DNASE1L3 deficiency, new phenotypes, and evidence for a transient type I IFN signaling

peer reviewedBACKGROUND: Deoxyribonuclease 1 like 3 (DNASE1L3) is a secreted enzyme that has been shown to digest the extracellular chromatin derived from apoptotic bodies, and DNASE1L3 pathogenic variants have been associated with a lupus phenotype. It is unclear whether interferon signaling is sustained in DNASE1L3 deficiency in humans. OBJECTIVES: To explore interferon signaling in DNASE1L3 deficient patients. To depict the characteristic features of DNASE1L3 deficiencies in human. METHODS: We identified, characterized, and analyzed five new patients carrying biallelic DNASE1L3 variations. Whole or targeted exome and/or Sanger sequencing was performed to detect pathogenic variations in five juvenile systemic erythematosus lupus (jSLE) patients. We measured interferon-stimulated gene (ISG) expression in all patients. We performed a systematic review of all published cases available from its first description in 2011 to March 24(th) 2022. RESULTS: We identified five new patients carrying biallelic DNASE1L3 pathogenic variations, including three previously unreported mutations. Contrary to canonical type I interferonopathies, we noticed a transient increase of ISGs in blood, which returned to normal with disease remission. Disease in one patient was characterized by lupus nephritis and skin lesions, while four others exhibited hypocomplementemic urticarial vasculitis syndrome. The fourth patient presented also with early-onset inflammatory bowel disease. Reviewing previous reports, we identified 35 additional patients with DNASE1L3 deficiency which was associated with a significant risk of lupus nephritis and a poor outcome together with the presence of anti-neutrophil cytoplasmic antibodies (ANCA). Lung lesions were reported in 6/35 patients. CONCLUSIONS: DNASE1L3 deficiencies are associated with a broad phenotype including frequently lupus nephritis and hypocomplementemic urticarial vasculitis with positive ANCA and rarely, alveolar hemorrhages and inflammatory bowel disease. This report shows that interferon production is transient contrary to anomalies of intracellular DNA sensing and signaling observed in Aicardi-Goutières syndrome or STING-associated vasculitis in infancy (SAVI)

Protein kinase cδ deficiency causes mendelian systemic lupus erythematosus with B cell-defective apoptosis and hyperproliferation

International audienceOBJECTIVE: Systemic lupus erythematosus (SLE) is a prototype autoimmune disease that is assumed to occur via a complex interplay of environmental and genetic factors. Rare causes of monogenic SLE have been described, providing unique insights into fundamental mechanisms of immune tolerance. The aim of this study was to identify the cause of an autosomal-recessive form of SLE. METHODS: We studied 3 siblings with juvenile-onset SLE from 1 consanguineous kindred and used next-generation sequencing to identify mutations in the disease-associated gene. We performed extensive biochemical, immunologic, and functional assays to assess the impact of the identified mutations on B cell biology. RESULTS: We identified a homozygous missense mutation in PRKCD, encoding protein kinase δ (PKCδ), in all 3 affected siblings. Mutation of PRKCD resulted in reduced expression and activity of the encoded protein PKCδ (involved in the deletion of autoreactive B cells), leading to resistance to B cell receptor- and calcium-dependent apoptosis and increased B cell proliferation. Thus, as for mice deficient in PKCδ, which exhibit an SLE phenotype and B cell expansion, we observed an increased number of immature B cells in the affected family members and a developmental shift toward naive B cells with an immature phenotype. CONCLUSION: Our findings indicate that PKCδ is crucial in regulating B cell tolerance and preventing self-reactivity in humans, and that PKCδ deficiency represents a novel genetic defect of apoptosis leading to SLE

PRKDC mutations associated with immunodeficiency, granuloma, and autoimmune regulator-dependent autoimmunity.

textabstractBackground PRKDC encodes for DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a kinase that forms part of a complex (DNA-dependent protein kinase [DNA-PK]) crucial for DNA double-strand break repair and V(D)J recombination. In mice DNA-PK also interacts with the transcription factor autoimmune regulator (AIRE) to promote central T-cell tolerance. Objective We sought to understand the causes of an inflammatory disease with granuloma and autoimmunity associated with decreasing T- and B-cell counts over time that had been diagnosed in 2 unrelated patients. Methods Genetic, molecular, and functional analyses were performed to characterize an inflammatory disease evocative of a combined immunodeficiency. Results We identified PRKDC mutations in both patients. These patients exhibited a defect in DNA double-strand break repair and V(D)J recombination. Whole-blood mRNA analysis revealed a strong interferon signature. On activation, memory T cells displayed a skewed cytokine response typical of TH2 and TH1 but not TH17. Moreover, mutated DNA-PKcs did not promote AIRE-dependent transcription of peripheral tissue antigens in vitro. The latter defect correlated in vivo with production of anti-calcium-sensing receptor autoantibodies, which are typically found in AIRE-deficient patients. In addition, 9 months after bone marrow transplantation, patient 1 had Hashimoto thyroiditis, suggesting that organ-specific autoimmunity might be linked to nonhematopoietic cells, such as AIRE-expressing thymic epithelial cells. Conclusion Deficiency of DNA-PKcs, a key AIRE partner, can present as an inflammatory disease with organ-specific autoimmunity, suggesting a role for DNA-PKcs in regulating autoimmune responses and maintaining AIRE-dependent tolerance in human subjects

PRKDC mutations associated with immunodeficiency, granuloma, and autoimmune regulator-dependent autoimmunity

Background PRKDC encodes for DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a kinase that forms part of a complex (DNA-dependent protein kinase [DNA-PK]) crucial for DNA double-strand break repair and V(D)J recombination. In mice DNA-PK also interacts with the transcription factor autoimmune regulator (AIRE) to promote central T-cell tolerance. Objective We sought to understand the causes of an inflammatory disease with granuloma and autoimmunity associated with decreasing T- and B-cell counts over time that had been diagnosed in 2 unrelated patients. Methods Genetic, molecular, and functional analyses were performed to characterize an inflammatory disease evocative of a combined immunodeficiency. Results We identified PRKDC mutations in both patients. These patients exhibited a defect in DNA double-strand break repair and V(D)J recombination. Whole-blood mRNA analysis revealed a strong interferon signature. On activation, memory T cells displayed a skewed cytokine response typical of TH2 and TH1 but not TH17. Moreover, mutated DNA-PKcs did not promote AIRE-dependent transcription of peripheral tissue antigens in vitro. The latter defect correlated in vivo with production of anti-calcium-sensing receptor autoantibodies, which are typically found in AIRE-deficient patients. In addition, 9 months after bone marrow transplantation, patient 1 had Hashimoto thyroiditis, suggesting that organ-specific autoimmunity might be linked to nonhematopoietic cells, such as AIRE-expressing thymic epithelial cells. Conclusion Deficiency of DNA-PKcs, a key AIRE partner, can present as an inflammatory disease with organ-specific autoimmunity, suggesting a role for DNA-PKcs in regulating autoimmune responses and maintaining AIRE-dependent tolerance in human subjects