-
Cold Spring Harbor Perspectives in... Jan 2019As key regulators of both innate and adaptive immunity, it is unsurprising that the activity of interleukin (IL)-1 cytokine family members is tightly controlled by decoy... (Review)
Review
As key regulators of both innate and adaptive immunity, it is unsurprising that the activity of interleukin (IL)-1 cytokine family members is tightly controlled by decoy receptors, antagonists, and a variety of other mechanisms. Additionally, inflammasome-mediated proteolytic maturation is a prominent and distinguishing feature of two important members of this cytokine family, IL-1β and IL-18, because their full-length gene products are biologically inert. Although vital in antimicrobial host defense, deregulated inflammasome signaling is linked with a growing number of autoimmune and autoinflammatory diseases. Here, we focus on introducing the diverse inflammasome types and discussing their causal roles in periodic fever syndromes. Therapies targeting IL-1 or IL-18 show great efficacy in some of these autoinflammatory diseases, although further understanding of the molecular mechanisms leading to unregulated production of these key cytokines is required to benefit more patients.
Topics: Adaptive Immunity; Anemia, Dyserythropoietic, Congenital; Animals; Autoimmune Diseases; Autoimmunity; Carrier Proteins; Cryopyrin-Associated Periodic Syndromes; Familial Mediterranean Fever; Fever; HMGB1 Protein; Humans; Immune System; Immunity, Innate; Immunologic Deficiency Syndromes; Inflammasomes; Inflammation; Interleukin 1 Receptor Antagonist Protein; Interleukin-18; Interleukin-1beta; Mice; Models, Biological; Osteomyelitis; Pyroptosis; S100 Proteins; Signal Transduction
PubMed: 29038114
DOI: 10.1101/cshperspect.a028563 -
Frontiers in Pediatrics 2023Autoinflammatory bone disorders are a group of diseases characterized by sterile osteomyelitis. This includes chronic nonbacterial osteomyelitis and the monogenic forms,... (Review)
Review
Autoinflammatory bone disorders are a group of diseases characterized by sterile osteomyelitis. This includes chronic nonbacterial osteomyelitis and the monogenic forms, Majeed syndrome and deficiency of the interleukin-1 receptor antagonist. These disorders result from innate immune system dysregulation and cytokine imbalance that triggers inflammasome activation causing downstream osteoclastogenesis and excessive bone remodeling. In this review, we will summarize the immunopathogenesis of pediatric autoinflammatory bone diseases with a special focus on the genetics and inborn errors of immunity, while briefly touching on the clinical manifestations and management of each disease as well as areas for future research.
PubMed: 37342528
DOI: 10.3389/fped.2023.1169659 -
Pediatric Rheumatology Online Journal Oct 2022Systemic autoinflammatory diseases (SAIDs) are hyperinflammatory and immune-dysregulation conditions that present in childhood. This kind of disease is a rare disease... (Review)
Review
BACKGROUND
Systemic autoinflammatory diseases (SAIDs) are hyperinflammatory and immune-dysregulation conditions that present in childhood. This kind of disease is a rare disease with early-onset, severe condition and difficult diagnosis, which seriously affects the growth and development of children. Most children need a genetic diagnosis. However, with the limitation of access to genetic testing and the detection of somatic mutations, the diagnosis of SAIDs remains challenging. IL-1 is one of the important cytokines involved in the pathogenesis of SAIDs. Here we briefly review monogenic SAIDs mediated by aberrant IL-1 production, with the aim to further understand the pathogenesis, clinical manifestations and treatments of IL-1 mediated SAIDs.
METHODS
Literature reviews were performed using "PubMed" and "Web of Science" by searching for the terms "autoinflammatory diseases" and "IL-1".
RESULTS
Monogenic SAIDs mediated by IL-1 include MKD, FMF, TRAPS, PAAND, PAPA, CAPS, DIRA, Majeed syndrome, NAIAD, NLRC4-MAS, PFIT, APLAID. Monogenic SAIDs have early onset, various clinical manifestations and difficult diagnosis, so early recognition and early treatment can reduce the complications and enhance the quality of life.
