Psoriasis is a chronic, immune-mediated, inflammatory disease that is pathogenically driven by proinflammatory cytokines. This article reviews the immunologic role of interleukin (IL)-17, the major effector cytokine in the pathogenesis of psoriatic disease, along with the rationale for targeting the IL-17 cytokine family (IL-17A, IL-17F, and IL-17 receptor A) in the treatment of psoriasis and psoriatic arthritis. Emerging evidence indicates that major sources of IL-17A in patients with psoriatic disease are mast cells, γδ T cells, αβ T cells, and innate lymphoid cells in lesional skin and synovial fluid. Within the skin and joints, IL-17A acts on cellular targets, including keratinocytes, neutrophils, endothelial cells, fibroblasts, osteoclasts, chondrocytes, and osteoblasts, to stimulate production of various antimicrobial peptides, chemokines, and proinflammatory and proliferative cytokines, which, in turn, promote tissue inflammation and bone remodeling. The critical importance of the IL-23/IL-17A axis to the pathogenesis of psoriatic disease has resulted in many new biologic treatments targeting these cytokines. These biologics dramatically improve skin and joint symptoms in patients with moderate-to-severe psoriasis and psoriatic arthritis.
T. Boonpiyathad, Z. Sözener, P. Satitsuksanoa
et al.
Asthma is a chronic airway disease, which affects more than 300 million people. The pathogenesis of asthma exhibits marked heterogeneity with many phenotypes defining visible characteristics and endotypes defining molecular mechanisms. With the evolution of novel biological therapies, patients, who do not-respond to conventional asthma therapy require novel biologic medications, such as anti-IgE, anti-IL-5 and anti-IL4/IL13 to control asthma symptoms. It is increasingly important for physicians to understand immunopathology of asthma and to characterize asthma phenotypes. Asthma is associated with immune system activation, airway hyperresponsiveness (AHR), epithelial cell activation, mucus overproduction and airway remodeling. Both innate and adaptive immunity play roles in immunologic mechanisms of asthma. Type 2 asthma with eosinophilia is a common phenotype in asthma. It occurs with and without visible allergy. The type 2 endotype comprises; T helper type 2 (Th2) cells, type 2 innate lymphoid cells (ILC2), IgE-secreting B cells and eosinophils. Eosinophilic nonallergic asthma is ILC2 predominated, which produces IL-5 to recruit eosinophil into the mucosal airway. The second major subgroup of asthma is non-type 2 asthma, which contains heterogeneous group of endoypes and phenotypes, such as exercise-induced asthma, obesity induced asthma, etc. Neutrophilic asthma is not induced by allergens but can be induced by infections, cigarette smoke and pollution. IL-17 which is produced by Th17 cells and type 3 ILCs, can stimulate neutrophilic airway inflammation. Macrophages, dendritic cells and NKT cells are all capable of producing cytokines that are known to contribute in allergic and nonallergic asthma. Bronchial epithelial cell activation and release of cytokines, such as IL-33, IL-25 and TSLP play a major role in asthma. Especially, allergens or environmental exposure to toxic agents, such as pollutants, diesel exhaust, detergents may affect the epithelial barrier leading to asthma development. In this review, we focus on the immunologic mechanism of heterogenous asthma phenotypes.
Background Crucial roles of hematologic and immunologic responses in progression of coronavirus disease 2019 (COVID-19) remain largely unclear. Objective We sought to address the dynamic changes in hematologic and immunologic biomarkers and their associations with severity and outcomes of COVID-19. Methods A retrospective study including 548 patients with COVID-19 with clarified outcome (discharged or deceased) from a national cohort in China was performed. Cross-sectional and longitudinal variations were compared and the associations with different severity and outcomes were analyzed. Results On admission, the counts of lymphocytes, T-cell subsets, eosinophils, and platelets decreased markedly, especially in severe/critical and fatal patients. Increased neutrophil count and neutrophils-to-lymphocytes ratio were predominant in severe/critical cases or nonsurvivors. During hospitalization, eosinophils, lymphocytes, and platelets showed an increasing trend in survivors, but maintained lower levels or dropped significantly afterwards in nonsurvivors. Nonsurvivors kept a high level or showed an upward trend for neutrophils, IL-6, procalcitonin, D-dimer, amyloid A protein, and C-reactive protein, which were kept stable or showed a downward trend in survivors. Positive correlation between CD8+ T-cell and lymphocytes count was found in survivors but not in nonsurvivors. A multivariate Cox regression model suggested that restored levels of lymphocytes, eosinophils, and platelets could serve as predictors for recovery, whereas progressive increases in neutrophils, basophils, and IL-6 were associated with fatal outcome. Conclusions Hematologic and immunologic impairment showed a significantly different profile between survivors and nonsurvivors in patients with COVID-19 with different severity. The longitudinal variations in these biomarkers could serve to predict recovery or fatal outcome.
