Autoimmune diseases are defined by an immune response against a specific autoantigen, driven by antigen-specific T cells or antibodies. While the mechanisms resolving brief episodes of acute inflammation elicited by microbial components or tissue injury are well understood, the mechanisms resolving tissue inflammation in autoimmune diseases are still largely elusive.

We have, therefore, addressed the mechanisms of resolution in IgG-mediated autoimmune diseases using a mouse model of the pemphigoid disease “bullous pemphigoid-like epidermolysis bullosa acquisita” (BP-like EBA) as prototypical example. We found that 12/15-LO is induced in skin lesions of BP-like EBA and is predominantly expressed in eosinophils. Dependent on the expression of 12/15-LO, large amounts of proresolving lipid mediators, are biosynthesized in the skin by the point disease peaks. Their production is timely correlated to the gradual reversal of tissue inflammation. Genetic deficiency in Alox15, the gene encoding 12/15-LO, disrupts this process significantly protracting and aggravating disease. This protraction is associated reduced recruitment of regulatory T cells (T_regs) into lesional skin. Intriguingly, Alox15^−/− mice also exhibit reduced recruitment of eosinophils into the skin, and the chemotaxis of cultured Alox15^−/− eosinophils towards CCL11/eotaxin-1 is compromised. Finally, we demonstrate that 15-lipoxygenase-1, the human homologue of 12/15-LO is induced in granulocytes in lesional skin of patients suffering from a pemphigoid disease.

Collectively, our result uncover key mechanisms resolving IgG-mediated skin inflammation. These mechanisms are orchestrated by 12/15-LO expressed in eosinophils promoting the recruitment of eosinophils and T_regs, which in turn inhibit neutrophils.

自身免疫性疾病的定义是针对特定自身抗原的免疫反应，由抗原特异性 T 细胞或抗体驱动。虽然解决由微生物成分或组织损伤引起的急性炎症的短暂发作的机制已广为人知，但解决自身免疫性疾病中组织炎症的机制仍然在很大程度上难以捉摸。

因此，我们使用类天疱疮“大疱性类天疱疮样大疱性表皮松解症”（BP 样 EBA）的小鼠模型作为典型例子，解决了 IgG 介导的自身免疫性疾病的消退机制。我们发现 12/15-LO 在 BP 样 EBA 的皮肤病变中被诱导，并且主要在嗜酸性粒细胞中表达。依赖于 12/15-LO 的表达，大量的脂质介质在皮肤中通过点疾病峰进行生物合成。它们的产生与组织炎症的逐渐逆转及时相关。编码 12/15-LO 的基因Alox15 的遗传缺陷会破坏这一过程，从而显着延长和加重疾病。这种延长与调节性 T 细胞（T _regs) 进入病变皮肤。有趣的是，Alox15 ^-/-小鼠还表现出减少的嗜酸性粒细胞募集到皮肤中，并且培养的Alox15 ^-/-嗜酸性粒细胞对 CCL11/eotaxin-1的趋化性受到损害。最后，我们证明 15-脂氧合酶-1，12/15-LO 的人类同源物在患有类天疱疮的患者的损伤皮肤的粒细胞中被诱导。

总的来说，我们的结果揭示了解决 IgG 介导的皮肤炎症的关键机制。这些机制由嗜酸性粒细胞中表达的 12/15-LO 协调，促进嗜酸性粒细胞和 T _regs的募集，进而抑制中性粒细胞。