Lupus-like autoimmune disease induced by interferon therapy for myeloproliferative disorders

Wandl, U.; Nagel-Hiemke, M.; May, Dieter; Kreuzfelder, E.; Kloke, O.; Kranzhoff, M.; Seeber, S.; Niederle, N.

doi:10.1016/0090-1229(92)90250-r

Cited by 154 publications

(73 citation statements)

References 19 publications

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“…IFN-a-based treatments are widely used for viral hepatitis and carcinoid tumors; however, several case reports have emerged describing autoimmune conditions that have developed during IFN-a therapy. [13][14][15] These observations in human and murine lupus implicate a complicated role of the type I IFN involved in lupus pathogenesis. We hypothesize that inappropriate activation of type I interferon (IFN) signaling pathways, combined with a genetic predisposition, may be important in SLE pathogenesis.…”

Section: Introductionmentioning

confidence: 95%

Genomic view of IFN-α response in pre-autoimmune NZB/W and MRL/lpr mice

Shen

et al. 2007

Genes Immun

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Interferon (IFN)-a is involved in the pathogenesis of systemic lupus erythematosus. Studies in murine lupus models have revealed that type I IFN exerts either a protective effect in MRL/lpr, or can detrimentally impact disease progression, as in NZB/ W mice. To understand this paradox, we examined the kinetic global gene expression in pre-autoimmune NZB/W-, MRL/lprand normal BALB/c-derived splenic mononuclear cells following ex vivo IFN-a treatment. Analysis of IFN-a-induced gene expression patterns revealed genes associated with antiproliferative activity of IFN-a including CDKN1A, GADD45B, pituitary tumor-transforming 1, SCOTIN, ataxia telangiectasia-mutated homolog and calcyclin-binding protein were upregulated in MRL/ lpr and/or BALB/c mice. Of IFN-a-induced genes differentially expressed in NZB/W vs BALB/c and MRL/lpr mice at 3 h time point, enhanced expression of CCND1, cyclin D2, matrix metalloproteinase 13 and a panel of cytokines and chemokines and impaired expression of negative inflammatory regulators CD69 and an Src family kinase hemopoietic cell kinase were notable. Interestingly, the splenic mononuclear cells from the NZB/W not MRL/lpr lupus-prone mice at the pre-autoimmune stage before ex vivo IFN-a treatment, have increased expression of many known IFN-regulated genes. These results provide a unique genomic view of ex vivo IFN-a response in two lupus-prone models, and help to have an insight into the role of IFN-a in lupus pathogenesis Genes and Immunity (2007) IntroductionSystemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease characterized by a break of immune tolerance to self antigens, resulting in inflammation and damage to a range of organ systems. The exact pathoetiology of SLE remains elusive. Elevated serum levels of IFN-a have long been observed and correlated with disease activity. A series of studies using microarray gene expression analysis in patient peripheral blood cells demonstrated an 'IFN signature' in SLE, which correlated with renal and hematological involvement of phenotypes. [1][2][3][4][5][6] Supporting evidence has also come from studies on murine lupus. The (New Zealand Black (NZB) Â New Zealand White (NZW))F1 hybrid female mice (NZB/W) develop a disease closely resembling human SLE, characterized by the production of antinuclear antibodies, severe glomerulonephritis and early mortality. In the NZB parental strain, which also develops a lupus-like syndrome, homozygous IFN-a/b R-deleted NZB mice had significantly reduced antierythrocyte autoantibodies, erythroblastosis, hemolytic anemia, anti-DNA autoantibodies, kidney disease and mortality. 7 In contrast to normal BALB/c mice, continuous in vivo treatment of IFN-a in pre-autoimmune NZB/W mice from 8 weeks of age precipitates the autoimmune process and kidney damage, leading to premature death from severe immune complex glomerulonephritis. This result provides a direct evidence that IFN-a is implicated in the pathogenesis of SLE. 8 Thus, the type I IFNs have emerged as a dominant target in the path...

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Section: Introductionmentioning

confidence: 95%

Genomic view of IFN-α response in pre-autoimmune NZB/W and MRL/lpr mice

Shen

et al. 2007

Genes Immun

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“…However, other types of autoimmune abnormalities have been described in IFN-treated chronic myelogenous leukemia patients, including antinuclear autoantibodies, immune-mediated hemolysis or thrombocytopenia, polyarthritis, glomerulonephritis and connective tissue diseases. [65][66][67][68] Mechanisms leading to the development of such abnormalities have not been clearly described, but they could include the direct immunomodulating properties of IFN or be initiated by a possible toxic effect in target organs, triggering self-directed immune response against altered cells. Some authors have raised the hypothesis that the development of autoimmune phenomena in IFN-treated chronic myelogenous leukemia patients could parallel and reflect the anti-leukemic efficacy of the drug, as patients presenting with autoimmune abnormalities had earlier and more frequent cytogenetic responses.…”

