Jayaraman Sahana, Wilson Andrew, Zheng Xuwen Alice, Montagne Janelle M, Pinal-Fernandez Iago, Mammen Andrew L, Lloyd Thomas E, Larman H Benjamin
Institute for Cell Engineering, Division of Immunology, Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
J Autoimmun. 2025 Jun;154:103437. doi: 10.1016/j.jaut.2025.103437. Epub 2025 May 26.
Sporadic inclusion body myositis (IBM) is the most common adult idiopathic inflammatory myopathy. IBM etiology has been elusive, due to both degenerative and autoimmune disease features found on muscle biopsy, and significant disease heterogeneity. Investigating the role of antibodies in the muscle of IBM patients may improve our understanding of disease pathogenesis.
We used an IBM xenograft mouse model in which muscle biopsy tissue from IBM patients (n = 98) and controls (n = 131; including 54 from other types of myopathy) were implanted into immunodeficient mice (NOD-Rag1-IL2rγ). We quantified the amount of human IgG, IgA, and IgM in xenografted mouse sera using MesoScale Diagnostics (MSD) assay. We detected donor-derived antibody reactivities targeting autoantigens and infectious agents using Phage ImmunoPrecipitation Sequencing (PhIP-Seq). Finally, we used FR3 AmplifiKation Sequencing (FR3AK-Seq) to sequence the antibody mRNAs from a separate cohort of 146 patient biopsies (14 IBM, 22 healthy controls, 110 other myositis subtypes).
With the MSD assay we found human IgG, IgA, and IgM in a larger percentage of IBM xenografted mice versus controls. Using PhIP-Seq, we found anti-microbial reactivities secreted from IBM muscle are prevalent amongst a healthy control population but autoantigen reactivities in IBM are more unique at the peptide and protein level. Additionally, NT5C1A (IgG/IgA and IgM) and TIF1γ (IgG/A) autoantibodies are secreted from muscle tissues of 4/18 and 10/18 IBM xenograft donors, respectively.
Our characterization of antibody responses within the muscle of IBM patients reveals that muscle-infiltrating B cells produce both disease-associated autoantibodies and a broad spectrum of antibodies targeting non-self antigens.
散发性包涵体肌炎（IBM）是最常见的成人特发性炎性肌病。由于在肌肉活检中发现了退行性和自身免疫性疾病特征，以及显著的疾病异质性，IBM的病因一直难以捉摸。研究抗体在IBM患者肌肉中的作用可能会增进我们对疾病发病机制的理解。
我们使用了一种IBM异种移植小鼠模型，将IBM患者（n = 98）和对照组（n = 131；包括54例其他类型肌病患者）的肌肉活检组织植入免疫缺陷小鼠（NOD-Rag1-IL2rγ）体内。我们使用MesoScale Diagnostics（MSD）检测法对异种移植小鼠血清中的人IgG、IgA和IgM含量进行了定量。我们使用噬菌体免疫沉淀测序（PhIP-Seq）检测了针对自身抗原和感染因子的供体来源抗体反应性。最后，我们使用FR3扩增测序（FR3AK-Seq）对来自另一组146例患者活检样本（14例IBM患者、22例健康对照、110例其他肌炎亚型患者）的抗体mRNA进行了测序。
通过MSD检测法，我们发现与对照组相比，在更大比例的IBM异种移植小鼠中检测到了人IgG、IgA和IgM。使用PhIP-Seq，我们发现IBM肌肉分泌的抗微生物反应性在健康对照人群中普遍存在，但IBM中的自身抗原反应性在肽和蛋白质水平上更为独特。此外，分别从4/18和10/18例IBM异种移植供体的肌肉组织中分泌出了NT5C1A（IgG/IgA和IgM）和TIF1γ（IgG/A）自身抗体。
我们对IBM患者肌肉中抗体反应的表征表明，肌肉浸润性B细胞产生了与疾病相关的自身抗体以及针对非自身抗原的广谱抗体。
