Peripheral Immune Markers Research Articles

Peripheral immune markers and antipsychotic non-response in psychosis

BackgroundPeripheral immune markers have previously been linked to a poor response to antipsychotic medication and more severe negative symptoms at the onset of psychosis. The present study investigated the association of blood cytokines and complement markers with the presence of antipsychotic non-response and symptom severity in patients with psychosis. MethodsThis cross-sectional study recruited 94 patients with schizophrenia and other psychoses, of whom 47 were defined as antipsychotic responders and 47 as antipsychotic non-responders. In all subjects we measured plasma levels of cytokines (IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, TNF-α, and IFN-γ), complement markers (C1-inhibitor, C3, C4, C3a, C3b, Bb, factor D, C5a, terminal complement complex) and high sensitivity C-reactive protein (hsCRP). Symptom severity was recorded using the Positive and Negative Syndrome scale for Schizophrenia (PANSS). Binary logistic regression tested each immune marker as predictor of response status while covarying for relevant socio-demographic variables. Correlation analyses tested the association between immune markers and the severity of symptoms. ResultsInterleukin (IL)-8 significantly predicted antipsychotic non-response (OR=24.70, 95% CI, 1.35–453.23, p = 0.03). Other immune markers were not associated with antipsychotic response. IL-6, IL-8, IL-10 and TNF-α significantly positively correlated with negative psychotic symptoms. ConclusionsHigher levels of IL-8 are associated with a poor response to antipsychotic treatment. Increased cytokines levels are specifically associated with more severe negative symptoms in patients with schizophrenia and other psychoses.

Examining the Role of Microbiota in Emotional Behavior: Antibiotic Treatment Exacerbates Anxiety in High Anxiety-Prone Male Rats

Intestinal microbiota are essential for healthy gastrointestinal function and also broadly influence brain function and behavior, in part, through changes in immune function. Gastrointestinal disorders are highly comorbid with psychiatric disorders, although biological mechanisms linking these disorders are poorly understood. The present study utilized rats bred for distinct emotional behavior phenotypes to examine relationships between emotionality, the microbiome, and immune markers. Prior work showed that Low Novelty Responder (LR) rats exhibit high levels of anxiety- and depression-related behaviors as well as myriad neurobiological differences compared to High Novelty Responders (HRs). Here, we hypothesized that the divergent HR/LR phenotypes are accompanied by changes in fecal microbiome composition. We used next-generation sequencing to assess the HR/LR microbiomes and then treated adult HR/LR males with an antibiotic cocktail to test whether it altered behavior. Given known connections between the microbiome and immune system, we also analyzed circulating cytokines and metabolic factors to determine relationships between peripheral immune markers, gut microbiome components, and behavioral measures. There were no baseline HR/LR microbiome differences, and antibiotic treatment disrupted the microbiome in both HR and LR rats. Antibiotic treatment exacerbated aspects of HR/LR behavior, increasing LRs’ already high levels of anxiety-like behavior while reducing passive stress coping in both strains. Our results highlight the importance of an individual’s phenotype to their response to antibiotics, contributing to the understanding of the complex interplay between gut microbes, immune function, and an individual’s emotional phenotype.

Management of lung transplantation in the COVID-19 era-An international survey.

It is unknown if solid organ transplant recipients are at higher risk for severe COVID-19. The management of a lung transplantation (LTx) program and the therapeutic strategies to adapt the immunosuppressive regimen and antiviral measures is a major issue in the COVID-19 era, but little is known about worldwide practice. We sent out to 180 LTx centers worldwide in June 2020 a survey with 63 questions, both regarding the management of a LTx program in the COVID-19 era and the therapeutic strategies to treat COVID-19 LTx recipients. We received a total of 78 responses from 15 countries. Among participants, 81% declared a reduction of the activity and 47% restricted LTx for urgent cases only. Sixteen centers observed deaths on waiting listed patients and eight centers performed LTx for COVID-19 disease. In 62% of the centers, COVID-19 was diagnosed in LTx recipients, most of them not severe cases. The most common immunosuppressive management included a decreased dose or pausing of the cell cycle inhibitors. Remdesivir, hydroxychloroquine, and azithromycin were the most proposed antiviral strategies. Most of the centers have been affected by the COVID-19 pandemic and proposed an active therapeutic strategy to treat LTx recipients with COVID-19.

