Sakkas Lazaros I, Bogdanos Dimitrios P, Chikanza Ian C
Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, 41 500, Greece.
Division of Rheumatology, IASO General Clinic, Larissa, Greece.
Clin Rev Allergy Immunol. 2025 May 27;68(1):51. doi: 10.1007/s12016-025-09062-1.
Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by microvasculopathy, extensive fibrosis, and autoantibodies. The disease affects mostly the female sex. In this review, we highlight sex bias in clinical manifestations in SSc, and the pathophysiological changes underlying this bias. Male sex is associated with the diffuse cutaneous form of the disease, digital ulcers, interstitial lung disease, and worse prognosis. These clinical differences can be attributed to sex hormones and sex chromosomes, as females differ from males in sex hormones (estrogens in females, androgens in males) and sex chromosomes (XX in females, XY in males). Estrogens in females generally have immunostimulatory and profibrotic effects, and androgens have immunosuppressive effects. The X-chromosome contains many immunity-related genes, but the double dose of X-linked genes in females is avoided by random inactivation of one X-chromosome (XCI). However, many X-linked immunity-related genes, including toll-like receptor (TLR)7, TLR8 and Bruton's tyrosine kinase (BTK), escape XCI resulting in a biallelic expression with pathophysiological implications. Also, autosomal genes are differentially expressed between sexes. Therefore, sex should be included in future studies on SSc to aid in forming predictive algorithms and helping therapeutic decisions in this difficult-to-treat disease.
系统性硬化症（SSc）是一种慢性自身免疫性疾病，其特征为微血管病变、广泛纤维化和自身抗体。该疾病主要影响女性。在本综述中，我们强调了SSc临床表现中的性别差异，以及这种差异背后的病理生理变化。男性与疾病的弥漫性皮肤型、指端溃疡、间质性肺疾病以及更差的预后相关。这些临床差异可归因于性激素和性染色体，因为女性与男性在性激素（女性为雌激素，男性为雄激素）和性染色体（女性为XX，男性为XY）方面存在差异。女性体内的雌激素通常具有免疫刺激和促纤维化作用，而雄激素具有免疫抑制作用。X染色体包含许多与免疫相关的基因，但女性通过随机失活一条X染色体（XCI）来避免X连锁基因的双倍剂量。然而，许多与X连锁的免疫相关基因，包括Toll样受体（TLR）7、TLR8和布鲁顿酪氨酸激酶（BTK），逃脱了XCI，导致双等位基因表达并产生病理生理影响。此外，常染色体基因在两性之间也存在差异表达。因此，在未来关于SSc的研究中应纳入性别因素，以帮助形成预测算法，并为这种难治性疾病的治疗决策提供帮助。
