The Type I Interferonopathies Lee-Kirsch, Min Ae
Annual review of medicine,
01/2017, Letnik:
68, Številka:
1
Journal Article
Recenzirano
Type I interferons (IFNs) play a central role in the immune defense against viral infections. Type I IFN activation is induced by pattern-recognition receptors of the innate immune system that sense ...pathogen-derived nucleic acids. Cellular responses to type I IFN signaling are orchestrated by a complex network of regulatory pathways that involve both the innate and adaptive immune system. The genetic and molecular dissection of rare Mendelian disorders associated with constitutive overproduction of type I IFN has provided unique insight into cell-intrinsic disease mechanisms that initiate and sustain autoinflammation and autoimmunity and that are caused by disturbances in the intracellular nucleic acid metabolism or in cytosolic nucleic acid-sensing pathways. Collectively, these findings have greatly advanced our understanding of mechanisms that protect the organism against inappropriate immune activation triggered by self nucleic acids while maintaining a prompt and efficient immune response to foreign nucleic acids derived from invading pathogens.
Loss-of-function mutations in SKIV2L underlie trichohepatoenteric syndrome (THES2), a rare inborn error of immunity characterized by diarrhea, skin lesions, brittle hair, and immunodeficiency. SKIV2L ...is part of a multiprotein complex required for exosome-mediated RNA surveillance through RNA decay. In this issue of the JCI, Yang et al. delineate a mechanism underlying autoinflammatory skin disease in Skiv2l-deficient mice. Thus, a lack of SKIV2L activates mTORC1 signaling in keratinocytes and T cells, impeding skin barrier integrity and T cell homeostasis. Interestingly, treatment with the mTOR inhibitor rapamycin improves skin symptoms in Skiv2l-deficient mice, suggesting a possible therapeutic avenue for patients with THES2.
Familial chilblain lupus is a monogenic form of cutaneous lupus erythematosus caused by loss-of-function mutations in the nucleases TREX1 or SAMHD1. In a family without TREX1 or SAMHD1 mutation, we ...sought to determine the causative gene and the underlying disease pathology.
Exome sequencing was used for disease gene identification. Structural analysis was performed by homology modelling and docking simulations. Type I interferon (IFN) activation was assessed in cells transfected with STING cDNA using an IFN-β reporter and Western blotting. IFN signatures in patient blood in response to tofacitinib treatment were measured by RT-PCR of IFN-stimulated genes.
In a multigenerational family with five members affected with chilblain lupus, we identified a heterozygous mutation of STING, a signalling molecule in the cytosolic DNA sensing pathway. Structural and functional analyses indicate that mutant STING enhances homodimerisation in the absence of its ligand cGAMP resulting in constitutive type I IFN activation. Treatment of two affected family members with the Janus kinase (JAK) inhibitor tofacitinib led to a marked suppression of the IFN signature.
A heterozygous gain-of-function mutation in STING can cause familial chilblain lupus. These findings expand the genetic spectrum of type I IFN-dependent disorders and suggest that JAK inhibition may be of therapeutic value.
Viral infection triggers innate immune sensors to produce type I interferon. However, infection of T cells and macrophages with human immunodeficiency virus (HIV) does not trip those alarms. How HIV ...avoids activating nucleic acid sensors is unknown. Here we found that the cytosolic exonuclease TREX1 suppressed interferon triggered by HIV. In Trex1(-/-) mouse cells and human CD4(+) T cells and macrophages in which TREX1 was inhibited by RNA-mediated interference, cytosolic HIV DNA accumulated and HIV infection induced type I interferon that inhibited HIV replication and spreading. TREX1 bound to cytosolic HIV DNA and digested excess HIV DNA that would otherwise activate interferon expression via a pathway dependent on the kinase TBK1, the adaptor STING and the transcription factor IRF3. HIV-stimulated interferon production in cells deficient in TREX1 did not involve known nucleic acid sensors.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In contrast to CRISPR/Cas9 nucleases, CRISPR base editors (BE) and prime editors (PE) enable predefined nucleotide exchanges in genomic sequences without generating DNA double strand breaks. Here, we ...employed BE and PE mRNAs in conjunction with chemically synthesized sgRNAs and pegRNAs for efficient editing of human induced pluripotent stem cells (iPSC). Whereas we were unable to correct a disease-causing mutation in patient derived iPSCs using a CRISPR/Cas9 nuclease approach, we corrected the mutation back to wild type with high efficiency utilizing an adenine BE. We also used adenine and cytosine BEs to introduce nine different cancer associated
mutations into human iPSCs with up to 90% efficiency, generating a panel of cell lines to investigate the biology of these mutations in an isogenic background. Finally, we pioneered the use of prime editing in human iPSCs, opening this important cell type for the precise modification of nucleotides not addressable by BEs and to multiple nucleotide exchanges. These approaches eliminate the necessity of deriving disease specific iPSCs from human donors and allows the comparison of different disease-causing mutations in isogenic genetic backgrounds.