Azathioprine immunosuppression and disease modification in Parkinson’s disease (AZA-PD): a randomised double-blind placebo-controlled phase II trial protocol

IntroductionThe immune system is implicated in the aetiology and progression of Parkinson’s disease (PD). Inflammation and immune activation occur both in the brain and in the periphery, and a proinflammatory...

DNA Methylation and Immune Cell Markers Demonstrate Evidence of Accelerated Aging in Patients with Chronic Hepatitis B Virus or Hepatitis C Virus, with or without Human Immunodeficienct Virus Co-infection.

Several chronic diseases accelerate biological aging. We investigated age acceleration and the association between peripheral blood DNA methylation (DNAm) and immune cell markers in patients chronically infected with the hepatitis B virus (HBV) or the hepatitis C virus (HCV) with and without human immunodeficiency virus (HIV) co-infection. Age acceleration was measured as the difference between epigenetic age (Horvath clock) and chronological age. The immune marker model of age acceleration was developed using Elastic Net regression to select both the immune markers and their associated weights in the final linear model. Patients with chronic HBV (n = 51) had a significantly higher median epigenetic age compared to chronological age (age accelerated) (P < .001). In patients with chronic HCV infection (n = 63), age acceleration was associated with liver fibrosis as assessed by histology (P < .05), or presence of HIV co-infection (P < .05), but not HCV mono-infection. Age acceleration defined by immune markers was concordant with age acceleration by DNA methylation (correlation coefficient = .59 in HBV; P = .0025). One-year treatment of HBV patients with nucleoside therapy was associated with a modest reduction in age acceleration, as measured using the immune marker model (-.65 years, P = .018). Our findings suggest that patients with chronic viral hepatitis have accelerated epigenetic aging, that immune markers define biological age, and have the potential to assess the effects of therapeutic intervention on age acceleration.

The association of peripheral immune markers with brain cortical thickness and surface area in South African people living with HIV.

A spectrum of cognitive impairments known as HIV-associated neurocognitive disorders (HAND) are consequences of the effects of HIV-1 within the central nervous system. Regardless of treatment status, an aberrant chronic neuro-immune regulation is a crucial contributor to the development of HAND. However, the extent to which inflammation affects brain structures critical for cognitive status remains unclear. The present study aimed to determine associations of peripheral immune markers with cortical thickness and surface area. Participants included 65 treatment-naïve HIV-positive individuals and 26 HIV-negative controls. Thickness and surface area of all cortical regions were derived using automated parcellation of T1-weighted images acquired at 3T. Peripheral immune markers included C-C motif ligand 2 (CCL2), matrix metalloproteinase 9 (MMP9), neutrophil gelatinase-associated lipocalin (NGAL), thymidine phosphorylase (TYMP), transforming growth factor (TGF)-β1, and vascular endothelial growth factor (VEGF), which were measured using enzyme-linked immunosorbent assays. Associations of these markers with thickness and surface area of cortical regions were evaluated. A mediation analysis examined whether associations of inflammatory markers with cognitive functioning were mediated by brain cortical thickness and surface area. After controlling for multiple comparisons, higher NGAL was associated with reduced thickness of the bilateral orbitofrontal cortex in HIV-positive participants. The association of NGAL with worse motor function was mediated by cortical thickness of the bilateral orbitofrontal region. Taken together, this study suggests that NGAL plays a potential role in the neuropathophysiology of neurocognitive impairments of HIV.

Expression of immune cell markers and tumor markers in patients with cervical cancer

ObjectiveCervical cancer is one of the most common cancers worldwide, and immune function may impact disease progression. Serum markers may also be associated with diagnosis and progression. The aim of...

