Autoinflammatory Research Articles

Understanding the Intricate Pathophysiology of Psoriasis and Related Skin Disorders

Psoriasis is a chronic inflammatory condition that is polygenic and multisystemic, impacting approximately 2–3% of the global population. The onset of this disease is influenced by an intricate interplay of genetic and environmental factors, predisposing individuals to the psoriasis phenotype. The complex pathogenesis of psoriasis contains certain key aspects found in other autoinflammatory and autoimmune dermatological diseases. Among these, vitiligo, alopecia areata, hidradenitis suppurativa, vitiligo, connective tissue diseases, bullous dermatoses, and atopic dermatitis are conditions that share overlapping immune system dysfunction, making their relationship with psoriasis particularly significant. For our research, we explored various terms including “shared”, “concomitant”, “coincident”, “overlap”, “coexist”, and “concurrent”, in relation to conditions such as “psoriasis”, “alopecia areata”, “hidradenitis suppurativa”, “atopic dermatitis”, “vitiligo”, “bullous pemphigoid”, “pemphigus vulgaris”, “lupus erythematosus”, “dermatomyositis”, and “systemic sclerosis.” Additionally, we used specific search queries like “atopic dermatitis overlapping syndrome” and “psoriasis and vitiligo concomitant disease” in the PubMed and Web of Science databases. While distinct in their clinical presentation, the skin diseases related to psoriasis may become associated, complicating diagnosis and treatment. In this narrative review, the complex pathophysiology of psoriasis is described, along with its close relationship to other skin conditions. This review provides an exhaustive description of both immunological and non-immunological pathways contributing to their development. Understanding the intricate interconnection between psoriasis and these conditions is of interest to scientists in developing novel research directions and to clinicians in providing holistic care, as managing one condition may influence the course of others.

Updates on the molecular spectrum of MEFV variants in lebanese patients with Familial Mediterranean Fever

Familial Mediterranean Fever (FMF) is a hereditary autoinflammatory disorder, particularly present in the Mediterranean populations, and associated with pathogenic variants in the MEFV gene. This study aims to investigate the distribution of MEFV variants in a large cohort of Lebanese patients, and to explore the genotype-phenotype correlation among affected individuals. A retrospective analysis was conducted on 3,167 patients referred for MEFV sequencing at the Medical Genetics and Genomics Center(CGGM) at Saint-Joseph University of Beirut-Lebanon, from 2006 to 2023. Sanger sequencing was used to detect MEFV variants, focusing initially on hot-spot exons. Among the 3,167 patients, 46.73% (N = 1,480) carried at least one MEFV variant. The most common variants detected were M694V and V726A, both found in 28.98% of cases, followed by E148Q(27.83%) and M694I(13.98%). Moreover, Shiites and Sunni Muslims, and individuals from South and North Lebanon exhibited the highest frequency of variants. Interestingly, family history was found to be significantly higher in patients having two MEFV variants than those with one variant (p = 0.0026). The most commonly reported symptoms were fever(78%), abdominal pain(88%), joint pain(65%), and thoracic pain(46%). The genotype-phenotype correlation analysis revealed a more severe phenotype in patients carrying the M694V or V726A mutations compared to those with the homozygous E148Q genotype. This study, the largest in Lebanon, highlights the high prevalence of MEFV variants, particularly M694V and V726A, in FMF patients. Our data provide valuable insights into the genetic landscape of FMF in Lebanon and emphasize the importance of early genetic screening for a better disease management and genetic counselling.

Proteomic analysis reveals dysregulation of peripheral blood neutrophils in patients with Multiple Sclerosis.

