Imbalance Of Immune Regulation Research Articles

Potential mechanism of CARD16 protein action and susceptibility to sepsis in the elderly infected population: Through transcriptome analysis of blood

As global aging accelerates, the super-elderly population is at higher risk of infectious diseases, especially sepsis, a condition that may be associated with declining immune system function and abnormal inflammatory responses. The aim of this study was to investigate the role of CARD16 protein in sepsis susceptibility in the elderly population and its potential mechanism, and to reveal the expression characteristics of CARD16-related genes through blood transcriptomic analysis. Transcriptome sequencing was conducted on peripheral blood samples obtained from patients suffering from senile sepsis, along with samples from a healthy elderly control group. To examine the differences in gene expression, bioinformatics techniques were employed to compare the expression levels of CARD16-related genes between the two groups. Additionally, a comprehensive analysis was performed on the downstream inflammatory pathways and cytokines that are regulated by CARD16.The findings from the transcriptome analysis indicated that the expression of CARD16 was markedly upregulated in the cohort of patients experiencing hypersenile sepsis. This upregulation was associated with an increase in a variety of pro-inflammatory factors. Further network analysis suggested that CARD16 may potentiate the inflammatory response by modulating the NF-κB signaling pathway, which could consequently heighten the patients' vulnerability to sepsis.In comparison to the healthy elderly control group, the levels of anti-inflammatory genes in the super-elderly cohort were found to be significantly diminished. This observation points to a notable imbalance in immune regulation, further emphasizing the altered immune response in individuals with senile sepsis.

A Versatile Chitosan-Based Hydrogel Accelerates Infected Wound Healing via Bacterial Elimination, Antioxidation, Immunoregulation, and Angiogenesis.

Drug-resistant bacterial infection of cutaneous wounds causes great harm to the human body. These infections are characterized by a microenvironment with recalcitrant bacterial infections, persistent oxidative stress, imbalance of immune regulation, and suboptimal angiogenesis. Treatment strategies available to date are incapable of handling the healing dynamics of infected wounds. A Schiff base and borate ester cross-linked hydrogel, based on phenylboronic acid-grafted chitosan (CS-PBA), dibenzaldehyde-grafted poly(ethylene glycol), and tannic acid (TA), is fabricated in the present study. Customized phenylboronic acid-modified zinc oxide nanoparticles (ZnO) are embedded in the hydrogel prior to gelation. The CPP@ZnO-P-TA hydrogel effectively eliminates methicillin-resistant Staphylococcus aureus (MRSA) due to the pH-responsive release of Zn2+ and TA. Killing is achieved via membrane damage, adenosine triphosphate reduction, leakage of intracellular components, and hydrolysis of bacterial o-nitrophenyl-β-d-galactopyranoside. The CPP@ZnO-P-TA hydrogel is capable of scavenging reactive oxygen and nitrogen species, alleviating oxidative stress, and stimulating M2 polarization of macrophages. The released Zn2+ and TA also induce neovascularization via the PI3K/Akt pathway. The CPP@ZnO-P-TA hydrogel improves tissue regeneration in vivo by alleviating inflammatory responses, stimulating angiogenesis, and facilitating collagen deposition. These findings suggest that this versatile hydrogel possesses therapeutic potential for the treatment of MRSA-infected cutaneous wounds.

B cell metabolism in autoimmune diseases: signaling pathways and interventions.

Autoimmune diseases are heterogeneous disorders believed to stem from the immune system's inability to distinguish between auto- and foreign- antigens. B lymphocytes serve a crucial role in humoral immunity as they generate antibodies and present antigens. Dysregulation of B cell function induce the onset of autoimmune disorders by generating autoantibodies and pro-inflammatory cytokines, resulting in an imbalance in immune regulation. New research in immunometabolism shows that cellular metabolism plays an essential role in controlling B lymphocytes immune reactions by providing the energy and substrates for B lymphocytes activation, differentiation, and function. However, dysregulated immunometabolism lead to autoimmune diseases by disrupting self-tolerance mechanisms. This review summarizes the latest research on metabolic reprogramming of B lymphocytes in autoimmune diseases, identifying crucial pathways and regulatory factors. Moreover, we consider the potential of metabolic interventions as a promising therapeutic strategy. Understanding the metabolic mechanisms of B cells brings us closer to developing novel therapies for autoimmune disorders.

