Peripheral Immune Cell Phenotypes Research Articles

Associations between immune cell traits and autoimmune thyroid diseases: a bidirectional two-sample mendelian randomization study.

Autoimmune thyroid diseases (AITDs), mainly including Graves' disease (GD) and Hashimoto's thyroiditis (HT), are common autoimmune disorders characterized by abnormal immune responses targeting the thyroid gland. We conducted a bidirectional two-sample MR analysis using the largest dataset of peripheral immune cell phenotypes from Sardinia, and the AITD dataset from the 10th round of the FinnGen and the UK Biobank project. Instrumental variables (IVs) were rigorously selected based on the three assumptions of MR and analyzed using the Wald ratio, inverse-variance weighted (IVW), MR-Egger, and weighted median methods. Additionally, sensitivity analyses were performed using Cochrane's Q, the Egger intercept, the MR-PRESSO, and the leave-one-out (LOO) method to ensure the robustness of the results. The Steiger test was utilized to identify and exclude potential reverse causation. The results showed that 3, 3, and 11 immune cell phenotypes were significantly associated with the risk of AITD. In GD, the proportion of naive CD4-CD8- (DN) T cells in T cells and the proportion of terminally differentiated CD4+T cells in T cells showed the strongest inducing and protective effects, respectively. In HT, lymphocyte count and CD45 on CD4+T cells showed the strongest inducing and protective effects, respectively. In autoimmune hypothyroidism, CD127 CD8+T cell count and terminally differentiated DN T cell count exhibited the strongest inducing and protective effects, respectively. Through MR analysis, our study provides direct genetic evidence of the impact of immune cell traits on AITD risk and lays the groundwork for potential therapeutic and diagnostic target discovery.

Investigating causal relationships between extensive peripheral immune cell phenotypes and preeclampsia: A bi-directional Mendelian randomization analysis.

Preeclampsia, a multifaceted condition during pregnancy characterized by hypertension and organ dysfunction, poses significant risks to both maternal and fetal health. This study aims to investigate the bidirectional causal relationship between peripheral immune cell phenotypes and preeclampsia using a two-sample Mendelian randomization (MR) approach. Genetic data from two sizable cohorts were utilized: 3757 individuals from Sardinia, providing information on 731 immune traits, and 200929 Finnish adult females, encompassing 6663 preeclampsia cases. Single-nucleotide polymorphisms served as instrumental variables. The MR analyses employed the inverse variance-weighted (IVW) method as the primary tool, supplemented by MR-Egger, weighted median, and weighted mode methods to enhance reliability and address potential heterogeneity and horizontal pleiotropy. Among the 731 immune cell phenotypes studied, 18 displayed a suggestive positive association (IVW p<.05) with heightened preeclampsia risk, while 20 exhibited a suggestive negative association linked to reduced risk. Following false discovery rate (FDR) adjustment, four immune phenotypes showed significant associations with decreased preeclampsia risk: CD27 on CD24+ CD27+ B cells (B-cell panel) (odds ratio [OR]=0.927, PFDR=0.061), CD33+ HLA DR+ CD14- absolute count (OR=0.963, PFDR=0.061), CD80 on plasmacytoid dendritic cells (OR=0.923, PFDR=0.061); and CD80 on CD62L+ plasmacytoid dendritic cells (OR=0.923, PFDR=0.061). In the reverse-direction MR analysis, no significant causal effects of preeclampsia on immune cell phenotypes were observed. This study provides quantifiable evidence linking specific immune cell phenotypes to the risk of developing preeclampsia. This novel understanding of the immunological aspects underlying preeclampsia's pathogenesis could lead to innovative therapeutic strategies centered on immune modulation.