Exploratory study of association between blood immune markers and cognitive symptom severity in major depressive disorder: Stratification by body mass index status

BackgroundA subset of patients with Major Depressive Disorder (MDD) have shown differences relative to healthy controls in blood inflammatory and immune markers. Meanwhile, MDD and comorbid obesity appear to present with distinct biological and symptom characteristics, categorised as “atypical” or “immunometabolic” depression, although the relevant underlying biological mechanisms are still uncertain. Therefore, this exploratory study aimed to better characterise the relationship between peripheral blood immune markers and symptoms of MDD, as well as the extent to which body mass index (BMI) may alter this relationship. MethodsLinear regression analyses were performed between selected baseline characteristics including clinical scales and blood inflammatory markers in participants with MDD (n = 119) enrolled in the PREDDICT randomised controlled trial (RCT), using age, sex and BMI as covariates, and then stratified by BMI status. Specifically, the Montgomery–Åsberg Depression Rating Scale (MADRS) for symptom severity, Clinical Global Impression scale (CGI) for functional impairment, Oxford Depression Questionnaire (ODQ) for emotional blunting, and THINC integrated tool (THINC-it) for cognitive function were considered as clinical measures. ResultsThere was a significant association between basophil count and THINC-it Codebreaker mean response time (associated with complex attention, perceptual motor, executive function, and learning and memory abilities) in overweight individuals and with THINC-it Trails total response time (associated with executive function ability) in moderately obese individuals, when controlling for age, sex, and years of education. No correlation was found between any tested blood markers and MADRS, CGI or ODQ clinical measures, regardless of BMI. DiscussionAlthough the present study is exploratory, the results suggest that targeting of the immune system and of metabolic parameters might confer benefits, specifically in patients with high BMI and experiencing cognitive impairment associated with MDD. Trial registrationAustralian New Zealand Clinical Trials Registry (ANZCTR), ACTRN12617000527369p. Registered on 11 April 2017.

O9.3. CANNABIS CONSUMPTION INCREASES RISK OF PSYCHOSIS IN A SUBGROUP OF PATIENTS WITH HIGH PERIPHERAL BLOOD INFLAMMATION

BackgroundAssociations between cannabis use and psychotic outcomes are consistently reported. Increased innate immune markers have also been suggested as risk factors for psychosis; nevertheless, no study has ever tested whether augmented blood inflammation could be a possible biological mechanism underlying the association between cannabis use and psychosis. We investigated: i) which patterns of peripheral blood cytokines (innate and adaptive immune markers) would be associated with the strongest effect on odds of psychosis; and ii) whether the contribution of cannabis use (lifetime use: yes/no; frequency of use: non-users, less than daily use; daily use) on risk of psychosis would vary between subgroups with low- or high-inflammation.MethodsThe Schizophrenia and Other Psychoses Translational Research: Environment and Molecular Biology (STREAM) is an epidemiological and case-sibling-control study, conducted in Ribeirão Preto catchment area (São Paulo, Brazil) between April 2012 and March 2015, which integrates the international multicentre consortium EU-GEI. We recruited 153 first-episode psychosis patients and 256 community-based controls aged between 16–64 years. Participants answered the Cannabis Experience Questionnaire and plasma cytokines (IL-1β, IL-6, TNF-α, IFN-γ, IL-4, IL-10, TGF-β) were measured by Multiplex. We firstly investigated which patterns of peripheral blood innate and adaptive immune markers would contribute to the strongest effect on the odds of psychosis. To do that, the sample was divided into quartiles according to cytokine’s percentile distribution (reference group: minimum value – 25th percentile; lower group: 25th – 50th percentile; middle group: 50th – 75th percentile; and upper group: 75th percentile – maximum value). We next investigated whether the effects of the different patterns of cannabis use (lifetime and frequency of use) on the risk of psychosis would differ between subgroups classified as low- or high-inflammatory, using the median (50th percentile) of each cytokine as the cut-off value. All the binary logistic regression analyses were correct for the effects of confounders (gender, age, ethnicity, years of education, body mass index, tobacco smoking, and recreational drugs).ResultsMore than 60% of the patients were classified as high-inflammatory, whereas in the control group, around the same percentage was classified as low-inflammatory. After adjusting for confounders, we observed a dose-response relationship between the percentile’s distribution of IL-10, IL-6, TNF-α, TGF-β and risk of psychosis, with participants classified in the upper percentile having the highest odds ratio when compared with the reference group. The adjusted odds ratio (adj ORs) and 95% CIs range for each cytokine were the following: IL-10 from 4.68 (2.02–10.85) to 11.86 (5.01–28.11), IL-6 from 3.74 (1.61–8.69) to 9.62 (4.15–22.31); TNF-α from 2.18 (1.01–4.73) to 6.88 (3.12–15.17); TGF-β from 2.17 (1.01–4.67) to 3.20 (1.50–6.80). Lifetime cannabis use only increased risk of psychosis in the high-inflammatory subgroup (adj ORs, 95% CIs: IL10: 4.66, 1.62–13.39; IL-6: 2.75, 1.05–7.21). Daily use increased the risk of psychosis even further, and only in the high-inflammatory but not in the low-inflammatory subgroup (adj OR, 95% CIs: IL-10: 14.09, 2.26–87.93; TNF-α: 6.16, 1.28–29.74; IL-6: 4.68, 1.08–20.36), with the exception of TGF-β, for which the effects were seen in the low-subgroup (adj OR, 95% CI: 5.23, 1.17–23.42).DiscussionThe existence of distinct inflammatory profiles indicates possible biological predisposition facilitating immune activation. This would translate into a higher vulnerability to the effects of cannabis use, especially daily use, on risk of psychosis.