The effect of omega-3 fatty acids supplementation on inflammatory biomarkers in subjects with migraine: a randomized, double-blind, placebo-controlled trial

Objective Imbalances in immune regulation are important features of migraine pathophysiology. In line with this, the current study investigated the efficacy of omega-3 fatty acids supplementation on inflammatory and anti-inflammatory markers in patients with migraines. Materials and Methods This randomized, double-blind, placebo-controlled trial consisted of 40 patients that were prone to experiencing episodic migraines. For two months, participants were randomized into one group that received omega-3 supplementation (n= 20), 600 mg of EPA and 300 mg of DHA, twice daily) or another group that received a placebo (n= 20). Transforming growth factor β (TGF-β), interleukin (IL)-4, interferon-gamma (IFN-γ), and interleukin (IL)-17 serum levels were assessed using enzyme-linked immunosorbent assay methods at baseline and following the intervention. The current study was registered on ClinicalTrials.gov with the registration number NCT02532023. Results After two months of intervention, the administration of omega-3 fatty acids resulted in a significant rise in the concentrations of anti-inflammatory cytokine IL-4 (p=0.010) as well as a significant reduction in concentrations of pro-inflammatory cytokine IFN-γ (p=0.001) compared with the placebo. However, no significant changes were observed in serum TGF-β and IL-17 levels. Discussion Our findings indicated consumption of omega-3 fatty acids may have a potentially beneficial response on the inflammatory immune response in patients with migraines. Larger trials are needed to corroborate these findings.

Molecular regulatory mechanism of LILRB4 in the immune response.

Immune diseases are caused by the imbalance of immune regulation. This imbalance is regulated by many factors, both negative and positive. Leukocyte immunoglobulin-like receptor B4 (LILRB4) is a member of leukocyte immunoglobulin-like receptors (LILRs). LILRs are expressed constitutively on the surface of multiple immune cells which associate with membrane adaptors to signal through multi- ple cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIMs) or immunoreceptor tyro-sine-based activation motifs (ITAMs). Through ITIM, LILRB4 could recruit the src homology domain type-2-containing tyrosine phosphatase 1 or 2 (SHP-1 or SHP-2) into the cell membrane. In addition, many factors can induce the expression of LILRB4, such as vitamin D, interferon and so on. Studies have demonstrated that LILRB4 had a negative regulatory role in various of immune diseases. The present review intends to expound the structure and function of LILRB4, as well as its regulators and receptors in the immune cells, so as to provide a theoretical basis for immune disease therapy.

Different Roles of Dendritic Cells for Chronic Rhinosinusitis Treatment According to Phenotype.

Dendritic cells (DCs) are antigen-presenting cells derived from the bone marrow that play an important role in the association between the innate and adaptive immune responses. The onset and development of chronic rhinosinusitis (CRS) involve a serious imbalance in immune regulation and mechanical dysfunction caused by an abnormal remodeling process. Recent studies have shown that an increase in DCs in CRS and their function of shaping the nasal mucosal immune response may play an important role in the pathogenesis of CRS. In this review, we discuss DC subsets in mice and humans, as well as the function of DCs in the nasal sinus mucosa. In addition, the mechanism by which DCs can be used as targets for therapeutic intervention for CRS and potential future research directions are also discussed.

Associations between vaginal flora, MIP-1α, IL-17A, and clinical pregnancy rate in AIH.