Inflammation in the pathogenesis of neurodegenerative diseases

INTRODUCTION: Neurodegenerative diseases are common chronic disorders that are associated with progressive damage to the nervous system. The role of the immune system in the development of neurodegenerative diseases was confirmed by data on the activation of microglia, the presence of an imbalance in the composition and phenotype of peripheral immune cells, and the presence of humoral immunity disorders and intestinal microbiota dysbiosis in patients with this pathology. DISCUSSION: Inflammation has been observed to play a key role in the pathogenesis of diseases associated with progressive damage to the nervous system. The article analyzes the mechanisms in the development of “subclinical” chronic inflammation that leads to development of old-age-related diseases, including neurodegenerative pathology. At least three groups of factors associated with old age play a role in the formation of a proinflammatory status: mitochondrial dysfunction, development of an age-related proinflammatory status of the immune system, and chronic stress. Mitochondrial dysfunction is primarily associated with disruption of mitophagy processes: failure of quality control mechanisms as a result of disruption of mitophagy processes leads to the accumulation of terminally damaged mitochondria, which become a threat to cell survival. Inadequate removal of damaged mitochondria leads to hyperactivation of inflammatory signaling pathways and subsequently to chronic systemic inflammation and the development of inflammatory diseases. A high level of deletions in the mitochondrial genetic apparatus that accumulates with age inevitably leads to increased formation of reactive oxygen species, which in turn are assumed as one of the leading activators of the cytosolic NLRP3 protein, the primary component of inflammasomes. Increased inflammasome formation eventually leads to caspase-1-dependent production of proinflammatory interleukins. Age-related inflammatory imbalance is associated with the fact that the immune system, the main protective mechanism characterized by the inflammatory response, copes with constant antigenic attacks. However, over time, upon reaching a certain threshold, the reaction of the immune system becomes excessive, characterized by increased production of coagulation factors, proinflammatory cytokines, acute phase proteins of inflammation, prostaglandins, and leukotrienes. CONCLUSIONS: Immunological changes that develop during chronic (long-term) stress are the result of a disruption of the homeostatic connection between the neuroendocrine and immune systems, leading to the formation of an inflammatory background that complements the “proinflammatory status” that develops as a result of age-related changes in the immune system and disruption of mitophagy mechanisms.

NEUROINFLAMMATION AND IMMUNE DYSFUNCTION IN THE PATHOGENESIS OF PARKINSON’S DISEASE

Parkinson’s disease (PD) is a chronic progressive neurodegenerative disorder, characterized by dopaminergic neuronal loss, aggregation of alpha-synuclein and severe motor impairments. This review summarizes current data on the key role of neuroinflammation and immune dysfunction in neurodegeneration and disease development. We examine clinical and experimental evidence for microglia activation, participation of Toll-like receptors in this process, a wide range of chemokines and pro- and anti-inflammatory cytokines in the course of the disease. Emphasis is also made on the impact of the innate and adaptive immune responses in the mechanisms of systemic inflammation both in the brain and in the periphery. The involvement of brain-infiltrating immune cells and their subpopulations in the process of neuroinflammation and neurodegeneration, changes in the composition and phenotype of peripheral immune cells and their functional characteristics are discussed. Analysis of immune cell subsets and their ratios reveals subtle PD-specific changes in cellular populations that can be used as reliable biomarkers for diagnosis, prognosis of the disease course, and development of new approaches for anti-inflammatory and targeted therapies in PD.

Immune landscape of patients with metastatic non-clear cell renal cell carcinoma (nccRCC) treated with atezolizumab plus bevacizumab.