CONCLUSIONS
There are many kinds of IL-1 mediated SAIDs. Pediatricians should be alert to SAIDs in the face of the patients with repeated fever, repeated rash and poor effect of routine treatment. The patients should be carried out with gene testing and treatment in time.
Topics: Animals; Child; Cytokines; Genetic Testing; Hereditary Autoinflammatory Diseases; Humans; Quality of Life; Simian Acquired Immunodeficiency Syndrome
PubMed: 36253853
DOI: 10.1186/s12969-022-00728-0 -
Current Rheumatology Reports Apr 2017We focus on recent advances in the understanding of the genetic, molecular, immunologic, and environmental factors implicated in the pathogenesis of autoinflammatory... (Review)
Review
PURPOSE OF REVIEW
We focus on recent advances in the understanding of the genetic, molecular, immunologic, and environmental factors implicated in the pathogenesis of autoinflammatory bone diseases including the syndromic and non-syndromic forms of chronic recurrent multifocal osteomyelitis (CRMO).
RECENT FINDINGS
Evidence implicating the IL-1 pathway in the pathogenesis of the Mendelian forms of CRMO is growing. LIPIN2 can regulate the NLRP3 inflammasome by affecting P2X7 receptor activation, and intracellular cholesterol can modulate P2X7R currents. Work in a mouse model of CRMO demonstrates that dietary manipulation can alter the microbiome and protect these mice from the development of sterile osteomyelitis in vivo. Although the genetic and immunologic basis of non-syndromic CRMO remains only partially understood, the IL-1 pathway is central to the pathogenesis in the syndromic autoinflammatory bone disorders. Recent work implicates lipids and the microbiome in sterile osteomyelitis.
Topics: Anemia, Dyserythropoietic, Congenital; Animals; Cell Adhesion Molecules; Cytoskeletal Proteins; Disease Models, Animal; Hereditary Autoinflammatory Diseases; Humans; Immunologic Deficiency Syndromes; Inflammasomes; Interleukin-1; Mice; Microbiota; Nuclear Proteins; Osteomyelitis
PubMed: 28361334
DOI: 10.1007/s11926-017-0645-9 -
Journal of Medical Genetics Jul 2005Majeed syndrome is an autosomal recessive, autoinflammatory disorder characterised by chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic...
BACKGROUND
Majeed syndrome is an autosomal recessive, autoinflammatory disorder characterised by chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia. The objectives of this study were to map, identify, and characterise the Majeed syndrome causal gene and to speculate on its function and role in skin and bone inflammation.
METHODS
Six individuals with Majeed syndrome from two unrelated families were identified for this study. Homozygosity mapping and parametric linkage analysis were employed for the localisation of the gene responsible for Majeed syndrome. Direct sequencing was utilised for the identification of mutations within the genes contained in the region of linkage. Expression studies and in silico characterisation of the identified causal gene and its protein were carried out.
RESULTS
The phenotype of Majeed syndrome includes inflammation of the bone and skin, recurrent fevers, and dyserythropoietic anaemia. The clinical picture of the six affected individuals is briefly reviewed. The gene was mapped to a 5.5 cM interval (1.8 Mb) on chromosome 18p. Examination of genes in this interval led to the identification of homozygous mutations in LPIN2 in affected individuals from the two families. LPIN2 was found to be expressed in almost all tissues. The function of LPIN2 and its role in inflammation remains unknown.
CONCLUSIONS
We conclude that homozygous mutations in LPIN2 result in Majeed syndrome. Understanding the aberrant immune response in this condition will shed light on the aetiology of other inflammatory disorders of multifactorial aetiology including isolated chronic recurrent multifocal osteomyelitis, Sweet syndrome, and psoriasis.