Immune profile differences between chronic GVHD and late acute GVHD: results of the ABLE/PBMTC 1202 studies

AbstractHuman graft-versus-host disease (GVHD) biology beyond 3 months after hematopoietic stem cell transplantation (HSCT) is complex. The Applied Biomarker in Late Effects of Childhood Cancer study (ABLE/PBMTC1202, NCT02067832) evaluated the immune profiles in chronic GVHD (cGVHD) and late acute GVHD (L-aGVHD). Peripheral blood immune cell and plasma markers were analyzed at day 100 post-HSCT and correlated with GVHD diagnosed according to the National Institutes of Health consensus criteria (NIH-CC) for cGVHD. Of 302 children enrolled, 241 were evaluable as L-aGVHD, cGVHD, active L-aGVHD or cGVHD, and no cGVHD/L-aGVHD. Significant marker differences, adjusted for major clinical factors, were defined as meeting all 3 criteria: receiver-operating characteristic area under the curve ≥0.60, P ≤ .05, and effect ratio ≥1.3 or ≤0.75. Patients with only distinctive features but determined as cGVHD by the adjudication committee (non-NIH-CC) had immune profiles similar to NIH-CC. Both cGVHD and L-aGVHD had decreased transitional B cells and increased cytolytic natural killer (NK) cells. cGVHD had additional abnormalities, with increased activated T cells, naive helper T (Th) and cytotoxic T cells, loss of CD56bright regulatory NK cells, and increased ST2 and soluble CD13. Active L-aGVHD before day 114 had additional abnormalities in naive Th, naive regulatory T (Treg) cell populations, and cytokines, and active cGVHD had an increase in PD-1− and a decrease in PD-1+ memory Treg cells. Unsupervised analysis appeared to show a progression of immune abnormalities from no cGVHD/L-aGVHD to L-aGVHD, with the most complex pattern in cGVHD. Comprehensive immune profiling will allow us to better understand how to minimize L-aGVHD and cGVHD. Further confirmation in adult and pediatric cohorts is needed.

