Type I interferon signature predicts response to JAK inhibition in haploinsufficiency of A20

Schwartz, Daniella M.; Blackstone, Sarah A.; Sampaio-Moura, Natalia; Rosenzweig, Sofia; Burma, Aarohan M; Stone, Deborah L.; Hoffmann, Patrycja; Jones, Anne; Romeo, Tina; Barron, Karyl S.; Waldman, Meryl; Aksentijevich, Ivona; Kastner, Daniel L.; Milner, Joshua D.; Ombrello, Amanda K.

doi:10.1136/annrheumdis-2019-215918

Cited by 28 publications

(23 citation statements)

References 7 publications

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“…Moreover, rare mutations leading to TNFAIP3 loss-of-function cause a systemic autoinflammatory disease ( 43 ). The affected individuals present a type I interferon (IFN) signature which correlates with the disease activity and predicts their response to treatment with janus kinase (JAK) inhibitors (JAK1 is a key kinase for type I interferon signaling) ( 44 ). In agreement with this, we have shown that the JAK 1 and 2 inhibitors ruxolitinib ( 45 ) and baricitinib ( 10 ) prevent IFNα-induced MHC class I and chemokine up-regulation in human islets, besides inhibiting IFNα + IL1β-induced beta cell apoptosis; another drug from this family was shown to prevent diabetes in NOD mice ( 46 ).…”

Section: Resultsmentioning

confidence: 99%

Molecular Footprints of the Immune Assault on Pancreatic Beta Cells in Type 1 Diabetes

2020

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Type 1 diabetes (T1D) is a chronic disease caused by the selective destruction of the insulin-producing pancreatic beta cells by infiltrating immune cells. We presently evaluated the transcriptomic signature observed in beta cells in early T1D and compared it with the signatures observed following in vitro exposure of human islets to inflammatory or metabolic stresses, with the aim of identifying "footprints" of the immune assault in the target beta cells. We detected similarities between the beta cell signatures induced by cytokines present at different moments of the disease, i.e., interferon-α (early disease) and interleukin-1β plus interferon-γ (later stages) and the beta cells from T1D patients, identifying biological process and signaling pathways activated during early and late stages of the disease. Among the first responses triggered on beta cells was an enrichment in antiviral responses, pattern recognition receptors activation, protein modification and MHC class I antigen presentation. During putative later stages of insulitis the processes were dominated by T-cell recruitment and activation and attempts of beta cells to defend themselves through the activation of anti-inflammatory pathways (i.e., IL10, IL4/13) and immune checkpoint proteins (i.e., PDL1 and HLA-E). Finally, we mined the beta cell signature in islets from T1D patients using the Connectivity Map, a large database of chemical compounds/drugs, and identified interesting candidates to potentially revert the effects of insulitis on beta cells.

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Section: Resultsmentioning

confidence: 99%

Molecular Footprints of the Immune Assault on Pancreatic Beta Cells in Type 1 Diabetes

2020

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“…Another study showed that patients with HA20 gradually progress to develop strong autoimmune features [98]. The autoimmune features may be attributed to a Type I interferon signature detected in peripheral blood of these patients among other highly elevated proinflammatory cytokines [99]. Haploinsufficiency of A20 was also identified in patients with childhood-onset autoimmune diseases and autoimmune lymphoproliferative syndrome (ALPS; OMIM 601859) [100].…”

Section: Relopathiesmentioning

confidence: 99%

New Horizons in the Genetic Etiology of Systemic Lupus Erythematosus and Lupus-Like Disease: Monogenic Lupus and Beyond

Demirkaya

Şahin

Romano

et al. 2020

JCM

Self Cite

107

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Systemic lupus erythematosus (SLE) is a clinically and genetically heterogeneous autoimmune disease. The etiology of lupus and the contribution of genetic, environmental, infectious and hormonal factors to this phenotype have yet to be elucidated. The most straightforward approach to unravel the molecular pathogenesis of lupus may rely on studies of patients who present with early-onset severe phenotypes. Typically, they have at least one of the following clinical features: childhood onset of severe disease (<5 years), parental consanguinity, and presence of family history for autoimmune diseases in a first-degree relative. These patients account for a small proportion of patients with lupus but they inform considerable knowledge about cellular pathways contributing to this inflammatory phenotype. In recent years with the aid of new sequencing technologies, novel or rare pathogenic variants have been reported in over 30 genes predisposing to SLE and SLE-like diseases. Future studies will likely discover many more genes with private variants associated to lupus-like phenotypes. In addition, genome-wide association studies (GWAS) have identified a number of common alleles (SNPs), which increase the risk of developing lupus in adult age. Discovery of a possible shared immune pathway in SLE patients, either with rare or common variants, can provide important clues to better understand this complex disorder, it’s prognosis and can help guide new therapeutic approaches. The aim of this review is to summarize the current knowledge of the clinical presentation, genetic diagnosis and mechanisms of disease in patents with lupus and lupus-related phenotypes.

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“…96,97 Importantly, the presence of a type I IFN signature predicted a good response to JAKinib treatment in HA20 cases that were resistant to anticytokine treatment. 98 Blau syndrome. Gain-of-function mutations in the cytoplasmic sensor NOD2 result in Blau syndrome, an autosomal-dominant disease characterized by arthritis, uveitis, and granulomatous dermatitis.…”

Section: Disorders Of Nf-kb And/or Aberrant Tnf Activitymentioning

confidence: 99%

Monogenic autoinflammatory disorders: Conceptual overview, phenotype, and clinical approach

Nigrović

Lee

Hoffman

2020

Journal of Allergy and Clinical Immunology

112

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Type I interferon signature predicts response to JAK inhibition in haploinsufficiency of A20

Cited by 28 publications

References 7 publications

Molecular Footprints of the Immune Assault on Pancreatic Beta Cells in Type 1 Diabetes

Molecular Footprints of the Immune Assault on Pancreatic Beta Cells in Type 1 Diabetes

New Horizons in the Genetic Etiology of Systemic Lupus Erythematosus and Lupus-Like Disease: Monogenic Lupus and Beyond

Monogenic autoinflammatory disorders: Conceptual overview, phenotype, and clinical approach

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