T follicular regulatory cells suppress Tfh-mediated B cell help and synergistically increase IL-10-producing B cells in breast carcinoma Abstract T follicular regulatory (Tfr) cell is a recently discovered subset of T regulatory (Treg) cells. The main function of Tfr cells is thought to suppress germinal cancer reaction and inhibit B cell proliferation and Ig production. However, recent studies demonstrate that Tfr cells may be required for high-affinity Ig formation during acute virus infections. The role of Tfr cells in breast cancer is not thoroughly investigated. In this study, total circulating CD4 T cells were sorted into CD25+CXCR5− Treg-like, CD25+CXCR5+ Tfr-like, and CD25−CXCR5+ Tfh-like subsets. Data showed that the Tfr-like subset presented intermediate levels of both Foxp3 and Bcl-6, while the Treg-like subset was high in Foxp3 and low in Bcl-6, and the Tfh-like was high in Bcl-6 and low in Foxp3. Of note, the frequencies of Tfr-like and Treg-like cells were significantly elevated in breast cancer (BC) patients than in non-cancer (NC) controls. Tfr-like cells in BC patients also expressed significantly higher levels of Foxp3 than those in NC controls. Neither Treg-like nor Tfr-like cells could support Ig production from naive B cells, while Tfh-like cells potently supported Ig production from naive B cells. Tfr-like cells increased the availability of IL-10, both by directly producing IL-10 and by increasing IL-10 production from B cells. Interestingly, Tfr-like cells increased IL-10 production from B cells synergistically with Tfh cells, but at the same time, significantly reduced Ig production in the Tfh-B cell coculture. These Tfr-mediated effects on Tfh cells were not found in canonical Treg cells. Overall, this study demonstrates several distinctive features in circulating Tfr cells and suggests that Tfr cells may promote the formation of IL-10-producing B cells in BC.

Comparison of immunomodulatory properties of exosomes derived from bone marrow mesenchymal stem cells and dental pulp stem cells Abstract Substantial discoveries suggested that exosomes released from multiple sources of stem cells can affect the biological functions of target cells. In present period, the immunosuppressive properties of exosomes derived from bone marrow mesenchymal stem cells (BMMSCs-E) have been extensively recognized, but few studies have been reported about exosomes secreted from dental pulp stem cells (DPSCs-E) in the field of medical immunity. Hence, the aim of this study is to compare the immunomodulatory capacity of BMMSCs-E and DPSCs-E. Peripheral blood mononuclear cells (PBMCs) were co-cultured with them respectively and the proportion of regulatory T cells (Treg) was detected to increase. Subsequently, we stimulated CD4+T cells with BMMSCs-E and DPSCs-E to observe their effects on the polarizations, chemokines secretion, apoptosis, and proliferation of CD4+T cells. We found that DPSCs-E inhibited the differentiation of CD4+T cells into T helper 17 cells (Th17) and reduced the secretions of pro-inflammatory factors IL-17 and TNF-α, while promoted the polarization of CD4+T cells into Treg and increased the release of anti-inflammatory factors IL-10 and TGF-β. What’s more, these capabilities of DPSCs-E were stronger than those of BMMSCs-E. In addition, DPSCs-E were more effective in inducing apoptosis of CD4+T cells compared with BMMSCs-E, and DPSCs-E inhibited the proliferation of CD4+T cells, which is similar to BMMSCs-E. We draw a conclusion that DPSCs-E have stronger immune-modulating activities than BMMSCs-E, and may be a new therapeutic tool for the treatment of immunological diseases.

On the immunoregulatory role of statins in multiple sclerosis: the effects on Th17 cells Abstract Statins, the cholesterol-lowering drugs, also possess immunomodulatory properties, affecting among others T cell activation and differentiation, antigen presentation, and regulatory T cell (Tregs) maintenance and differentiation. Their effects on autoagression have led investigators to assess their clinical significance in autoimmune disease, such as multiple sclerosis (MS), a chronic progressive demyelinating disease of autoimmune nature. The dysregulated immunity noted in MS features a profound shift from Tregs dominance to Th17 cell superiority. In this review, we discuss the immunobiological basis of statins, their role in autoimmunity related to MS, and the data from experimental models and human studies on their effect on Th17 cells.

IgM ANCA in healthy individuals and in patients with ANCA-associated vasculitis Abstract Low levels of IgM auto-antibodies have been reported in health and disease. IgM anti-neutrophil cytoplasmic antibodies (ANCA) have been reported in patients with ANCA-associated vasculitis (AAV). We sought to investigate if healthy individuals may have IgM ANCA in their sera. The first aim of the study was to determine whether IgM ANCA was present in healthy individuals and in patients with ANCA-associated vasculitis. The second aim was to determine what happens to IgM ANCA levels over time. The third aim was to determine whether bacterial infections affected IgM ANCA levels in non-AAV patients. Sera from healthy individuals and patients with AAV were tested for IgM ANCA by immunofluorescence on fixed neutrophils, immunoprecipitation, Western blot and ELISA. Peripheral blood mononuclear cells were isolated and tested by ELISpot for circulating IgM ANCA B cells. To determine whether infection affected IgM ANCA levels, we studied non-AAV patients with bacterial endocarditis or Staphylococcus aureusbacteraemia and measured IgM ANCA levels over time. IgM ANCA is detectable in both healthy individuals and patients with AAV and the titres decreased with increasing age. Circulating IgM ANCA B cells were identified by ELISpot. In the presence of infection, we could not find a significant change in IgM ANCA levels. We report the presence of low-level specific IgM ANCA in the sera of healthy individuals and in patients with ANCA-associated vasculitis. Bacterial infection did not affect the level of IgM ANCA in this small study.