Topics: Adult; Anemia, Dyserythropoietic, Congenital; Animals; Causality; Chronic Disease; Conserved Sequence; DNA Mutational Analysis; Family; Female; Genetic Linkage; Homozygote; Humans; Jordan; Male; Mutation; Nuclear Proteins; Organ Specificity; Osteomyelitis; Pedigree; Phenotype; Recurrence; Sweet Syndrome; Syndrome
PubMed: 15994876
DOI: 10.1136/jmg.2005.030759 -
Current Rheumatology Reports Apr 2012Chronic recurrent multifocal osteomyelitis (CRMO) is an inflammatory disorder that primarily affects children. Its hallmark is recurring episodes of sterile... (Review)
Review
Chronic recurrent multifocal osteomyelitis (CRMO) is an inflammatory disorder that primarily affects children. Its hallmark is recurring episodes of sterile osteomyelitis. The clinical presentation is insidious onset of bone pain with or without fever. Laboratory studies typically reveal nonspecific evidence of inflammation. Radiologic imaging and histologic appearance resemble those of infectious osteomyelitis. There is a strong association with inflammatory disorders of the skin and intestinal tract in affected individuals and their close relatives, suggesting a shared pathophysiology and supporting a genetic component to disease susceptibility. Two genetic syndromes have CRMO as a prominent phenotype-Majeed syndrome and deficiency of the interleukin-1 receptor antagonist-and suggest that interleukin-1 may be a key cytokine in disease pathogenesis. This review briefly summarizes the main clinical and radiologic aspects of the disease and then focuses on genetics and pathophysiology and provides an update on treatment.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Diphosphonates; Humans; Osteomyelitis; Radiography; Recurrence
PubMed: 22359228
DOI: 10.1007/s11926-012-0239-5 -
Current Opinion in Lipidology Jun 2009The family of three lipin proteins act as phosphatidate phosphatase (PAP) enzymes required for glycerolipid biosynthesis, and also as transcriptional coactivators that... (Review)
Review
PURPOSE OF REVIEW
The family of three lipin proteins act as phosphatidate phosphatase (PAP) enzymes required for glycerolipid biosynthesis, and also as transcriptional coactivators that regulate expression of lipid metabolism genes. The genes for lipin-1, lipin-2 and lipin-3 are expressed in key metabolic tissues, including adipose tissue, skeletal muscle and liver, but the physiological functions of each member of the family have not been fully elucidated. Here we examine the most recent studies that provide information about the roles of lipin proteins in metabolism and human disease.
RECENT FINDINGS
Recent studies have identified mutations that cause lipin-1 or lipin-2 deficiency in humans, leading to acute myoglobinuria in childhood or the inflammatory disorder Majeed syndrome, respectively. The effects of lipin-1 deficiency appear to include both the loss of glycerolipid building blocks and the accumulation of lipid intermediates that disrupt cellular function. Several studies have demonstrated that polymorphisms in the LPIN1 and LPIN2 genes are associated with metabolic disease traits, including insulin sensitivity, diabetes, blood pressure and response to thiazolidinedione drugs. Furthermore, lipin-1 expression levels in adipose tissue and/or liver are positively correlated with insulin sensitivity. Studies of lipin-1 in adipocytes have shed some light on its relationship with insulin sensitivity.
SUMMARY
Lipin-1 and lipin-2 are required for normal lipid homeostasis and have unique physiological roles. Future studies, for example using engineered mouse models, will be required to fully elucidate their specific roles in normal physiology and disease.
Topics: Animals; Disease; Gene Expression Regulation; Humans; Mutation; Nuclear Proteins; Polymorphism, Genetic
PubMed: 19369868
DOI: 10.1097/MOL.0b013e32832adee5 -
Allergy, Asthma, and Clinical... Aug 2023Respiratory conditions, such as asthma, are infrequently associated with auto-inflammatory diseases. We describe five patients with uncontrolled respiratory symptoms...
BACKGROUND
Respiratory conditions, such as asthma, are infrequently associated with auto-inflammatory diseases. We describe five patients with uncontrolled respiratory symptoms that were seen at St. Joesph's Healthcare in Hamilton for severe asthma management diagnosed with rare autoinflammatory conditions using genetic molecular analysis.
