Increase of MZB1 in B cells in systemic lupus erythematosus: proteomic analysis of biopsied lymph nodes

Abstract

BackgroundSystemic 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).MethodsLymph 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.ResultsMZB1, 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.ConclusionsMZB1 may be a potential therapeutic target in excessive antibody-secreting cells in SLE.Electronic supplementary materialThe online version of this article (10.1186/s13075-018-1511-5) contains supplementary material, which is available to authorized users.

An Autoantigen-ome from HS-Sultan B-Lymphoblasts Offers a Molecular Map for Investigating Autoimmune Sequelae of COVID-19

“…MZB1 plays important roles in humoral immunity and helps diversify peripheral B-cell functions by regulating calcium stores, antibody secretion, and integrin activation. MZB1 mRNA expression was found increased by >2-fold in B-cells of SLE patients with active disease [ 45 ]. High MZB1 gene expression predicted adverse prognosis in chronic lymphocytic leukemia, follicular lymphoma, and diffuse large B-cell lymphoma [ 46 ].…”

Development and validation of the first consensus gene-expression signature of operational tolerance in kidney transplantation, incorporating adjustment for immunosuppressive drug therapy

“…Furthermore, we have previously argued that the downregulation of the pro-inflammatory mineralocorticoid receptor gene NR3C2 and the upregulation of the anti-inflammatory cortisol-activating enzyme gene HSD11B1 in stable and CR KTRs is likely a response to the immunological challenge presented by the kidney allograft, which was not observed in KTRs with OT [9] . Moreover, the silencing of the MZB1 gene with methylation described in hepatocellular and gastric cancers could be seen as a form of immunological tolerance [ 36 , 37 ], while MZB1 protein was increased in B-cells from patients with the autoimmune condition systemic lupus erythematosus [38] . Finally, RAB40C protein regulates, via an ubiquitin-proteasome system, the degradation of RACK1 protein, which is important in tumour growth and T-cell migration [39] .…”

Role of Polymeric Immunoglobulin Receptor in IgA and IgM Transcytosis

“…Upregulation of MZB1 has been reported in patients of several chronic auto-immune diseases, including periodontitis [ 156 , 157 , 158 ], systemic lupus erythematosus [ 159 ], multiple sclerosis, juvenile idiopathic arthritis-associated uveitis [ 160 ], Crohn’s disease [ 161 ], and, by extension, rejection of kidney transplant [ 162 ]. It is possible that MZB1 overexpression leads to higher levels of local IgA and IgM secretion from plasma cells and their subsequent pIgR-dependent transcytosis in the mucus.…”