Association of HLA-B27 with spondyloarthritis (SpA) has been known for 50 years, but still remains unexplained. We recently showed that HLA-B27 expressed in wing imaginal disc from HLA-B27/human-β2 microglobulin (hβ2m) transgenic Drosophila deregulated bone morphogenetic protein (BMP) pathway by interacting physically with type I BMP receptor (BMPR1) Saxophone (Sax), leading to crossveinless phenotype. Genetic interaction was studied between activin/transforming growth factor β (TGFβ) pathway and HLA-B27/hβ2m in transgenic Drosophila wings. The HLA-B27-bound peptidome was characterized in wing imaginal discs. In mesenteric lymph node (mLN) T cells from HLA-B27/hβ2m rat (B27 rat), physical interaction between HLA-B27 and activin receptor-like kinase-2 (ALK2), ALK3 and ALK5 BMPR1s, phosphorylation of small mothers against decapentaplegic (SMADs) and proteins of the non-canonical BMP/TGFβ pathways induced by its ligands, and the transcript level of target genes of the TGFβ pathway, were evaluated. In HLA-B27/hβ2m transgenic Drosophila, inappropriate signalling through the activin/TGFβ pathway, involving Baboon (Babo), the type I activin/TGFβ receptor, contributed to the crossveinless phenotype, in addition to deregulated BMP pathway. We identified peptides bound to HLA-B27 with the canonical binding motif in HLA-B27/hβ2m transgenic Drosophila wing imaginal disc. We demonstrated specific physical interaction, between HLA-B27/hβ2m and mammalian orthologs of Sax and Babo, i.e. ALK2 and ALK5 (i.e. TGFβ receptor I), in the mLN cells from B27 rat. The magnitude of phosphorylation of SMAD2/3 in response to TGFβ1 was increased in T cells from B27 rats, showing evidence for deregulated TGFβ pathway. Accordingly, expression of several target genes of the pathway was increased in T cells from B27 rats, in basal conditions and/or after TGFβ exposure, including Foxp3, Rorc, Runx1 and Maf. Interestingly, Tgfb1 expression was reduced in naive T cells from B27 rats, even premorbid, an observation consistent with a pro-inflammatory pattern. This study shows that HLA-B27 alters the TGFβ pathways in Drosophila and B27 rat. Given the importance of this pathway in CD4 + T cells differentiation and regulation, its disturbance could contribute to the abnormal expansion of pro-inflammatory T helper 17 cells and altered regulatory T cell phenotype observed in B27 rats.

中文翻译：

---

HLA-B27 表达改变 TGFβ 信号通路，导致与脊柱关节炎相关的致病后果


HLA-B27 与脊柱关节炎 (SpA) 的关联已为人所知 50 年，但仍无法解释。我们最近发现，HLA-B27/人β2微球蛋白（hβ2m）转基因果蝇在翼成虫盘中表达的HLA-B27通过与I型BMP受体（BMPR1）萨克斯管（Sax）物理相互作用，失调了骨形态发生蛋白（BMP）通路，导致无交叉静脉表型。研究了转基因果蝇翅膀中激活素/转化生长因子 β (TGFβ) 途径与 HLA-B27/hβ2m 之间的遗传相互作用。 HLA-B27 结合肽组在翅成虫盘中进行了表征。在来自 HLA-B27/hβ2m 大鼠（B27 大鼠）的肠系膜淋巴结 (mLN) T 细胞中，HLA-B27 与激活素受体样激酶 2 (ALK2)、ALK3 和 ALK5 BMPR1 之间的物理相互作用，小母亲对抗十肢瘫痪的磷酸化评估了SMADs及其配体诱导的非经典BMP/TGFβ途径的蛋白质，以及TGFβ途径靶基因的转录水平。在 HLA-B27/hβ2m 转基因果蝇中，通过激活素/TGFβ 途径的不当信号传导，涉及 I 型激活素/TGFβ 受体 Baboon (Babo)，除了 BMP 途径失调外，还导致了无交叉静脉表型。我们鉴定了与 HLA-B27 结合的肽，其具有 HLA-B27/hβ2m 转基因果蝇翼成虫盘中的典型结合基序。我们在 B27 大鼠的 mLN 细胞中证明了 HLA-B27/hβ2m 与 Sax 和 Babo 的哺乳动物直系同源物（即 ALK2 和 ALK5（即 TGFβ 受体 I））之间的特定物理相互作用。 B27 大鼠 T 细胞中 SMAD2/3 响应 TGFβ1 的磷酸化程度增加，表明 TGFβ 通路失调的证据。 因此，在基础条件下和/或接触 TGFβ 后，B27 大鼠 T 细胞中该途径的几个靶基因的表达增加，包括 Foxp3、Rorc、Runx1 和 Maf。有趣的是，B27 大鼠的初始 T 细胞中的 Tgfb1 表达降低，甚至在病前也是如此，这一观察结果与促炎症模式一致。这项研究表明 HLA-B27 改变果蝇和 B27 大鼠的 TGFβ 通路。鉴于该通路在 CD4+T 细胞分化和调节中的重要性，其干扰可能导致促炎 T 辅助 17 细胞的异常扩增以及在 B27 大鼠中观察到的调节性 T 细胞表型的改变。