Multiple Sclerosis (MS) is a complex auto-inflammatory disease affecting the brain and spinal cord, which results in axonal de-myelination and symptoms including fatigue, pain, and difficulties with vision and mobility. The involvement of the immune system in the pathology of MS is well established, particularly the adaptive T cell response, and there has been a particular focus on the IL-17-producing subset of Th17 cells and their role in driving disease. However, the importance of innate immune cells has not been so well characterised. Here we focused on neutrophils, which are innate immune cells and rapid responders to inflammation, and which have recently been linked to other chronic autoimmune conditions. Multiple strands of evidence in patients with MS and in mice with the experimental autoimmune encephalomyelitis MS model suggest neutrophils may play a role in driving MS inflammation. Here, we performed proteomic analysis on neutrophils from patients with MS and healthy donors, revealing striking differences. In particular, granule proteins were significantly more abundant in the MS neutrophils compared to the healthy controls, with a particular over-abundance of proteins in primary and secondary granules. In addition, members of the MAVS signalling pathway were differently regulated compared to healthy donor cells. Finally, we find that MS neutrophils do not suppress T cell activation equivalently to healthy neutrophils, and in particular are unable to suppress expression of CD161 on the T cells, indicative of a suppression of Th17 differentiation. We propose that neutrophil dysregulation in MS may contribute to dysfunctional T cell responses.

Familial Mediterranean fever in Romania: a case report and literature review

Familial Mediterranean Fever (FMF) is a hereditary autoinflammatory disease characterized by recurrent fever and systemic inflammation, most prevalent in Eastern Mediterranean populations. Rare in regions like Romania, FMF presents diagnostic challenges and risks severe complications if untreated. We report a 7-year-old Romanian girl, from a non-classical ethnic background, with recurrent febrile episodes and elevated inflammatory markers. Genetic testing confirmed a homozygous MEFV c.2082G>A (p.Met694Ile) variant. Colchicine therapy reduced flare frequency and normalized inflammatory markers. FMF should be considered in atypical populations with recurrent inflammation. Genetic testing aids diagnosis in non-endemic regions, enabling early colchicine treatment to prevent complications.

Associated diseases and their effects on disease course in patients with chronic non-bacterial osteomyelitis: retrospective experience from a single center.

Chronic non-bacterial osteomyelitis (CNO) is a rare autoinflammatory bone disease associated with other chronic inflammatory diseases such as familial Mediterranean fever (FMF), juvenile idiopathic arthritis (JIA), spondylarthropathies, inflammatory bowel disease (IBD), and pyoderma gangrenosum. We aimed to describe the clinical and follow-up characteristics of patients with CNO and to compare findings between patients with and without comorbidities. The clinical records of patients with CNO who were followed up in our pediatric rheumatology clinic between 2018 and 2023 were reviewed. Patients were divided into two groups according to the presence or absence of comorbidities. The clinical, laboratory, and radiological characteristics and treatments of the groups were compared. The study included 40 patients (65% male) diagnosed with CNO. The median (IQR) age at symptom onset was 10 (6.4) and at diagnosis was 11.5 (5.9) years. Fourteen (35%) patients had comorbidities. The comorbidities were FMF (n = 9), IBD (n = 3), uveitis (n = 3), psoriasis (n = 1) and acne conglabatae (n = 2). The group with comorbidities had higher number of bones involved (3 or more bones) (78.6% versus 42.3%) (p = 0.028), and 78.6% of patients with comorbidities received biologic treatment, while only 23.1% of patients without comorbidities were treated with biologics (p = 0.001). Familial Mediterranean fever, uveitis, IBD, psoriasis and acne conglabata were found to be the clinical conditions associated with CNO. Patients with CNO who had comorbidities appeared to have a more severe phenotype of the disease accompanied with more bone involvement and requiring more biologic treatment. Key Points • Chronic non-bacterial osteomyelitis (CNO), an auto-inflammatory bone disease, can be seen in association with other inflammatory conditions such as familial Mediterranean fever (FMF), uveitis, inflammatory bowel disease (IBD), psoriasis, and acne conglobata. • If CNO is associated with another inflammatory disease, the number of bones involved may be higher and patients may need more intensive treatments, such as biologics. • CNO may coexist with one or more inflammatory diseases, which may exacerbate the disease phenotype.

Off-Label Use of Anakinra in Inflammatory Conditions in Neonates and Infants Up to 3 Months of Age: A Case Series and a Review of the Literature.

