Small Vessel Vasculitis Syndrome with Autoinflammation Caused by De Novo Mutations in LYN Kinase

Adriana de Jesus¹, Gina Montealegre Sanchez ², Helen Freeman ³, Neil Martin ⁴, Ebun Omoyinmi ⁵, Katherine Calvo ⁶, Richard Chyi-chia Lee ⁷, Murray Passo ⁸, Natasha Ruth ⁸, David Kleiner ⁷, Yan Huang ⁹, Nirali Shah ¹⁰, Paul Brogan ¹¹, SuJin Hwang ¹², HyeSun Kuehn ¹², Sergio Rosenzweig ¹², Zuoming Deng ¹³, Anna Huttenlocher ¹⁴, Susan Moir ¹⁵, Douglas Kuhns ¹⁶ and Raphaela Goldbach-Mansky ¹⁷, ¹Translation Autoinflammatory Diseases Section/NIAID/NIH, Silver Spring, MD, ²Translational Autoinflammatory Disease Section/NIAID/NIH, Bethesda, ³Raigmore Hospital, Inverness, United Kingdom, ⁴Royal Hospital for Children, Glasgow, United Kingdom, ⁵University College London Institute of Child Health, London, United Kingdom, ⁶Hematology Service/Department of Laboratory Medicine/NIH, Bethesda, MD, ⁷Laboratory of Pathology/NCI/NIH, Bethesda, MD, ⁸Medical University of South Carolina, Charleston, SC, ⁹Translational Autoinflammatory Disease Section/NIAID/NIH, Bethesda, MD, ¹⁰Pediatric Oncology Branch/NCI/NIH, Bethesda, MD, ¹¹Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom, ¹²Immunology Service/Department of Laboratory Medicine/NIH, Bethesda, MD, ¹³Biomining and Discovery Section/NIAMS/NIH, Bethesda, MD, ¹⁴Department of Pediatrics/University of Wisconsin, Madison, WI, ¹⁵Immunopathogenesis Section/NIAID/NIH, Bethesda, MD, ¹⁶Collaborative Clinical Research Branch/NIAID/NIH, Bethesda, MD, ¹⁷Translational Autoinflammatory Diseases Section/NIAID/NIH, Bethesda, MD

Meeting: 2019 ACR/ARP Annual Meeting

Keywords: Autoinflammatory Disease, neutrophils, tyrosine kinase inhibition and anti-TNF therapy, Vasculitis

Session Information

Date: Sunday, November 10, 2019

Title: 3S077: Pediatric Rheumatology – Basic Science (810–814)

Session Type: ACR Abstract Session

Session Time: 2:30PM-4:00PM

Background/Purpose: Lyn kinase is a member of the Src family of non-receptor tyrosine-protein kinases that modifies signals from various cell surface receptors and regulates innate and adaptive immune responses in myeloid cells, B cells and non-hematopoietic cells. We describe two unrelated patients, with de novo Lyn kinase (LYN) mutations, whose disease sheds light on the pathogenesis of neutrophilic small vessel vasculitis.

Methods: The patients were assessed clinically, immunological parameters, trio whole exome sequencing (WES) and pathogenic studies of the disease-causing LYN mutations were investigated in transfection studies and in patients’ cells. Cytokine and chemokine panels were measured in patient’s serum and monocyte culture supernatants; neutrophil function was assessed.

Results: Both patients presented with perinatal onset of neutrophilic small vessel vasculitis and systemic inflammation including hepatosplenomegaly, periorbital erythema, colitis and epididymitis. Low titer autoantibodies (ANA, anti-Sm, anti-SSA, anti-phospholipids and anti-mitochondrial) and vanishing bile duct disease and liver fibrosis were present in one patient. Both patients had a de novo mutation in Lyn kinase (LYN) (c.1524C >G, p.Y508* and c.1523A >T, p.Y508F). One patient responded to a TNF inhibitor alone, the other patient required combination with the src kinase inhibitor, dasatinib. Patients B cells had constitutive phosphorylation of LYN and downstream kinases (CD19, BTK, CD22, PLCg2) by flow cytometry. Skin biopsy sowed capillaritis with myeloperoxidase (MPO)+ neutrophils attached to small vessel walls. LYN was expressed neutrophils and upregulated in endothelial cells of capillaries with and without vasculitis, but not in endothelial cells of larger vessels. Markers of patient neutrophils had constitutively and stimulated increased expression of activated CD11b (granulocyte adhesion marker), CD64 (FC-receptor), and CD63 (marker of primary granule release) compared to normal controls. However, response to higher doses of chemoattractants was blunted in patient compared to control neutrophils. On dasatinib, bridging fibrosis and FibroScan measurements improved and RNA-seq from 3 liver biopsies showed progressive decrease in gene expression pathways related to wound healing and fibrosis. On dasatinib monotherapy, patient monocytes exhibited constitutive activation of proinflammatory cytokines including TNF-a, G-CSF, IL-6, MIP-1a and MIP-1b, which was mitigated with combination therapy with src-kinase and TNF inhibitors.

Conclusion: Lyn tyrosine kinase mutations at Tyr508 lead to GOF and an autoinflammatory syndrome characterized by skin vasculitis, colitis, variable liver fibrosis and autoantibody production that sheds light on the role of neutrophil and endothelial cell activation in the pathogenesis of small vessel vasculitis and illustrates a therapeutic role for TNF inhibition alone or in combination with dasatinib.

Funding for this study was provided in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health.

Disclosure: A. de Jesus, None; G. Montealegre Sanchez, None; H. Freeman, None; N. Martin, None; E. Omoyinmi, None; K. Calvo, None; R. Lee, None; M. Passo, None; N. Ruth, None; D. Kleiner, None; Y. Huang, None; N. Shah, None; P. Brogan, None; S. Hwang, None; H. Kuehn, None; S. Rosenzweig, None; Z. Deng, None; A. Huttenlocher, None; S. Moir, None; D. Kuhns, None; R. Goldbach-Mansky, None.

To cite this abstract in AMA style:

de Jesus A, Montealegre Sanchez G, Freeman H, Martin N, Omoyinmi E, Calvo K, Lee R, Passo M, Ruth N, Kleiner D, Huang Y, Shah N, Brogan P, Hwang S, Kuehn H, Rosenzweig S, Deng Z, Huttenlocher A, Moir S, Kuhns D, Goldbach-Mansky R. Small Vessel Vasculitis Syndrome with Autoinflammation Caused by De Novo Mutations in LYN Kinase [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/small-vessel-vasculitis-syndrome-with-autoinflammation-caused-by-de-novo-mutations-in-lyn-kinase/. Accessed .

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