Nitric oxide (NO) is a short-lived gas molecule which has been studied for its role as a signaling molecule in the vasculature and later, in a broader view, as a cellular messenger in many other biological processes such as immunity and inflammation, cell survival, apoptosis, and aging. Fractional exhaled nitric oxide (FeNO) is a convenient, easy-to-obtain, and non-invasive method for assessing active, mainly Th2-driven, airway inflammation, which is sensitive to treatment with standard anti-inflammatory therapy. Consequently, FeNO serves as a valued tool to aid the diagnosis and monitoring of several asthma phenotypes. More recently, FeNO has been evaluated in several other respiratory and/or immunological conditions, including allergic rhinitis, chronic rhinosinusitis with/without nasal polyps, atopic dermatitis, eosinophilic esophagitis, and food allergy. In this review, we aim to provide an extensive overview of the current state of knowledge about FeNO as a biomarker in type 2 inflammation, outlining past and recent data on the application of its measurement in patients affected by a broad variety of atopic/allergic disorders.
Lesia Semenova, Yingfan Wang, Shane Falcinelli
et al.
Understanding the interplay between the HIV reservoir and the host immune system may yield insights into HIV persistence during antiretroviral therapy (ART) and inform strategies for a cure. Here, we applied machine learning (ML) approaches to cross-sectional high-parameter HIV reservoir and immunology data in order to characterize host–reservoir associations and generate new hypotheses about HIV reservoir biology. High-dimensional immunophenotyping, quantification of HIV-specific T cell responses, and measurement of genetically intact and total HIV proviral DNA frequencies were performed on peripheral blood samples from 115 people with HIV (PWH) on long-term ART. Analysis demonstrated that both intact and total proviral DNA frequencies were positively correlated with T cell activation and exhaustion. Years of ART and select bifunctional HIV-specific CD4 T cell responses were negatively correlated with the percentage of intact proviruses. A leave-one-covariate-out inference approach identified specific HIV reservoir and clinical–demographic parameters, such as age and biological sex, that were particularly important in predicting immunophenotypes. Overall, immune parameters were more strongly associated with total HIV proviral frequencies than intact proviral frequencies. Uniquely, however, expression of the IL-7 receptor alpha chain (CD127) on CD4 T cells was more strongly correlated with the intact reservoir. Unsupervised dimension reduction analysis identified two main clusters of PWH with distinct immune and reservoir characteristics. Using reservoir correlates identified in these initial analyses, decision tree methods were employed to visualize relationships among multiple immune and clinical–demographic parameters and the HIV reservoir. Finally, using random splits of our data as training-test sets, ML algorithms predicted with approximately 70% accuracy whether a given participant had qualitatively high or low levels of total or intact HIV DNA . The techniques described here may be useful for assessing global patterns within the increasingly high-dimensional data used in HIV reservoir and other studies of complex biology.
IntroductionGut microbiota (GM) influences the occurrence and development of pancreatic cancer (PC), potentially through the involvement of inflammatory cytokines (IC) and immune cells (IM). We aimed to investigate the causal impact of the gut microbiota (GM) on pancreatic cancer (PC) and identify potential IC and IM mediators.MethodsThe summary statistics data from whole-genome association studies of gut microbiota, immune cells, inflammatory cytokines, and four types of pancreatic tumors (MNP: Malignant neoplasm of pancreas; BNP: Benign neoplasm of pancreas; ADCP: Adenocarcinoma and ductal carcinoma of pancreas; NTCP: Neuroendocrine tumor and carcinoma of pancreas). Two-sample univariable Mendelian randomization (UVMR), multivariable Mendelian randomization (MVMR), and mediation analysis were employed to assess the causal relationship between gut microbiota (GM) and pancreatic cancer (PC), as well as potential IC and IM mediators.ResultsThe two-sample UVMR analysis showed causal relationships between 20 gut microbiota species and pancreatic cancer, with pancreatic cancer affecting the abundance of 37 gut microbiota species. Mediation analysis revealed that Interleukin-6 (IL-6), “CD4 on naive CD4+ T cell” and “SSC-A on HLA DR+ Natural Killer” mediated the causal effects of gut microbiota on pancreatic cancer.ConclusionThis Mendelian randomization study demonstrates causal relationships between several specific gut microbiota and pancreatic cancer, as well as potential mediators (IC, IM).
