Lupus‐like disease and high interferon levels corresponding to trisomy of the type I interferon cluster on chromosome 9p

Zhuang, Haoyang; Kosboth, Mona; Lee, Pui Y.; Rice, Amanda D.; Driscoll, Daniel J.; Zori, Roberto T.; Narain, Sonali; Lyons, Robert H.; Satoh, Minoru; Sobel, Eric S.; Reeves, Westley H.

doi:10.1002/art.21800

Cited by 42 publications

(25 citation statements)

References 42 publications

(62 reference statements)

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“…As shown by the observation of an IFN signature, it appears that mosaic tetrasomy 9p results in an increased expression of genes induced by IFN, which is in accordance with the findings of Zhuang et al 13 who reported SLE-like disease associated with elevated levels of IFN-a/b in 2 patients with a trisomy of 9p-containing type I IFN cluster. Our report supports the hypothesis that several copies of the type I IFN cluster result in high levels of type I IFN due to a gene-dosage effect, and hence an increased susceptibility to some autoimmune diseases.…”

Section: Figuresupporting

confidence: 90%

Mosaic Tetrasomy 9p: A Mendelian Condition Associated With Pediatric-Onset Overlap Myositis

et al. 2015

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Pediatric-onset inflammatory myositis (IM) and systemic lupus erythematosus (SLE) are rare inflammatory diseases. Both result from the complex interaction of genetic and environmental factors. An increasing number of Mendelian conditions predisposing to the development of SLE have been recently identified. These include monogenic conditions, referred to as the type I interferonopathies, associated with a primary upregulation of type I interferon (IFN), a key cytokine in the pathogenesis of SLE and some cases of IM. Here, we report on a pediatric-onset inflammatory overlap phenotype in a 6-year-old girl who was shown to carry mosaic tetrasomy 9p. The patient presented with myositis overlapping with lupuslike features. Myositis was characterized by a proximal muscular weakness and HLA class I antigen myofiber overexpression on muscle biopsy. Lupus-like manifestations consisted of pericarditis, pleuritis, and positive antinuclear and anti-SSA (Sjögren-syndrome A) antibodies. Complete remission was achieved with corticosteroids and mycophenolate mofetyl. Analysis of tetrasomy 9p showed mosaic tetrasomy in the 9p24.3q12 region, including the type I IFN cluster, and increased expression of IFN-stimulated genes. These data suggest that mosaic tetrasomy 9p can be associated with an upregulation of type I IFN signaling, predisposing to inflammatory myositis and lupus-like features. Thus, unexplained muscle or other organ involvement in patients carrying mosaic tetrasomy of the type IFN cluster of chromosome 9p should lead to the search for IM and/or lupuslike disease, and karyotype should be performed in patients with SLE or IM with mental retardation.

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Section: Figuresupporting

confidence: 90%

Mosaic Tetrasomy 9p: A Mendelian Condition Associated With Pediatric-Onset Overlap Myositis

et al. 2015

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“…29 Furthermore, 129Sv mice deficient for interferon alpha receptor (IFNAR) are protected from experimental lupus 30 and IFN-a therapy for unrelated disorders is associated with autoimmune manifestations, including lupus-like symptoms. 31 We hypothesized that the SLE-associated increase in CD56 bright NK cell proportion described here could be induced by high IFN-a levels.…”

Section: Discussionmentioning

confidence: 99%

Increased proportion of CD56^bright natural killer cells in active and inactive systemic lupus erythematosus

