STİNG (stimulatorof interferon genes protein) in systemic Vasculitis

Project no. 32411 · Status: Kapanmış (Yayın bekleniyor) · 2024

Summary

<p class="ql-align-justify">Gain-of-function&nbsp;mutations&nbsp;in&nbsp;transmembrane&nbsp;protein&nbsp;173&nbsp;(TMEM173),&nbsp;which&nbsp;encodes&nbsp;the&nbsp;stimulator&nbsp;of&nbsp;interferon&nbsp;genes&nbsp;(STING),&nbsp;have&nbsp;been&nbsp;identified&nbsp;as&nbsp;chronic&nbsp;activation&nbsp;of&nbsp;the&nbsp;interferon&nbsp;pathway,&nbsp;leading&nbsp;to&nbsp;the&nbsp;development&nbsp;of&nbsp;autoinflammatory&nbsp;syndrome&nbsp;(SAVI),&nbsp;an&nbsp;infantile&nbsp;vasculopathy&nbsp;affecting&nbsp;mostly&nbsp;the&nbsp;skin,&nbsp;lungs,&nbsp;and&nbsp;central&nbsp;nervous&nbsp;system.&nbsp;More&nbsp;recent&nbsp;reports&nbsp;have&nbsp;demonstrated&nbsp;a&nbsp;broader&nbsp;phenotypic&nbsp;and&nbsp;disease-onset&nbsp;spectrum,&nbsp;including&nbsp;infectious,&nbsp;autoimmune,&nbsp;and&nbsp;renal&nbsp;manifestations.&nbsp;Mouse&nbsp;model&nbsp;experiments&nbsp;have&nbsp;demonstrated&nbsp;increased&nbsp;cGAMP&nbsp;levels&nbsp;and&nbsp;an&nbsp;IFN-I&nbsp;signature&nbsp;in&nbsp;anti-neutrophil&nbsp;cytoplasmic&nbsp;antibody&nbsp;(ANCA)-associated&nbsp;vasculitis&nbsp;(AAV),&nbsp;a&nbsp;group&nbsp;of&nbsp;life-threatening&nbsp;diseases&nbsp;whose&nbsp;underlying&nbsp;pathogenic&nbsp;mechanisms&nbsp;remain&nbsp;poorly&nbsp;understood.&nbsp;Elucidating&nbsp;the&nbsp;etiology&nbsp;and&nbsp;pathogenesis&nbsp;of&nbsp;AAV&nbsp;is&nbsp;essential&nbsp;for&nbsp;the&nbsp;development&nbsp;of&nbsp;new&nbsp;biomarkers&nbsp;and&nbsp;targeted&nbsp;therapeutic&nbsp;agents.&nbsp;In&nbsp;our&nbsp;study,&nbsp;we&nbsp;aimed&nbsp;to&nbsp;evaluate&nbsp;the&nbsp;presence&nbsp;of&nbsp;TMEM173&nbsp;mutation&nbsp;in&nbsp;AAVs&nbsp;seen&nbsp;in&nbsp;the&nbsp;adult&nbsp;age&nbsp;group&nbsp;and&nbsp;especially&nbsp;with&nbsp;interstitial&nbsp;fibrosis&nbsp;and&nbsp;therefore&nbsp;whether&nbsp;the&nbsp;type&nbsp;1&nbsp;interferon&nbsp;pathway&nbsp;is&nbsp;active.&nbsp;A&nbsp;total&nbsp;of&nbsp;90&nbsp;patients&nbsp;with&nbsp;previously&nbsp;diagnosed&nbsp;<span style="color: black;">Microscopic&nbsp;polyangiitis&nbsp;(</span>MPA)&nbsp;(n:&nbsp;30),&nbsp;Granulomatosis&nbsp;with&nbsp;polyangiitis&nbsp;(GPA)&nbsp;(n:&nbsp;20),&nbsp;Takayasu&nbsp;(n:&nbsp;20),&nbsp;and&nbsp;healthy&nbsp;controls&nbsp;(n:&nbsp;20)&nbsp;were&nbsp;included&nbsp;in&nbsp;the&nbsp;study&nbsp;at&nbsp;Ege&nbsp;University&nbsp;Faculty&nbsp;of&nbsp;Medicine&nbsp;Hospital.