Search Results (260)

Background/Objectives: Inborn errors of immunity (IEIs) represent a wide spectrum of diseases characterized by a predisposition to recurrent infections, as well as increased susceptibility to autoimmune, atopic, and autoinflammatory diseases and malignancies. The aim of this study was to report the registry-based frequency and describe the clinical characteristics of IEIs among patients in the Republic of Kazakhstan. Methods: We analyzed data from 269 patients belonging to 204 families who were either self-referred or referred by healthcare providers to the University Medical Center of Nazarbayev University with suspected IEIs. All patients resided in various regions across Kazakhstan. Results: A total of 269 diagnosed cases were identified in the national registry. The estimated prevalence was 1.3 per 100,000 population. The gender ratio was nearly equal, with 139 males and 130 females. The median age at diagnosis was 5 years (range: 1 month to 70 years), while the mean age was 11.3 years. The most common diagnosis was humoral immunodeficiency, observed in 120 individuals (44.6%), followed by complement deficiencies in 83 individuals (30.8%). Combined immunodeficiencies with syndromic features were found in 35 patients (13%), and phagocytic cell defects were identified in 12 patients (4.5%). The predominant clinical manifestations included severe recurrent infections and autoimmune cytopenias, while atopic and autoinflammatory symptoms were reported less frequently. Conclusions: These findings contribute to a better understanding of the registry-based distribution and clinical spectrum of IEIs in Kazakhstan and underscore the importance of early diagnosis and targeted care for affected individuals. Full article

Anticytokine autoantibodies (AAbs), particularly anti-interferon-gamma (anti-IFN-γ) AAbs, disrupt cytokine functions, leading to infections, autoimmune-like diseases, and conditions resembling interleukin-12 (IL-12)/IFN-γ pathway defects. Advances in genetic testing have clarified overlaps between autoinflammatory, autoimmune disorders, and primary immunodeficiencies but reveal complex phenotypes and pathways. While these insights deepen our understanding of immune mechanisms, they also complicate diagnosis and treatment, with limited options for IFN-γ deficiencies caused by genetic mutations. The adult-onset immunodeficiency with disseminated lymphadenitis due to nontuberculous mycobacteria (NTM) and other opportunistic infections has been linked to high levels of anti-IFN-γ AAbs. This syndrome, initially identified in HIV-negative Asian patients, frequently affects individuals of Asian descent and may be associated with specific human leukocyte antigen (HLA) alleles. The presence of neutralizing anti-IFN-γ AAbs impairs the IFN-γ-dependent immune response, likely contributing to the persistent NTM infection. This study underscores the potential for late-onset anti-IFN-γ AAb syndrome to manifest with disseminated NTM (dNTM) infections, highlights the importance of timely diagnosis and considers rituximab as a potential therapeutic option. Full article

Background/Objectives: Hidradenitis suppurativa (HS) is a chronic autoinflammatory skin disease characterized by recurrent, painful, and persistently draining purulent lesions. Alterations in the composition of the microbiome may be associated with immune dysregulation and HS progression. The objective of this study was to investigate the correlations between the gut microbiome and HS. Methods: A total of 80 participants (40 HS patients and 40 healthy controls [HCs]) were included in this study. Each participant filled out a specially designed questionnaire, which included demographics, HS severity, physical characteristics, dietary habits, and gastrointestinal disorders. DNA isolation and sequencing of microbiota were performed from fecal samples collected from each participant. Results: No statistically significant difference was observed in the alpha diversity between the microbiota of HS and HC. Nevertheless, HS was found to significantly decrease the chances of, among others, Collinsella, Izemoplasmatales, Clostridia, Lachnospiraceae, eligens group, xylanophilum group, and Pseudoflavonifractor occurrence. Conversely, HS significantly increased the chances of Enterorhabdus, Senegalimassilia, Gastranaerophilales, Candidatus Stoquefichus, Erysipelatoclostridiaceae, Holdemanella, Solobacterium, Ruminiclostridium, [Eubacterium] fissicatena group, Angelakisella, Comamonas, and Enterobacter occurrence. The logistic regression analysis, performed separately for each genus, showed a significant influence of disease severity (based on the Hurley scale) on the chances of occurrence for the following genera: Chloroplast (OR = 5.778), Dielma (OR = 5.75), Eisenbergiella (OR = 5.75) and Paludicola (OR = 5.778). Conclusions: In conclusion, our study adds to the growing body of literature on the gut microbiome in HS and provides valuable insights into the specific alterations in microbial occurrence and abundance associated with the disease. Full article

Gout, a metabolic and autoinflammatory disease, is the most common form of inflammatory arthritis worldwide. Hyperuricemia may result in monosodium urate (MSU) crystals forming and depositing in joints and surrounding tissues, triggering an autoinflammatory response. Effective urate-lowering therapies, as well as anti-inflammatory medications, are used to treat gout. Over the past few decades, new antihyperglycemic drug classes with different modes of action have been added to treat hyperglycemia in type 2 diabetes mellitus (T2DM). Two of these drug classes, sodium–glucose co-transporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists (RAs), have reduced cardiovascular and renal events and mortality. Several clinical studies have demonstrated that SGLT2 inhibitors possess urate-lowering properties, which may be beneficial for treating gout patients, particularly those with comorbid T2DM. Regarding SGLT2 inhibitors, some researchers have suggested that their benefits are partly explained by their ability to reduce serum urate (SU) levels, probably through increased urinary uric acid excretion. The effect of GLP-1 RA on SU levels and urinary excretion of uric acid in humans is unclear. This paper reviews the mechanisms of action of SGLT2 inhibitors and GLP-1RA, both approved and in development. Additionally, it examines what is known about their structure–activity relationships, uricosuric effects, pharmacokinetic profiles, and adverse effects. Full article

Background: Deficiency of IL-36 Receptor Antagonist (DITRA) is a rare monogenic autoinflammatory disease, characterized by dysregulation of IL-36 signaling and phenotypically classified as a subtype of generalized pustular psoriasis. Objectives: This study aimed to explore the role of potentially coding and non-coding RNAs (ncRNAs) in the IL36RN interactome to identify putative pathogenic mechanisms, biomarkers, and therapeutic targets for DITRA. Methods: A systems biology approach was applied using the STRING database to construct the IL36RN protein–protein interaction network. Key ncRNA interactions were identified using RNAInter. The networks were visualized and analyzed with Cytoscape v3 and the CytoHubba plugin to identify central nodes and interaction hubs. Pathway enrichment analysis was then performed to determine the biological relevance of candidate ncRNAs and genes. Results: Analysis identified thirty-eight ncRNAs interacting with the IL36RN network, including six lncRNAs and thirty-two miRNAs. Of these, thirty-three were associated with key DITRA-related signaling pathways, while five remain to be validated. Additionally, seven protein-coding genes were highlighted, with three (TINCR, PLEKHA1, and HNF4A) directly implicated in biological pathways related to DITRA. Many of the identified ncRNAs have prior associations with immune-mediated diseases, including psoriasis, supporting their potential relevance in DITRA pathogenesis. Conclusions: This study provides novel insights into the ncRNA-mediated regulation of IL36RN and its network in the context of DITRA. The findings support the potential utility of specific ncRNAs and genes, such as TINCR, PLEKHA1, and HNF4A, as key genomic elements warrant further functional characterization to confirm their mechanistic roles and may inform biomarker discovery and targeted therapeutic development in DITRA. Full article

