Spinal muscular atrophy (SMA) is a progressive neurodegenerative disease that is the leading genetic cause of infantile death. It is caused by a severe deficiency of the ubiquitously expressed Survival Motor Neuron (SMN) protein. SMA is characterized by α-lower motor neuron loss and muscle atrophy, however, there is a growing list of tissues impacted by a SMN deficiency beyond motor neurons. The non-neuronal defects are observed in the most severe Type I SMA patients and most of the widely used SMA mouse models, however, as effective therapeutics are developed, it is unclear whether additional symptoms will be uncovered in longer lived patients. Recently, the immune system and inflammation has been identified as a contributor to neurodegenerative diseases such as ALS. To determine whether the immune system is comprised in SMA, we analyzed the spleen and immunological components in SMA mice. In this report, we identify: a significant reduction in spleen size in multiple SMA mouse models and a pathological reduction in red pulp and extramedullary hematopoiesis. Additionally, red pulp macrophages, a discrete subset of yolk sac-derived macrophages, were found to be altered in SMA spleens even in pre-symptomatic post-natal day 2 animals. These cells, which are involved in iron metabolism and the phagocytosis of erythrocytes and blood-borne pathogens are significantly reduced prior to the development of the neurodegenerative hallmarks of SMA, implying a differential role of SMN in myeloid cell ontogeny. Collectively, these results demonstrate that SMN deficiency impacts spleen development and suggests a potential role for immunological development in SMA.

Upon exposure to Ag on the day of birth, neonatal mice mount balanced primary Th1 and Th2 responses with the former displaying up-regulated IL-13 receptor alpha 1 (IL-13Rα1) expression. This chain associates with IL-4Rα to form a heteroreceptor (IL-4Rα/IL-13Rα1) that marks the Th1 cells for death by IL-4 produced by Th2 cells during re-challenge with Ag, hence, the Th2 bias of murine neonatal immunity. The up-regulation of IL-13Rα1 on neonatal Th1 cells was due to the paucity of IL-12 in the neonatal environment. Herein, we show that by day 8 after birth, naïve splenic T cells are no longer susceptible to IL-13Rα1 up-regulation even when exposed to Ag within the neonatal environment. Furthermore, during the 8-day lapse, the naïve splenic T cells spontaneously and progressively up-regulate the IL-12Rβ2 chain, perhaps due to colonization by commensals which induce production of IL-12 by cells of the innate immune system such as dendritic cells. In fact, mature T cells from the thymus, a sterile environment not accessible to microbes, did not up-regulate IL-12Rβ2 and were unable to counter IL-13Rα1 up-regulation. Finally, the 8 day naïve T cells were able to differentiate into Th1 cells even independently of IL-12 but required the cytokine to counter up-regulation of IL-13Rα1. Thus, in neonatal mice, IL-12, which accumulates in the environment progressively, utilizes IL-12Rβ2 to counter IL-13Rα1 expression in addition to promoting Th1 differentiation.

This study assesses the potential effect of micafungin, an antifungal agent known to inhibit 1,3-β-D-glucan synthesis in Candida albicans, on biofilm formation of selected Pseudomonas aeruginosa isolates by decreasing the synthesis of extracellular matrix β-D-glucan forming units. The effect of an optimal therapeutic dose of 10 mg ml(-1) micafungin on the production of biofilm was monitored in vitro using a microtiter plate assay. Phenotypic reduction in the formation of biofilm was significant (based on average optical density; p < 0.05) in most of the isolates. Moreover, the relative gene expression of biofilm encoding genes for alginate and pellicles (algC and pelC, respectively), and the cell wall 1,3-β-D-glucan encoding gene (ndvB) was evaluated using quantitative reverse transcription PCR. For all the genes tested, the levels of mRNA transcription were also decreased significantly (p < 0.05) in micafungin-treated samples cf. their untreated counterparts. In conclusion, this study presents micafungin as a potential agent for disrupting the structure of a biofilm of P. aeruginosa allowing the possible exposure and treatment of core-planktonic cells.

Dendritic cells (DCs) have been shown to play a major role in oral tolerance and this function has been associated with their ability to produce anti-inflammatory cytokines and to induce suppressive T regulatory cells. Herein, we demonstrate that upon oral administration of Ag, lamina propia (LP) DCs engage specific T cells and acquire a novel mechanism by which they transfer tolerance against diverse T cell specificities. Indeed, when Ig-MOG carrying the myelin oligodendrocyte glycoprotein (MOG)35–55 epitope was orally administered into either T cell sufficient or deficient mice, only the T cell sufficient hosts yielded CD8α+ and CD8α− LP DCs that were able to transfer tolerance to a variety of MHC class II-restricted effector T cells. Surprisingly, these LP DCs up-regulated programmed cell death ligand 1 (PD-L1) during the initial interaction with MOG-specific T cells and utilized this inhibitory molecule to suppress activation of T cells regardless of Ag specificity. Furthermore, oral Ig-MOG was able to overcome experimental allergic encephalomyelitis (EAE) induced with central nervous system (CNS) homogenate, indicating that the DCs are able to modulate disease involving diverse T cell specificities. This previously unrecognized attribute potentiates DCs against autoimmunity.