Anakinra is an interleukin-1 receptor antagonist (IL-1Ra). Since IL-1 has been shown to play a key role in the etiology of different autoinflammatory diseases, blocking its pathway has become an important therapeutic target, even in neonates. We aimed to report our experience in using anakinra to treat specific neonatal inflammatory conditions. We described the clinical management with anakinra of five cases of neonates or infants up to 3 months of age admitted to the neonatal intensive care unit (NICU) of Bambino Gesù Children's Hospital IRCCS in Rome (Italy) from 2020 onwards. Medical history and clinical data concerning NICU hospitalization were collected from the electronic medical records. Furthermore, we performed a literature review of off-label anakinra in the first 3 months of life, up to 5 April 2024. We excluded from this review cases of cryopyrin-associated periodic syndrome, deficiency of the interleukin-1 receptor antagonist, and mevalonate kinase deficiency, for which anakinra is a known treatment. We reported three off-label cardiorespiratory reasons to use IL-1Ra from our series: (i) chronic lung disease with pulmonary hypertension, (ii) interstitial lung disease with pulmonary hypertension to facilitate the weaning from respiratory support, and (iii) post-surgical polyserositis if effusions accumulate despite drainage. In all our patients, the drug was administered at a dosage of 10mg/kg/day. The route of administration was chosen based on the patient's clinical characteristics, with the subcutaneous and intravenous routes being comparable in efficacy. The duration of therapy was modulated based on the patient's clinical response, with a minimum duration of 4 months. A total of 308 retrieved articles were screened, and then full texts of records deemed eligible for inclusion were assessed. Based on the literature search and our five cases, a total of 17 infants were treated with anakinra outside its approved indications. The major off-label use was for hemophagocytic lymphohistiocytosis/macrophage activation syndrome, followed by multisystem inflammatory syndrome in children and Kawasaki disease, as in two of our cases. According to the results of our case series and review of the literature, the off-label use of anakinra in neonates with inflammatory conditions refractory to first-line therapy could be considered. Prospective, multicenter research is necessary to determine whether anakinra is a safe treatment option for these infants to prevent early inflammatory illnesses and in which situations it could enhance clinical results.

Background and Clinical Features of a Unique and Mysterious Autoinflammatory Disease, Schnitzler Syndrome

Schnitzler syndrome is a unique autoinflammatory disease, of which 747 cases have been described worldwide to date. The main features of the syndrome are a triad of recurrent urticaria, monoclonal IgM gammopathy, systemic inflammation associated with recurrent fever, joint and bone pain, and atypical bone remodeling (osteosclerosis). The abnormal activation of the NLRP3 inflammasome produces IL-1, which drives the disease pathology, but it also involves IL-6 and IL-18. Unlike other autoinflammatory diseases, Schnitzler syndrome lacks evidence of the gene divergence causing the abnormal activation of NLRP3. However, mutations in the MEFV and MYD88 genes can be associated with the development of the disease. Due to its rarity, diagnosing the disease can be a challenging task. IL-1 inhibitors (i.e., anakinra, canakinumab, and rilonacept) are prominent in the treatment of the disease, but the IL-6 receptor inhibitor tocilizumab and the Bruton’s tyrosine kinase inhibitor ibrutinib are also promising alternatives. In this summary article, we aim to provide a comprehensive overview of the clinical and molecular background of the disease and potential therapeutic targets, based on the cases reported so far. We diagnosed a patient who, to the best of our knowledge, represents the 748th documented case of this specific pathology. In the context of this patient, we would also like to draw attention to the potential pathogenic role of two novel gene mutations (variants of the MEFV gene “c.2084A>G” and the F2 gene “3′UTR c.*97G>A”).

Familial Mediterranean fever with sigmoid colon stricture.

We describe a case of familial Mediterranean fever (FMF) with sigmoid colon stricture. The patient, a woman in her 30s, had a 12-year history of ileocolitis-type Crohn's disease. The colonoscope could not pass because of the sigmoid colon stricture, and the patient was referred to our hospital with complaints of abdominal pain and fever. At 2-month postreferral, the patient presented with severe abdominal pain and fever. Computed tomography and intestinal ultrasonography revealed no bowel obstruction, whereas wall thickening was observed in the sigmoid colon and small bowel. Our medical interview revealed a cyclical nature to the symptoms. We diagnosed FMF and initiated colchicine. Subsequently, for more than 2years, the patient remained asymptomatic, and the sigmoid colon stricture improved. FMF should be considered in patients with inflammatory bowel disease with periodic abdominal pain and fever.