&nbsp;STING&nbsp;(TMEM&nbsp;173&nbsp;mutation)&nbsp;was&nbsp;evaluated&nbsp;by&nbsp;DNA&nbsp;sequence&nbsp;analysis&nbsp;in&nbsp;blood&nbsp;samples&nbsp;collected&nbsp;from&nbsp;89&nbsp;patients&nbsp;(GPA,&nbsp;MPA,&nbsp;Takayasu)&nbsp;during&nbsp;follow-up&nbsp;between&nbsp;2004&nbsp;and&nbsp;2025&nbsp;and&nbsp;20&nbsp;healthy&nbsp;controls.&nbsp;A&nbsp;total&nbsp;of&nbsp;90&nbsp;patients&nbsp;with&nbsp;previously&nbsp;diagnosed&nbsp;MPA&nbsp;(n:&nbsp;30,&nbsp;female:&nbsp;median&nbsp;age:&nbsp;),&nbsp;GPA&nbsp;(n:&nbsp;20,&nbsp;female:&nbsp;median&nbsp;age:&nbsp;),&nbsp;Takayasu&nbsp;(n:&nbsp;20,&nbsp;female:&nbsp;median&nbsp;age:&nbsp;),&nbsp;and&nbsp;healthy&nbsp;controls&nbsp;(n:&nbsp;20,&nbsp;female:&nbsp;median&nbsp;age:&nbsp;)&nbsp;were&nbsp;included&nbsp;in&nbsp;the&nbsp;study&nbsp;at&nbsp;Ege&nbsp;University&nbsp;Faculty&nbsp;of&nbsp;Medicine&nbsp;Hospital.&nbsp;TMEM173&nbsp;gene&nbsp;analysis&nbsp;was&nbsp;performed&nbsp;in&nbsp;the&nbsp;blood&nbsp;of&nbsp;89&nbsp;patients&nbsp;using&nbsp;DNA&nbsp;sequence&nbsp;analysis.&nbsp;TMEM173&nbsp;mutations&nbsp;were&nbsp;detected&nbsp;in&nbsp;two&nbsp;patients:&nbsp;one&nbsp;Takayasu&nbsp;and&nbsp;one&nbsp;GPA.&nbsp;No&nbsp;other&nbsp;study&nbsp;in&nbsp;the&nbsp;literature&nbsp;has&nbsp;investigated&nbsp;the&nbsp;presence&nbsp;of&nbsp;STING&nbsp;using&nbsp;TMEM173&nbsp;mutation&nbsp;analysis&nbsp;in&nbsp;systemic&nbsp;vasculitis;&nbsp;our&nbsp;study&nbsp;is&nbsp;the&nbsp;first&nbsp;in&nbsp;this&nbsp;regard.&nbsp;In&nbsp;conclusion,&nbsp;although&nbsp;TMEM173&nbsp;mutations&nbsp;are&nbsp;rare,&nbsp;the&nbsp;phenotypes&nbsp;of&nbsp;positive&nbsp;cases&nbsp;suggest&nbsp;that&nbsp;the&nbsp;STING&nbsp;pathway&nbsp;may&nbsp;play&nbsp;a&nbsp;role,&nbsp;particularly&nbsp;in&nbsp;AAV&nbsp;with&nbsp;pulmonary&nbsp;involvement&nbsp;and&nbsp;certain&nbsp;Takayasu&nbsp;arteritis&nbsp;subtypes.&nbsp;This&nbsp;pathway&nbsp;stands&nbsp;out&nbsp;as&nbsp;an&nbsp;important&nbsp;area&nbsp;of&nbsp;research&nbsp;for&nbsp;biomarker&nbsp;and&nbsp;targeted&nbsp;therapy&nbsp;development.&nbsp;The&nbsp;findings&nbsp;are&nbsp;important&nbsp;in&nbsp;terms&nbsp;of&nbsp;shedding&nbsp;light&nbsp;on&nbsp;future&nbsp;studies.&nbsp;Future&nbsp;studies&nbsp;with&nbsp;larger&nbsp;cohorts,&nbsp;interferon&nbsp;signatures,&nbsp;and&nbsp;functional&nbsp;analyses&nbsp;may&nbsp;further&nbsp;clarify&nbsp;the&nbsp;role&nbsp;of&nbsp;TMEM173&nbsp;variants&nbsp;in&nbsp;the&nbsp;pathogenesis&nbsp;of&nbsp;vasculitis.</p><p class="ql-align-justify"></p>

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