To investigate how asymptomatic bacterial imbalance affects the clinical pregnancy rate after artificial insemination with the husband's semen (AIH). This study included married heterosexual couples who underwent AIH. According to the follow-up results, participants were divided into the pregnancy and non-pregnancy groups. Based on the first 10 pair participants in each group with vaginal flora bacterial 16S rRNA sequencing results, six semen samples received bacterial-sperm mixed test. Moreover, 34 cytokines were detected in the peripheral blood sera of the first three pairs by high-throughput Luminex, which were verified in vaginal secretions, cervical mucus, and blood sera from the first 200 pairs by ELISA. The results of the 16S sequencing of vaginal secretions showed that compared with the pregnant group, the non-pregnant group had a significantly increased bacterial species diversity, which was mainly manifested by a decrease in Lactobacillus crispatus and an increase in Prevotella bivia. When Prevotella bivia or Lactobacillus crispatus were mixed with sperms, the sperm motility was decreased (p<.05). The vaginal posterior fornix secretions, cervical mucus, and peripheral blood sera of the non-pregnant group showed decreased levels of MIP-1α and increased levels of IL-17A (p<.05). The imbalance of vaginal flora leading to the increase of Prevotella bivia and the decrease of Lactobacillus crispatus may cause an imbalance of immune regulation. Low expression of MIP-1α and high expression of IL-17A were associated with reduced clinical pregnancy rate in AIH.

The emerging role of epigenetics and gut microbiota in Vogt-Koyanagi-Harada syndrome.

Vogt-Koyanagi-Harada (VKH) syndrome is an autoimmune disorder characterized often by acute diffuse uveitis, also known as idiopathic uveoencephalitis. The associated complications can potentially affect multiple systems throughout the body, including eyes, ears, skin and nervous system. Although the pathogenesis of VKH syndrome remains unclear, it has been established that the various genetic factors, epigenetic factors and the imbalance in immune regulation can significantly contribute to the development of this disease. In addition, the experimental autoimmune uveitis (EAU) has been commonly used to further explore the pathogenesis of the disease. Herein, in this review article, we discuss about the major research advances made in understanding of the different epigenetic factors and gut microbes involved in the pathogenesis of VKH syndrome as well as EAU. The information discussed can help to better understand the pathogenesis of VKH syndrome, and thereby might provide a basis for finding novel molecular targets and innovative treatment strategies in the future.

Long-term biodiversity intervention shapes health-associated commensal microbiota among urban day-care children.

In modern urban environments children have a high incidence of inflammatory disorders, including allergies, asthma, and type1 diabetes. The underlying cause of these disorders, according to the biodiversity hypothesis, is an imbalance in immune regulation caused by a weak interaction with environmental microbes. In this 2-year study, we analyzed bacterial community shifts in the soil surface in day-care centers and commensal bacteria inhabiting the mouth, skin, and gut of children. We compared two different day-care environments: standard urban day-care centers and intervention day-care centers. Yards in the latter were amended with biodiverse forest floor vegetation and sod at the beginning of the study. Intervention caused a long-standing increase in the relative abundance of nonpathogenic environmental mycobacteria in the surface soils. Treatment-specific shifts became evident in the community composition of Gammaproteobacteria, Negativicutes, and Bacilli, which jointly accounted for almost 40 and 50% of the taxa on the intervention day-care children's skin and in saliva, respectively. In the year-one skin swabs, richness of Alpha-, Beta-, and Gammaproteobacteria was higher, and the relative abundance of potentially pathogenic bacteria, including Haemophilus parainfluenzae, Streptococcus sp., and Veillonella sp., was lower among children in intervention day-care centers compared with children in standard day-care centers. In the gut, the relative abundance of Clostridium sensu stricto decreased, particularly among the intervention children. This study shows that a 2-year biodiversity intervention shapes human commensal microbiota, including taxa that have been associated with immune regulation. Results indicate that intervention enriched commensal microbiota and suppressed the potentially pathogenic bacteria on the skin. We recommend future studies that expand intervention strategies to immune response and eventually the incidence of immune-mediated diseases.