The correlation of thyroid autoimmunity and peripheral and uterine immune status in women with recurrent miscarriage

ProblemThyroid autoimmunity (TAI), which is the most prevalent cause of thyroid dysfunction in women of reproductive age, is associated with increased risk of miscarriages and adverse pregnancy outcomes. However, the exact pathophysiology of TAI is still unknown. We aim at investigating the relationship between TAI and the peripheral and uterine immune markers in women with recurrent miscarriage (RM). Method of studyPeripheral blood and endometrial tissue samples were collected during mid-luteal phase of 242 RM women to evaluate the prevalence of TAI, the thyroid function, the percentages of peripheral blood and endometrial lymphocytes, the levels of peripheral blood T helper 1 (Th1) cytokine and natural killer (NK) cell cytotoxicity. ResultsThere was no relationship between TAI and peripheral immune parameters. However, the percentage of endometrial Regulatory T (Treg) cells was significantly higher in RM women who were thyroid antibody positive than in those who were antibody negative (p ＜ 0.05). ConclusionThyroid antibody positivity seems to be part of a more generalized immune dysfunction. The increased endometrial Treg cells in RM patients with TAI may ameliorate coincidental TAI during pregnancy by linked suppression and prevent the over-reactive status of the immune system.

IMMUNOLOGICAL CELULLAR-MOLECULAR MARKERS OF THE PERIPHERAL BLOOD OF А53Т MICE WITH GENETIC PREDISPOSITION TO PARKINSON’S DISEASE

The present experimental study aimed to find the most informative peripheral cellular-molecular immune markers, which can determine a risk of the development of Parkinson’s disease. The experiments were performed in transgenic mice of the A53T strain (2 months) characterized by an increased expression of alpha synuclein and genetically predisposed to Parkinson’s disease during aging. In comparison with the WT strain mice (control), A53T mice were found to have a reduced emotionality (increased horizontal motor activity and a significant decrease in defecation acts in the open field test) along with unchanged coordination and balance, tested using the Rotarod + hardware-software complex. These mice were also characterized by significant changes in the content of immune cell subpopulations in the peripheral blood - an increase in the percentage of CD3+T cells and CD3+4+T helper cells, a decrease in the content of CD19+B cells, with unaltered numbers of CD3+4+25+ 27-regulatory, CD19+25+B-regulatory cells and CD11b+115+monocytes. The percentage of T-regulatory cells expressing Toll-like receptors of the 2nd and 4th types (TLR2 and TLR4) was higher in A53T mice than in controls, while the number of cells expressing only TLR4 was reduced. The TLR2 expression did not differ between A53T and control mice. Analysis of the TLR2 and TLR4 expression on CD11b+115+monocytes has shown that the percentage of these cells with TLR4 was reduced in A53T mice compared to the control, while the content of cells with both TLR types did not depend on genotype. Proinflammatory cytokines (IL-6) prevailed over antiinflammatory (IL-10) in the supernatant of mononuclear blood cells of A53T mice suggesting the development of neuroinflammation.The study was supported by Russian Foundation of Basic Research (grant N18-015-00226 А).

Post-Radiotherapy Inflammation Predicts Recurrence and Mortality in Stage I-III Triple-Negative Breast Cancer