Oatmeal and wheat flour as the sources of thyroid peroxidase and proinflammatory enzymes modulators in the prevention of thyroid diseases

Polyphenolic plant compounds possess nutritional and pro-healthy potential, reducing the risk of auto-inflammatory and neoplastic diseases. However, their interference with the progression of thyroid gland dysfunctions has remained largely unaddressed. For this purpose, we combined the analyses of phenolic content and antioxidative activity with the thyroid peroxidase (TPO), lipoxygenase (LOX), xanthine oxidase (XO) and cyclooxygenase-2 (COX-2) activity assays, isobolographic approach and the estimation of thyroid cancer cells’ proliferation and motility in vitro. Bioaccessible oatmeal (OM) and wheat flour (WF) compounds activated TPO while inhibiting LOX and XO’s in vitro activity. OM extracts also inhibited COX-2 activity. Isobolographic and combination index studies revealed cooperation of compounds from OM and WF. However, the relatively strong inhibitory activity of bioaccessible OM compounds on LOX activity correlated with their mildly cytostatic and relatively distinct pro-invasive effects in the thyroid cancer model in vitro. Collectively, the application of OM and WF products for the prophylactics of inflammatory thyroid diseases should be considered with care, especially in the context of the oncological status of the patient.

Familial Mediterranean Fever (FMF): Emerging Concepts in Diagnosis, Pain Management, and Novel Treatment Options: A Narrative Review.

Familial Mediterranean Fever (FMF) is a hereditary autoinflammatory disorder predominantly affecting individuals of Mediterranean and Middle Eastern descent, including those with certain heritages including Sephardic Jewish, Armenian, Turkish, and Arab. The disorder affects up to 1 in 200 people making it a very common etiology for pain states worldwide, including serositis mediated painful states of the chest, joint, and abdomen. Defined by recurrent episodes of fever and inflammation, FMF can lead to not only severe pain, but complications such as renal amyloidosis, if untreated. This narrative review explores the genetic basis, clinical manifestations, diagnostic criteria, and current management strategies for FMF. Mutations in the MEFV gene result in the dysregulation of the pyrin inflammasome, leading to excessive production of inflammatory cytokines. Diagnosis primarily relies on clinical criteria supported by genetic testing. Colchicine remains the cornerstone of treatment, effectively preventing inflammatory attacks and complications. For colchicine-resistant patients, IL-1 antagonists like anakinra and canakinumab show promise, although their long-term benefits require further investigation. The present investigation underscores the importance of early diagnosis and integrated treatment approaches to improve patient outcomes, pain management, and quality of life.

RNA sensing at the crossroads of autoimmunity and autoinflammation.

Immune-mediated diseases are common in humans. The immune system is a complex host defense system that evolved to protect us from pathogens, but also plays an important role in homeostatic processes, removing dead or senescent cells, and participating in tumor surveillance. The human immune system has two arms: the older innate immune system, and the newer adaptive immune system. Sensing of foreign RNA is critical to the innate immune system's ability to recognize pathogens, especially viral infections. However, RNA sensors are also strongly implicated in autoimmune and autoinflammatory diseases, highlighting the importance of balancing pathogen recognition with tolerance to host RNAs that can resemble their viral counterparts. We describe how RNA sensors bind their ligands, how this binding is coupled to upregulation of Type I interferon-stimulated genes, and the ways in which mutations in RNA sensors and genes that play important roles in RNA homeostasis have been linked to autoimmune and autoinflammatory diseases.

Characteristics of Siblings with Familial Mediterranean Fever: A Single-Center Experience.