4535 Background: The treatment of metastatic nccRCC remains an area of unmet clinical need. A multicenter phase II trial of atezolizumab/bevacizumab in patients with advanced nccRCC or any RCC type with ≥ 20% sarcomatoid differentiation (NCT02724878) demonstrated clinical activity of these agents, with objective response rates of 50% in patients with sarcomatoid clear-cell RCC (sccRCC) and 26% in patients with nccRCC. We aim to understand the intratumoral and circulating factors that impact immunotherapy response in this population. Methods: We collected blood samples prior to therapy and on-treatment (following 2 cycles of therapy) and quantified levels of plasma soluble factors (cytokines and growth factors) using a fluorescent bead array platform. We used high dimensional flow cytometry on peripheral blood mononuclear cells to analyze the composition and phenotype of peripheral immune cells. Immunohistochemistry and immunofluorescence were performed on available formalin-fixed, paraffin-embedded tumor tissue samples (archival or on-study biopsy) collected prior to the start of therapy. We assessed relationships between biomarkers and outcomes using pairwise Wilcoxon rank-sum test and log-rank tests, and univariate Cox regression models. Results: We collected blood samples from 60 patients with paired tumor samples from 38 patients. Baseline circulating inflammatory cytokines MIP-1b, IL-1, MCP-1, IL-6, and IL-13 were highly correlated with one another, forming an “inflammatory module” that was increased in IMDC-poor risk patients and associated with worse progression-free survival (PFS) (p = 0.028). At baseline, elevated circulating VEGF-A was associated with a lack of response (p=0.03) and worse PFS (p=0.021). Whereas a larger increase in on-treatment levels of circulating VEGF-A was associated with clinical benefit as defined by Braun et al. (Nat Med. 2020) (p=0.01) and improved overall survival (p=0.006). Among peripheral immune cell populations, an on-treatment decrease in circulating PD-L1+ T cells was associated with improved outcomes: reductions in CD4+ PD-L1+ (HR:0.62[0.49-0.91], p=0.016) and CD8+ PD-L1+ T cells (HR:0.59[0.39-0.87], p=0.009) correlated with improved PFS. Within the tumor, a higher percentage of terminally exhausted (PD-1+, TIM-3+ and/or LAG-3+) CD8+ T cells at baseline was associated with worse PFS (p=0.028). Conclusions: Among patients with advanced nccRCC or sccRCC, a baseline high systemic inflammatory state and high circulating VEGF-A are associated with worse outcomes after treatment with atezolizumab and bevacizumab. High levels of intratumor terminally exhausted CD8+ T cells were associated with worse PFS. These results highlight the importance of an integrative approach to explore biomarkers of response in advanced variant histology RCC which may inform future therapeutic approaches.

RNA expression levels from peripheral immune cells, a minimally invasive liquid biopsy source to predict response to therapy, survival and immune-related adverse events in patients with triple negative breast cancer enrolled in the GeparNuevo trial.

1011 Background: The impact of immune checkpoint therapy on the tumor microenvironment including tumor-infiltrating immune cells is well described. However, little is known about the circulating immune repertoire and its association with treatment outcome. Hence, we set out to investigate the RNA phenotype of peripheral immune cells before and during treatment of patients enrolled in the GeparNuevo trial (Loibl S et al. Annals Oncol 2022). Methods: The GeparNuevo trial investigated the outcome after neoadjuvant nabP-EC-chemotherapy in combination with the anti-PD-L1 immune checkpoint inhibitor durvalumab versus placebo in patients with non-metastatic triple negative breast cancer. Blood was collected before therapy (baseline), after window, before epirubicin/cyclophosphamide and at end of treatment. RNA from circulating leucocytes of 117 patients was extracted and analyzed using a custom NanoString nCounter CodeSet. Expression of 290 immune-related genes was quantified. The association of RNA expression and signatures with outcome parameters like pathologic complete response (pCR), distant disease-free survival (DDFS), invasive disease-free survival (iDFS), overall survival (OS), and immune-related adverse events (irAEs) were investigated. Results: Immune cell type scores representing macrophages and neutrophils significantly increased during treatment, while B cell, T and Th1 cell scores decreased (p &lt; 0.0001, respectively) regardless of treatment arm. Multivariate logistic respectively multivariate Cox regression analysis revealed a significant association of each baseline DPP4 and MYC gene expression with pCR, DDFS, iDFS, and OS in patients. CDK2, F5 and HLA-DR mRNA expressions were associated with the presence of irAEs. The signature score for TNFR2 non-canonical NF-kB pathway, which is known for its protective capacity, was inversely associated with irAEs in the durvalumab arm (OR = 0.454, 95% CI 0.231-0.892, p = 0.0220). Multiple immune-related signatures at baseline were associated with tumor mutational burden. Conclusions: Our study indicates the importance of the peripheral immune phenotype for treatment response and survival. This association between RNA expression levels of circulating immune cells and outcome seems to be not only relevant for patients receiving immune checkpoint therapy, but also for those under standard chemotherapy alone. Clinical trial information: NCT02685059 .

