Immunopathological Changes in the Brain of Immunosuppressed Mice Experimentally Infected with Toxocara canis

Toxocariasis is a soil-transmitted helminthozoonosis due to infection of humans by larvae of Toxocara canis. The disease could produce cognitive and behavioral disturbances especially in children. Meanwhile, in our modern era, the incidence of immunosuppression has been progressively increasing due to increased incidence of malignancy as well as increased use of immunosuppressive agents. The present study aimed at comparing some of the pathological and immunological alterations in the brain of normal and immunosuppressed mice experimentally infected with T. canis. Therefore, 180 Swiss albino mice were divided into 4 groups including normal (control) group, immunocompetent T. canis-infected group, immunosuppressed group (control), and immunosuppressed infected group. Infected mice were subjected to larval counts in the brain, and the brains from all mice were assessed for histopathological changes, astrogliosis, and IL-5 mRNA expression levels in brain tissues. The results showed that under immunosuppression, there were significant increase in brain larval counts, significant enhancement of reactive gliosis, and significant reduction in IL-5 mRNA expression. All these changes were maximal in the chronic stage of infection. In conclusion, the immunopathological alterations in the brains of infected animals were progressive over time, and were exaggerated under the effect of immunosuppression as did the intensity of cerebral infection.     

Immunosuppression by Mutated Calreticulin Released from Malignant Cells

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ABCA1 promotes the efflux of bacterial LPS from macrophages and accelerates recovery from LPS-induced tolerance

Macrophages play important roles in both lipid metabolism and innate immunity. We show here that macrophage ATP-binding cassette transporter A1 (ABCA1), a transporter known for its ability to promote apolipoprotein-dependent cholesterol efflux, also participates in the removal of an immunostimulatory bacterial lipid, lipopolysaccharide (LPS). Whereas monocytes require an exogenous lipoprotein acceptor to remove cell-associated LPS, macrophages released LPS in the absence of an exogenous acceptor by a mechanism that was driven, in part, by endogenous apolipoprotein E (apoE). Agents that increased ABCA1 expression increased LPS efflux from wild-type but not ABCA1-deficient macrophages. Preexposure of peritoneal macrophages to LPS for 24 h increased the expression of ABCA1 and increased LPS efflux with a requirement for exogenous apolipoproteins due to suppression of endogenous apoE production. In contrast, LPS preconditioning of ABCA1-deficient macrophages significantly decreased LPS efflux and led to prolonged retention of cell-surface LPS. Although the initial response to LPS was similar in wild-type and ABCA1-deficient macrophages, LPS-induced tolerance was greater and more prolonged in macrophages that lacked ABCA1. Our results define a new role for macrophage ABCA1 in removing cell-associated LPS and restoring normal macrophage responsiveness.     

Histamine releasing factor and elongation factor 1 alpha secreted via malaria parasites extracellular vesicles promote immune evasion by inhibiting specific T cell responses

Protozoan pathogens secrete nanosized particles called extracellular vesicles (EVs) to facilitate their survival and chronic infection. Here, we show the inhibition by Plasmodium berghei NK65 blood stage‐derived EVs of the proliferative response of CD4⁺ T cells in response to antigen presentation. Importantly, these results were confirmed in vivo by the capacity of EVs to diminish the ovalbumin‐specific delayed type hypersensitivity response. We identified two proteins associated with EVs, the histamine releasing factor (HRF) and the elongation factor 1α (EF‐1α) that were found to have immunosuppressive activities. Interestingly, in contrast to WT parasites, EVs from genetically HRF‐ and EF‐1α‐deficient parasites failed to inhibit T cell responses in vitro and in vivo. At the level of T cells, we demonstrated that EVs from WT parasites dephosphorylate key molecules (PLCγ1, Akt, and ERK) of the T cell receptor signalling cascade. Remarkably, immunisation with EF‐1α alone or in combination with HRF conferred a long‐lasting antiparasite protection and immune memory. In conclusion, we identified a new mechanism by which P. berghei‐derived EVs exert their immunosuppressive functions by altering T cell responses. The identification of two highly conserved immune suppressive factors offers new conceptual strategies to overcome EV‐mediated immune suppression in malaria‐infected individuals.     

Morphological profiling using machine learning reveals emergent subpopulations of interferon-γ–stimulated mesenchymal stromal cells that predict immunosuppression

Background

Although a preponderance of pre-clinical data demonstrates the immunosuppressive potential of mesenchymal stromal cells (MSCs), significant heterogeneity and lack of critical quality attributes (CQAs) based on immunosuppressive capacity likely have contributed to inconsistent clinical outcomes. This heterogeneity exists not only between MSC lots derived from different donors, tissues and manufacturing conditions, but also within a given MSC lot in the form of functional subpopulations. We therefore explored the potential of functionally relevant morphological profiling (FRMP) to identify morphological subpopulations predictive of the immunosuppressive capacity of MSCs derived from multiple donors, manufacturers and passages.