Adjunct therapy with probiotics for chronic urticaria in children: randomised placebo-controlled trial

BackgroundsChronic urticaria is a common disorder of the skin, characterised by recurrent skin wheals and angioedema. Recent reports have shown that altered diversity and composition of the gut microbiota may lead to imbalances in immune regulation, a causal factor in the occurrence of chronic urticaria.ObjectiveThis study aimed to evaluate the efficacy of the Yimingjia® probiotic formula in the adjuvant treatment of chronic urticaria in children.MethodsWe enrolled 206 children with confirmed diagnoses of chronic urticaria and randomly assigned them to the treatment (n = 104) or placebo group (n = 102). The children in each group were treated with desloratadine dry suspension, and those in the treatment group also received Yimingjia®. Clinical efficacy was evaluated at 1, 2 and 4 weeks.ResultsClinical symptom scores did not differ significantly at weeks 1 and 2 (p > 0.05), but at 4 weeks, wheal size and attack frequency were significantly reduced in the treatment group (p = 0.049 and 0.03, respectively). The overall response rate (significant improvement + complete response) significantly differed between the treatment (80.8%) and placebo groups (62.5%) (χ2 = 4.20, p = 0.04).ConclusionAdjunct therapy with Yimingjia® was safe and effective at 4 weeks in the treatment of chronic urticaria in children. The study was registered under trial number NCT03328897.

Thrombospondin 1 in Metabolic Diseases.

The thrombospondin family comprises of five multifunctional glycoproteins, whose best-studied member is thrombospondin 1 (TSP1). This matricellular protein is a potent antiangiogenic agent that inhibits endothelial migration and proliferation, and induces endothelial apoptosis. Studies have demonstrated a regulatory role of TSP1 in cell migration and in activation of the latent transforming growth factor beta 1 (TGFβ1). These functions of TSP1 translate into its broad modulation of immune processes. Further, imbalances in immune regulation have been increasingly linked to pathological conditions such as obesity and diabetes mellitus. While most studies in the past have focused on the role of TSP1 in cancer and inflammation, recently published data have revealed new insights about the role of TSP1 in physiological and metabolic disorders. Here, we highlight recent findings that associate TSP1 and its receptors to obesity, diabetes, and cardiovascular diseases. TSP1 regulates nitric oxide, activates latent TGFβ1, and interacts with receptors CD36 and CD47, to play an important role in cell metabolism. Thus, TSP1 and its major receptors may be considered a potential therapeutic target for metabolic diseases.

Serum levels of soluble programmed death-1 (sPD-1) and soluble programmed death ligand 1(sPD-L1) in systemic lupus erythematosus: Association with activity and severity.

The programmed cell death-1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway is an important host immunosuppression mechanism. Soluble PD-1 (sPD-1) and PD-L1 (sPD-L1) expression regulates co-inhibitory signals in autoimmune disorders. Here, we evaluated whether serum sPD-1 and sPD-L1 are involved in immune dysfunction and assessed its relationship with SLE. Blood samples were obtained from 130 patients with SLE and 44 healthy controls. Serum sPD-1 and sPD-L1 were tested by enzyme-linked immunosorbent assay (ELISA). Relevant immune parameters were analysed. Both serum sPD-1 and sPD-L1 were significantly higher in the SLE patients than in the controls. A series of severe disease clinical manifestations and laboratory features such as presence of decreased complement component 3, complement component 4 and SLEDAI >8 were associated with elevated sPD-1 and sPD-L1. Our study suggests that abnormal sPD-1 and sPD-L1 expression may be involved in the imbalance of immune regulation in SLE.

Study on the correlation among dysbacteriosis, imbalance of cytokine and the formation of intrauterine adhesion.

