1. Increase of MZB1 in B cells in systemic lupus erythematosus: proteomic analysis of biopsied lymph nodes
- Author
-
Toshiki Nakajima, Hajime Yoshifuji, Kaori Kiso, Norishige Yamada, Takuma Oku, Aya Miyagawa-Hayashino, Hironori Haga, Adeeb Salah, Koji Kitagori, Yoshitaka Hirayama, Shinji Ito, and Tatsuaki Tsuruyama
- Subjects
Proteomics ,0301 basic medicine ,Pathology ,lcsh:Diseases of the musculoskeletal system ,Proteome ,Apoptosis ,Mass Spectrometry ,Unfolded protein response ,chemistry.chemical_compound ,0302 clinical medicine ,immune system diseases ,Lupus Erythematosus, Systemic ,Medicine ,skin and connective tissue diseases ,TUNEL ,B-Lymphocytes ,Mice, Inbred NZB ,biology ,medicine.diagnostic_test ,Tunicamycin ,Marginal zone ,Cytokines ,Immunohistochemistry ,Lymph ,SLE lymphadenopathy ,Antibody ,Research Article ,medicine.medical_specialty ,Formalin-fixed paraffin-embedded ,Proteomic analysis ,Flow cytometry ,03 medical and health sciences ,Systemic lupus erythematosus ,Animals ,Humans ,Lupus-prone mice ,Adaptor Proteins, Signal Transducing ,030203 arthritis & rheumatology ,Autoimmune disease ,business.industry ,Germinal center ,medicine.disease ,Mice, Inbred C57BL ,030104 developmental biology ,chemistry ,biology.protein ,Lymph Nodes ,lcsh:RC925-935 ,business ,Chromatography, Liquid - Abstract
Background Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease in which dysregulation of B cells has been recognized. Here, we searched for potential biomarkers of SLE using liquid chromatography-tandem mass spectrometry (LC-MS). Methods Lymph nodes from SLE patients and controls were analyzed by LC-MS. To validate the identified molecules, immunoblotting and immunohistochemistry were performed and B cells from SLE patients were analyzed by quantitative RT-PCR. B-cell subsets from NZB/W F1 mice, which exhibit autoimmune disease resembling human SLE, were analyzed by flow cytometry. Endoplasmic reticulum (ER) stress was induced by tunicamycin and the serum concentration of anti-dsDNA antibodies was determined by ELISA. TUNEL methods and immunoblotting were used to assess the effect of tunicamycin. Results MZB1, which comprises part of a B-cell-specific ER chaperone complex and is a key player in antibody secretion, was one of the differentially expressed proteins identified by LC-MS and confirmed by immunoblotting. Immunohistochemically, larger numbers of MZB1+ cells were located mainly in interfollicular areas and scattered in germinal centers in specimens from SLE patients compared with those from controls. MZB1 colocalized with CD138+ plasma cells and IRTA1+ marginal zone B cells. MZB1 mRNA was increased by 2.1-fold in B cells of SLE patients with active disease (SLE Disease Activity Index 2000 ≥ 6) compared with controls. In aged NZB/W F1 mice, splenic marginal zone B cells and plasma cells showed elevated MZB1 levels. Tunicamycin induced apoptosis of MZB1+ cells in target organs, resulting in decreased serum anti-dsDNA antibody levels. Additionally, MZB1+ cells were increased in synovial tissue specimens from patients with rheumatoid arthritis. Conclusions MZB1 may be a potential therapeutic target in excessive antibody-secreting cells in SLE. Electronic supplementary material The online version of this article (10.1186/s13075-018-1511-5) contains supplementary material, which is available to authorized users.
- Published
- 2018