Eosinophils in glioblastoma biology

Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults. The development of this malignant glial lesion involves a multi-faceted process that results in a loss of genetic or epigenetic gene control, un-regulated cell growth, and immune tolerance. Of interest, atopic diseases are characterized by a lack of immune tolerance and are inversely associated with glioma risk. One cell type that is an established effector cell in the pathobiology of atopic disease is the eosinophil. In response to various stimuli, the eosinophil is able to produce cytotoxic granules, neuromediators, and pro-inflammatory cytokines as well as pro-fibrotic and angiogenic factors involved in pathogen clearance and tissue remodeling and repair. These various biological properties reveal that the eosinophil is a key immunoregulatory cell capable of influencing the activity of both innate and adaptive immune responses. Of central importance to this report is the observation that eosinophil migration to the brain occurs in response to traumatic brain injury and following certain immunotherapeutic treatments for GBM. Although eosinophils have been identified in various central nervous system pathologies, and are known to operate in wound/repair and tumorstatic models, the potential roles of eosinophils in GBM development and the tumor immunological response are only beginning to be recognized and are therefore the subject of the present review

Distinct "asthma" phenotypes of four mouse strains correlate with different responses to house dust mite (HDM) allergens

Background: Asthma is a heterogeneous disease comprising different phenotypes. The corresponding “endotypes” are currently insufficiently understood thus hampering the development of personalized treatments. As a first step in this direction, models for experimental asthma reflecting different asthma phenotypes and endotypes need to be developed. Thus, we aimed to develop a murine model for the investigation of different responses to single Der p allergens. Method: Female mice of four different strains were obtained from Jackson Laboratory. Experimental asthma was induced by intranasal administration of 20 μg HDM extract (D. pteronyssinus extract, Greer, USA) three times weekly/ three weeks. Asthma phenotypes were evaluated by lung function measurements, histology, gene expression, immune cell infiltration, cytokine levels in broncho‐alveolar lavage (BAL) and total and allergen specific IgE in sera. Results: Higher airway resistance, elevated levels of BAL cell and eosinophil numbers, increased levels of IgE in sera and goblet cell hyperplasia were observed in all HDM treated animals in contrast to PBS‐treated controls. Initial tests measuring single anti‐Der p‐IgE reactivities (Der p 1, Der p 2, Der p 7, Der p 20, Der p 21, Der p 23) revealed distinct sensitization patterns for the different strains. The gene expression levels of MUC5B (fold‐change to control A/J: 7.5; BALB/cJ: 3.5; C57Bl/6J: 4.1; C3H/HeJ: 8.5) and CCL11(foldchange to control A/J: 72.7; BALB/cJ: 8.1; C57Bl/6J: 21.1; C3H/HeJ: 21.1) showed differences among the four strains. Combining all these results allowed us to characterize distinct “asthma” phenotypes, ranging from low eosinophilic, Th2 low (“low susceptible”) over an “intermediate susceptible” Th17 high to a mainly eosinophilic, Th2‐dominated phenotype with pronounced changes in lung histology (“high susceptible”). Conclusion: Applying the same HDM treatment in four different mouse strains resulted in distinct asthma phenotypes and showed for the very first time different sensitization patterns. In future studies, we will investigate the mechanisms underlying these different responses to different single Der p allergens and if possible investigate these in human asthma patients as well

A regulatory role for CD37 in T cell proliferation

CD37 is a leukocyte-specific protein belonging to the tetraspanin superfamily. Previously thought to be predominantly a B cell molecule, CD37 is shown in this study to regulate T cell proliferation. CD37-deficient (CD37 -/-) T cells were notably hyperproliferative in MLR, in response to Con A, or CD3-TCR engagement particularly in the absence of CD28 costimulation. Hyperproliferation was not due to differences in memory to naive T cell ratios in CD37-/- mice, apoptosis, or TCR down-modulation. Division cycle analyses revealed CD37-/- T cells to enter first division earlier than wild-type T cells. Importantly, proliferation of CD37-/- T cells was preceded by enhanced early IL-2 production. We hypothesized CD37 to be involved in TCR signaling and this was supported by the observation that CD4/CD8-associated p56Lck kinase activity was increased in CD37 -/- T cells. Remarkably, CD37 cross-linking on human T cells transduced signals that led to complete inhibition of CD3-induced proliferation. In the presence of CD28 costimulation, CD37 engagement still significantly reduced proliferation. Taken together, these results demonstrate a regulatory role for CD37 in T cell proliferation by influencing early events of TCR signaling

Иммунорегулирующее действие лимфоцитов больных пневмонией на функции фибробластов

The lymphocytal regulation action onto fibroblasts in cell cultures was studied in 32 patients with pneumonia: 15 with typical course, 9 with prolonged course and the complete clinical healing, 8 with focal pneumofibrosis. The dependence between direction, manifestation of regulation stimuli of lymphocytes, and clinical course of the disease was found. It was concluded that regulatory and effectory function impairments in lymphocytes may cause the sharp count increase of active fibroblasts in the inflammation focus. It may cause inadequate collagen production and exhaustive collagen structure vegetation with pneumofibrosis and pneumosclerosis formation. It was aslo concluded that the fibrogenic process can be managed by correction of lymphocyte function.У 32 больных пневмонией (15 пациентов с типичным течением, 9 — с затяжным течением и полным клинико-рентгенологическим разрешением, 8 больных — с исходом заболевания в очаговый пневмофиброз) изучено регуляторное действие лимфоцитов на функции фибробластов в клеточных культурах. Установлена зависимость между направленностью и выраженностью регуляторных стимулов лимфоцитов и клиническим вариантом течения заболевания. Авторы заключают, что выраженное нарушение- регуляторных и эффекторных функций лимфоцитов у больных пневмонией может приводить к резкому увеличению в очаге воспаления числа активированных фибробластов, несбалансированному синтезу коллагена и чрезмерному разрастанию коллагенсодержащих структур с формированием пневмофиброза и пневмосклероза. Сделан вывод о возможности управления ходом фиброгенеза через коррекцию функций лимфоцитов

Mast cells as protectors of health.

Mast cells (MCs), which are well known for their effector functions in T(H)2-skewed allergic and also autoimmune inflammation, have become increasingly acknowledged for their role in protection of health. It is now clear that they are also key modulators of immune responses at interface organs, such as the skin or gut. MCs can prime tissues for adequate inflammatory responses and cooperate with dendritic cells in T-cell activation. They also regulate harmful immune responses in trauma and help to successfully orchestrate pregnancy. This review focuses on the beneficial effects of MCs on tissue homeostasis and elimination of toxins or venoms. MCs can enhance pathogen clearance in many bacterial, viral, and parasitic infections, such as through Toll-like receptor 2-triggered degranulation, secretion of antimicrobial cathelicidins, neutrophil recruitment, or provision of extracellular DNA traps. The role of MCs in tumors is more ambiguous; however, encouraging new findings show they can change the tumor microenvironment toward antitumor immunity when adequately triggered. Uterine tissue remodeling by alpha-chymase (mast cell protease [MCP] 5) is crucial for successful embryo implantation. MCP-4 and the tryptase MCP-6 emerge to be protective in central nervous system trauma by reducing inflammatory damage and excessive scar formation, thereby protecting axon growth. Last but not least, proteases, such as carboxypeptidase A, released by Fc epsilon RI-activated MCs detoxify an increasing number of venoms and endogenous toxins. A better understanding of the plasticity of MCs will help improve these advantageous effects and hint at ways to cut down detrimental MC actions