Melanoma, a malignant skin cancer arising from melanocytes, exhibits rapid metastasis and a high mortality rate, especially in advanced stages. Current treatment modalities, including surgery, radiation, and immunotherapy, offer limited success, with immunotherapy using immune checkpoint inhibitors (ICIs) being the most promising. However, the high mortality rate underscores the urgent need for robust, non-invasive biomarkers to predict patient response to adjuvant therapies. The immune microenvironment of melanoma comprises various immune cells, which influence tumor growth and immune response. Melanoma cells employ multiple mechanisms for immune escape, including defects in immune recognition and epithelial-mesenchymal transition (EMT), which collectively impact treatment efficacy. Single-cell analysis technologies, such as single-cell RNA sequencing (scRNA-seq), have revolutionized the understanding of tumor heterogeneity and immune microenvironment dynamics. These technologies facilitate the identification of rare cell populations, co-expression patterns, and regulatory networks, offering deep insights into tumor progression, immune response, and therapy resistance. In the realm of biomarker discovery for melanoma, single-cell analysis has demonstrated significant potential. It aids in uncovering cellular composition, gene profiles, and novel markers, thus advancing diagnosis, treatment, and prognosis. Additionally, tumor-associated antibodies and specific genetic and cellular markers identified through single-cell analysis hold promise as predictive biomarkers. Despite these advancements, challenges such as RNA-protein expression discrepancies and tumor heterogeneity persist, necessitating further research. Nonetheless, single-cell analysis remains a powerful tool in elucidating the mechanisms underlying therapy response and resistance, ultimately contributing to the development of personalized melanoma therapies and improved patient outcomes.
Tatiane Assone, Tatiane Assone, Tatiane Assone
et al.
Human T-Lymphotropic Virus type-1 (HTLV-1) is a unique retrovirus associated with both leukemogenesis and a specific neuroinflammatory condition known as HTLV-1-Associated Myelopathy (HAM). Currently, most proposed HAM biomarkers require invasive CSF sampling, which is not suitable for large cohorts or repeated prospective screening. To identify non-invasive biomarkers for incident HAM in a large Brazilian cohort of PLwHTLV-1 (n=615 with 6,673 person-years of clinical follow-up), we selected all plasma samples available at the time of entry in the cohort (between 1997–2019), in which up to 43 cytokines/chemokines and immune mediators were measured. Thus, we selected 110 People Living with HTLV-1 (PLwHTLV-1), of which 68 were neurologically asymptomatic (AS) at baseline and 42 HAM patients. Nine incident HAM cases were identified among 68 AS during follow-up. Using multivariate logistic regression, we found that lower IL-10, IL-4 and female sex were independent predictors of clinical progression to definite HAM (AUROC 0.91), and outperformed previously suggested biomarkers age, sex and proviral load (AUROC 0.77). Moreover, baseline IL-10 significantly predicted proviral load dynamics at follow-up in all PLwHTLV-1. In an exploratory analysis, we identified additional plasma biomarkers which were able to discriminate iHAM from either AS (IL6Rα, IL-27) or HAM (IL-29/IFN-λ1, Osteopontin, and TNFR2). In conclusion, female sex and low anti-inflammatory IL-10 and IL-4 are independent risk factors for incident HAM in PLwHTLV-1,while proviral load is not, in agreement with IL-10 being upstream of proviral load dynamics. Additional candidate biomarkers IL-29/IL-6R/TNFR2 represent plausible therapeutic targets for future clinical trials in HAM patients.