Intrauterine adhesion (IUA) is one of the most important causes of female infertility, while iatrogenic endometrial injury is the main, but not the entire, cause of IUA. The microorganisms of the female reproductive tract play an important role in its health and disease. The imbalance of immune regulation caused by the imbalance of reproductive tract dysbacteriosis may be an important link in the formation mechanism of uterine cavity adhesion. We prospectively enrolled 30 patients diagnosed with IUA and 30 women with a history of intrauterine surgery, but without IUA, as control subjects. All participants were diagnosed with hysteroscopy while two swabs-one being leucorrhea drawn from the middle of the vagina and the other being cervical mucus drawn from the cervical canal-were taken. The bacterial load and community were identified by 16S rDNA quantitative polymerase chain reaction and pyrosequencing. Immunocytokines in serum were quantitatively detected by human T-helper cytokine kit. The correlation between Th cytokines and microorganisms in IUA and non-IUA groups was analyzed. Compared with non-IUA participants at the phylum level, patients with IUA had a significantly higher percentage of firmicutes in most samples, while the diversity of bacteria was significantly decreased. Some species that were members of vaginal and cervical canal bacterial phyla, including Euryarchaeota, Acidobacteria, Chlamydiae, Chlorobi, Planctomycetes and TM6 (Dependentiae), almost disappeared. The quantity in serum of IUA patients of classical proinflammatory cytokines IL-6 and TNF-γ, released from immune cells, also known as profibrotic cytokines, were significantly higher than that of the non-IUA women in our study (P<0.05). IUA is characterized by an increased bacterial burden, decreased diversity of bacterial communities in the vagina/cervical canal, and increased immune cytokines of pro-fibrosis, which may predict new and more effective therapeutic schemes for the treatment of IUA.

The effect of sex on immune responses to a homocitrullinated peptide in the DR4-transgenic mouse model of Rheumatoid Arthritis

Rheumatoid Arthritis (RA) is more common and severe in women compared to men. Both women and men with RA express autoantibodies to post-translationally modified antigens, including citrullinated and homocitrullinated proteins or peptides. These autoantibodies are strongly linked with the HLA-DR4 gene. The objective of this study was to determine sex differences in immune responses to homocitrullinated antigens. We used a humanized animal model of RA, DR4-transgenic mice and immunized them with a homocitrullinated peptide called HomoCitJED. Immune responses in these mice were measured for splenocyte proliferation by tritiated thymidine incorporation, serum autoantibody production by ELISA and cytokine levels by multiplex. We found that T cell and antibody responses to homocitrullinated antigens were similar in male and female mice. However, we found sex differences in serum cytokine profiles with female mice having higher ratio of IL-1α to IL-5, suggesting imbalances in immune regulation. This is the first study to report that immune responses to homocitrullinated antigens can be differentiated by sex.

Immune Homeostasis: Effects of Chinese Herbal Formulae and Herb-Derived Compounds on Allergic Asthma in Different Experimental Models.

Allergic asthma is thought to arise from an imbalance of immune regulation, which is characterized by the production of large quantities of IgE antibodies by B cells and a decrease of the interferon-γ/interleukin-4 (Th1/Th2) ratio. Certain immunomodulatory components and Chinese herbal formulae have been used in traditional herbal medicine for thousands of years. However, there are few studies performing evidence-based Chinese medicine (CM) research on the mechanisms and effificacy of these drugs in allergic asthma. This review aims to explore the roles of Chinese herbal formulae and herb-derived compounds in experimental research models of allergic asthma. We screened published modern CM research results on the experimental effects of Chinese herbal formulae and herb-derived bioactive compounds for allergic asthma and their possible underlying mechanisms in English language articles from the PubMed and the Google Scholar databases with the keywords allergic asthma, experimental model and Chinese herbal medicine. We found 22 Chinese herb species and 31 herb-derived anti-asthmatic compounds as well as 12 Chinese herbal formulae which showed a reduction of airway hyperresponsiveness, allergen-specifific immunoglobulin E, inflflammatory cell infifiltration and a regulation of Th1 and Th2 cytokines in vivo, in vitro and ex vivo, respectively. Chinese herbal formulae and herbderived bioactive compounds exhibit immunomodulatory, anti-inflflammatory and anti-asthma activities in different experimental models and their various mechanisms of action are being investigated in modern CM research with genomics, proteomics and metabolomics technologies, which will lead to a new era in the development of new drug discovery for allergic asthma in CM.