CTIM-06. EVALUATING THE ASSOCIATION BETWEEN PERIPHERAL BLOOD IMMUNOLOGIC RESPONSE AND THERAPEUTIC RESPONSE TO IMMUNE CHECKPOINT INHIBITION IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA AND GLIOSARCOMA

Abstract Immune checkpoint inhibition (ICI) has failed to demonstrate significant efficacy in glioblastoma. With the underlying hypothesis that generation of an immune response in peripheral is necessary for a brain tumor response, we are enrolling patients with newly diagnosed glioblastoma on an ICI immunotherapy clinical trial with longitudinal monitoring of immune function. The purpose of this work is to improve patient selectivity for response to ICI treatment by identifying peripheral immunologic response via immunophenotyping and functional analyses. Currently, 10 of a planned 48 patients have been treated with combination nivolumab and ipilimumab (NCI-21-C-0015). We analyzed blood samples of the first two patients, from pretreatment through cycle 5 of combination ICI to confirm methods used in this clinical trial. Longitudinal evaluation of immunologic response using comprehensive flow cytometric analysis and an in vitro T cell stimulation paradigm with nivolumab and ipilimumab supplementation, serving as an ex vivo predictor of immune response, are reported. Immunophenotyping via flow cytometry successfully documented patients’ peripheral immune cell phenotypes, and ELISpot and in vitro stimulation assays successfully measured patients’ immune cell functional capacitance. Both patients analyzed have shown increased proportions of effector/memory phenotypes within peripheral T cells, and a decrease in peripheral lymphocyte/monocyte ratio during treatment, potentially indicating lymphocyte sequestration in bone marrow or recruitment to the tumor microenvironment. ELISpot analysis documented interferon-γ production capability of T cell is maintained during treatment. Moreover, preliminary analysis of patients’ T cell proliferative capacity in PBMC utilizing in vitro anti-CD3 stimulation indicated T cells become increased in proliferative capability during treatment. These findings support the feasibility of longitudinal assessments, demonstrating that immunologic responsiveness and functionality can be detected with these blood monitoring strategies. Additional patients’ samples will be tested to allow confirmation of trends in immunologic response, and correlations with patient outcomes will be reported at time of presentation.

Metformin increases natural killer cell functions in head and neck squamous cell carcinoma through CXCL1 inhibition

BackgroundMetformin slows tumor growth and progression in vitro, and in combination with chemoradiotherapy, resulted in high overall survival in patients with head and neck cancer squamous cell carcinoma (HNSCC) in...

Malnutrition and immune cell subsets in children undergoing kidney transplantation.

Malnutrition, including obesity and undernutrition, among children is increasing in prevalence and is common among children on renal replacement therapy. The effect of malnutrition on the pre-transplant immune system and how the pediatric immune system responds to the insult of both immunosuppression and allotransplantation is unknown. We examined the relationship of nutritional status with post-transplant outcomes and characterized the peripheral immune cell phenotypes of children from the Immune Development of Pediatric Transplant (IMPACT) study. Ninety-eight patients from the IMPACT study were classified as having obesity, undernutrition, or normal nutrition-based pre-transplant measurements. Incidence of infectious and alloimmune outcomes at 1-year post-transplantation was compared between nutritional groups using Gray's test and Fine-Gray subdistribution hazards model. Event-free survival was estimated by Kaplan-Meier method and compared between groups. Differences in immune cell subsets between nutritional groups over time were determined using generalized estimating equations accounting for the correlation between repeated measurements. We did not observe that nutritional status was associated with infectious or alloimmune events or event-free survival post-transplant. We demonstrated that children with obesity had distinct T-and B-cell signatures relative to those with undernutrition and normal nutrition, even when controlling for immunosuppression. Children with obesity had a lower frequency of CD8 Tnaive cells 9-month post-transplant (p < .001), a higher frequency of CD4 CD57 + PD1- T cells, and lower frequencies of CD57-PD1+ CD8 and CD57-PD1- CD8 T cells at 12-month transplant (p < .05 for all). Children with obesity have distinct immunophenotypes that may influence the tailoring of immunosuppression.