Objective: Familial Mediterranean fever (FMF) is a hereditary, autoinflammatory disease. The characteristics of siblings with FMF have not been described in large cohorts up to now. This study aimed to examine the features of siblings with FMF. Materials and Methods: This was a retrospective, cross-sectional study. Patients were divided into 2 groups according to the time of diagnosis (group I, the child diagnosed first in the family, and group II, the sibling diagnosed later). Results: A total of 143 siblings (65 families) with FMF were included in the study. Seventy-two percent of the patients had the same genetic mutation as their siblings. Despite having the same genetic mutation, 59% of the patients had different attack symptoms from their siblings. In 56% of the patients, the Pras disease severity score and in 45% of the patients, the response to colchicine treatment differed from their siblings with the same mutation. Fever and abdominal pain were statistically significantly more frequent in group I than in group II (P = .032). The age of disease onset in group I was statistically lower than in group II (P = .031). Genetic mutations, attack symptoms, and colchicine response were the same in twin pairs. The age of disease onset and age at diagnosis were also the same in half of the twin pairs. Conclusion: Parents of children diagnosed with FMF should be informed of all the symptoms of FMF disease and that siblings may present with different clinical findings.

Autoinflammatory Bone Diseases.

Autoinflammatory bone diseases (AIBDs) constitute a recently identified subset of autoinflammatory diseases. These conditions are characterized by an exaggerated inflammatory response in the bones without any apparent etiology. Inflammatory bone lesions associated with AIBDs exhibit chronic inflammation, are typically culture-negative, and do not exhibit discernible microorganisms on histopathological examination. The most common and representative AIBD is chronic non-bacterial osteomyelitis (CNO), which is also known as chronic recurrent multifocal osteomyelitis. Another variant of CNO, which is typically observed in older teenagers or adults, is known as synovitis, acne, hyperostosis, pustulosis, osteitis syndrome. This condition is distinguished by its notable skin manifestations. Advancements in genetic research have led to the identification of three novel monogenic subtypes within the category of AIBDs. These include Majeed syndrome, pyogenic arthritis, pyoderma gangrenosum, and acne syndrome, and interleukin-1 receptor antagonist deficiency syndrome. Another monogenic AIBD, called cherubism, affects only the maxilla and mandible. Data on the diagnosis and treatment of these rare diseases are extremely limited. However, if not diagnosed and treated promptly, it can result in significant complications, including severe disability and mortality. Thus, it is imperative to maintain a high level of clinical awareness of these diseases. These rare diagnoses should be considered in patients with musculoskeletal complaints in whom no specific etiology can be identified or in patients with systemic manifestations such as cutaneous and gastrointestinal symptoms or fever. In such patients, the diagnostic process, which encompasses imaging and genetic studies, should be initiated promptly.

Current landscape of monogenic autoinflammatory actinopathies: A literature review.

Autoinflammatory diseases (AID) are conditions leading to a hyperactivation of innate immunity without any underlying infection, and may be poly- (e.g. Still's disease) or monogenic. The number of monogenic AID is continuously expanding, with the discovery of novel pathologies and pathophysiological mechanisms, facilitated in part by easier access to pangenomic sequencing. Actinopathies with autoinflammatory manifestations represent a newly emerging subgroup of AID, associated with defects in the regulation of actin cytoskeleton dynamics. These diseases typically manifest in the neonatal period and variably combine a primary immunodeficiency of varying severity, cytopenia (particularly thrombocytopenia), autoinflammatory manifestations primarily affecting the skin and digestive system, as well as atopic and autoimmune features. Diagnosis should be considered primarily when encountering an early-onset autoinflammatory skin and digestive disorder, along with a primary immunodeficiency and either thrombocytopenia or a bleeding tendency. Some of these diseases exhibit specific features, such as a risk of macrophage activation syndrome (MAS) or a predisposition to atopy or lymphoproliferation. The complete pathophysiology of these diseases is not yet fully understood, and further studies are required to elucidate the underlying mechanisms, which could guide therapeutic choices. In most cases, the severity of the conditions necessitates allogeneic marrow transplantation as a treatment option. In this review, we discuss these novel diseases, providing a practical approach based on the main associated biological abnormalities and specific clinical characteristics, with a special focus on the newly described actinopathies DOCK11 and ARPC5 deficiency. Nonetheless, genetic testing remains essential for definitive diagnosis, and various differential diagnoses must be considered.

Advances in chimeric antigen receptor T cell therapy for autoimmune and autoinflammatory diseases and their complications.

