profound capacity of bone to compensate these deleterious changes of minor nutrition with increasing age presumably via reorganization of trabecular bone. Especially in lumbar vertebrae, lifelong CR lasting 20 or 74 weeks had beneficial effects on trabecular bone mineral density (Tb.BMD), bone volume fraction (BV/TV), and trabecular number (Tb.N). In parallel, lifelong CR groups showed reduced structure model index values compared to age-matched controls indicating a transformation of vertebral trabecular bone microarchitecture toward a platelike geometry. This effect was not visible in senile mice after short-term 12-week CR. In summary, CR has differential effects on cortical and trabecular bone dependent on bone localization and starting age. Our study underlines that bone compartments possess a lifelong capability to cope with changing nutritional influences.
CD30 is a costimulatory molecule of the TNF receptor superfamily, expressed on activated T and B cells. Previously, we have shown in a murine asthma model the crucial role of CD30 signaling for the development of this Th2-cell-mediated disease. In the present study, we investigated the role of CD30 in the maintenance of the immune response. In contrast to the acute model, in the chronic model CD30 À/À mice developed a severe asthma-like phenotype with eosinophilic inflammation and high serum IgE levels. Collagen content, ECM protein deposition and proliferation of smooth muscle cells as signs for airway remodeling were equally increased in both CD30 À/À and WT mice. Reduced expression of the costimulatory molecule OX40 on CD3 1 T cells in the acute and up-regulation in the chronic model indirectly supported a compensatory role of OX40 for CD30 signaling. In accordance, application of agonistic OX40 antibody restored the asthma phenotype in CD30 À/À mice in the acute model, whereas chronic airway inflammation was reduced in the presence of an inhibitory anti-OX40 ligand antibody. These data demonstrate that the crucial role of CD30 signaling in the development of acute asthma may be taken over by other costimulatory molecules like OX40 after long-term exposure to the antigen.
Allergic asthma is a widespread chronic inflammatory disease of the airways. The role of different B cell subsets in developing asthma and respiratory tolerance is not well known. Especially regulatory B (Breg) cells are proposed to be important in asthma regulation. Using wild-type (WT) and B cell-deficient (μMT) mice we investigated how B cells are affected by induction of allergic airway inflammation and respiratory tolerance and whether they are necessary to develop these conditions. WT mice with an asthma-like phenotype, characterized by increased airway hyper reactivity, eosinophilic airway inflammation, mucus hypersecretion and elevated Th2 cytokines, exhibited increased MHCII and CD23 expression on follicular mature B cells in lung, bronchial lymph nodes (bLN) and spleen, which contributed to allergen-specific T cell proliferation in vitro. Germinal center B cell numbers were elevated and associated with increased production of allergen-specific immunoglobulins especially in bLN. In contrast, respiratory tolerance clearly attenuated these B cell alterations and directly enhanced marginal zone precursor B cells, which induced regulatory T cells in vitro. However, μMT mice developed asthma-like and tolerized phenotypes like WT mice. Our data indicate that although B cell subsets are affected by asthma-like and respiratory tolerant phenotypes, B cells are not required for tolerance induction.
Understanding the response to viral infection in the context of respiratory diseases is of significant importance. Recently, there has been more focus on the role of the nasal epithelium in disease modeling. Here, we provide an overview of different submerged, organotypic 3D and spheroid cell culture models of nasal epithelial cells, which were used to study asthma and allergy with a special focus on virus infection. In detail, this review summarizes the importance, benefits, and disadvantages of patient-derived cell culture models of nasal- and bronchial epithelial cells, including a comparison of these cell culture models and a discussion on why investigators should consider using nasal epithelial cells in their research. Exposure experiments, simple virus transduction analyses as well as genetic studies can be performed in these models, which may provide first insights into the complexity of molecular signatures and may open new doors for drug discovery and biomarker research.
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