Abstract 1266: Circulating immune biomarkers in peripheral blood reflect the effect of a CD200 immune checkpoint targeted immunotherapy in pet dogs with high-grade glioma

Abstract The extent to which immune cell phenotypes in the peripheral blood reflect intratumoral immune activity prior to and early in cancer immunotherapy is unclear. Here we studied the population dynamics of immune cells and immune phenotypic changes, using clinical blood samples and a multicolor flow cytometry analysis. These samples were serially obtained from a cohort of high-grade glioma canine patients enrolled in a trial with an immunotherapy that targets the CD200/CD200R immunological synapse. This therapy consists of an alternative checkpoint inhibitor peptide (CD200AR-L) that modulates the CD200 immune checkpoint, currently being used in an adult phase I safety trial for recurrent glioblastoma trial (NCT04642937) and a canine high-grade spontaneous glioma trial (U01CA224160-01). We found evidence of a strong effect of the therapy on peripheral immune cells in responder versus nonresponder dogs. Upon initiation of therapy, immune effector cell proliferation increased in responsive patients, whereas in nonresponders immune cell populations either didn’t change significantly or an increase in immunosuppressive phenotypes was observed. Cell populations such as MDSC, regulatory T cells and exhausted T cells were predominantly higher in nonresponder dogs. These data showed that peripheral immune cell phenotypes were linked to the outcome of the immunotherapy, thus dogs with better immune cell profiles, including increased cytotoxic differentiation, had a better prognosis and longer overall survival rates. Taken together, these results suggest that variation in patient responsiveness can be explained by differences in peripheral immune cell proliferation and differentiation soon after the initiation of immunotherapy. Citation Format: Francisco W. Puerta Martinez, Sathya Schnell, Susan Arnold, Elizabeth G. Pluhar, Michael Olin. Circulating immune biomarkers in peripheral blood reflect the effect of a CD200 immune checkpoint targeted immunotherapy in pet dogs with high-grade glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1266.

Tumor immune-gene expression profiles and peripheral immune phenotypes associated with clinical outcomes of locally advanced pancreatic cancer following FOLFIRINOX

BackgroundA comprehensive analysis of peripheral immune cell phenotypes and tumor immune-gene expression profiles in locally advanced pancreatic cancer patients treated with neoadjuvant chemotherapy in a phase II clinical trial was carried out.MethodsPatients were treated with neoadjuvant modified folinic acid, fluorouracil, irinotecan hydrochloride, oxaliplatin (mFOLFIRINOX) followed by surgery and adjuvant gemcitabine at the Asan Medical Center. Correlations between survival outcomes and baseline peripheral immune cells and their changes during preoperative chemotherapy were analyzed. Patients who had surgery were divided into two groups according to achievement of disease-free survival >10 months (achieved versus failed). Differential expression and pathway analysis of immune-related genes were carried out using the Nanostring platform, and immune cells within the tumor microenvironment were compared by immunohistochemistry.ResultsForty-four patients were treated in the phase II clinical trial. Higher baseline CD14+CD11c+HLA-DR+ monocytes (P = 0.044) and lower Foxp3+CD4+ T cells (P = 0.02) were associated with poor progression-free survival of neoadjuvant mFOLFIRINOX. During the preoperative chemotherapy, PD-1 T cells significantly decreased (P = 0.0110). Differential expression and pathway analysis of immune-genes from the resected tumor after neoadjuvant treatment revealed transforming growth factor-β pathway enrichment and higher expression of MARCO (adjusted P < 0.05) associated with early recurrence. Enrichment of the Th1 pathway and higher peritumoral CD8+ T cells (P = 0.0103) were associated with durable disease-free survival from surgery (>10 months) following neoadjuvant mFOLFIRINOX.ConclusionsOur results identify potential immune biomarkers for locally advanced pancreatic cancer and provide insights into pancreatic cancer immunity.

