B cells and in particular IL-10-secreting B cells emerge as important players in immune balance during pregnancy. We have recently revealed that CD19-deficient (CD19−/−), B cell-specific ...IL-10-deficient (BIL-10−/−) and B cell-deficient µMT pregnant mice are highly susceptible to LPS-induced preterm birth (PTB). We aimed to analyze the ability of IL-10-secreting cells to protect from PTB and the underlying mechanisms. Wild type (WT), CD19−/−, BIL-10−/− and µMT mice were treated with LPS at gd16 and the cellular immune response was investigated 24 h later. LPS-treated BIL-10−/− dams showed a more pronounced PTB phenotype compared to WT, CD19−/− and µMT females, and increased inflammatory and reduced anti-inflammatory mediator concentrations in the peritoneal cavity and serum. CD19−/−, BIL-10−/− and µMT mice displayed altered immune cell population frequencies in the blood and uterus with lower numbers of IL-10-secreting B cells and T cells. BIL-10−/− mothers presented decreased frequencies of uterine CD4+CD25+Foxp3+ Treg cells. Co-stimulatory molecules are critical for feto-maternal tolerance and IL-10 secretion. We found dysregulated PD-1 expression in peripheral blood and ICOS expression in the uterus of CD19−/−, BIL-10−/− and µMT dams. Our data show that B cell-specific IL-10-signaling is essential for a balanced maternal immune response to an inflammatory stimulant that cannot be hampered without IL-10-secreting B cells.
Cellular therapy with chimeric antigen receptor (CAR)-redirected cytotoxic T cells has shown impressive efficacy in the treatment of hematologic malignancies. We explored a regulatory T cell ...(Treg)-based therapy in the treatment of allergic airway inflammation, a model for asthma, which is characterized by an airway hyper-reactivity (AHR) and a chronic, T helper-2 (Th2) cell-dominated immune response to allergen. To restore the immune balance in the lung, we redirected Tregs by a CAR toward lung epithelia in mice upon experimentally induced allergic asthma, closely mimicking the clinical situation. Adoptively transferred CAR Tregs accumulated in the lung and in tracheobronchial lymph nodes, reduced AHR and diminished eosinophilic airway inflammation, indicated by lower cell numbers in the bronchoalveolar lavage fluid and decreased cell infiltrates in the lung. CAR Treg cells furthermore prevented excessive pulmonary mucus production as well as increase in allergen-specific IgE and Th2 cytokine levels in exposed animals. CAR Tregs were more efficient in controlling asthma than non-modified Tregs, indicating the pivotal role of specific Treg cell activation in the affected organ. Data demonstrate that lung targeting CAR Treg cells ameliorate key features of experimental airway inflammation, paving the way for cell therapy of severe allergic asthma.
The maternal balance between B regulatory (Breg) cells and inflammatory B cells is of central importance for protection against preterm birth (PTB). However, the impact of B cell signaling in early ...maternal and fetal immune responses on inflammatory insults remains underinvestigated. To understand which role B cells and B-cell-specific signaling play in the pathogenesis of PTB, the later was induced by an injection of LPS in B cell-sufficient WT mice, CD19−/−, BMyD88−/− and µMT murine dams at gestational day 16 (gd 16). WT dams developed a strong inflammatory response in their peritoneal cavity (PC), with an increased infiltration of granulocytes and enhanced IL-6, TNF-α, IL-17 and MCP-1 levels. However, they demonstrated a reduced NOS2 expression of PC macrophages 4 h after the LPS injection. Simultaneously, LPS-challenged WT dams upregulated pregnancy-protective factors like IL-10 and TARC. The concentrations of inflammatory mediators in the placental supernatants, amniotic fluids, fetal serums and gestational tissues were lower in LPS-challenged WT dams compared to CD19−/−, BMyD88−/− and µMT dams, thereby protecting WT fetuses from being born preterm. B cell deficiency, or the loss of B-cell-specific CD19 or MyD88 expression, resulted in an early shift from immune regulation towards inflammation at the fetomaternal interface and fetuses, resulting in PTB.
IL‐17 is associated with different phenotypes of asthma, however, it is not fully elucidated how it influences induction and maintenance of asthma and allergy. In order to determine the role of IL‐17 ...in development of allergic asthma, we used IL‐17A/F double KO (IL‐17A/F KO) and WT mice with or without neutralization of IL‐17 in an experimental allergic asthma model and analyzed airway hyperresponsiveness, lung inflammation, T helper cell polarization, and DCs influx and activation. We report that the absence of IL‐17 reduced influx of DCs into lungs and lung draining LNs. Compared to WT mice, IL‐17A/F KO mice or WT mice after neutralization of IL‐17A showed reduced airway hyperresponsiveness, eosinophilia, mucus hypersecretion, and IgE levels. DCs from draining LNs of allergen‐challenged IL‐17A/F KO mice showed a reduction in expression of migratory and costimulatory molecules CCR7, CCR2, MHC‐II, and CD40 compared to WT DCs. Moreover, in vivo stimulation of adoptively transferred antigen‐specific cells was attenuated in lung‐draining LNs in the absence of IL‐17. Thus, we report that IL‐17 enhances airway DC activation, migration, and function. Consequently, lack of IL‐17 leads to reduced antigen‐specific T cell priming and impaired development of experimental allergic asthma.