Objective
Autoinflammatory type I interferonopathies, chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature/proteasome‐associated autoinflammatory syndrome ...(CANDLE/PRAAS), stimulator of interferon genes (STING)–associated vasculopathy with onset in infancy (SAVI), and Aicardi‐Goutières syndrome (AGS) are rare and clinically complex immunodysregulatory diseases. With emerging knowledge of genetic causes and targeted treatments, a Task Force was charged with the development of “points to consider” to improve diagnosis, treatment, and long‐term monitoring of patients with these rare diseases.
Methods
Members of a Task Force consisting of rheumatologists, neurologists, an immunologist, geneticists, patient advocates, and an allied health care professional formulated research questions for a systematic literature review. Then, based on literature, Delphi questionnaires, and consensus methodology, “points to consider” to guide patient management were developed.
Results
The Task Force devised consensus and evidence‐based guidance of 4 overarching principles and 17 points to consider regarding the diagnosis, treatment, and long‐term monitoring of patients with the autoinflammatory interferonopathies, CANDLE/PRAAS, SAVI, and AGS.
Conclusion
These points to consider represent state‐of‐the‐art knowledge to guide diagnostic evaluation, treatment, and management of patients with CANDLE/PRAAS, SAVI, and AGS and aim to standardize and improve care, quality of life, and disease outcomes.
Immune recognition of cytosolic DNA represents a central antiviral defence mechanism. Within the host, short single-stranded DNA (ssDNA) continuously arises during the repair of DNA damage induced by ...endogenous and environmental genotoxic stress. Here we show that short ssDNA traverses the nuclear membrane, but is drawn into the nucleus by binding to the DNA replication and repair factors RPA and Rad51. Knockdown of RPA and Rad51 enhances cytosolic leakage of ssDNA resulting in cGAS-dependent type I IFN activation. Mutations in the exonuclease TREX1 cause type I IFN-dependent autoinflammation and autoimmunity. We demonstrate that TREX1 is anchored within the outer nuclear membrane to ensure immediate degradation of ssDNA leaking into the cytosol. In TREX1-deficient fibroblasts, accumulating ssDNA causes exhaustion of RPA and Rad51 resulting in replication stress and activation of p53 and type I IFN. Thus, the ssDNA-binding capacity of RPA and Rad51 constitutes a cell intrinsic mechanism to protect the cytosol from self DNA.
We conducted a genome-wide association study in 939 individuals with atopic dermatitis and 975 controls as well as 270 complete nuclear families with two affected siblings. SNPs consistently ...associated with atopic dermatitis in both discovery sets were then investigated in two additional independent replication sets totalling 2,637 cases and 3,957 controls. Highly significant association was found with allele A of rs7927894 on chromosome 11q13.5, located 38 kb downstream of C11orf30 (Pcombined = 7.6 × 10−10). Approximately 13% of individuals of European origin are homozygous for rs7927894A, and their risk of developing atopic dermatitis is 1.47 times that of noncarriers.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The genetically determined impairment of the skin barrier is a primary cause of eczema. As numerous genes essential for an intact epidermis reside within the epidermal differentiation complex (EDC), ...we screened the National Center for Biotechnology Information (NCBI) database for putatively functional polymorphisms in the EDC genes and tested them for association with eczema. We identified 20 polymorphisms with predicted major impact on protein function. Of these, 4 were validated in 94 eczema patients: a nonsense mutation in FLG2 (rs12568784), a stop codon mutation in LCE1D (rs41268500), a 24-bp deletion in SPRR3 (rs28989168), and a frameshift mutation in S100A3 (rs11390146). The minor allele frequencies were 15.1, 6.1, 47.2, and 0.4%, respectively. Association testing of the validated polymorphisms in 555 eczema patients and 375 controls identified a significant effect of rs28989168 (SPRR3) on eczema. The association was replicated in another 1,314 cases and 1,322 controls, yielding an overall odds ratio of 1.30 (95% confidence interval 1.12–1.51; P=0.00067) for a dominant mode of inheritance. Small proline-rich proteins (SPRRs) are crossbridging proteins in the cornified cell envelope (CE), which provides the main barrier function of stratified squamous epithelia. The SPRR3 variant associated with eczema carried an extra 24-bp repeat in the central domain, which may alter the physical properties of the CE.
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