Circulating immune cell phenotype dynamics reflect the effect of a CD200 immune checkpoint targeted immunotherapy in pet dogs with high-grade glioma

Abstract The extent to which immune cell phenotypes in the peripheral blood reflect intratumoral immune activity prior to and early in cancer immunotherapy is unclear. Here we studied the population dynamics of immune cells and immune phenotypic changes, using clinical blood samples and a multicolor flow cytometry analysis. These samples were serially obtained from a cohort of high-grade glioma canine patients enrolled in a trial with an immunotherapy that targets the CD200/CD200R immunological synapse. This therapy consists of an alternative checkpoint inhibitor peptide (CD200AR-L) that modulates the CD200 immune checkpoint, currently being used in an adult phase I safety trial for recurrent glioblastoma trial (NCT04642937) and a canine high-grade spontaneous glioma trial (U01CA224160-01). We found evidence of a strong effect of the therapy on peripheral immune cells in responder versus nonresponder dogs. Upon initiation of therapy, immune effector cell proliferation increased in responsive patients, whereas in nonresponders immune cell populations either didn’t change significantly or an increase in immunosuppressive phenotypes was observed. Cell populations such as MDSC, regulatory T cells and exhausted T cells were predominantly higher in nonresponder dogs. These data showed that peripheral immune cell phenotypes were linked to the outcome of the immunotherapy, thus dogs with better immune cell profiles, including increased cytotoxic differentiation, had a better prognosis and longer overall survival rates. Taken together, these results suggest that variation in patient responsiveness can be explained by differences in peripheral immune cell proliferation and differentiation soon after the initiation of immunotherapy.

Phenotype of Innate Immune Cells in Uveitis Associated with Axial Spondyloarthritis- and Juvenile Idiopathic Arthritis-associated Uveitis

ABSTRACT Purpose: To analyze circulating immune cells in patients with anterior uveitis (AU) associated to axial spondyloarthritis (SpA), or juvenile idiopathic arthritis (JIA). Methods: Venous blood samples were collected from healthy controls (n = 16), and either SpA (n = 19) or JIA (n = 23) patients with associated anterior uveitis (AU) during active flare, or after ≥3 months of inactivity. Frequencies of CD56+, MHC-I+, and S100A9+ monocytes, CCR7+ dendritic cells, CD56+dim natural killer (NK) cells and CD3+CD56bright T-cells were analyzed via flow cytometry. Serum S100A8/A9 levels were determined via ELISA. Results: SpA patients showed a reduced frequency of CD56+dim NK cells during uveitis activity, a constitutively activated monocyte phenotype, and elevated S100A8/A9 serum levels. In contrast, JIAU patients showed elevated frequencies of CD56+ monocytes and CCR7+ DC. Conclusion: Phenotype of peripheral immune cells differ between patients, probably contributing to different courses of acute onset AU in SpA and insidious onset AU in JIAU patients. Abbreviations: AU: anterior uveitis, AR: arthritis, JIA: juvenile idiopathic arthritis, SpA: axial spondyloarthritis

Distinctive association of peripheral immune cell phenotypes with capillaroscopic microvascular patterns in systemic sclerosis.