Health disparities are health differences linked with economic, social and environmental disadvantage. They adversely affect groups that have systematically experienced greater social or economic obstacles to health. Renewed efforts are needed to reduced health disparities in the US, highlighted by the disparate impact on racial minorities during the coronavirus pandemic. Institutional or systemic patterns of racism are promoted and legitimated through accepted societal standards and organizational processes within the field of medicine and contribute to health disparities. Herein, we review current evidence regarding health disparities in allergic rhinitis, asthma, atopic dermatitis, food allergy, drug allergy, and primary immune deficiency disease in racial and ethnic underserved populations. Best practices to address these disparities involve addressing social determinants of health and adopting policies to improve access to specialty care and treatment for the underserved through telemedicine and community partnerships, cross cultural provider training to reduce implicit bias, inclusion of underserved patients in research, implementation of culturally competent patient education, and recruitment and training of healthcare providers from underserved communities. Addressing health disparities requires a multi-level approach involving patients, health providers, local agencies, professional societies and national governmental agencies.
Childhood allergy, including asthma, eczema, and food allergies, is a major global health burden, with prevalence increasing dramatically and novel interventions needed. Emerging research suggests that human milk oligosaccharides (HMOs), complex glycans found in breastmilk, have allergy-protective properties, indicating exciting therapeutic potential. This review evaluates current literature on the role of HMOs in allergy, assesses underlying immunological mechanisms, and discusses future research needed to translate findings into clinical implications. HMOs may mediate allergy risk through multiple structure-specific mechanisms, including microbiome modification, intestinal barrier maturation, immunomodulation, and gene regulation. Findings emphasize the importance of breastfeeding encouragement and HMO-supplemented formula milk for high allergy-risk infants. Although further investigation is necessary to determine the most efficacious structures against varying allergy phenotypes and their long-term efficacy, HMOs may represent a promising complementary tool for childhood allergy prevention.
Background: The persistently high prevalence of allergic diseases in Western industrial nations and the limited possibilities of causal therapy make evidence-based recommendations for primary prevention necessary. Methods: The recommendations of the S3 Guideline Allergy Prevention, published in its last version in 2014, were revised and consented on the basis of a current systematic literature search. The evidence search was conducted for the period 06/2013 – 11/2020 in the electronic databases Cochrane and MEDLINE, as well as in the reference lists of current reviews and through references from experts. The literature found was screened in two filtering processes, first by title and abstract, and the remaining papers were screened in the full text for relevance. The studies included were sorted by level of evidence, and the study quality was indicated in terms of potential bias (low/high). The revised recommendations were formally agreed and consented upon with the participation of representatives of the relevant professional societies and (self-help) organizations (nominal group process). Of 5,681 hits, 286 studies were included and assessed. Results: Recommendations on maternal nutrition during pregnancy and breastfeeding as well as on infant nutrition in the first months of life again play an important role in the updated guideline: Many of the previous recommendations were confirmed by the current data. It was specified that breastfeeding should be exclusive for the first 4 – 6 months after birth, if possible, and that breastfeeding should continue with the introduction of complementary foods. A new recommendation is that supplementary feeding of cow’s milk-based infant formula should be avoided in the first days of life if the mother wishes to breastfeed. Furthermore, it was found that the evidence for a clear recommendation for hydrolyzed infant formula in non-breastfed infants at risk of atopic diseases is currently insufficient. It is therefore recommended to check whether an infant formula with proven efficacy, demonstrated in allergy prevention studies, is available until the introduction of complementary feeding. Finally, based on the EAACI guideline, recommendations were made for the prevention of hen’s egg allergy by introducing and regularly giving thoroughly heated (e.g., baked or hard-boiled) but not “raw” hen’s egg (also no scrambled egg) with the complementary food. The recommendation to introduce peanut in complementary feeding was formulated cautiously for the German-speaking countries: In families with regular peanut consumption, the regular administration of peanut-containing foods in age-appropriate form (e.g., peanut butter) with the complementary diet can be considered for the primary prevention of peanut allergy in infants with atopic dermatitis (AD). Before introduction, a clinically relevant peanut allergy must be ruled out, especially in infants with moderate to severe AD. There is still insufficient evidence for an allergy-preventive efficacy of prebiotics or probiotics, vitamin D, or other vitamins in the form of supplements so that recommendations against their supplementation were adopted for the first time in the current