The extensive research and studies conducted over the past decade have greatly improved our comprehension of the pathogenesis and risk factors associated with Spondyloarthritis (SpA). In addition, they have contributed to the advancement of novel therapeutic approaches. Although genetics still represents the primary risk factor for SpA, increasing evidence presented in this review suggests that environmental factors—such as air pollution, smoking, gut microbiota (GM), infections, and diet—also contribute to its pathogenesis. In detail, environmental particulate matters (PMs), which include ligands for the aryl hydrocarbon receptor—a cytosolic transcription factor responsive to toxic substances—facilitate the differentiation of T Helper 17 (Th17) cells, potentially exacerbating the autoinflammatory processes associated with SpA. Furthermore, smoking influences both the cellular and humoral aspects of the immune response, resulting in leukocytosis, impaired leukocyte functionality, and a decrease in various cytokines and soluble receptors, including interleukin (IL) 15, IL-1 receptor antagonist (IL-1Ra), IL-6, soluble IL-6 receptor (sIL-6R), as well as the vascular endothelial growth factor (VEGF) receptor. Studies have indicated that patients with SpA exhibit an increased prevalence of antibodies directed against a conserved epitope shared by the human leukocyte antigen B27 (HLA-B27)- and Klebsiella nitrogenase, in comparison to HLA-B27-positive controls. Additionally, current evidence regarding the GM suggests the presence of a gut–joint–skin axis, wherein the disruption of the mucosal barrier by specific bacterial species may enhance permeability to the gut-associated lymphoid tissue (GALT), resulting in localized inflammation mediated by Th1 and Th17 cells, as well as IL-17A. Finally, this review discusses the role of diet in shaping the microbial composition and its contribution to the pathogenesis of SpA. A comprehensive understanding of the mechanisms by which environmental factors influence the pathogenesis and progression of the disease could facilitate the development of novel personalized therapies targeting both external and internal environmental exposures, such as the gut microbial ecosystem. Full article

Macrophage activation syndrome (MAS) is a complex, life-threatening, hyperinflammatory condition occurring as a form of hemophagocytic lymphohistiocytosis (HLH), commonly associated with several autoimmune and autoinflammatory diseases, and certain infections such as Parvovirus B19 (P19V). The onset of systemic lupus erythematosus (SLE) presenting as MAS during pregnancy is uncommon, posing significant diagnostic and therapeutic challenges. We present a case of a 30-year-old woman at the 12th gestational week with fever, arthralgia, rash, cervical lymphadenopathy, cytopenia, and elevated liver enzyme. Bone marrow biopsy revealing hemophagocytosis, elevated ferritin and triglycerides, high interleukin-2, fever and cytopenia, confirmed the diagnosis of HLH. Further evaluation revealed the diagnosis of SLE. Treatment was initiated with intravenous immunoglobulin and corticosteroids. Given the deterioration in the patient’s clinical condition, a decision was made to terminate the pregnancy. She continued in the following months to receive SLE treatment with corticosteroids, cyclophosphamide, hydroxychloroquine, and later with mycophenolate mofetil due to the development of Class IV of lupus nephritis. P19V IgM antibodies were initially positive, later seroconverted to IgG, indicating that infection may have acted as a trigger for the onset of SLE and MAS development during pregnancy. The overlapping clinical features of P19V infection, SLE, and MAS pose significant diagnostic and therapeutic challenges. Early recognition and comprehensive diagnostic evaluation are crucial for the management of these conditions, especially during pregnancy, where both maternal outcomes are at risk. Full article

VEXAS syndrome and Alzheimer’s disease (AD), though distinct in clinical manifestations, share overlapping pathophysiological mechanisms, including systemic inflammation, protein misfolding, and vascular dysfunction. VEXAS syndrome, a rare autoinflammatory disorder characterized by somatic UBA1 mutations, systemic inflammation, and hematologic abnormalities, presents primarily in older males. Meanwhile, AD, the leading cause of dementia, involves progressive neurodegeneration driven by amyloid-beta plaques, tau tangles, and chronic neuroinflammation. This article explores potential connections between the two conditions, focusing on inflammation, neurovascular changes and cellular stress. Systemic inflammation observed in VEXAS syndrome may potentiate neuroinflammatory processes in Alzheimer’s disease (AD), as circulating proinflammatory cytokines have the capacity to cross the blood–brain barrier (BBB), thereby inducing glial activation and promoting neuroinflammation. Additionally, coexisting vascular dysfunctions characteristic of both conditions may synergistically contribute to accelerated cognitive decline. Both conditions involve disruption of the ubiquitin–proteasome system, with UBA1 mutations being specific to VEXAS. Given the established role of UBA1 in maintaining neuronal homeostasis, investigating the overlapping and distinct molecular mechanisms may provide valuable insights into their pathophysiology. The review underscores the need for further research to elucidate these links and improve therapeutic strategies, especially for individuals affected by both disorders. Full article