Chimeric antigen receptor T (CAR-T) cells are genetically engineered T cells expressing transmembrane chimeric antigen receptors with specific targeting abilities. As an emerging immunotherapy, the use of CAR-T cells has made significant breakthroughs in cancer treatment, particularly for hematological malignancies. The success of CAR-T cell therapy in blood cancers highlights its potential for other conditions in which the clearance of pathological cells is therapeutic, such as liver diseases, infectious diseases, heart failure, and diabetes. Given the limitations of current therapies for autoimmune diseases, researchers have actively explored the potential therapeutic value of CAR-T cells and their derivatives in the field of autoimmune diseases. This review focuses on the research progress and current challenges of CAR-T cells in autoimmune diseases with the aim of providing a theoretical basis for the precise treatment of autoimmune diseases. In the future, CAR-T cells may present new therapeutic modalities and ultimately provide hope for patients with autoimmune diseases.

Revealing the dance of NLRP3: spatiotemporal patterns in inflammasome activation.

The nucleotide-binding domain, leucine-rich repeat, and pyrin domain containing-protein 3 (NLRP3) inflammasome is a multiprotein complex that plays a critical role in the innate immune response to both infections and sterile stressors. Dysregulated NLRP3 activation has been implicated in a variety of autoimmune and inflammatory diseases, including cryopyrin-associated periodic fever syndromes, diabetes, atherosclerosis, Alzheimer's disease, inflammatory bowel disease, and cancer. Consequently, fine-tuning NLRP3 activity holds significant therapeutic potential. Studies have implicated several organelles, including mitochondria, lysosomes, the endoplasmic reticulum (ER), the Golgi apparatus, endosomes, and the centrosome, in NLRP3 localization and inflammasome assembly. However, reports of conflict and many factors regulating interactions between NLRP3 and subcellular organelles remain unknown. This review synthesizes the current understanding of NLRP3 spatiotemporal dynamics, focusing on recent literature that elucidates the roles of subcellular localization and organelle stress in NLRP3 signaling and its crosstalk with other innate immune pathways converging at these organelles.

A20 haploinsufficiency diagnosis beyond systemic lupus erythematosus: A systematic review of the literature.

Systemic lupus erythematosus (SLE) is an autoimmune disease whose pathophysiology remains incompletely understood, involving genetic and epigenetic factors. However, an increasing small subset of patients present with monogenic lupus, providing insight into the pathogenesis of the disease. This systematic review focuses on SLE associated with A20 haploinsufficiency (HA20), a monogenic disorder associated with tumor necrosis factor alpha-induced protein 3 gene (TNFAIP3) variants. Besides the mainly auto-inflammatory phenotypic expression of HA20 mimicking Behçet's disease spectrum, some of its clinical and biological manifestations are part of the spectrum of autoimmune diseases, including glomerulonephritis as well as the frequent presence of antinuclear antibodies, sometimes with anti-DNA specificity. Among all the 191 HA20 patients reported in the literature, we identified 16 patients (8.4 %) with a compatible diagnosis of SLE. When estimable, the SLICC 2012 and EULAR/ACR 2019 classification criteria were positive for 92.9 % of them. A majority had multi-system involvement, mainly cutaneous (81.3 %), musculoskeletal (56.3 %), and/or renal (56.3 %) manifestations. They also seemed to exhibit differences compared to other SLE patients: higher prevalence of fever, chronic cutaneous lupus erythematosus, oral and genital ulcers, neuropsychiatric manifestations, autoimmune cytopenia, and elevated biologic inflammatory markers. This review highlights the necessity of considering TNFAIP3 variants in SLE patients with early-onset disease, familial history, and/or specific clinical manifestations suggestive of autoinflammatory diseases. Recognizing HA20-SLE patients may improve our understanding of SLE pathogenesis and lead to better therapeutic strategies for these patients.

Adaptive ımmune system evaluation in familial mediterranean fever: clinical and ımmunological analysis.