et al. 2008

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Summary Natural killer (NK) cells belong to the innate immune system but can also affect adaptive immune reactions. This immune regulatory function is often ascribed to the CD56bright subpopulation of NK cells that is prevalent in secondary lymphoid tissues and has potent cytokine‐producing ability. The NK cells have been described as affecting autoimmune disease and stimulating B‐cell production of antibodies, but their role in systemic lupus erythematosus (SLE) pathology has not been extensively studied. We have studied NK cells in SLE, a B‐cell‐driven systemic autoimmune disease, and phenotypically characterized peripheral blood NK cells in comparison to NK cells from patients with immunoglobulin A nephritis, rheumatoid arthritis and healthy individuals. We have found an increased proportion of CD56bright NK cells in SLE, regardless of disease activity. We detected a somewhat increased expression of the activating receptor NKp46/CD335 on NK cells from SLE patients, although neither the percentage of NK cells of all lymphocytes nor the expression of other NK receptors analysed (LIR‐1/CD85j, CD94, NKG2C/CD159c, NKG2D/CD314, NKp30/CD337, NKp44/CD336, CD69) differed between patient groups. We show that type I interferon, a proinflammatory cytokine known to be abundant in SLE, can cause increases of CD56bright NK cells in vitro. We confirmed that serum levels of interferon‐α were increased in active, but not in inactive, disease in the SLE patient group. In conclusion, we found an increased proportion of CD56bright NK cells in the blood of SLE patients, although it remains to be examined whether and how this relates to the disease process.

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“…Global gene expression studies on blood lymphoid cells and kidneys from SLE patients have shown that IFN-regulated genes (IFN-signature) are selectively upregulated in these patients [158,161]. Some typical lupus symptoms have been described in individuals with trisomy of the type I IFN gene cluster [162] and with single nucleotide polymorphisms in the IRF5 and tyrosine kinase 2 (TYK2) genes, the products of which are involved in regulating type I IFN production [163, Cell. Mol.…”

Section: Dcs and Autoimmunitymentioning

confidence: 99%

Central role of dendritic cells in the regulation and deregulation of immune responses

Granucci

Zanoni

Ricciardi‐Castagnoli

2008

Cell. Mol. Life Sci.

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Dendritic cells (DCs) play a critical role in orchestrating the innate and adaptive components of the immune system so that appropriate, coordinated responses are mounted against infectious agents. Tissue-resident DCs interact with microbes through germline-encoded pattern-recognition receptors (PRRs), which recognize molecular patterns expressed by various microorganisms. Antigens use PRR activation to instruct DCs for the appropriate priming of natural killer (NK) cells, followed by specific T-cell responses. Due to the central role of DCs in regulating the activation and progression of immune responses, minor imbalances in the feedback control of Toll-like receptor (TLR)-activated cells have been associated with autoimmunity in genetically prone individuals. We review here recent findings on the role of DCs in the priming of innate and adaptive immune responses and the possible involvement of DCs in inducing and maintaining autoimmune reactions.

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Lupus‐like disease and high interferon levels corresponding to trisomy of the type I interferon cluster on chromosome 9p

Abstract: Trisomy of the type I IFN cluster of chromosome 9p was associated with lupus-like autoimmunity and increased IFNalpha/beta and IFN receptor signaling. The data support the idea that abnormal regulation of type I IFN production is involved in the pathogenesis of SLE.

Cited by 42 publications

References 42 publications

Mosaic Tetrasomy 9p: A Mendelian Condition Associated With Pediatric-Onset Overlap Myositis

Mosaic Tetrasomy 9p: A Mendelian Condition Associated With Pediatric-Onset Overlap Myositis

Increased proportion of CD56^bright natural killer cells in active and inactive systemic lupus erythematosus

Central role of dendritic cells in the regulation and deregulation of immune responses

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Lupus‐like disease and high interferon levels corresponding to trisomy of the type I interferon cluster on chromosome 9p

Abstract: Trisomy of the type I IFN cluster of chromosome 9p was associated with lupus-like autoimmunity and increased IFNalpha/beta and IFN receptor signaling. The data support the idea that abnormal regulation of type I IFN production is involved in the pathogenesis of SLE.

Cited by 42 publications

References 42 publications

Mosaic Tetrasomy 9p: A Mendelian Condition Associated With Pediatric-Onset Overlap Myositis

Mosaic Tetrasomy 9p: A Mendelian Condition Associated With Pediatric-Onset Overlap Myositis

Increased proportion of CD56bright natural killer cells in active and inactive systemic lupus erythematosus

Central role of dendritic cells in the regulation and deregulation of immune responses

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Increased proportion of CD56^bright natural killer cells in active and inactive systemic lupus erythematosus