Background: Ankylosing Spondylitis (AS) is a rare autoinflammatory disorder affecting 0.1–1.4% of the population, with increasing recognition over the past 20 years. Although the specific causes of AS remain unclear, the presence of the HLA-B27 gene is associated with increased risk, though only 1–5% of carriers develop the disease. Despite extensive research, no definitive lab tests exist, and many patients are diagnosed years after symptom onset. Methods: In the present study, in order to investigate the disease’s genetic background in correlation with autoimmune diseases, a metanalysis has been performed following PRISMA guidelines using Scopus and PubMed publications towards extracting single-nucleotide polymorphisms (SNPs) of high importance for the disease. Moreover, the polymorphisms have been annotated and analyzed using information from several databases, including PubMed, LitVar2, ClinVar, and Gene Ontology. Results: From 1940 screened titles and abstracts, 57,909 studies were selected, with 539 meeting the inclusion criteria. The genetic background of AS is described through 794 genetic variants, of which 76 SNPs are directly associated with AS (Classes A and B), predominantly located in intronic regions. ERAP1 and IL23R emerged as key genes implicated in AS, while chromosomes 1, 2, and 5 accumulated the most associated SNPs. Functional enrichment revealed strong associations with immune regulation and interleukin signaling pathways, particularly IL6 and IL10 signaling. IL-6 promotes inflammation in AS, while IL-10 tries to suppress it, acting as an anti-inflammatory cytokine. Of the 78 AS-related SNPs, 16 were unique to AS, while 66 were common to autoimmune diseases, especially rheumatoid arthritis (RA) and psoriasis (PsO), suggesting genetic overlap between these diseases. Conclusions: This study creates a comprehensive genetic map of AS-associated SNPs, highlighting key pathways and genetic overlap with autoimmune diseases. These findings contribute to understanding disease mechanisms and could guide therapeutic interventions, advancing precision medicine in AS management. Full article

Selenium (Se) is an essential micronutrient for antioxidant defense. Selenoproteins are involved in metabolic and signaling pathways of autoimmune and autoinflammatory diseases. Copper (Cu) and zinc (Zn) are integral components of key enzymes and regulatory proteins. Trace element (TE) dysregulations have potential relevance as disease biomarkers. In this study, we compare TE status and TE profiles between patients with axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA), and relate the results to markers of inflammation, remission, and healthy controls. Serum TE was measured using total reflection X-ray fluorescence. The Se transporter SELENOP and extracellular glutathione peroxidase (GPx3) were determined by ELISA and enzymatic assay, respectively. Both groups of patients (axSpA; n = 84, and PsA; n = 76) displayed TE deficiency compared to healthy European adults. Serum Cu, Se, Zn, SELENOP, and GPx3 levels were not different between the groups. The serum Cu and Cu-Zn ratio correlated positively with C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). An inverse correlation of serum Se, Zn, and SELENOP with CRP was observed in axSpA, but not in PsA. On average, all TE, including the inflammation-responsive Cu levels, were below reference ranges, indicating a TE deficiency in both groups. Increasing CRP was associated with low SELENOP levels, suggesting personalized Se substitution as indicated to maintain systemic Se supply and protect from ferroptotic cell loss under inflammatory conditions. Full article

