B Cells Induce Early-Onset Maternal Inflammation to Protect against LPS-Induced Fetal Rejection.

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.

An increased proportion of progesterone receptor A in peripheral B cells from women who ultimately underwent spontaneous preterm birth.

The enormous challenge in unraveling the etiology of preterm birth (PTB) is to understand the complex interactions between gestational hormones, the immune system and reproductive tissues. PTB can be divided into spontaneous PTB (sPTB) and medically-indicated PTB, e.g. due to preeclampsia (PE) or HELLP syndrome. Progesterone (P4), important for establishment and maintenance of pregnancy, exerts anti-inflammatory effects. The impact of P4 on B cells and its support of maintaining maternal-fetal tolerance is widely unexplored. Therefore, we aimed to determine whether B cells express the progesterone receptor (PR) and to dissect a possible role of PR+ B cells in PTB. We found enhanced IL-6, IL-21 and TNF-α concentrations in maternal plasma in patients with sPTB and PE/HELLP compared to term delivery (TD), accompanied by enhanced PR-A expression by CD19+ B cells. In a second phase of the study, we recruited patients with imminent PTB (iPTB) and controls. Samples were collected at hospital admission and to a later time point, then divided into iPTB patients who delivered preterm and patients whose PTB was prevented. Within the group of iPTB patients, we observed very clear differences: enhanced levels of pro-inflammatory cytokines and increased percentages of PR-A+CD19+ B cells were found in iPTB patients that delivered preterm compared to patients who did not deliver preterm. We conclude that PTB is associated with the activation of an inflammatory pathway leading to the induction of PR-A by B cells. This might further trigger inflammation, result in the break of maternal-fetal tolerance and induce delivery.

IL-10 Producing B Cells Protect against LPS-Induced Murine Preterm Birth by Promoting PD1- and ICOS-Expressing T Cells.

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.

Depletion of Foxp3+ regulatory T cells but not the absence of CD19+IL-10+ regulatory B cells hinders tumor growth in a para-orthotopic neuroblastoma mouse model.

Adaptive immune cells with regulatory function reportedly mediate immune escape in a variety of tumors. Little is known regarding the relevance of the most prominent regulatory cell populations, namely Foxp3+ T regulatory cells (Tregs) and CD19+IL-10+ B regulatory cells (Bregs), for neuroblastoma (NB) survival. After establishing a novel immunocompetent syngeneic NB mouse model where orthotopic tumors can be generated after intrarenal injection of NB975A cells, we studied the importance of Tregs and Bregs in Foxp3-DTR mice whose Tregs can be depleted by diphtheria toxin (DT) application as well as in CD19-specific IL-10 deficient mice that lack IL-10+ Bregs (CD19cre+/- × IL-10fl/fl mice). We observed Foxp3 Treg cells in tumors from wild type mice. On the contrary, Bregs or B cells were scarce. Specific depletion of Tregs in Foxp3-DTR mice resulted in an 85% reduction of tumor volume and weight compared to DT-treated wild type mice and untreated Foxp3-DTR mice. In contrast, NB tumor growth was not affected in CD19-specific IL-10 deficient mice. Similarly, mice lacking mature B cells (µMT mice) and CD19 deficient mice (CD19cre mice) showed no change in growth pattern of NB tumors. In Treg-depleted mice, reduced tumor growth was associated with an increased concentration of IFN-gamma, TNF-alpha, IL-4, IL-6, and IL-10 in isolated splenocytes. In summary, transient ablation of Tregs but not absence of Bregs hindered the growth of NB, strongly suggesting the therapeutic potential of targeting Tregs for this aggressive childhood tumor.

Enhanced S100B expression in T and B lymphocytes in spontaneous preterm birth and preeclampsia.

