Immunology in the Clinic Review Series: Focus on autoinflammatory diseases: update on monogenic autoinflammatory diseases: the role of interleukin (IL)-1 and an emerging role for cytokines beyond IL-1

Translational Autoinflammatory Disease Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Clinical & Experimental Immunology (Impact Factor: 3.04). 03/2012; 167(3):391-404. DOI: 10.1111/j.1365-2249.2011.04533.x
Source: PubMed


Allergy, Host Responses, Cancer, Type 1 diabetes and viruses, Metabolic diseases.
The disease-based discovery of the molecular basis for autoinflammatory diseases has led not only to a rapidly growing number of clinically and genetically identifiable disorders, but has unmantled key inflammatory pathways such as the potent role of the alarm cytokine interleukin (IL)-1 in human disease. Following its initial failures in the treatment of sepsis and the moderate success in the treatment of rheumatoid arthritis, IL-1 blocking therapies had a renaissance in the treatment of a number of autoinflammatory conditions, and IL-1 blocking therapies have been Food and Drug Administration (FDA)-approved for the treatment of the autoinflammatory conditions: cryopyrin-associated periodic syndromes (CAPS). CAPS and deficiency of the IL-1 receptor antagonist (DIRA), both genetic conditions with molecular defects in the IL-1 pathway, have provided a pathogenic rationale to IL-1 blocking therapies, and the impressive clinical results confirmed the pivotal role of IL-1 in human disease. Furthermore, IL-1 blocking strategies have shown clinical benefit in a number of other genetically defined autoinflammatory conditions, and diseases with clinical similarities to the monogenic disorders and not yet identified genetic causes. The discovery that IL-1 is not only triggered by infectious danger signals but also by danger signals released from metabolically ‘stressed’ or even dying cells has extended the concept of autoinflammation to disorders such as gout, and those that were previously not considered inflammatory, such as type 2 diabetes, coronary artery disease, obesity and some degenerative diseases, and provided the conceptual framework to target IL-1 in these diseases. Despite the tremendous success of IL-1 blocking therapy, the use of these agents in a wider spectrum of autoinflammatory conditions has uncovered disease subsets that are not responsive to IL-1 blockade, including the recently discovered proteasome-associated autoinflammatory syndromes such as chronic atypical neutrophilic dermatitis with lipodystrophy and elevated temperatures (CANDLE), Japanese autoinflammatory syndrome with lipodystrophy (JASL), Nakajo–Nishimura syndrome (NNS) and joint contractures, muscle atrophy, panniculitis induced lipodystrophy (JMP), and urge the continued quest to characterize additional dysregulated innate immune pathways that cause autoinflammatory conditions.

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Available from: Raphaela Goldbach-Mansky
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    ABSTRACT: Biliary atresia (BA) is characterized by progressive inflammation and fibrosis of bile ducts. A theory of pathogenesis entails autoimmune-mediated injury targeting bile duct epithelia. One of the strongest genetic associations with autoimmunity is with HLA genes. In addition, apparently dissimilar HLA alleles may have similar antigen-binding sites, called shared epitopes, that overlap in their capacity to present antigens. In autoimmune disease, the incidence of the disease may be related to the presence of shared epitopes, not simply the HLA allelic association. Aim: To determine HLA allele frequency (high-resolution genotyping) and shared epitope associations in BA. Results: Analysis of every allele for HLA-A, -B, -C, -DRB1, -DPB1 and -DQB1 in 180 BA and 360 racially-matched controls did not identify any significant HLA association with BA. Furthermore, shared epitope analysis of greater than 10 million possible combinations of peptide sequences was not different between BA and controls. Conclusions: This study encompasses the largest HLA allele frequency analysis for BA in the United States and is the first study to perform shared epitope analysis. When controlling for multiple comparisons, no HLA allele or shared epitope association was identified in BA. Future studies of genetic links to BA that involve alterations of the immune response should include investigations into defects in regulatory T cells and non-HLA linked autoinflammatory diseases. Electronic supplementary material The online version of this article (doi:10.1186/2193-1801-2-42) contains supplementary material, which is available to authorized users.
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    • "Therefore, the managing premedications for reactions to infusional monoclonal antibody therapy are mandatory [41, 42]. Among other inhibitors of inflammatory cytokines, IL-1ra is used to treat the symptoms of moderate to severe rheumatoid arthritis [43]. The most common side effect has included injection site reactions [44]. "
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    • "CAPS comprise the mild familial cold-induced autoinflammatory syndrome (FCAS), the moderate MWS, and the severe neonatal-onset multisystem inflammatory disease (NOMID), also known as chronic infantile neurologic, cutaneous, articular (CINCA) syndrome [1-3]. Most CAPS patients carry mutations in the NLRP3 gene encoding the protein cryopyrin/NALP3 [4,5] which is essential for the activation of intracellular caspase 1 and the processing of interleukin-1β (IL-1β) [6-11]. Macrophages from MWS patients show a constitutive increase of IL-1β [2,10,12,13]. "
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