Analysis of Complement Gene Expression, Clinical Associations, and Biodistribution of Complement Proteins in the Synovium of Early Rheumatoid Arthritis Patients Reveals Unique Pathophysiologic Features.
Analysis of Complement Gene Expression, Clinical Associations, and Biodistribution of Complement Proteins in the Synovium of Early Rheumatoid Arthritis Patients Reveals Unique Pathophysiologic Features.
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DOI：
10.4049/jimmunol.2101170
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发表时间：
2022-06-01
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影响因子：
--
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类风湿性关节炎（RA）是一种以滑膜增生和炎症为特征的自身免疫性疾病。血清阳性RA中自身抗体的发现表明，由于关节中免疫复合物的局部存在，补体系统激活可能发挥病理生理作用。我们的第一个目标是探索早期关节炎队列（PEAC）mRNA测序数据的病理生物学，以确定通过DAS 28-ESR测量的临床疾病严重程度与滑膜和血液中补体系统基因表达之间的相关性。我们的第二个目的是使用多重免疫组织化学（MIHC）染色的特定补体激活蛋白和抑制剂的加速药物伙伴关系（AMP）RA/SLE研究的受试者，以确定生物分布。在PEAC研究中，滑膜中特异性补体基因mRNA表达水平与以下补体基因的DAS 28-ESR之间存在显著正相关：C2、FCN 1、FCN 3、CFB、CFP、C3 AR 1、C5 AR 1和CR 1。DAS 28-ESR与Colec 12、C5、C6、MASP-1、CFH和MCP呈显著负相关。在滑膜中，DAS 28-ESR与Fcγ R1 A、Fcγ R1 B、Fcγ R2 A和Fcγ R3 A也呈显著正相关。值得注意的是，CFHR 4滑膜表达与DAS 28-ESR治疗后6个月呈正相关，表明在更差的治疗反应中起作用。滑膜中C5 RNA表达的负相关性可能是在RA患者中进行的临床试验中C5/C5 aR抑制剂未能显著获益的基础。对早期RA滑膜的MIHC分析揭示了激活和抑制因子局部改变的重要证据，这些因子可能促进局部补体激活。
Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial hyperplasia and inflammation. The finding of autoantibodies in seropositive RA suggests that complement system activation might play a pathophysiologic role due to the local presence of immune complexes in the joints. Our first objective was to explore the Pathobiology of Early Arthritis Cohort (PEAC) mRNA sequencing data for correlations between clinical disease severity as measured by DAS28-ESR and complement system gene expression, both in the synovium and in blood. Our second objective was to determine the biodistribution using multiplex immunohistochemical (MIHC) staining of specific complement activation proteins and inhibitors from subjects in the Accelerating Medicines Partnership (AMP) RA/SLE study. In the PEAC study, there were significant positive correlations between specific complement gene mRNA expression levels in the synovium and DAS28-ESR for the following complement genes: C2, FCN1, FCN3, CFB, CFP, C3AR1, C5AR1, and CR1. Additionally, there were significant negative correlations between DAS28-ESR and Colec12, C5, C6, MASP-1, CFH and MCP. In the synovium there were also significant positive correlations between DAS28-ESR and FcγR1A, FcγR1B, FcγR2A and FcγR3A. Notably, CFHR4 synovial expression was positively correlated following treatment with the DAS28-ESR at six months, suggesting a role in worse therapeutic responses. The inverse correlation of C5 RNA expression in the synovium may underlie the failure of significant benefit from C5/C5aR inhibitors in clinical trials performed in patients with RA. MIHC analyses of Early RA synovium reveal significant evidence of regional alterations of activation and inhibitory factors that likely promote local complement activation.
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影响因子：
--
作者：
Happonen KE;Saxne T;Aspberg A;Mörgelin M;Heinegård D;Blom AM
通讯作者：
Blom AM
DOI：
10.4049/jimmunol.1102310
发表时间：
2012-02-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Banda NK;Hyatt S;Antonioli AH;White JT;Glogowska M;Takahashi K;Merkel TJ;Stahl GL;Mueller-Ortiz S;Wetsel R;Arend WP;Holers VM
通讯作者：
Holers VM
影响因子：
--
作者：
Hootman, JM;Helmick, CG
通讯作者：
Helmick, CG
影响因子：
4.6
作者：
Banda, N. K.;Levitt, B.;Arend, W. P.
通讯作者：
Arend, W. P.
影响因子：
7.3
作者：
Holers VM;Banda NK
通讯作者：
Banda NK