OBJECTIVES: S100B belongs to the family of danger signaling proteins. It is mainly expressed by glial-specific cells in the brain. However, S100B was also detected in other cell likewise immune cells. This molecule was suggested as biomarker for inflammation and fetal brain damage in spontaneous preterm birth (sPTB), preeclampsia (PE) and HELLP (hemolysis, elevated liver enzymes, and low platelet count). METHODS: The aim of our study was to determine the concentration of S100B in maternal and cord blood (CB) plasma and placenta supernatant as well as the expression of S100B in maternal and CB CD4+ T cells and CD19+ B cells in sPTB and patients delivering following PE/HELLP diagnosis compared to women delivering at term (TD). The S100B expression was further related to the birth weight in our study cohort. RESULTS: S100B concentration was enhanced in maternal and CB plasma of sPTB and PE/HELLP patients and positively correlated with interleukin-6 (IL-6) levels. Increased S100B was also confirmed in CB of small-for-gestational-age (SGA) infants. S100B expression in maternal blood was elevated in CD4+ T cells of PE/HELLP patients and patients who gave birth to SGA newborns as well as in CD19+ B cells of sPTB and PE/HELLP patients and patients with SGA babies. In CB, the expression of S100B was increased in CD19+ B cells of sPTB, PE/HELLP and SGA babies. CONCLUSIONS: Our results support the hypothesis that S100B expression is enhanced in inflammatory events associated with preterm birth and that S100B expression in immune cells is a relevant marker for inflammation during pregnancy complications.

Maternal B cell signaling orchestrates fetal development in mice.

B cell participation in early embryo/fetal development and the underlying molecular pathways have not been explored. To understand whether maternal B cell absence or impaired signaling interferes with placental and fetal growth, we paired CD19-deficient (CD19-/-) mice, females with B cell-specific MyD88 (BMyD88-/-) or IL10 (BIL10-/-) deficiency as well as wild-type and MyD88-/- controls on C57Bl/6 background with BALB/c males. Pregnancies were followed by ultrasound and Doppler measurements. Implantation number was reduced in BMyD88-/- and MyD88-/- mice. Loss of MyD88 or B cell-specific deletion of MyD88 or IL10 resulted in decreased implantation areas at gestational day (gd) 5, gd8 and gd10, accompanied by reduced placental thickness, diameter and areas at gd10. Uterine artery resistance was enhanced in BIL10-/- dams at gd10. Challenge with 0.4 mg lipopolysaccharide/kg bodyweight at gd16 revealed that BMyD88-/-, BIL10-/- and CD19-/- mothers delivered preterm, whereas controls maintained their pregnancy. B cell-specific MyD88 and IL10 expression is essential for appropriate in utero development. IL10+B cells are involved in uterine blood flow regulation during pregnancy. Finally, B cell-specific CD19, MyD88 and IL10 expression influences susceptibility towards preterm birth.

Altered expression of costimulatory molecules in dementias.

Although the expression of co-stimulatory molecules plays an important role in the immune system, only little is known about their regulation in dementias. Therefore, we determined the expression of CD28, ICOS (CD278) and CTLA-4 (CD152) by CD4 + and CD8 + T cells in the peripheral blood of patients with mild cognitive impairment (MCI; N = 19), Alzheimer's disease (AD; N = 51), vascular dementia (VD; N = 21) and frontotemporal dementia (FTD; N = 6) at the point in time of diagnosis compared to 19 non-demented elderly persons. The expression of CD28 and ICOS by CD4 + and CD8 + T cells was not changed in AD, FTD or VD patients. The expression of the negative regulator CTLA-4 was increased by CD4 + T cells from AD and FTD patients and by CD8 + T cells from VD patients. The classification of the AD patients according to the severity of the disorder showed stage-dependent alterations of CD28, ICOS and CTLA-4 expression. In AD patients, the correlation analysis showed an association between the decline in CD28 + T cells and the increase in CTLA-4 + T cells with cognitive decline, measured by the mini-mental state examination (MMSE), tau proteins and Amyloid-ß, important AD biomarkers in cerebrospinal fluid (CSF). In FTD patients, a positive association between Q Albumin, a marker for blood-CSF-barrier function, and CD28 and a negative correlation between Q Albumin and ICOS expression were determined. Our data suggest a dysregulated balance between the expression of negative and positive co-stimulatory molecules by T cells in AD patients, which might contribute to chronic inflammation observed in dementia.

Maternal B Cell-Intrinsic MyD88 Signaling Mediates LPS-Driven Intrauterine Fetal Death.

Immunological networks balance tolerance towards paternal alloantigens during pregnancy with normal immune response to pathogens. Subclinical infections can impact this balance and lead to preterm birth or even intrauterine fetal death (IUFD). We recently showed that loss of maternal B cells renders murine fetuses susceptible to IUFD after LPS exposure. Since the signaling pathway involved in this B-cell mediated response remains unclear, we aimed to understand the participation of MyD88 in this response using B-cell-specific MyD88-deficient (BMyD88-/-) mice. B cells isolated from wild-type (WT), BMyD88-/-, CD19-/- and MyD88-/- dams on gestational day (gd) 10 responded differently to LPS concerning cytokine secretion. In vivo LPS challenge on gd 10 provoked IUFD in CD19-/- mothers with functional MyD88, while fetuses from BMyD88-/- and MyD88-/- mice were protected. These outcomes were associated with altered cytokine levels in the maternal serum and changes in CD4+ T-cell responses. Overall, the loss of MyD88 signaling in maternal B cells prevents the activation of cytokine release that leads to IUFD. Thus, while MyD88 signaling in maternal B cells protects the mother from infection, it ultimately kills the fetus. Understanding the cellular mechanisms underlying infection-driven pregnancy complications is the first step to designing powerful therapeutic strategies in the future.

Dementia-associated changes of immune cell composition within the cerebrospinal fluid.

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 â€‹= â€‹33), Alzheimer's disease (AD; N â€‹= â€‹90), vascular dementia (VD; N â€‹= â€‹35) and frontotemporal dementia (FTD; N â€‹= â€‹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-ß 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.

Association Between Homocysteine and Vitamin Levels in Demented Patients.

BACKGROUND: Although it is known that the nutritional status among elderly persons and, in particular, patients with dementia, is compromised, malnutrition that results in insufficient uptake of several vitamins is often not diagnosed. OBJECTIVE: An elevated homocysteine level is a known strong risk factor for vascular dementia (VaD) and Alzheimer's disease (AD). Several B vitamins are involved in the metabolism of homocysteine. Therefore, we investigated the serum levels of vitamin B1, vitamin B6, folate, and vitamin B12 in 97 patients with mild cognitive impairment (MCI) or different forms of dementia and 54 elderly control persons without dementia. RESULTS: Compared to aged non-demented people, vitamins B1, B6, B12, and folate were decreased in serum of patients with AD, and patients with Lewy body dementia had reduced vitamin B12 level. Vitamin B6 was diminished in VaD. Patients with frontotemporal dementia showed no alterations in vitamin levels. Age was identified as an important factor contributing to the concentrations of vitamin B1 and B6 in serum, but not vitamin B12 and folate. Increased levels of total homocysteine were detected especially in MCI and AD. Homocysteine correlated negatively with levels of vitamins B6, B12, and folate and positively with Q Albumin. CONCLUSION: Our data suggest that despite increased homocysteine already present in MCI, vitamin levels are decreased only in dementia. We propose to determine the vitamin levels in patients with cognitive decline, but also elderly people in general, and recommend supplementing these nutrients if needed.

Imbalance between inflammatory and regulatory cord blood B cells following pre-term birth.

Preterm birth (PTB) is one of the most frequent pregnancy complications. It affects millions of babies each year worldwide and is associated with increased morbidity and mortality. PTB-associated alterations in the maternal immune response may have a direct effect on the developing fetal immune system. Having recently shown that B regulatory (Breg) cells are decreased in number and functionally impaired in maternal blood from women delivering preterm, we now addressed the question whether the adaptive immune system is also altered in cord blood (CB) after the onset of PTB. PTB was associated with increased concentrations of IL-6, TNF-α and IL-21 in CB and enhanced IL-6, but decreased IFN-γ and IL-4 in amniotic fluid (AF) samples compared to term delivery (TD). We found no differences in the frequency of CD19 + B cells, CD4 + T cells or CD4+Foxp3+CD25+ T regulatory (Treg) cells in CB cells in PTB vs TD. The frequency of CD86 + B cells was increased, while the percentage of CD24hiCD38hiCD19 + Breg and CD1dhiCD5+ Breg cells and the ability of B cells to convert into Breg cells was diminished in PTB compared to TD. CB B cells from PTB secreted more IL-6, TNF-α, IL-9 and IL-2 compared to B cells obtained from term samples. We conclude that, after PTB onset, a shift from immunoregulation towards inflammation takes place in CB cells that are reportedly representative of the fetal compartment. B cells have a substantial contribution herein. This phenomenon might account for the observed enhanced mortality and morbidity in prematurely born infants. Further studies will clarify how to employ this easy-to-obtain information for closely monitoring newborns at risk.