Section: Other Toxicitiesmentioning

confidence: 99%

Interferon-α therapy in bcr-abl-negative myeloproliferative neoplasms

2008

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Interferon (IFN) was the first cytokine discovered 50 years ago, with a wide range of biological properties, including immunomodulatory, proapoptotic and antiangiogenic activities, that rapidly raised interest in its therapeutic use in malignancies. IFN-receptor characterization was also pivotal in the discovery of the JAK/STAT signaling pathway. Among the large IFN family, mainly one of the type I IFN, IFN-a2, is used in therapy. Many clinical trials have shown remarkable efficacy of IFN-a in bcr-abl-negative myeloproliferative neoplasms (MPNs), especially polycythemia vera (PV), and essential thrombocythemia (ET). IFN-a induces about 80% of hematological responses in those diseases and is able to reduce splenomegaly, as well as relieve pruritus and other constitutional symptoms. Yet its use was limited by toxicity, leading to early treatment discontinuation in about 20% of the patients. However, its lack of leukemogenic potential and its possible use during pregnancy have already made IFN-a the drug of choice for younger MPN patients. In addition, several studies have shown a probably selective effect of IFN-a on PV and ET clones, as shown by cytogenetic remissions, reversions to polyclonal hematopoiesis, and more recently by induction of JAK2V617F complete molecular remissions in PV which may widen the indications of IFN-a in JAK2-mutated MPN.

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“…Among the different genes located within the Sle2 interval, IFN-I appeared to be an attractive candidate in view of its documented effect on the immune system and its implied role in murine and human lupus (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). Previous reports and results of more recent transcriptomic profiling studies had implied that increased IFN-I may be important in lupus pathogenesis (13)(14)(15)(16).…”

Section: Discussionmentioning

confidence: 99%

“…Most importantly, IFN-I therapy in patients with various malignancies has been reported to trigger the unexpected side effect of autoimmunity, with 2 common presentations: autoimmune thyroid disease and lupus (4)(5)(6)(7)(8)(9)(10)(11)(12). The incidence of SLE among patients treated with IFN␣ varies from 0.15% to 2.2% (4)(5)(6)(7)(8)(9)(10)(11)(12); these frequencies are greater than the incidence of lupus in the general population. The reported onset time from the initiation of IFN␣ therapy to the development of lupus varies from 1 month to 7 years (6).…”

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confidence: 95%

Deficiency of type I interferon contributes to Sle2‐associated component lupus phenotypes

Liu

Xie

et al. 2005

Arthritis & Rheumatism

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Objective. Studies in mice and humans have implicated type I interferon (IFN-I) in the pathogenesis of lupus. Given that the locus for IFN-I is positioned within the Sle2 murine lupus susceptibility interval on chromosome 4, we undertook this study to investigate whether differences in IFN-I levels might potentially contribute to the phenotypes ascribed to this locus.Methods. IFN-I, anti-IFN-I, isotype control antibody, or phosphate buffered saline was administered to C57BL/6 and B6.Sle2 mice, and the serologic and cellular phenotypes were studied. In addition, B6.Sle2 mice were examined for structural and expression polymorphisms in the IFN-I gene.Results. In both B6.Sle2 congenic mice and C57BL/6 control mice, antibody-mediated blockade of IFN-I augmented serum autoantibody levels and boosted B1a cell numbers. Administration of IFN-I ameliorated these 2 features previously attributed to this disease locus. Importantly, compared with B6 controls, B6.Sle2 mice had reduced levels of IFN-I in their sera and cell culture supernatants, following stimulation. Although several sequence polymorphisms were noted in the Sle2 alleles of various IFN-I genes, it was not established whether any of the noted sequence variations were causally related to the observed phenotypes.Conclusion. Unexpectedly, reduction of IFN-I levels reproduced the serologic and cellular phenotypes previously associated with the Sle2 lupus susceptibility interval. Placing these findings in the context of other studies, the effect of IFN-I on systemic autoimmunity appears to be far more complex than originally perceived.

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Lupus-like autoimmune disease induced by interferon therapy for myeloproliferative disorders

Cited by 154 publications

References 19 publications

Genomic view of IFN-α response in pre-autoimmune NZB/W and MRL/lpr mice

Genomic view of IFN-α response in pre-autoimmune NZB/W and MRL/lpr mice

Interferon-α therapy in bcr-abl-negative myeloproliferative neoplasms

Deficiency of type I interferon contributes to Sle2‐associated component lupus phenotypes

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