Dataset Information

Genetic associations in type I interferon related pathways with autoimmunity.

ABSTRACT: Type I interferons play an outstanding role in innate and adaptive immunity by enhancing functions of dendritic cells, inducing differentiation of monocytes, promoting immunoglobulin class switching in B cells and stimulating effector functions of T cells. The increased production of IFN?/? by plasmacytoid dendritic cells could be responsible for not only efficient antiviral defence, but it also may be a pathological factor in the development of various autoimmune disorders. The first evidence of a genetic link between type I interferons and autoimmune diseases was the observation that elevated IFN? activity is frequently detected in the sera of patients with systemic lupus erythematosus, and that this trait shows high heritability and familial aggregation in their first-degree healthy relatives. To date, a number of genes involved in interferon signalling have been associated with various autoimmune diseases. Patients with systemic lupus erythematosus, Sjögren's syndrome, dermatomyositis, psoriasis, and a fraction of patients with rheumatoid arthritis display a specific expression pattern of interferon-dependent genes in their leukocytes, termed the interferon signature. Here, in an attempt to understand the role of type I interferons in the pathogenesis of autoimmunity, we review the recent advances in the genetics of autoimmune diseases focusing on the association of genes involved in type I interferon pathways.

SUBMITTER: Delgado-Vega AM

PROVIDER: S-EPMC2991775 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Genetic associations in type I interferon related pathways with autoimmunity.

Delgado-Vega Angélica M AM Alarcón-Riquelme Marta E ME Kozyrev Sergey V SV

Arthritis research & therapy 20100414

Type I interferons play an outstanding role in innate and adaptive immunity by enhancing functions of dendritic cells, inducing differentiation of monocytes, promoting immunoglobulin class switching in B cells and stimulating effector functions of T cells. The increased production of IFNα/β by plasmacytoid dendritic cells could be responsible for not only efficient antiviral defence, but it also may be a pathological factor in the development of various autoimmune disorders. The first evidence o ...[more]

PMID: 20392289

Similar Datasets

Project description:Type I interferons (IFNs), mostly IFNα and IFNβ, and the type I IFN Signature are important in the pathogenesis of Systemic Lupus Erythematosus (SLE), an autoimmune chronic condition linked to inflammation. Both IFNα and IFNβ trigger a signaling cascade that, through the activation of JAK1, TYK2, STAT1 and STAT2, initiates gene transcription of IFN stimulated genes (ISGs). Noteworthy, other STAT family members and IFN Responsive Factors (IRFs) can also contribute to the activation of the IFN response. Aberrant type I IFN signaling, therefore, can exacerbate SLE by deregulated homeostasis leading to unnecessary persistence of the biological effects of type I IFNs. The etiopathogenesis of SLE is partially known and considered multifactorial. Family-based and genome wide association studies (GWAS) have identified genetic and transcriptional abnormalities in key molecules directly involved in the type I IFN signaling pathway, namely TYK2, STAT1 and STAT4, and IRF5. Gain-of-function mutations that heighten IFNα/β production, which in turn maintains type I IFN signaling, are found in other pathologies like the interferonopathies. However, the distinctive characteristics have yet to be determined. Signaling molecules activated in response to type I IFNs are upregulated in immune cell subsets and affected tissues of SLE patients. Moreover, Type I IFNs induce chromatin remodeling leading to a state permissive to transcription, and SLE patients have increased global and gene-specific epigenetic modifications, such as hypomethylation of DNA and histone acetylation. Epigenome wide association studies (EWAS) highlight important differences between SLE patients and healthy controls in Interferon Stimulated Genes (ISGs). The combination of environmental and genetic factors may stimulate type I IFN signaling transiently and produce long-lasting detrimental effects through epigenetic alterations. Substantial evidence for the pathogenic role of type I IFNs in SLE advocates the clinical use of neutralizing anti-type I IFN receptor antibodies as a therapeutic strategy, with clinical studies already showing promising results. Current and future clinical trials will determine whether drugs targeting molecules of the type I IFN signaling pathway, like non-selective JAK inhibitors or specific TYK2 inhibitors, may benefit people living with lupus.

Dataset Information

Genetic associations in type I interferon related pathways with autoimmunity.

Publications

Genetic associations in type I interferon related pathways with autoimmunity.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets