Dow Coad Thomas, Chan Edward D
McPherson Eye Research Institute, University of Wisconsin, Madison, WI, USA.
Department of Academic Affairs, National Jewish Health, Denver, CO, USA.
J Transl Autoimmun. 2021 Feb 5;4:100085. doi: 10.1016/j.jtauto.2021.100085. eCollection 2021.
Sjogren's syndrome (SS) is a common, systemic autoimmune disorder primarily affecting the exocrine glands resulting in xerostomia and xerophthalmia. SS may also manifest with polyarthralgia, polyarthritis, polymyalgia, cutaneous/other organ vasculitis, interstitial lung disease, and/or various other disorders. The primary autoantibodies associated with SS and used as adjuncts to diagnosis are anti-Ro (SSA) and anti-La (SSB). The pathogenesis of SS is considered to involve genetic susceptibility and environmental triggers. An identified genetic susceptibility for SS lies in variants of the tumor necrosis factor alpha inducible protein 3 () gene, the product of which is known as A20. Deficiency or dysfunction of A20 is known to induce macrophage inflammatory response to mycobacteria, potentially increasing the repertoire of mycobacterial antigens available and predisposing to autoimmunity the paradigm of molecular mimicry; , providing a mechanistic link between genetic susceptibility to SS and exposure to environmental non-tuberculous mycobacteria (NTM). ss. () is an NTM that causes Johne's disease, an enteritis of ruminant animals. Humans are broadly exposed to or its antigens in the environment and in food products from infected animals. has also been implicated as an environmental trigger for a number of autoimmune diseases cross reactivity of its heat shock protein 65 (hsp65) with host-specific proteins. In the context of SS, mycobacterial hsp65 shares epitope homology with the Ro and La proteins. A recent study showed a strong association between SS and antibodies to mycobacterial hsp65. If and when this association is validated, it would be important to determine whether bacillus Calmette-Guerin (BCG) vaccination (known to be protective against NTM likely through epigenetic alteration of innate and adaptive immunity) and anti-mycobacterial drugs (to decrease mycobacterial antigenic load) may have a preventive or therapeutic role against SS. Evidence to support this concept is that BCG has shown benefit in type 1 diabetes mellitus and multiple sclerosis, autoimmune diseases that have been linked to hsp65 and disease-specific autoantibodies. In conclusion, a number of factors lend credence to the notion of a pathogenic link between environmental mycobacteria and SS, including the presence of antibodies to mycobacterial hsp65 in SS, the homology of hsp65 with SS autoantigens, and the beneficial effects seen with BCG vaccination against certain autoimmune diseases. Furthermore, given that BCG may protect against NTM, has immune modifying effects, and has a strong safety record of billions of doses given, BCG and/or anti-mycobacterial therapeutics should be studied in SS.
干燥综合征（SS）是一种常见的全身性自身免疫性疾病，主要影响外分泌腺，导致口干和眼干。SS还可能表现为多关节痛、多关节炎、多肌痛、皮肤/其他器官血管炎、间质性肺病和/或各种其他疾病。与SS相关并用作诊断辅助的主要自身抗体是抗Ro（SSA）和抗La（SSB）。SS的发病机制被认为涉及遗传易感性和环境触发因素。已确定的SS遗传易感性在于肿瘤坏死因子α诱导蛋白3（）基因的变体，其产物称为A20。已知A20的缺乏或功能障碍会诱导巨噬细胞对分枝杆菌的炎症反应，可能增加可用的分枝杆菌抗原库，并易患自身免疫性疾病——分子模拟的范例； ，在SS的遗传易感性与暴露于环境非结核分枝杆菌（NTM）之间提供了一种机制联系。ss。 （）是一种导致反刍动物肠炎——约内氏病的NTM。人类在环境中以及在来自受感染动物的食品中广泛接触到 或其抗原。 也被认为是多种自身免疫性疾病的环境触发因素——其热休克蛋白65（hsp65）与宿主特异性蛋白的交叉反应性。在SS的背景下，分枝杆菌hsp65与Ro和La蛋白具有表位同源性。最近的一项研究表明SS与分枝杆菌hsp65抗体之间存在很强的关联。如果且当这种关联得到验证，确定卡介苗（BCG）接种（已知可能通过先天和适应性免疫的表观遗传改变对NTM具有保护作用）和抗分枝杆菌药物（以降低分枝杆菌抗原负荷）是否可能对SS具有预防或治疗作用将很重要。支持这一概念的证据是，BCG已在1型糖尿病和多发性硬化症中显示出益处，这两种自身免疫性疾病已与hsp65和疾病特异性自身抗体相关联。总之，许多因素支持环境分枝杆菌与SS之间存在致病联系的观点，包括SS中存在分枝杆菌hsp65抗体、hsp65与SS自身抗原的同源性，以及BCG接种对某些自身免疫性疾病的有益作用。此外，鉴于BCG可能预防NTM、具有免疫调节作用，并且有数十亿剂的强大安全记录，应在SS中研究BCG和/或抗分枝杆菌疗法。
