Ankylosing spondylitis (AS) is associated with autoantibody production to class II MHC‐associated invariant chain peptide, CD74/CLIP. In this study, we considered that anti‐CD74/CLIP autoantibodies present in sera from AS might recognize CD74 degradation products that accumulate upon deficiency of the enzyme signal peptide peptidase‐like 2A (SPPL2a). We analyzed monocytes from healthy controls (n  = 42), psoriatic arthritis (n  = 25), rheumatoid arthritis (n  = 16), and AS patients (n  = 15) for SPPL2a enzyme activity and complemented the experiments using SPPL2a‐sufficient and ‐deficient THP‐1 cells. We found defects in SPPL2a function and CD74 processing in a subset of AS patients, which culminated in CD74 and HLA class II display at the cell surface. These findings were verified in SPPL2a‐deficient THP‐1 cells, which showed expedited expression of MHC class II, total CD74 and CD74 N‐terminal degradation products at the plasma membrane upon receipt of an inflammatory trigger. Furthermore, we observed that IgG anti‐CD74/CLIP autoantibodies recognize CD74 N‐terminal degradation products that accumulate upon SPPL2a defect. In conclusion, reduced activity of SPPL2a protease in monocytes from AS predisposes to endosomal accumulation of CD74 and CD74 N‐terminal fragments, which, upon IFN‐γ‐exposure, is deposited at the plasma membrane and can be recognized by anti‐CD74/CLIP autoantibodies.

中文翻译：

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SPPL2a的蛋白水解受损会导致CD74片段积聚，可被人类强直性脊柱炎的抗CD74自身抗体识别

强直性脊柱炎（AS）与II类MHC相关的恒定链肽CD74 / CLIP的自身抗体产生有关。在这项研究中，我们认为AS血清中存在的抗CD74 / CLIP自身抗体可能识别CD74降解产物，这些降解产物在缺乏酶信号肽肽酶样2A（SPPL2a）时积累。我们分析了健康对照者（n  = 42），银屑病关节炎（n  = 25），类风湿关节炎（n  = 16）和AS患者（n = 15）的SPPL2a酶活性，并使用SPPL2a充足和不足的THP-1细胞对实验进行补充。我们在一部分AS患者中发现了SPPL2a功能和CD74加工的缺陷，最终在细胞表面出现了CD74和HLA II类显示。这些发现在缺乏SPPL2a的THP-1细胞中得到了证实，该细胞显示在收到炎症触发信号后，MHC II类，总CD74和CD74 N末端降解产物在细胞膜上的表达加快。此外，我们观察到，IgG抗CD74 / CLIP自身抗体识别在SPPL2a缺陷时积累的CD74 N末端降解产物。总之，来自AS单核细胞的SPPL2a蛋白酶活性降低是CD74和CD74 N末端片段的内体积累的诱因，这些物质在IFN-γ暴露后，