Background: Germline alleles near genes encoding certain immune checkpoints (CTLA4, CD200) are associated with autoimmune/autoinflammatory disease and cancer, but in opposite ways. This motivates a systematic search for additional germline alleles with this pattern with the aim of identifying potential cancer immunotherapeutic targets using human genetics. Methods: Pairwise fixed effect cross-disorder meta-analyses combining genome-wide association studies (GWAS) for breast, prostate, ovarian and endometrial cancers (240,540 cases/317,000 controls) and seven autoimmune/autoinflammatory diseases (112,631 cases/895,386 controls) coupled with in silico follow-up. Results: Meta-analyses followed by linkage disequilibrium clumping identified 312 unique, independent lead variants with p < 5 × 10⁻⁸ associated with at least one of the cancer types at p < 10⁻³ and one of the autoimmune/autoinflammatory diseases at p < 10⁻³. At each lead variant, the allele that conferred autoimmune/autoinflammatory disease risk was protective for cancer. Mapping led variants to nearest genes as putative functional targets and focusing on immune-related genes implicated 32 genes. Tumor bulk RNA-Seq data highlighted that the tumor expression of 5/32 genes (IRF1, IKZF1, SPI1, SH2B3, LAT) was each strongly correlated (Spearman’s ρ > 0.5) with at least one intra-tumor T/myeloid cell infiltration marker (CD4, CD8A, CD11B, CD45) in every one of the cancer types. Tumor single-cell RNA-Seq data from all cancer types showed that the five genes were more likely to be expressed in intra-tumor immune versus malignant cells. The five lead SNPs corresponding to these genes were linked to them via the expression of quantitative trait locus mechanisms and at least one additional line of functional evidence. Proteins encoded by the genes were predicted to be druggable. Conclusions: We provide population-scale germline genetic and functional genomic evidence to support further evaluation of the proteins encoded by IRF1, IKZF1, SPI1, SH2B3 and LAT as possible targets for cancer immunotherapy. Full article

Background and Objectives: Canakinumab, a human recombinant monoclonal antibody against interleukin-1ß (IL-1ß), is indicated for the treatment of selected autoinflammatory periodic fever syndromes and rheumatic diseases. Data on its use during pregnancy remain limited and all are primarily derived from case reports. Although animal studies indicate no evidence of reproductive toxicity, the risk to the fetus or mother remains unknown. This study aims to provide more findings about this important topic. Methods: A retrospective analysis was conducted on three patients followed and treated in the National Center for Periodic Fever Syndromes. Although due to the small sample size, no general conclusions regarding the safety of canakinumab during pregnancy can be drawn. Results: Three maternal-exposed pregnancies were assessed, with no paternal exposure. Diagnoses included mevalonate kinase deficiency, familiar Mediterranean fever and TNF-receptor-associated periodic syndrome. All mothers were treated with canakinumab, and two of those continued the canakinumab treatment during the whole course of pregnancy. The diseases remained under full control during pregnancy, enabling conception in two cases where attempts prior to treatment were unsuccessful. The therapy led to disease control, a reduction in inflammation and subsequently successful conception. One patient underwent IVF repeatedly. All pregnancies resulted in three healthy infants, with no reported miscarriages during the canakinumab-exposed pregnancies, no complications during pregnancies and no serious infections in the newborns. The children had normal development, without any developmental delays or chronic illnesses. Conclusions: The current data, including our findings, indicate no harmful effects of canakinumab during pregnancy. However, because of the scarcity of data, the use of canakinumab during pregnancy should be carefully managed, and women who want to become pregnant should continue treatment only after a thorough benefit–risk evaluation. Full article

Background/Objectives: This study analyzes the impact of PFAPA syndrome (periodic fever, aphthous stomatitis, pharyngitis, and adenitis) on health-related quality of life (HRQoL) and the psychological functioning of children and adolescents aged 2 to 1 years. Methods: A cross-sectional descriptive study was conducted with 62 participants (31 males and 31 females) diagnosed with PFAPA. The Strengths and Difficulties Questionnaire (SDQ) and the Family Impact Module scale of Pediatric Quality of Life Inventory (PedsQL) were used to assess psychological functioning and HRQoL, respectively. Results: Participants exhibited predominantly low HRQoL, particularly in physical health and emotional functioning. School functioning was also affected. However, social functioning and family relationships showed more favorable scores. A positive correlation was observed between age and emotional symptoms. Family concern was the most significantly impacted aspect. Conclusions: PFAPA syndrome has a significant impact on the HRQoL of affected children and adolescents, particularly in physical and emotional aspects. A holistic approach is necessary for disease management, considering not only physical symptoms but also psychosocial and academic factors, as well as the impact on the family. Full article