The pathological changes in SSc include immune system dysregulation and microvascular damage. However, the association of immune cell phenotype heterogeneity and microvascular abnormalities is unclear. The aim of this study is to elucidate this association in SSc. Peripheral blood mononuclear cells obtained from 150 SSc patients were used for comprehensive flow cytometric analysis based on the Human Immunology Project. Hierarchical cluster analysis was used to classify SSc patients into subgroups and their association with microvascular abnormalities, as assessed by nailfold videocapillaroscopy (i.e. 'early', 'active' and 'late' patterns), was analysed. The proportions of activated CD4+ T cells, T cells re-expressing CD45RA, activated Th1 and Th17 cells and IgD-CD27- B cells were higher in SSc patients than in healthy individuals. Hierarchical cluster analysis stratified SSc patients into three groups: patients with few immune abnormalities (fewer abnormalities group), patients with high proportions of activated T and Treg cells (Treg-dominant group) and patients with high proportions of Tfh and plasmablasts (Tfh-dominant group). Age and disease duration were comparable among the groups. On the other hand, microvascular abnormalities, especially the 'late' nailfold videocapillaroscopy pattern, correlated with internal organ involvement. Among the groups stratified according to immune cell phenotype, the progression to the 'late' nailfold videocapillaroscopy pattern was more frequent in the Tfh-dominant group. Our study confirmed the presence of immunophenotypic abnormalities in SSc. Immunological abnormalities were not uniform but rather limited to subpopulations, particularly the Tfh-dominant group, where they were highly associated with microvascular abnormalities and organ involvement.

Differential effects of biological DMARDs on peripheral immune cell phenotypes in patients with rheumatoid arthritis.

The aim of this study was to assess the therapeutic effects of biological DMARDs (bDMARDs) on the diversity of immune cell phenotypes in peripheral blood of patients with RA. Peripheral immune cell phenotypes were determined in 108 RA patients who were non-responsive to conventional DMARDs and 33 healthy control subjects by eight-colour flow cytometry. We also examined the correlation between the phenotypes and clinical findings and assessed the effects of 24-week treatment with bDMARDs. The proportions of T follicular helper (Tfh) cells, IgD- CD27- double negative B cells and plasmacytoid dendritic cells (pDCs) were higher in patients with active RA than in healthy control. The percentages of memory T cells, Th17 and Tfh cells correlated with autoantibody titres, whereas that of plasmablasts correlated with disease activity scores. Treatment with TNF inhibitors reduced the proportion of pDCs, while tocilizumab reduced the proportion of double-negative B cells but increased naïve and activated Treg cells. Abatacept treatment resulted in marked decrease in the proportion of activated Tfh but slightly reduced Th17 and Treg cells. The proportion of Tfh cells was an independent and significant predictor of the response to abatacept therapy. Molecular targeted therapies induced different changes in different immune cell phenotypes. Among the phenotypes, Tfh cells seem a potential target for abatacept. Immunophenotypic analysis might be useful for prediction of the response to bDMARDs.

Evidence of inflammatory system involvement in Parkinson's disease.

Parkinson's disease (PD) is a chronic neurodegenerative disease underpinned by both genetic and environmental etiologic factors. Recent findings suggest that inflammation may be a pathogenic factor in the onset and progression of both familial and sporadic PD. Understanding the precise role of inflammatory factors in PD will likely lead to understanding of how the disease arises. In vivo evidence for inflammation in PD includes dysregulated molecular mediators such as cytokines, complement system and its receptors, resident microglial activation, peripheral immune cells invasion, and altered composition and phenotype of peripheral immune cells. The growing awareness of these factors has prompted novel approaches to modulate the immune system, although it remains whether these approaches can be used in humans. Influences of ageing and differential exposure to environmental agents suggest potential host-pathogen specific pathophysiologic factors. There is a clear need for research to further unravel the pathophysiologic role of immunity in PD, with the potential of developing new therapeutic targets for this debilitating condition.

