Rheumatology Service, Maimonides Institute of Biomedical Research of Cordoba (IMIBIC), Reina Sofia University Hospital, University of Córdoba, 14004, Córdoba, Spain.
Rheumatology Service, Maimonides Institute of Biomedical Research of Cordoba (IMIBIC), Reina Sofia University Hospital, University of Córdoba, 14004, Córdoba, Spain.
J Autoimmun. 2023 Feb;135:102990. doi: 10.1016/j.jaut.2022.102990. Epub 2023 Jan 6.
To characterize the splicing machinery (SM) of leukocytes from primary antiphospholipid syndrome (APS), systemic lupus erythematosus (SLE) and antiphospholipid syndrome with lupus (APS + SLE) patients, and to assess its clinical involvement.
Monocytes, lymphocytes and neutrophils from 80 patients (22 APS, 35 SLE and 23 APS + SLE) and 50 HD were purified, and 45 selected SM components were evaluated by qPCR-microfluidic array. Relationship with clinical features and underlying regulatory mechanisms were assessed.
APS, SLE and APS + SLE leukocytes displayed significant and specific alterations in SM-components (SMC), associated with clinical features [autoimmune profiles, disease activity, lupus nephritis (LN), and CV-risk markers]. A remarkable relationship among dysregulated SMC in monocytes and the presence of LN in SLE was highlighted, revealing a novel pathological mechanism, which was further explored. Immunohistology analysis of renal biopsies highlighted the pathological role of the myeloid compartment in LN. Transcriptomic analysis of monocytes from SLE-LN(+) vs SLE-LN(-) identified 271 genes differentially expressed, mainly involved in inflammation and IFN-signaling. Levels of IFN-related genes correlated with those of SMC in SLE-LN(+). These results were validated in two external SLE-LN(+) datasets of whole-blood and kidney biopsies. In vitro, SLE-LN(+)-serum promoted a concomitant dysregulation of both, the IFN signature and several SMC, further reversed by JAKinibs treatment. Interestingly, IFNs, key inflammatory cytokines in SLE pathology, also altered SMC. Lastly, the over/down-expression of selected SMC in SLE-monocytes reduced the release of inflammatory cytokines and their adhesion capacity.
Overall, we have identified, for the first time, a specific alteration of SMC in leukocytes from APS, SLE and APS + SLE patients that would be responsible for the development of distinctive clinical profiles.
描述原发性抗磷脂综合征（APS）、系统性红斑狼疮（SLE）和抗磷脂综合征伴狼疮（APS+SLE）患者白细胞中的剪接体（SM），并评估其临床相关性。
从 80 名患者（22 名 APS、35 名 SLE 和 23 名 APS+SLE）和 50 名健康对照组（HD）中纯化单核细胞、淋巴细胞和中性粒细胞，并通过 qPCR-微流控阵列评估 45 种选定的 SM 成分。评估其与临床特征的关系及潜在的调控机制。
APS、SLE 和 APS+SLE 白细胞中的 SM 成分（SMC）发生显著且特异性改变，与临床特征（自身免疫谱、疾病活动度、狼疮肾炎（LN）和心血管风险标志物）相关。SLE 患者单核细胞中失调的 SMC 与 LN 的存在之间存在显著关系，揭示了一种新的病理机制，并进一步进行了探索。狼疮肾炎患者肾活检的免疫组织化学分析强调了骨髓细胞在 LN 中的病理作用。对 SLE-LN(+)与 SLE-LN(-)患者单核细胞的转录组分析确定了 271 个差异表达的基因，主要涉及炎症和 IFN 信号。SLE-LN(+)患者中 IFN 相关基因的水平与 SMC 相关。这些结果在两个 SLE-LN(+)的全血和肾活检外部数据集得到验证。体外，SLE-LN(+)患者的血清可同时促进 IFN 特征和几个 SMC 的失调，用 JAKinibs 治疗可逆转这种失调。有趣的是，SLE 病理中的关键炎症细胞因子 IFNs 也改变了 SMC。最后，SLE 单核细胞中选定的 SMC 的过表达/低表达可降低炎症细胞因子的释放及其黏附能力。
总之，我们首次发现 APS、SLE 和 APS+SLE 患者白细胞中的 SMC 发生特定改变，这可能是导致独特临床表型的原因。
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