Correction: Definition of the Nature and Hapten Threshold of the β-Lactam Antigen Required for T Cell Activation In Vitro and in Patients.

Covalent modification of protein by drugs may disrupt self-tolerance, leading to lymphocyte activation. Until now, determination of the threshold required for this process has not been possible. Therefore, we performed quantitative mass spectrometric analyses to define the epitopes formed in tolerant and hypersensitive patients taking the β-lactam antibiotic piperacillin and the threshold required for T cell activation. A hydrolyzed piperacillin hapten was detected on four lysine residues of human serum albumin (HSA) isolated from tolerant patients. The level of modified Lys541 ranged from 2.6 to 4.8%. Analysis of plasma from hypersensitive patients revealed the same pattern and levels of modification 1-10 d after the commencement of therapy. Piperacillin-responsive skin-homing CD4+ clones expressing an array of Vβ receptors were activated in a dose-, time-, and processing-dependent manner; analysis of incubation medium revealed that 2.6% of Lys541 in HSA was modified when T cells were activated. Piperacillin-HSA conjugates that had levels and epitopes identical to those detected in patients were shown to selectively stimulate additional CD4+ clones, which expressed a more restricted Vβ repertoire. To conclude, the levels of piperacillin-HSA modification that activated T cells are equivalent to the ones formed in hypersensitive and tolerant patients, which indicates that threshold levels of drug Ag are formed in all patients. Thus, the propensity to develop hypersensitivity is dependent on other factors, such as the presence of T cells within an individual's repertoire that can be activated with the β-lactam hapten and/or an imbalance in immune regulation.

Different expression patterns and clinical significance of mAxl and sAxl in systemic lupus erythematosus

Axl is one of the TAM family members that downregulates activated immune responses to maintain immune homeostasis. We analyzed the expression and clinical relevance of Axl on the surface of CD14+ monocytes/macrophages (mAxl, membrane Axl) and in the plasma (sAxl, soluble Axl) from patients with systemic lupus erythematosus (SLE). Compared to healthy subjects, the concentrations of sAxl were significantly elevated in plasma from SLE patients, while the mAxl expression on CD14+ monocytes/macrophages from SLE patients was significantly downregulated. A series of severe disease clinical manifestations and laboratory features such as presence of autoantibodies, 24-hour proteinuria excretion or SLEDAI ≥10 were associated with decreased mAxl expression on monocytes/macrophages but elevated sAxl levels in plasma. The plasma level of Gas6, the main ligand of Axl, was slightly decreased in SLE patients, and was negatively correlated with anti-dsDNA antibodies and C-reactive protein. SLE patients with SLEDAI ≥10 showed significantly lower Gas6 levels. Our study suggests that abnormal mAxl and sAxl expression may be involved in the imbalance of immune regulation in SLE.

IRAK4 and TLR3 Sequence Variants may Alter Breast Cancer Risk among African-American Women

