Constitutively active Lyn kinase causes a cutaneous small vessel vasculitis and liver fibrosis syndrome

Abstract

Neutrophilic inflammation is a hallmark of many monogenic autoinflammatory diseases; pathomechanisms that regulate extravasation of damaging immune cells into surrounding tissues are poorly understood. We identified three unrelated boys with perinatal-onset of neutrophilic cutaneous small vessel vasculitis and systemic inflammation. Two patients developed liver fibrosis in their first year of life. Next-generation sequencing identified two de novo truncating variants in the Src-family tyrosine kinase, LYN, p.Y508*, p.Q507* and a de novo missense variant, p.Y508F, that result in constitutive activation of Lyn kinase. Functional studies reveal increased expression of ICAM-1 on induced patient-derived endothelial cells (iECs) and of beta-2-integrins on neutrophils that increase neutrophil adhesion and vascular transendothelial migration (TEM). Treatment with TNF inhibition improved systemic inflammation; and liver fibrosis resolved on treatment with the Src kinase inhibitor dasatinib. These findings reveal a critical role for Lyn kinase in modulating inflammatory signals, regulating microvascular permeability and neutrophil recruitment, and in promoting hepatic fibrosis.

Cellular models in autoinflammatory disease research

“…98 Another study used patient-specific iPSC-derived endothelial cells from a patient with gain-of-function mutation of Lyn kinase. 99 This study demonstrated the contribution of mutant Lyn in endothelial to the phenotype of leucocytoclastic vasculitis for the first time.…”

“…The CRISPR-Cas9 platform has been used to generate genetically edited iPS-derived macrophage lines to study Blau 100,101 and CANDLE 102,103 syndromes as well as the Lyn kinase mutation mentioned above. 99 In all three cases, the disease-causing mutation was corrected in patient-derived iPSCs while the same mutation was introduced into iPSCs derived from healthy controls, creating two isogenic diseasecontrol pairs. This approach enables the use of more relevant controls than traditional options, such as cells from healthy family members.…”

The Src-family kinase Lyn plays a critical role in establishing and maintaining B cell anergy by suppressing PI3K-dependent signaling

“…It is still unclear which B cell tolerance mechanisms are dependent on Lyn function. There is some evidence that central tolerance mechanisms are impacted by Lyn dysregulation, resulting in a higher frequency of autoreactive B cells in the periphery (50,51). Among the peripheral B cell populations that harbor autoreactive B cells both B-1a (52,53) and T-bet expressing Age-associated B Cells (ABC-B cells) (54) contribute to the autoantibody producing cell population in Lyn-deficient animals.…”

Expert Perspective: Diagnostic Approach to the Autoinflammatory Diseases

“…These include syndromes related to mutations in RIPK1 and LYN as well as the type I interferonopathies. [12][13][14][15][16] Much more common is the presumed multifactorial AID termed periodic fever with aphthous stomatitis, pharyngitis, and adenopathy (PFAPA). PFAPA is the only truly periodic of the fever syndromes, presenting with near-clockwork fever episodes every 21 to 28 days and lasting 4 to 6 days, often (despite the acronym) without other associated clinical features.…”

“…However, patients should be regularly screened with a spirometer and eventually a lung computed tomography. Patients with systemic JIA and recurrent MAS may even develop a pulmonary alveolar proteinosis, as highlighted by de Jesus et al 12,41 The role laboratory examinations and functional tests. Elevated levels of inflammatory markers, such as C-reactive protein, erythrocyte sedimentation rate, and serum amyloid A, are commonly observed in most AIDs.…”