Syringotropic cell infiltration is recognized as histological hallmarks in autoimmune diseases, including lupus eythematosus (LE) and Sjögren syndrome (SjS). Previously, we implicated the existence of immune privilege (IP) in the human sweat gland (SG). In this study, we adopted in-depth digital histological image analyses in combination with human skin organ culture to dissect the role of SG IP collapse in syringotropic inflammation. The digital image analysis allows the quantification and statistical analyses of differential expression of IP molecules in immunohistochemically stained sections. In the normal SG (n=10), MHC class І expression was decreased in the sweat duct and the secretory portion compared to the basal layer of the epidermis (BE) at the ratio of 0.79 and 0.67 respectively. In addition, IP-guardians, macrophage migration inhibitory factor (MIF) and α melanocytic stimulating hormone (αMSH), were most up-regulated in the SG secretory portion with minimal expression in BE. In LE (n=7) and scleroderma/ morphea (Scl/morph; n=9), MHC class І was upregulated in the ductal and the secretary portion when compared to the control, while, in SjS (n=4), differential expression was noted in the secretory portion alone. Interestingly, the expression level of MIF inversely correlated with that of MHC class I (r=-0.76, p<0.01). Down-regulation of αMSH in SG was detected only in LE (p<0.01). Of note, the severity of inflammatory change and MIF and ⍺MSH expression levels were inversely correlated in LE respectively (r=0.85, 0.76, p<0.05). Importantly, in human skin organ culture model, intratissue injection of IFN-γ, the master IP dysregulater, up-regulated MHC class I by 2.52-fold besides down-regulating MIF and αMSH by 0.74-, 0.75-folds, respectively. These findings unveil previously less recognized dysregulation of IP-related molecules in SG and suggest a putative role of SG-IP collapse in the etiopathogenesis of syringotropic autoimmune disorders.

Digital histological image analysis underpins the role of immune privilege collapse in the sweat glands in the etiopathogenesis of syringotropic autoimmune diseases