guideline. Biodiversity plays an important role in the development of immunological tolerance to environmental and food allergens: there is clear evidence that growing up on a farm is associated with a lower risk of developing asthma and allergic diseases. This is associated with early non-specific immune stimulation due to, among other things, the greater microbial biodiversity of house dust in this habitat. This aspect is also reflected in the recommendations on animal husbandry, on which a differentiated statement was made: In families without a recognizable increased allergy risk, pet keeping with cats or dogs should not generally be restricted. Families with an increased allergy risk or with children with already existing AD should not acquire a new cat – in contrast, however, dog ownership should not be discouraged. Interventions to reduce exposure to dust mite allergens in the home, such as the use of mite allergen-proof mattress covers (“encasings”), should be restricted to patients with already proven specific sensitization against house dust mite allergen. Children born by caesarean section have a slightly increased risk of asthma – this should be taken into account when advising on mode of delivery outside of emergency situations. Recent work also supports the recommendations on air pollutants: Active and passive exposure to tobacco smoke increase the risk of allergies, especially asthma, and should therefore be avoided. Exposure to nitrogen oxides, ozone, and small particles (PM 2.5) is associated with an increased risk, especially for asthma. Therefore, exposure to emissions of nitrogen oxides, ozone, and small particles (PM 2.5) should be kept low. The authors of this guideline are unanimously in favor of enacting appropriate regulations to minimize these air pollutants. There is no evidence that vaccinations increase the risk of allergies, but conversely there is evidence that vaccinations can reduce the risk of allergies. All children, including children at risk, should be vaccinated according to the current recommendations of the national public health institutes, also for allergy prevention. Conclusion: The consensus of recommendations in this guideline is based on an extensive evidence base. The update of the guideline enables evidence-based and up-to-date recommendations for the prevention of allergic diseases including asthma and atopic dermatitis.
Across all settings, adult females self-report more drug allergies than adult males. Although there is epidemiological evidence of increased drug allergy labeling in post-pubertal females, the evidence base for female sex as a risk factor for true immune-mediated drug hypersensitivity reactions (DHR), particularly in fatal drug-induced anaphylaxis, is low. Focusing on the known immunological mechanisms described in immediate and delayed DHR, layered on known hormonal and genetic sex differences that drive other immune-mediated diseases, could be the key to understanding biological sex variations in DHR. Particular conditions that highlight the impact of drug allergy in women include (1) pregnancy, where a drug allergy label is associated with increased maternal and fetal complications; (2) multiple drug intolerance syndrome, associated with anxiety and depression; and (3) female-predominant autoimmune medical conditions in the context of mislabeling of the drug allergy or increased underlying risk. In this review, we aim to describe the importance of drug allergy in the female population, mainly focusing on the epidemiology and risk, the mechanisms, the associated conditions and psychosocial factors. By performing a detailed analysis of the current literature, we provide focused conclusions and identify existing knowledge gaps that should be prioritized for future research.
IgE-mediated food allergy has an estimated prevalence of 6%–10% in developed countries. Allergen avoidance has long been the main focus in the prevention of food allergy and late solid food introduction after 6–12 months of age was recommended in high-risk infants. However, the rising prevalence of food allergy despite delayed exposure to allergens and the observations that IgE-mediated sensitization to food products could even occur before the introduction of solid foods resulted in a shift towards early solid food introduction as an attempt to prevent IgE-mediated food allergy. Since then, many trials focused on the clinical outcome of early allergen introduction and overall seem to point to a protective effect on the development of IgE-mediated food allergies. For non-IgE-mediated diseases of food allergy, evidence of early food introduction seems less clear. Moreover, data on the underlying immunological processes in early food introduction is lacking. The goal of this review is to summarize the available data of immunological changes in early food introduction to prevent IgE and non-IgE mediated food allergy.
Humans inhale, ingest, and touch thousands of fungi each day. The ubiquity and diversity of the fungal kingdom, reflected by its complex taxonomy, are in sharp contrast with our scarce knowledge about its distribution, pathogenic effects, and effective interventions at the environmental and individual levels. Here, we present an overview of salient features of fungi as permanent players of the human exposome and key determinants of human health, through the lens of fungal allergy and other fungal hypersensitivity reactions. Improved understanding of the fungal exposome sheds new light on the epidemiology of fungal‐related hypersensitivity diseases, their immunological substratum, the currently available methods, and biomarkers for environmental and medical fungi. Unmet needs are described and potential approaches are highlighted as perspectives.