Familial Mediterranean Fever is a common genetic autoinflammatory disease prevalent in the Mediterranean region. The clinical course of the disease is characterized by fever and serositis attacks. While defects in the innate immune system are known to play a role in the pathogenesis of the disease, the impact of the adaptive immune system remains unclear. Therefore, the main objective of this study is to analyze the adaptive immune system cells in FMF patients and investigate their relationship with the disease. Our study includes 88 FMF patients with confirmed MEFV gene mutations. The demographic characteristics, clinical symptoms, genetic profiles, treatment methods, and any accompanying diseases of the patients were thoroughly examined. Additionally, lymphocyte subpopulations were analyzed using flow cytometry, and inflammatory markers and immunoglobulin levels were evaluated. Significant differences were observed in the distribution of adaptive immune system cells in FMF patients compared to the healthy reference group. In the analysis of lymphocyte subgroups, levels of CD3, CD4, CD19, CD16+56+, CD3CD4CD45RACD31, CD4+CD45RA+, CD8+CD45RA+, CD19+CD27+IgD+IgM+, CD19+CD27+IgD-IgM-, and CD19+CD38+CD21 were found to be lower compared to healthy individuals. Additionally, CD8, CD19+CD27-IgD+, and CD3/CD8/TCRGD cells were found to be higher. Moreover, in FMF patients with accompanying diseases, CD3, CD4, and CD19 values were statistically lower (p<0.001). This study reveals that adaptive immune system cells are affected in FMF patients, suggesting their significant role in the disease's pathophysiology. Immunological evaluations should be prioritized in the management of FMF, enabling personalized treatment plans for more effective outcomes.

The Distribution of MEFV Mutations in Iranian FMF Patients: Multicenter Study

Background/aim: The distribution of Mediterranean fever (MEFV) gene mutations in Iranian familial Mediterranean fever (FMF) patients varies according to geographic area of Iranian. There is a need for highly representative data for Iranian FMF patients. The aim of my study was to investigate the distribution of the common MEFV mutations in Iranian FMF patients in a nationwide, multicenter study. (Tehran, Mashhad, Kermanshah, Tabriz) that were visited by me for 20 years. Materials and Methods: Data of the 324 FMF patients, from 4 pediatric clinics located in different parts of the country, were evaluated retrospectively. The following mutations have been tested in all patients: M694V, M680I, M694I, V726A, and E148Q. Results: There were 324 FMF patients with available genetic testing. According to the genotyping, hetrozygous E148Q, present in 254 patients (78%), was the most common mutation .25 of patients had no detectable mutations. Allele frequencies of common mutations were: E148Q (n = 254, 78%), M694V (n= 23, 7%), V726A (n = 13, 4%), M694I (n =7 ,2%), and M680I (n = 2, &lt;1%).298 of them were Males&amp;26 Females. The ages of them between 1.5 year to 48 year. The common symptoms were(Abdominal pain, Recurrent vomiting, Artheralgia, Headche, Skin rash, Chest pain, Diarreha) and the common sign was periodic fever. Conclusion: In this large-scale multicenter study, we provided information about the frequencies of common MEFV gene mutations obtained from children to adults Iranian FMF patients. The maximal of the patients were carrying at least one E148Q mutations in their alleles.

Determining synchronously updated fixed points and attractors in a prototype boolean gene regulation model of diphtheria pathogenesis

This study employs dynamic modeling and simulation to provide theoretical insights into the systemic behaviors underlying diphtheria pathogenesis. A Boolean network model was developed to formalize the hypothesized interactions among eight genes identified in the literature as central to toxin production, immune response, and disease transmission. Computational exploration of the state-space dynamics within this model revealed three distinct attractors, each hypothesized to represent key disease states. Structural analysis of these attractors and their basins of attraction offered insights into network architectures potentially responsible for bistable switches between chronic infection and recovery, endogenous inflammatory oscillations reflective of periodic fever cycles, and modular topologies enabling alternative developmental pathways. These findings demonstrate the utility of Boolean modeling in uncovering organizing principles—such as periodicity, bistability, and evolvability—that govern disease emergence in complex systems. The study highlights testable network signatures that could refine our understanding of diphtheria and similar pathologies, and while preliminary, it underscores the potential of iterative computational and experimental approaches to inform more effective control strategies.