Regulatory B cells control airway hyperreactivity and lung remodeling in a murine asthma model.

BACKGROUND: Asthma is a widespread, multifactorial chronic airway disease. The influence of regulatory B cells on airway hyperreactivity (AHR) and remodeling in asthma is poorly understood. OBJECTIVE: Our aim was to analyze the role of B cells in a house dust mite (HDM)-based murine asthma model. METHODS: The influence of B cells on lung function, tissue remodeling, and the immune response were analyzed by using wild-type and B-cell-deficient (µMT) mice and transfer of IL-10-proficient and IL-10-deficient B cells to µMT mice. RESULTS: After HDM-sensitization, both wild-type and µMT mice developed AHR, but the AHR was significantly stronger in µMT mice, as confirmed by 2 independent techniques: invasive lung function measurement in vivo and examination of precision-cut lung slices ex vivo. Moreover, airway remodeling was significantly increased in allergic µMT mice, as shown by enhanced collagen deposition in the airways, whereas the numbers of FoxP3+ and FoxP3- IL-10-secreting regulatory T cells were reduced. Adoptive transfer of IL-10-proficient but not IL-10-deficient B cells into µMT mice before HDM-sensitization attenuated AHR and lung remodeling. In contrast, FoxP3+ regulatory T cells were equally upregulated by transfer of IL-10-proficient and IL-10-deficient B cells. CONCLUSION: Our data in a murine asthma model illustrate a central role of regulatory B cells in the control of lung function and airway remodeling and may support future concepts for B-cell-targeted prevention and treatment strategies for allergic asthma.

Regulatory B Cells Are Decreased and Impaired in Their Function in Peripheral Maternal Blood in Pre-term Birth.

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.

IL-17 regulates DC migration to the peribronchial LNs and allergen presentation in experimental allergic asthma.

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.

IL-10 producing B cells rescue mouse fetuses from inflammation-driven fetal death and are able to modulate T cell immune responses.

Understanding the mechanisms leading to fetal death following maternal subclinical infections is crucial to develop new therapeutic strategies. Here we addressed the relevance of IL-10 secreting B cells (B10) in the maintenance of the immune balance during gestation. µMT females lacking mature B cells presented normal pregnancies, although their fetuses were smaller and their Treg pool did not expand as in B cell sufficient controls. Pregnant µMT females were more susceptible to LPS despite having less Treg; their fetuses died at doses compatible with pregnancy in WT animals. Adoptive transfer of IL-10 negative B effector cells or B cells from IL-10 deficient mice did not modify this outcome. The transfer of B10 cells or application of recombinant murine IL-10 reduced the fetal loss, associated with a normalization of Treg numbers and cytokine modulation at the feto-maternal interface. B cell-derived IL-10 suppressed the production of IL-17A and IL-6 by T cells and promoted the conversion of naïve cells into Treg. B10 cells are required to restore the immune balance at the feto-maternal interface when perturbed by inflammatory signals. Our data position B cells in a central role in the maintenance of the balance between immunity and tolerance during pregnancy.

Increased quinolinic acid in peripheral mononuclear cells in Alzheimer's dementia.

The role of monocytes and macrophages in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease (AD) is poorly understood. Recently, we have shown that the number of CD14+ monocytes remained constant during healthy aging and in AD patients. Although only little is known about the function of activated macrophages and microglia in AD, one important mechanism involves the expression of quinolinic acid (QUIN), an endogenous N-methyl-D-aspartate glutamate receptor (NMDA-R) agonist which mediates excitotoxicity especially in the hippocampus. We used immunofluorescence stainings of PBMCs to determine the expression of quinolinic acid (QUIN) and the MHC class II molecule HLA-DR in peripheral monocytic cells in 51 healthy volunteers aged 22-87 years and 43 patients with AD at diagnosis (0 weeks) and during the course of rivastigmine treatment at 0.25 year (12 weeks), 0.5 year (30 weeks), 1 year, and 1.5 years. The number of QUIN+ HLA-DR+ cells rises in healthy persons aged 30-40 years compared to persons aged 60-70 years, indicating that this cell population increases with aging. AD patients at diagnosis had an increased frequency of QUIN+, QUIN+ HLA-DR+, and QUIN+ HLA-DR+/HLA-DR+ cells compared to aged-matched controls. These cell populations remained increased in AD for up to one year after initiation of treatment with rivastigmine; no alterations were detected in aged healthy persons. We conclude that the expression of the neurotoxic agent QUIN is increased in peripheral monocytes from AD patients. These cells could enter the brain and contribute to excitotoxicity.