CASE PRESENTATION
Five patients are included in this case series. Gene mutations associated with familial Mediterranean fever, Yao syndrome, Cryopyrin-associated periodic syndrome, and Majeed syndrome were considered to explain partly the patient's clinical manifestation after comprehensive clinical, biochemical, hematological investigations ruled out other disorders such as parasitosis, Allergic Bronchopulmonary Fungosis, Eosinophilic Granulomatosis with Poly Angitis, IgG4 disease, and Hypereosinophilia syndrome.
CONCLUSIONS
Complex patients initially presenting with respiratory conditions in addition to unexplained autoinflammatory conditions are a diagnostic challenge. Genetic molecular testing provides healthcare practitioners with useful information that may diagnose underlying auto-inflammatory diseases in undifferentiated patients. Role of inflammasome-activation in asthma and eosinophilia needs further investigation.
PubMed: 37644591
DOI: 10.1186/s13223-023-00837-9 -
Ugeskrift For Laeger Jul 2014Chronic non-bacterial osteomyelitis (CNO) is an autoinflammatory disease with unpredictable, painful courses of osteolytic lesions in the bones. CNO is frequently... (Review)
Review
Chronic non-bacterial osteomyelitis (CNO) is an autoinflammatory disease with unpredictable, painful courses of osteolytic lesions in the bones. CNO is frequently associated with psoriasis and inflammatory bowel disease. In cases with multifocal lesions the term chronic recurrent multifocal osteomyelitis (CRMO) is preferably used. SAPHO (synovitis, acne, pustulosis palmoplantaris, hyperostosis and osteitis) syndrome is regarded as CRMO in adults. New knowledge of the hereditary forms like Majeed syndrome, deficiency of IL-1-receptor antagonist and cherubism is described.
Topics: Acquired Hyperostosis Syndrome; Anemia, Dyserythropoietic, Congenital; Cherubism; Child; Hereditary Autoinflammatory Diseases; Humans; Immunologic Deficiency Syndromes; Osteochondrodysplasias; Osteomyelitis; Receptors, Interleukin-1
PubMed: 25292328
DOI: No ID Found -
Current Opinion in Rheumatology Sep 2013To provide an update on the genetics and immunologic basis of autoinflammatory bone disorders including chronic recurrent multifocal osteomyelitis including the... (Review)
Review
PURPOSE OF REVIEW
To provide an update on the genetics and immunologic basis of autoinflammatory bone disorders including chronic recurrent multifocal osteomyelitis including the monogenic forms of the disease.
RECENT FINDINGS
Ongoing research in murine, canine and human models of sterile bone inflammation has solidified the hypothesis that sterile bone inflammation can be genetically driven. Mutations in Pstpip2, LPIN2 and IL1RN have been identified in monogenic autoinflammatory bone disorders that have allowed more detailed dissection of the immunologic defects that can produce sterile osteomyelitis. Recent studies in murine chronic multifocal osteomyelitis, deficiency of the interleukin-1 receptor antagonist (DIRA), Majeed syndrome and SAPHO syndrome reveal abnormalities in innate immune system function. IL-1 pathway dysregulation is present in several of these disorders and blocking IL-1 therapeutically has resulted in control of disease in DIRA, Majeed syndrome and in some cases of SAPHO and CRMO. Basic research demonstrates the importance of the innate immune system in disease pathogenesis and offers clues about potential disease triggers.
SUMMARY
Research and clinical data produced over the last several years support the important role of innate immunity in sterile osteomyelitis. Based on what has been learned in the monogenic autoinflammatory bone disorders, IL-1 is emerging as an important pathway in the development of sterile bone inflammation.
Topics: Acquired Hyperostosis Syndrome; Anemia, Dyserythropoietic, Congenital; Animals; Chronic Disease; Disease Models, Animal; Dogs; Gram-Positive Bacterial Infections; Hereditary Autoinflammatory Diseases; Humans; Immunity, Innate; Immunologic Deficiency Syndromes; Interleukin-1; Mice; Osteomyelitis; Propionibacterium acnes; Recurrence; Tumor Necrosis Factor-alpha
PubMed: 23917160
DOI: 10.1097/BOR.0b013e328363eb08