Cellular mechanisms influenced by IL‐17 are yet to be fully elucidated. Here, we show that the presence of IL‐17 enhances antigen uptake and in vivo activation of DCs and their migration to the draining LNs in an experimental model of allergic asthma.
Disturbances of glutamatergic neurotransmission and mononuclear phagocyte system activation have been described uni- and bipolar depression (UD/BD). Linking the glutamate and immune hypotheses of ...depression, quinolinic acid (QUIN) is synthesized by activated microglia and acts as an endogenous N-methyl-D-aspartate glutamate receptor (NMDA-R) agonist with neurotoxic properties. Recently, we observed an increased microglial QUIN expression in the subgenual and supracallosal, but not in the pregenual part of the anterior cingulate cortex in postmortem brains of suicide cases with severe depression. Since several hints point to a role of the hippocampus in depression, we extended our study and addressed the question whether microglial QUIN is also changed in subregions of the hippocampus (CA1 and CA2/3 areas) in these patients. Postmortem brains of 12 acutely depressed patients (UD,
n
= 6; BD,
n
= 6) and 10 neuropsychiatric healthy age- and gender-matched control subjects were analyzed using QUIN-immunohistochemistry. Hippocampal volumes were determined in order to assess possible neurotoxic or neurodegenerative aspects. Microglial QUIN expression in the whole group of depressed patients was either comparable (left CA1, right CA2/3) or decreased (right CA1:
p
= 0.004, left CA2/3:
p
= 0.044) relative to controls. Post hoc tests showed that QUIN was reduced both in UD and BD in the right CA1 field (UD,
p
= 0.048; BD,
p
= 0.031). No loss of hippocampal volume was detected. Our data indicate that UD and BD are associated with a local reduction in QUIN-immunoreactive microglia in the hippocampus and underline the importance of the NMDA-R signaling in depressive disorders.
Different models of experimental allergic asthma have shown that the TLR7/8 agonist resiquimod (R848) is a potential inhibitor of type 2 helper cell-driven inflammatory responses. However, the ...mechanisms mediating its therapeutic effects are not fully understood. Using a model of experimental allergic asthma, we show that induction of IL-27 by R848 is critical for the observed ameliorative effects. R848 significantly inhibited all hallmarks of experimental allergic asthma, including airway hyperreactivity, eosinophilic airway inflammation, mucus hypersecretion, and Ag-specific Ig production. Whereas R848 significantly reduced IL-5, IL-13, and IL-17, it induced IFN-γ and IL-27. Neutralization of IL-27 completely reversed the therapeutic effect of R848 in the experimental asthma model, demonstrating dependence of R848-mediated suppression on IL-27. In vitro, R848 induced production of IL-27 by murine alveolar macrophages and dendritic cells and enhanced expression of programmed death-ligand 1, whose expression on monocytes and dendritic cells has been shown to regulate peripheral tolerance in both murine and human studies. Moreover, in vitro IL-27 enhanced secretion of IFN-γ whereas it inhibited IL-5 and IL-13, demonstrating its direct effect on attenuating Th2 responses. Taken together, our study proves that R848-mediated suppression of experimental asthma is dependent on IL-27. These data provide evidence of a central role of IL-27 for the control of Th2-mediated allergic diseases.
•We examined the presence of NMDA-R Abs in serum of patients with MCI, AD, SIVD, FTD and LBD.•IgA and IgM NMDA-R Abs were detected in serum of all investigated patients’ groups and aged ...volunteers.•Seropositivity was in MCI, AD and/or SIVD associated with depressive or psychotic co-symptoms.
The N-methyl-d-aspartate glutamate receptor (NMDA-R) plays a central role in learning and memory and has therefore a potential role in the pathophysiology of neuropsychiatric disorders. Recently, we detected NMDA-R autoantibodies in aged healthy volunteers without neuropsychiatric disorders.