BACKGROUND Urbanization and biodiversity loss are linked to chronic disorders, in particular allergic diseases. The aim of this scoping review was to provide a synopsis of intervention studies specifically examining the influence of exposure to natural environments on human microbiota as well as immunological markers as suggested interlink between natural environment and the development of allergic diseases. METHODS We searched PubMed (MEDLINE®) and all references cited in the included studies following the PRISMA statement guidelines. No restrictions regarding age and sex of study participants, language or publication date were made. The protocol was registered at OSF REGISTRIES (https://osf.io/musgr). RESULTS After screening, eight intervention studies were included. The interventions reported were mainly of pilot character and various, ranging from nature-related educational programs, biodiversity interventions in day-cares to short-term contact with soil- and sand-preparations. Most of the studied interventions appeared to increase human microbiota richness and diversity in specific taxa groups in the short-time. Immunological markers were assessed in only two studies. In these, their associations with human microbiota richness were pre-dominantly reported. CONCLUSION There is some evidence that the so-called biodiversity interventions have the potential to diversify human microbiota, at least over a short period. Adequately powered randomized controlled trials with long term follow-up are required to examine sustainable effects on microbiota and immune system.
Liquid biopsy strategies enable the noninvasive detection of changes in the levels of circulating biomarkers in body fluid samples, providing an opportunity to diagnose, dynamically monitor, and treat a range of diseases, including cancers. Glioma is among the most common forms of intracranial malignancy, and affected patients exhibit poor prognostic outcomes. As such, diagnosing and treating this disease in its early stages is critical for optimal patient outcomes. Exosomal circular RNAs (circRNAs) are involved in both the onset and progression of glioma. Both the roles of exosomes and methods for their detection have received much attention in recent years and the detection of exosomal circRNAs by liquid biopsy has significant potential for monitoring dynamic changes in glioma. The present review provides an overview of the circulating liquid biopsy biomarkers associated with this cancer type and the potential application of exosomal circRNAs as tools to guide the diagnosis, treatment, and prognostic evaluation of glioma patients during disease progression.
Tomoyuki Ito, Thuy Duong Nguyen, Yutaka Saito
et al.
Despite the advances in surface-display systems for directed evolution, variants with high affinity are not always enriched due to undesirable biases that increase target-unrelated variants during biopanning. Here, our goal was to design a library containing improved variants from the information of the “weakly enriched” library where functional variants were weakly enriched. Deep sequencing for the previous biopanning result, where no functional antibody mimetics were experimentally identified, revealed that weak enrichment was partly due to undesirable biases during phage infection and amplification steps. The clustering analysis of the deep sequencing data from appropriate steps revealed no distinct sequence patterns, but a Bayesian machine learning model trained with the selected deep sequencing data supplied nine clusters with distinct sequence patterns. Phage libraries were designed on the basis of the sequence patterns identified, and four improved variants with target-specific affinity (EC50 = 80–277 nM) were identified by biopanning. The selection and use of deep sequencing data without undesirable bias enabled us to extract the information on prospective variants. In summary, the use of appropriate deep sequencing data and machine learning with the sequence data has the possibility of finding sequence space where functional variants are enriched.
Anna Zaninoni, Bruno Fattizzo, Bruno Fattizzo
et al.
Autoimmune hemolytic anemia (AIHA) is due to autoantibodies with or without complement activation and involves cellular and cytokine dysregulation. Here, we investigated cytokine single-nucleotide polymorphisms (SNPs) of TNF-α, TGF-β1, IL-10, IL-6, and IFN-γ, along with their serum levels. The former were related to hematological parameters, therapy, and clinical outcome. The study included 123 consecutive patients with primary AIHA [77 warm AIHA and 46 cold agglutinin disease (CAD)], followed up for a median of 49 months. Results show that the allelic frequency of TNF-α -308 G/A polymorphisms was significantly lower in patients versus controls. Moreover, the genotypic frequency of TNF-α -308G/A and TGF-β gene codon 25 G/C genotypes was significantly lower in patients versus controls. Considering cytokine SNP genotypes associated with different gene expression levels, TNF-α high gene expression was significantly more frequent in patients, TGF-β and IL-10 high gene expression was higher in patients with more severe anemia, and TGF-β high gene expression was higher in patients with active disease. Considering treatment, TNF-α and TGF-β high gene expression was more frequent in multitreated patients and particularly in CAD. It may be speculated that this genetic predisposition to a stronger inflammatory response may result in a greater immune dysregulation and in a relapsed/refractory disease. Regarding cytokine serum levels, TNF-α and TGF-β were significantly lower, and IL-10 and IL-6 were significantly higher in patients versus controls, underlying the complex interplay between genetic background and disease features.