Recent studies suggest that a pro-inflammatory lymphopenic microenvironment associated with radiotherapy (RT) may contribute to recurrence of triple-negative breast cancer (TNBC). Furthermore, adiposity may exacerbate this pro-tumor inflammation. To study how RT affects the immune system in this high-risk cancer, we investigated the systemic inflammatory response to RT in patients with TNBC. We hypothesized that inflammation in a lymphopenic setting within one year after RT correlates with recurrence and mortality in stage I-III TNBC. We also hypothesized that obesity would intensify the relapse risk associated with inflammation. We performed a single-institutional retrospective cohort study of adult women treated with definitive RT for stage I-III TNBC between 1999 and 2012. Patients had a minimum follow-up of 5 years. Clinicopathologic characteristics and complete blood counts were recorded. Neutrophil:lymphocyte ratio (NLR), platelet:lymphocyte ratio (PLR), and monocyte:lymphocyte ratio (MLR) were calculated. Time-to-event analyses for recurrence and mortality were analyzed by Cox proportional-hazards regression. Confounders were adjusted using forward stepwise selection to avoid multicollinearity. Optimal inflammatory marker cutoffs from receiver operating characteristic curves were analyzed by log-rank after stratification on Kaplan-Meier plots. After a median follow-up of 6.9 years after RT, 110 patients with stage I (n=32, 29%), stage II (n=53, 48%) and stage III (n=25, 23%) TNBC were studied. We evaluated early (2 mo) and long term (8-12 mo) effects of RT on peripheral immune markers in relation to TNBC outcomes. Within 2 months of RT, elevated neutrophil count was associated with metastasis (Hazard ratio 1.25, p=0.04). Patients with absolute lymphocyte count (ALC) less than 0.55 K/μL (HR 3.12, p=0.04) or monocyte count above 0.5 K/μL (HR 2.67, p=0.03) had greater TNBC-specific mortality. PLR > 345 predicted reduced overall survival (HR 2.50, p=0.04), and patients with MLR > 0.9 had a greater risk of TNBC-specific mortality (HR 5.72, p=0.001). After adjustment, elevated NLR was associated with TNBC-specific mortality (HR 1.2, p=0.04), and high PLR predicted local recurrence (HR 1.01, p<0.05). Sustained lymphopenia 8-12 mo following RT (ALC < 1.16 K/μL) predicted mortality (HR 3.77, p=0.02). Finally, body mass index was an independent poor prognostic factor in each inflammatory model. Systemic inflammation and lymphopenia after RT may represent novel prognostic biomarkers associated with recurrence, metastasis, and mortality in stage I-III TNBC. Further studies evaluating RT immune effects are needed to validate this finding and develop treatment strategies.

The Association of Immune Markers with Cognitive Performance in South African HIV-Positive Patients.

Dysregulated expression of neuro-immune markers has previously been linked to HIV-associated neurocognitive impairment. We undertook an exploratory approach in a HIV clade-C cohort, investigating the association between eight immune markers and neurocognitive performance in 99 HIV+ and 51 HIV- participants. Markers were selected on preliminary and putative evidence of their link to key neuro-immune functions. Cognitive performance was established using a battery of tests sensitive to HIV-associated neurocognitive impairment, with domain-based scores utilized in analysis. The markers Thymidine phosphorylase (TYMP) and Neutrophil gelatinase-associated lipocalin (NGAL) were significantly higher while Matrix Metalloproteinase (MMP)9 was significantly lower in HIV+ participants. Our results further showed that in the HIV+ group, worse psychomotor processing speed was associated with higher TYMP and NGAL levels and worse motor function was associated with higher NGAL levels. Future studies should explore the underlying mechanisms of these markers in HIV-associated neurocognitive impairment. Graphical Abstract The association of peripheral immune markers with neurocognitive performance in South African HIV-positive patients.

Neuroinflammation and Schizophrenia.

There are longstanding, intriguing findings of immune dysfunction in schizophrenia. These findings span peripheral immune markers, especially cytokine abnormalities. This review describes recent genetic and immune marker studies and emergent treatment studies. Collectively, this provides a synthesis and current appraisal of the neuroimmune hypothesis of schizophrenia.

Peripheral immune cell markers in children with recurrent respiratory infections in the absence of primary immunodeficiency.

The immune system of a child has a degree of immaturity that is maintained until 6–7 years of age. Immaturity may be due to age-related functional disorders in the immune response. A healthy child can contract a series of infections which contribute to the maturation of the immune system during the pre-pubertal period. If repeated infections with prolonged or severe complications occur during childhood, the presence of an immunodeficiency should then be considered. Much more frequent than primary immunodeficiency are recurrent infections (frequently involving the upper respiratory tract), which are less severe and occur under the conditions of an immune system with no apparent major defects. A child can present with 4 to 8 episodes of respiratory infections within a year, during the first 5 years of its life. The average duration of infection is 8 days and up to 2 weeks; if the child presents with 3 episodes of acute infections over a period of 6 months, the respiratory infections are then considered recurrent. The aim of this study was to identify the immunological changes or deviations that cause this clinical syndrome in children. For this purpose, 30 children with recurrent respiratory infections and 10 healthy children were included. Immunoglobulin levels were examined and immunophenotyping was performed. We found that the serum immunoglobulin levels were in the normal range in 70% of the children. On the contrary, our data revealed changes in peripheral cell populations, the most important being the decrease in the T-cluster of differentiation (CD)8+ and total B cell percentages and the increase in the number of memory B cells. The data obtained herein indicated that the decrease in the number of total B cells was mainly due to the decrease in the number of naive IgD+ B cells. On the whole, the findings of this study indicate that recurrent respiratory infections may be associated with an altered cellular immune response. In such situations, the investigation of immunological parameters, such as T and B cell subtypes could complete the clinical diagnosis and guide the treatment strategy, thus increasing the quality of life of patients.