Rheumatoid arthritis (RA) is a highly prevalent systemic autoimmune disease. Recently, natural small molecules have been explored as alternative therapeutic agents. Iris halophila Pall is the traditional herbal medicine, and it is rich in active ingredients with anti-inflammatory and immunomodulatory effects. In our previous study, LC-MS analysis revealed that piceatannol (PIC) is one of the primary active ingredients in the root of Iris tectorum. The purpose of this study was to explore the immunomodulatory effects of PIC on the maturation and function of dendritic cells, as well as on experimental arthritis induced by complete Freund’s adjuvant (CFA) and incomplete Freund’s adjuvant (IFA). Additionally, we aimed to probe into the potential mechanisms underlying the effects of PIC. We first verified the immunosuppressive effect of PIC using flow cytometry and an ELISA. The immunosuppressive mechanism of PIC on dendritic cells (DCs) was investigated through a joint analysis of network pharmacology and Western blotting. Our findings revealed that under Lipopolysaccharide (LPS)-induced inflammatory conditions, PIC could restrain the maturation and function of DCs (p < 0.001) and decrease the secretion of inflammatory cytokines (p < 0.001) compared to the LPS group. Furthermore, PIC suppressed the activation and polarization of CD4⁺ T cells, resulting in a decreased proportion of Th1 and Th17 cells (p < 0.001), ultimately improving the symptoms of CFA-induced arthritis in comparison to the model group. The PIC-induced shift in the T helper cell differentiation correlated with the secretion of polarizing cytokines from DCs in the AIA model. Mechanistically, PIC exerted its immunosuppressive function mainly by down-regulating the Mitogen-Activated Protein Kinase (MAPK) and Nuclear Factor kappa-B (NF-κB) signaling pathways. Collectively, these data unveil the anti-inflammatory mechanisms of a traditional medicine via the inhibition of the immune activation function of DCs in vivo and open up a therapeutic approach for autoinflammatory diseases. Full article

Introduction. The pathophysiology of Pyoderma Gangrenosum (PG) involves altered innate and adaptive immunity, mutagenic and epigenetic changes, the autoinflammatory state, and the overexpression of cytokines. This study investigated the potential contribution of inflammation, redox signaling, and the immune system in the pathogenesis of PG. Materials and Methods. This case–control study included 36 patients with PG and 30 controls. We have determined the serum concentrations of acute phase proteins (C-reactive protein—CRP, alpha1 glycoprotein acid—AGPA, Albumin), interleukin-17A -IL-17A, β2 microglobulin-β2MG, reduced glutathione-GSH, oxidized glutathione- GSSG, the GSH/GSSG ratio, and hematological parameters (white blood cells-WBC, neutrophil-lymphocyte ratio-NLR, erythrocyte sedimentation rate-ESR) in patients with PG compared with controls. Furthermore, we have evaluated the variations in these markers before and after treatment in PG patients. Results. The serum concentrations of acute phase proteins (CRP, AGPA, and Albumin) and the IL-17A, β2MG, GSH, GSSG, and GSH/GSSG ratio were significantly different between the PG group and controls. Hematological parameters (WBC, NLR, and ESR), acute phase proteins (CRP, AGPA, and albumin), and IL-17A showed an exaggerated and persistent inflammatory response in patients with PG. In patients with PG associated with systemic diseases, the dysregulation of the biochemical events was more severe. Conclusions. The acute phase proteins, β2MG-MHC class I complex, and the GSH-GSSG system are unbalanced in PG. Our results could improve the diagnosis and our understanding of the pathogenic basis of PG. Full article