Mounting evidence suggests that imbalances in immune regulation contribute to cell transformation. Women of African descent are an understudied group at high risk for developing aggressive breast cancer (BrCa). Therefore, we examined the role of 16 innate immune single nucleotide polymorphisms (SNPs) in relation to BrCa susceptibility among 174 African-American women in Atlanta, GA, USA. SNPs were examined in germ-line DNA collected from 102 BrCa patients and 72 women with benign nodules using SNPstream methodology. Inheritance of the TLR3 rs10025405 GG genotype was associated with an 82% decrease in BrCa risk. In contrast, individuals who possessed at least one IRAK4 rs4251545 T allele had a 1.68- to 4.99-fold increase in the risk of developing BrCa relative to those with the referent genotype (OR = 4.99; 95% CI = 1.00, 25.00; p = 0.0605). However, the IRAK4 rs4251545 locus was only significant under the additive genetic model (p trend = 0.0406). In silico predictions suggest IRAK4 rs4251545 SNP falls within a transcription enhancer/silencer region of the gene and codes for an Ala428Thr amino acid change. This missense mutation introduces a potential phosphorylation site in the extreme carboxy terminus (XCT) of the IRAK4 kinase domain. Preliminary molecular modeling predicts that this SNP stabilizes two alpha helices within the XCT on the surface of the IRAK4 kinase domain and increases the size of the groove between them. Our in silico results, combined with previous reports noting the presence of IRAK4 and XCT fragments in mouse and human serum, suggest the possibility that the XCT subdomain of IRAK4 possesses biological function. These findings require further evaluation and validation in larger populations, additional molecular modeling as well as functional studies to explore the role of IRAK4 and its XCT in cell transformation and innate immunity.

PD-L1 gene expression in Japanese lung cancer patients

An imbalance in immune regulation affects tumor-specific T-cell immunity in the cancer microenvironment and reshapes tumor progression and metastasis. Blockade of interactions of immune function mediates anti-tumor activity in preclinical models. In the present study, we investigated programmed cell death 1 ligand 1 (PD-L1) mRNA expression by real-time polymerase chain reaction (RT-PCR) using a LightCycler in surgically treated non-small cell lung cancer (NSCLC) cases. This study included 123 surgically removed NSCLC cases for mRNA level analyses. The PD-L1/β-actin mRNA levels showed no marked difference in lung cancer (131.398±421.596) and adjacent normal lung tissues (78.182±254092, P=0.1482). The tumor/normal (T/N) ratio of PD-L1/β-actin mRNA levels was more than 2 in 49 cases and more than 1 in 63 cases. No difference was found in the T/N ratio of PD-L1/β actin mRNA levels among factors inlcuding gender, age, smoking status and pathological subtypes. The T/N ratio of PD-L1/β actin mRNA levels was markedly higher in pathological T4 cases (15.811±36.883) compared to T1 cases (3.492±8.494, P=0.0235). However, the PD-L1 mRNA status did not correlate with lymph node metastasis status. Thus, PD-L1 may drive tumor invasion, while providing a candidate for blockade of its function as a strategy to antagonize the progression process in NSCLC.

Bone involvement in clusters of autoimmune diseases: Just a complication?

Bone loss, described in individual groups of patients with Type 1 diabetes (T1D), autoimmune thyroid disease (ATD) or celiac disease (CD) is usually viewed as a complication of these diseases. There is increasing evidence that alterations in the immune system may directly affect bone mass. Clustering of autoimmune diseases in the same individual might predispose to higher risk of osteopenia due to imbalance in immune regulation. The aim of this study was to evaluate bone involvement in clusters of the most common autoimmune diseases (T1D, ATD and CD) in children.The study was performed at a tertiary care center for the care of pediatric diabetes. One-hundred-two patients with T1D alone or associated with ATD and/or CD were studied; 13 patients had cluster of three autoimmune diseases. Amplitude-dependent speed of sound (AD-SoS) was measured by phalangeal quantitative ultrasound and expressed as standard deviation score (SDS). AD-SoS SDS < −2 was considered indicative of osteopenia.Osteopenia was equally distributed among children with T1D alone (8.1%), T1D associated with ATD (7.7%) or CD (10.3%), while it was 53.8% in patients presenting with three autoimmune diseases. Poor compliance to gluten-free diet increased osteopenia to 18.8% in patients with T1D and CD and 80% in patients with three autoimmune disorders. No difference among groups was found with regard to gluco-metabolic control, calcium metabolism, thyroid function.In conclusion bone impairment in multiple autoimmune diseases might be considered not only a complication due to endocrine or nutritional mechanisms, but also a consequence of an immunoregulatory imbalance. Alterations of homeostatic mechanisms might explain an imbalance of osteoclast activity leading to osteopenia.