Correlation of immune-related adverse events with peripheral baseline immune markers and overall survival in patients with metastatic melanoma on ipilimumab and chemotherapy.

9561 Background: Very few predictive markers have been validated for immune-related adverse events (irAE), which are the number one reason for cessation of treatment and treatment-related deaths on checkpoint inhibitors. In a phase II trial of combined ipilimumab (ipi) with carboplatin/paclitaxel (C/P) (NCT01676649), we sought to determine baseline peripheral blood markers predictive of irAEs and to correlate these adverse with subsequent survival. Methods: Thirty patients with untreated unresectable/metastatic melanoma were treated with C (AUC = 6) and P (175mg/m2) every 3 weeks x 5 and Ipi (3mg/kg) every 3 weeks x 4. irAEs were graded according to the CTCAE v5.0. Median follow-up was 60 months. Baseline blood markers was assessed by a 37 multiplex cytokine-chemokine platform (Meso Scale Discovery) and multiparameter flow cytometry. Results: Grade 2 or higher irAE occurred in 11/30 of patients (4 colitis, 2 hepatitis, 2 hypophysitis, 3 rash). Median survival was 43.8 months in patients with irAE and 14.5 months for those without irAE (p = 0.001). Pts with irAE had lower baseline circulating levels of IL-6 (3.6 vs. 19.8 pg/mL, p = 0.049), TNF alpha (7.6 vs. 11.6 pg/mL, p = 0.003), CXCL9 (83.4 vs. 116.8 pg/mL, p = 0.042) and CCL3 (52.3 vs. 76.4 pg/mL, p = 0.012), but higher baseline circulating dendritic cells (DC) (4.9 vs. 2.9 % of total PBMC, p = 0.002) and a lower level of myeloid-derived suppressor cells (MDSC) (0.8 vs. 1.7 %, p = 0.049). There was no correlation between baseline B cell circulating numbers or differentiation and irAEs. Conclusions: Although results from previous studies of ipi monotherapy vary, our small study shows a highly significant correlation between irAEs and improved long term outcome for patients treated with ipi/C/P. Our exploratory analysis also identifies putative predictive immune and cytokine-chemokine markers of irAEs, which are associated with: 1) Antigen presentation dysregulation (high DC cells) and lack of adequate auto-immune suppression (low MDSC), as also seen in classic autoimmune diseases; and 2) A low inflammatory baseline signature (low TNF, IL-6, CCL3, CXCL9) consistent with possible immune exhaustion and reduced lymphocytic homeostatic fitness. Our combined markers depict a dysregulated immune landscape favorable to the expansion of self-reactive immune cells under CTLA-4 blockade. Our results are hypothesis generating and require further evaluation in a larger group of patients, including PD-1 treated cohorts. Clinical trial information: NCT01676649.

MRI investigation of immune dysregulation in schizophrenia.

Immune dysregulation has been suggested as a pathophysiological pathway in schizophrenia. MRI could aid in investigating this pathological process in more detail. This review aims to provide an overview of recent MRI findings of immune dysregulation in schizophrenia. In addition, we discuss the potential of more recently developed MRI techniques. Subtle and indirect signs of immune dysregulation are detected in schizophrenia, particularly in the early stages of the disease. In recently diagnosed schizophrenia patients, findings based on conventional and novel MRI techniques suggest increased glutamate levels and increases in extracellular free water that may be associated with glial activation. As the disease progresses, reductions in white matter, myelin and grey matter seem present, that may point to neurodegeneration. These MRI findings support the notion of immune dysregulation in early psychosis, which may result in neurodegeneration in later stages. However, these findings are not unequivocal. Therefore, we recommend multimodal MRI studies to further elucidate the role of different immune-related processes in schizophrenia. Future studies should consider inter-individual variability in immune dysregulation, for example, by focusing on recent-onset psychosis and/or by using stratification based on central or peripheral immune markers.