Since studies showing the involvement of NMDA-R antibodies in mild cognitive impairment and different forms of dementia are rare, we examined NMDA-R antibodies (Abs) in serum of 46 patients with Alzheimer's disease (AD), 26 patients with subcortical ischemic vascular dementia (SIVD), 18 patients with frontotemporal dementia (FTD), 11 patients with Lewy body disease (LBD) and 33 patients with mild cognitive impairment (MCI) and in 21 healthy aged, gender-matched volunteers. While IgM and/or IgA NMDA-R Abs were present in all groups, IgG was only detected in one AD sample. Seropositivity could be correlated with the presence of co-symptoms: MCI and AD patients suffering from depression and AD and SIVD patients with a psychosis were almost all NMDA-R Ab positive.
We conclude that the presence of NMDA-R Abs in dementia could influence the incidence of comorbid depressive and/or psychotic states.
Inflammation and alterations in essential protein structures in the brain might also change the cellular distribution in the cerebrospinal fluid (CSF).
Using flow cytometry, we analyzed cell ...populations of the innate and adaptive immune system associated with the most frequent forms of dementias. We included patients with mild cognitive impairment (MCI; N = 33), Alzheimer’s disease (AD; N = 90), vascular dementia (VD; N = 35) and frontotemporal dementia (FTD; N = 17) at the time of diagnosis, before onset of treatment and 11 elderly non-demented individuals. Dependent on the form of dementia, an increased frequency of CD14+ monocytes, NK cells and NKT cells was measured. Within the T cell population, a dementia-associated shift from central memory towards (late-stage) effector cells was detected. T cells and NKT cells were correlated with MMSE, NK and NKT cells were correlated with ptau, CD14+ monocytes and NK cells were correlated with Amyloid-β 1–40.
Our data suggest that each investigated immune cell type is involved in dementia-associated alterations within the CSF, possibly having distinct functions in their pathogenesis.
ABSTRACT
The high susceptibility of newborn infants to sepsis is as cribed to animmaturity of the neonatal immune system, but the molecular mechanisms remain unclear. Newborn monocytes massively ...release the alarmins S100A8/S100A9. In adults, these are major regulators of immunosuppressive myeloid‐derived suppressor cells (MDSCs). We investigated whether S100A8/S100A9 cause an expansion of monocytic MDSCs (Mo‐MDSCs) in neonates, thereby contributing to an immunocompromised state. Mo‐MDSCs have been assigned to CD14+/human leukocyte antigen (HLA)‐DR−/low/CD33+ monocytes in humans and to CD11b+/Gr‐1int/Ly6G−/Ly6Chi cells in mice. We found monocytes with these phenotypes significantly expanded in their respective newborns. Functionally, however, they did not prove immunosuppressive but rather responded inflammatorily to microbial stimulation. Their expansion did not correlate with high S100A8/S100A9 levels in cord blood. Murine studies revealed an excessive expansion of CD11b+/Gr‐1int/Ly6G−/Ly6Chi monocytes in S100A9−/− neonates compared to wild‐type neonates. This strong baseline expansion was associated with hyperinflammatory responses during endotoxemia and fatal septic courses. Treating S100A9−/− neonates directly after birth with S100A8/S100A9 alarmins prevented excessive expansion of this inflammatory monocyte population and death from septic shock. Our data suggest that a specific population of inflammatory monocytes promotes fatal courses of sepsis in neonates if its expansion is not regulated by S100A8/S100A9 alarmins.—Heinemann, A. S., Pirr, S., Fehlhaber, B., Mellinger, L., Burgmann, J., Busse, M., Ginzel, M., Friesenhagen, J., von Köckritz‐Blickwede, M., Ulas, T., von Kaisenberg, C. S., Roth, J., Vogl, T., Viemann, D. In neonates S100A8/S100A9 alarmins prevent the expansion of a specific inflammatory monocyte population promoting septic shock. FASEB J. 31, 1153–1164 (2017). www.fasebj.org
Preterm birth (PTB) is defined as birth before 37 completed weeks of gestation. The causes of PTB are multiple and complex, the underlying pathophysiology being largely unknown. Interferences in the ...fine-tuned balance of the maternal immune system have been pointed to as one possible cause of PTB. Regulatory B cells (Breg) are part of the adaptive immune response, and recent data suggest that they may contribute to a healthy pregnancy by their regulatory/suppressive function. We investigated the frequency of Breg cells in peripheral blood of women undergoing PTB and control women immediately before giving birth via cesarean section. We detected an enhanced number of B cells, but a reduced number of Breg cells in women delivering preterm. In addition, the percentage of IL-10-producing B cells was decreased in PTB following stimulation with TLR agonists CpG or LPS, alone or combined with CD40L. This was associated with increased levels of pro-inflammatory cytokines in maternal serum. Moreover, isolated maternal B cells before delivering premature babies secreted higher level of the pro-inflammatory cytokine IL-6. No alterations in the frequency of regulatory T cells were found. Our data indicate that alterations in the number and function of Breg cells in peripheral maternal blood contribute to the immunological changes observed in preterm delivery and suggest these cells as important regulators of maternal immune responses.
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