Overall corrections and assessments of “Correlations between TLR polymorphisms and inflammatory bowel disease: a meta-analysis of 49 case-control studies”

Evaluation of serum cytokine and chemokine levels in dermatitis herpetiformis: a systematic review and meta-analysis

Late relapse of primary hemophagocytic lymphohistiocytosis after hematopoietic stem cell transplantation: a consequence of low-level chimerism from a carrier donor?

Patients with atopy exhibit reduced cortisol awakening response but not cortisol concentrations during the rest of the day Abstract It has been documented that cortisol release in response to acute stressors is reduced in patients with atopic dermatitis, allergic rhinitis, and other atopic diseases compared to that in healthy subjects. We aimed to test the hypothesis that atopic patients exert reduced salivary cortisol awakening response (CAR) in comparison with healthy subjects. The hypothesis was tested on a stressful and a relax day selected subjectively. Moreover, we evaluated the impact of trait anxiety. The sample consisted of 60 subjects, out of which 28 were patients with atopy and 32 healthy volunteers of both sexes. Saliva samples were collected in the morning to evaluate CAR as well as in the early afternoon and evening to look at cortisol concentrations during the rest of the day. The results showed reduced CAR in atopic patients compared to that in healthy subjects. This effect was modulated by sex with a significant difference observed in males. While CAR was reduced, atopic patients had unchanged cortisol concentrations throughout the day. The evening cortisol was even higher in atopic patients. If the subjects were stratified according to the trait anxiety, no significant differences in CAR between high and low anxiety were observed. No differences in cortisol variables including CAR were observed between the stressful and relax day. In conclusion, this study presents evidence on reduced CAR suggesting an insufficient HPA axis reactivity in atopy. Furthermore, the data in atopic patients demonstrate that reduced HPA axis reactivity does not necessarily mean lower cortisol concentrations throughout the day. This might be of relevance to immune system function and the course of the disease.

Regulation of Staphylococcus aureus -induced CXCR1 expression via inhibition of receptor mobilization and receptor shedding during dual receptor (TNFR1 and IL-1R) neutralization Abstract Our earlier studies proposed a radically new idea suggesting interdependency between TNF-α/TNFR1 and IL-1β/IL-1R pathways in modulation of Staphylococcus aureus-induced CXCL8/CXCR1 axis. However, the effects of inhibition of cytokine receptor mobilization at intracellular level and surface TNFR1 and IL-1R shedding on S. aureus-induced CXCR1 expression have not been studied so far in peritoneal macrophages. This study aimed to investigate the role of inhibition of receptor mobilization from the intracellular pool (using brefeldin A) and surface receptor shedding (using TAPI-1) on CXCR1 expression during dual receptor (TNFR1 plus IL-1R) neutralization in peritoneal macrophages isolated from wild-type Swiss Albino mice. Release of superoxide anion, nitric oxide, and hydrogen peroxide was measured and cytokine production was done by ELISA. Expression of surface receptors (TNFR1, IL-1R, and CXCR1) and inflammatory mediators was studied by Western blot. It was observed that S. aureus-infected macrophages showed elevated ROS production, secretion of TNF-α, IL-1β, and CXCL8, along with increased expression of surface receptors (TNFR1, IL-1R, and CXCR1), and inflammatory markers (iNOS and COX-2) compared with control or treated groups (p < 0.05). However, prior treatment of macrophages with BFA or TAPI-1 in the presence of anti-TNFR1 antibody and IRAP during S. aureus infection showed significant reduction of all these parameters (p < 0.05). We can conclude that targeting of TNFR1 and IL-1R (with major focus on surface expression study) either through blockage of intracellular receptor trafficking pathway or via surface receptor shedding diminishes TNFR1/IL-1R interaction and consequently downregulates CXCR1 expression along with inflammatory signalling pathways during bacterial infections.

Dysregulation of helper T lymphocytes in esophageal squamous cell carcinoma (ESCC) patients is highly associated with aberrant production of miR-21 Abstract Dysregulation of helper T (Th) cell subsets has been contributed to the initiation and propagation of esophageal squamous cell carcinoma (ESCC). Different microRNAs (miRNAs) have been reported to control the development and functions of tumor-associated immune cells in ESCC. Here, we aimed to assess the IL-10, TGF-β, IFN-γ, and IL-17a-producing CD3+CD8− T cells in association whit miR-21, miR-29b, miR-106a, and miR-155 expression in ESCC patients. A total of 34 ESCC patients including 12 newly diagnosed (ND) and 22 under-treatment (UT) cases and also 34 age-matched healthy donors were enrolled. Flow cytometric characterization of stimulated T cells was performed by staining of the cells with fluorescent conjugated specific anti-human CD3 and CD8 cell surface markers as well as IL-17a, IFN-γ, IL-10, and TGF-β intracytoplasmic cytokines. Circulating RNA was extracted from the plasma, and qRT-PCR was used to evaluate the expression of microRNAs. TGF-β plasma levels were also assessed by ELISA. Results showed that the frequency of Th cells was significantly reduced in patients. A significant increase in Treg as well as Th17 cells population in both patient subgroups was observed. ND patients showed elevated level of Th1 cells and IL-10. However the mean expression of IFN-γ was significantly decreased in Th cells. We also detected higher level of miR-21 in the ESCC patients which was significantly correlated with different subsets of Th cells. Our findings revealed that immune response related to the Th cells is highly impaired in ESCC patients. Association between miR-21 and Th subsets could be correlated with the impairment of anti-tumor immunity and ESCC pathogenesis, which could be potentially used as an important target for immunotherapeutic approaches.