Stability of peripheral blood immune markers in patients with asthma

BackgroundAsthma is a complex disease with variable course. Efforts to identify biomarkers to predict asthma severity, the course of disease and response to treatment have not been very successful so far. We have previous suggested that PAR-2 and CRTh2 expression on specific peripheral blood cell subtypes may be biomarkers of asthma severity. We reasoned that parameters that remain stable when asthma symptoms are controlled would be the most appropriate to evaluate for their utility to predict loss of asthma control and/or severity of the disease.MethodsNineteen stable asthmatics were recruited from the University of Alberta Asthma clinic and followed in clinic every 3 months for a total of 4 visits. Patients had spirometry and completed the ACQ questionnaire in every visit. Blood was drawn in every visit and analyzed for a number of immune parameters by flow cytometry. These parameters included PAR-2 and CRTh2 expression on monocyte subgroups and T lymphocytes respectively, as well as numbers of eosinophils, innate lymphoid type-2 cells (ILC2) and dendritic cells. Within person stability of immune and physiological parameters was calculated using the intraclass correlation (ICC) using R version 3.4.0.ResultsFEV1 (% predicted), FEV1/FVC ratio, ACQ5 and ACQ7 did not differ significantly over the 4 visits, as would be expected for patients with stable asthma. Peripheral blood eosinophil numbers by Kimura stain and by flow cytometry showed ICC scores of 0.44 and 0.52 respectively, indicating moderate stability. The % of ILC2 cells in peripheral blood also showed moderate stability [ICC score of 0.45 (0.14–0.67)]. The stability for all other immune parameters was poor.ConclusionAmong the peripheral blood immune parameters we studied, only numbers of eosinophils and ILC2 in peripheral blood were moderately stable over a year in stable asthmatics. Further studies are required to understand the reasons for the variability of the other cell types.

Specific T-cell activation in peripheral blood and cerebrospinal fluid in central disorders of hypersomnolence

An autoimmune-mediated process in the pathophysiology of narcolepsy type 1 (NT1) is highly suspicious, if this pathomechanism is transferable to other types of central disorders of hypersomnolence (CDH), is still controversial. The association of NT1 with HLA class II system implicates a T-cell-mediated autoimmunity, in which helper CD4+ T-cells and cytotoxic CD8+ T-cells may be pathogenic. This study aimed to identify specific immune profiles in peripheral blood (PB) and cerebrospinal fluid (CSF) in different types of CDH. Forty-three people with polysomnographically confirmed CDH (24 idiopathic hypersomnia [IH], 12 NT1, and 7 NT2) were compared with 24 healthy controls (HC). PB and CSF were analyzed with multiparameter flow cytometry to distinguish between subclasses of peripheral and intrathecal immune cells and specific surface markers of T-cells. The overall proportion of helper CD4+ T-cells and cytotoxic CD8+ T-cells in PB and CSF did not differ between the patients and HC. Activated HLA-DR+ CD4+ T-cells and HLA-DR+ CD8+ T-cells in PB and CSF both in NT1, NT2 and IH were significantly increased compared with HC. A significant correlation of HLA-DR+ CD4+- and HLA-DR+ CD8+ T-cells with higher amounts of excessive daytime sleepiness was found in the NT1 and IH groups, indicating an association of activated T-cells in the central nervous system with an increase in sleepiness. These findings provide further evidence of a T-cell-mediated autoimmunity not only in NT1, but also in NT2 and IH. Moreover, the identification of activated cytotoxic CD8+ T-cells further supports the evidence of T-cell-mediated neuronal damage, which has previously been suggested in NT1.