Dysfunction of the blood-cerebrospinal fluid-barrier and N-methyl-D-aspartate glutamate receptor antibodies in dementias.

N-Methyl-D-aspartate glutamate receptor (NMDA-R) antibodies (Abs) could play a role in neurodegenerative disorders. Since, in these diseases, NMDA-R Abs were detected in serum, but only sporadic in cerebrospinal fluid (CSF), the origin and impact of the Abs are still unresolved. We examined the presence of NMDA-R Abs in serum and CSF using a cell-based immunofluorescence assay as well as the function of the blood-CSF-barrier (B-CSF-B) by determination of Q albumin (ratio of albumin in CSF and serum) in patients with mild cognitive impairment (MCI; N = 59) and different types of dementia, Alzheimer's disease (AD; N = 156), subcortical ischemic vascular dementia (SIVD; N = 61), and frontotemporal dementia (FTD; N = 34). Serum IgA/IgM NMDA-R Abs and/or a disturbed B-CSF-B were sporadically present in all investigated patients' groups. In AD, these Abs often developed during the disease course. Patients with either no hippocampal atrophy and/or no AD-related characteristic changes in CSF, referred to "non-classical" AD, were characterized by seropositivity at diagnosis and loss of function of the B-CSF-B showed a progressive decline in cognitive functions and a poor prognosis. Our data indicate that NMDA-R Abs are present in different types of dementia and elderly healthy individuals. In combination with disturbed B-CSF-B integrity, they seem to promote their pathological potential on cognitive decline, and thus, a subgroup of dementia patients with these unique characteristics might inform clinicians.

Chimeric Antigen Receptor-Redirected Regulatory T Cells Suppress Experimental Allergic Airway Inflammation, a Model of Asthma.

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.

Alterations in the Peripheral Immune System in Dementia.

Alterations in the immune response that result in inflammation might play a role in the pathology of dementias. In order to analyze changes of the peripheral immune system associated with different types of dementias, we determined several innate and adaptive cell populations in whole blood using flow cytometry. We included patients with Alzheimer's disease (AD; n = 60), vascular dementia (VaD; n = 20), and frontotemporal dementia (FTD; n = 12) at the time point of diagnosis and 24 age-matched neuropsychiatric healthy persons. Monocytes and NK cells were diminished in VaD, but not in AD and FTD. B cell and T cell numbers were decreased in all investigated forms of dementia. Changes in the contribution of naïve/memory T cells were only present in AD. Correlation and regression analyses revealed associations between altered immune cell populations and Q Albumin as marker for the integrity of the blood-cerebrospinal fluid-barrier, Mini-Mental State Examination values, and age. The peripheral immune system is altered in AD, VaD, and FTD. However, each disorder presents unique changes in the investigated cell types indicating different mechanisms underlying the pathology.

Psychotic Symptoms Associated with Poor Renal Function in Mild Cognitive Impairment and Dementias.

Patients suffering from cognitive decline such as mild cognitive impairment or neurodegenerative disorders including Alzheimer's dementia, vascular dementia, frontotemporal dementia, and Lewy body dementia are often accompanied by symptoms like psychosis, depression, agitation, and apathy. Aging increases not only the prevalence of dementia but also the development of kidney disorders, which had emerged as possible risk factor of cognitive impairment and dementia. However, a contribution of renal dysfunction to psychosis associated with cognitive decline remains to be investigated. We addressed the question whether patients diagnosed with mild cognitive impairment or dementia and co-symptoms show alterations in serum parameters. Analyzing 309 patients in total, we detected a positive correlation between the occurrence of psychotic symptoms and increased retention parameters in serum, including creatinine and urea levels and the estimated glomerular filtration rates. This was in particular detected in female patients. In male patients, psychotic symptoms were associated with an increased number of leukocytes in blood. We propose that clinicians should be aware of psychotic symptoms in patients with reduced cognitive functions that could be associated with changes in the retention parameters.