Immune cells after prolonged Natalizumab therapy: implications for effectiveness and safety

Previous studies on Natalizumab (NAT) have shown increased circulation of most white blood cells (WBC) in multiple sclerosis (MS) patients shortly after its introduction. To describe peripheral immune cell phenotypes after more than 2 years of continuous NAT therapy and test for associations with clinical response to therapy. Peripheral immune cell subsets were analyzed in 44 NAT-MS patients receiving NAT for over 24 months, and in 22 NAT-free control-MS patients. NAT-MS patients displayed significantly higher numbers of all WBC when compared with controls. B lymphocytes exhibited a more pronounced increase when compared with CD4+, CD8+ and NK T-cells (P = 0.011). CD4/CD8 ratio was significantly decreased in NAT-MS patients (P = 0.018) and showed no correlation with the number of NAT doses. The reduced CD4/CD8 ratio was attributable to the 'EDSS improvement' group only, irrespective of age, sex and disease severity. The study suggests that there is no desensitization effect after prolonged NAT exposure. A reduced CD4/CD8 ratio was associated with long-term response to therapy; thus, those patients who most benefitted from the drug might be at greater risk for opportunistic infections like progressive multifocal leucoencephalopathy (PML). We provide implications for future research for the CD4/CD8 ratio as a possible contributor to the recently developed risk stratification scheme for PML.

The role of innate and adaptive immunity in Parkinson's disease.

In recent years, inflammation has become implicated as a major pathogenic factor in the onset and progression of Parkinson's disease. Understanding the precise role for inflammation in PD will likely lead to understanding of how sporadic disease arises. In vivo evidence for inflammation in PD includes microglial activation, increased expression of inflammatory genes in the periphery and in the central nervous system (CNS), infiltration of peripheral immune cells into the CNS, and altered composition and phenotype of peripheral immune cells. These findings are recapitulated in various animal models of PD and are reviewed herein. Furthermore, we examine the potential relevance of PD-linked genetic mutations to altered immune function and the extent to which environmental exposures that recapitulate these phenotypes, which may lead to sporadic PD through similar mechanisms. Given the implications of immune system involvement on disease progression, we conclude by reviewing the evidence supporting the potential efficacy of immunomodulatory therapies in PD prevention or treatment. There is a clear need for additional research to clarify the role of immunity and inflammation in this chronic, neurodegenerative disease.

Nutritional status influences peripheral immune cell phenotypes in healthy men in rural Pakistan

Immune status is influenced by malnutrition, but how this factor interacts in developing countries and whether these differences are similar to those determined in industrialized countries, is unclear. To establish whether malnutrition-associated immune profiles in a developing country are similar to those in industrialized countries we analyzed peripheral blood immune cell phenotypes by polychromatic flow cytometry in 50 young and 50 elderly subjects. Data on anthropometrics and diet were collected through interviews. Plasma samples were analyzed for common clinical chemistry variables. Subjects in 4 BMI categories differed in their immune parameters demonstrating influence of nutritional status on immunity. This was greater within the young group and affected the CD4 subset more profoundly than the CD8 subset. No nutrition-associated differences were seen in B or NK cells. CD8+ cells as a percentage of CD3+ T cells were positively associated with plasma CRP levels but not other factors. We conclude that there are differences in the immune signatures of obese, overweight and underweight versus normal-weight young and elderly, which seem broadly similar to the more extensively-documented state reported in industrialized countries, despite the marked societal, nutritional and many other differences.

Aging affects the proportions of T and B cells in a group of elderly men in a developing country—a pilot study from Pakistan

Immune status is different in the elderly and the young, but whether age-associated differences are similar in developing and industrialized countries is unclear. To approach this question, peripheral blood immune cell phenotypes were analyzed by polychromatic flow cytometry in 50 young and 50 elderly men in a pilot study in a rural area of Pakistan. As a group, the elderly had a significantly lower CD4:CD8 ratio, a lower percentage of CD8+ naïve T cells, and significantly higher percentage of late-differentiated memory cells than the young. No age-associated differences were seen in B cells or NK cells. CD8+ cells as a percentage of CD3+ T cells were positively associated with plasma CRP levels but not other factors. We conclude that there are differences between the peripheral immune cell phenotypes of young and elderly Pakistani men and that these seem broadly similar to those more extensively documented in industrialized countries, despite the marked societal, nutritional, and many other differences in these populations.