Expression of toll‐like receptors and their regulatory roles in murine cardiac telocytes

Telocytes, newly discovered in the last decade, are interstitial cells found in numerous organs, with multiple proposed potential biological functions. Toll‐like receptors (TLRs) play an important role in innate and adaptive immunity by recognizing pathogen‐associated molecular patterns (PAMPs). However, it is still unknown whether telocytes express these innate receptors. We sought to determine the expression and role of TLRs in telocytes. In our study, we primarily detected TLR1‐9 expression in telocytes. The proliferation, apoptosis and immunoregulatory activity of telocytes activated with or without TLR ligands were determined. Our results showed that purified telocytes expressed TLR2, TLR3 and TLR5. In particular, telocytes expressed high levels of TLR2 as observed using flow cytometry. When we stimulated telocytes with TLR2 or TLR3 agonists (Pam3CSK4, PolyI:C), iNOS expression was greatly increased after Pam3CSK4 treatment. Additionally, telocyte proliferation was reduced and cell apoptosis was increased after TLR agonist stimulation. A co‐culture experiment showed that supernatant from telocytes pretreated with Pam3CSK4 inhibited T cell activation much more than that from untreated telocytes and this effect was mediated by iNOS. Overall, our results demonstrated TLR expression on telocytes for the first time and provided evidence of an immunoregulatory role of telocytes, indicating their clinical potential.     

Local control of the host immune response performed with mesenchymal stem cells: perspectives for functional intracerebral xenotransplantation

Foetal pig neuroblasts are interesting candidates as a cell source for transplantation, but xenotransplantation in the brain requires the development of adapted immunosuppressive treatments. As systemic administration of high doses of cyclosporine A has side effects and does not protect xenotransplants forever, we focused our work on local control of the host immune responses. We studied the advantage of cotransplanting syngenic mesenchymal stem cells (MSC) with porcine neuroblasts (pNb) in immunocompetent rat striata. Two groups of animals were transplanted, either with pNb alone or with both MSC and pNb. At day 63, no porcine neurons were detected in the striata that received only pNb, while four of six rats transplanted with both pNb and MSC exhibited healthy porcine neurons. Interestingly, 50% of the cotransplanted rats displayed healthy grafts with pNF70+ and TH+ neurons at 120 days post‐transplantation. qPCR analyses revealed a general dwindling of pro‐ and anti‐inflammatory cytokines in the striata that received the cotransplants. Motor recovery was also observed following the transplantation of pNb and MSC in a rat model of Parkinson's disease. Taken together, the present data indicate that the immunosuppressive properties of MSC are of great interest for the long‐term survival of xenogeneic neurons in the brain.     

Lysosomal-associated Transmembrane Protein 4B (LAPTM4B) Decreases Transforming Growth Factor β1 (TGF-β1) Production in Human Regulatory T Cells

Production of active TGF-β1 is one mechanism by which human regulatory T cells (Tregs) suppress immune responses. This production is regulated by glycoprotein A repetitions predominant (GARP), a transmembrane protein present on stimulated Tregs but not on other T lymphocytes (Th and CTLs). GARP forms disulfide bonds with proTGF-β1, favors its cleavage into latent inactive TGF-β1, induces the secretion and surface presentation of GARP·latent TGF-β1 complexes, and is required for activation of the cytokine in Tregs. We explored whether additional Treg-specific protein(s) associated with GARP·TGF-β1 complexes regulate TGF-β1 production in Tregs. We searched for such proteins by yeast two-hybrid assay, using GARP as a bait to screen a human Treg cDNA library. We identified lysosomal-associated transmembrane protein 4B (LAPTM4B), which interacts with GARP in mammalian cells and is expressed at higher levels in Tregs than in Th cells. LAPTM4B decreases cleavage of proTGF-β1, secretion of soluble latent TGF-β1, and surface presentation of GARP·TGF-β1 complexes by Tregs but does not contribute to TGF-β1 activation. Therefore, LAPTM4B binds to GARP and is a negative regulator of TGF-β1 production in human Tregs. It may play a role in the control of immune responses by decreasing Treg immunosuppression.     

广叶绣球菌多糖对免疫低下小鼠肠道免疫功能的调节作用

通过研究广叶绣球菌多糖对免疫低下小鼠肠道菌群、细胞因子表达量及短链脂肪酸的影响,探究广叶绣球菌多糖的免疫作用机制。腹腔注射环磷酰胺构建免疫低下小鼠模型,将小鼠分为6组：正常对照组、模型组、广叶绣球菌多糖低、中、高剂量组以及阳性对照组,连续饲养30d后处死取样,HE染色观察小肠组织结构,酶联免疫吸附法测定小肠白细胞介素-6（IL-6）、IL-10、肿瘤坏死因子-α（TNF-α）、干扰素-γ（IFN-γ）的表达水平,高通量测序技术分析小鼠肠道菌群的变化,气-质联用（GC-MS）技术分析盲肠内容物短链脂肪酸（SCFAs）的含量。结果表明,广叶绣球菌多糖高剂量组可显著改善绒毛肿胀和变短现象,提高绒毛长度/隐窝深度的比值（V/C值）和小肠IL-6、IL-10、TNF-α、IFN-γ细胞因子含量（P<0.05或P<0.01）,提高拟杆菌属Bacteroides、拟普雷沃菌属Alloprevotella、丁酸弧菌属Butyrivibrio、Intestinimonas、链球菌属Streptococcus的相对丰度（P<0.05或P<0.01）;各剂量组均可提高盲肠内6种主要短链脂肪酸含量,差异达显著或极显著水平（P<0.05或P<0.01）。试验组与阳性对照组趋势一致。广叶绣球菌多糖可通过改善免疫低下小鼠的肠道粘膜形态,提高小肠细胞因子水平,调节肠道菌群结构,增加SCFAs产生菌的相对丰度,提高短链脂肪酸含量,调节免疫低下小鼠的肠道免疫功能。