Circulating plasmablasts/plasma cells: a potential biomarker for IgG4-related disease.
BACKGROUND
Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a multisystem fibroinflammatory disease. We previously reported that a circulating cell population expressing CD19+CD24-CD38hiwas increased in patients with IgG4-RD. In this study, we aimed to document that this cell population represented circulating plasmablasts/plasma cells, to identify the detailed phenotype and gene expression profile of these IgG4-secreting plasmablasts/plasma cells, and to determine whether this B-cell lineage subset could be a biomarker in IgG4-related disease (IgG4-RD).


METHODS
A total of 42 untreated patients with IgG4-RD were evaluated. Peripheral B-cell subsets, including CD19+CD24-CD38hiplasmablasts/plasma cells, CD19+CD24+CD38-memory B cells, CD19+CD24intCD38intnaïve B cells, and CD19+CD24hiCD38hiregulatory B cells, were assessed and sorted by flow cytometry. Microarray analysis was used to measure gene expression of circulating B-cell lineage subsets. Further characterization of CD19+CD24-CD38hiplasmablasts/plasma cells was carried out by evaluating additional surface markers, including CD27, CD95, and human leukocyte antigen (HLA)-DR, by flow cytometric assay. In addition, various B-cell lineage subsets were cultured in vitro and IgG4 concentrations were measured by cytometric bead array.


RESULTS
In untreated patients with IgG4-RD, the peripheral CD19+CD24-CD38hiplasmablast/plasma cell subset was increased and positively correlated with serum IgG4 levels, the number of involved organs, and the IgG4-related Disease Responder Index. It decreased after treatment with glucocorticoids. Characterization of the plasmablast/plasma cell population by gene expression profiling documented a typical plasmablast/plasma cell signature with higher expression of X-box binding protein 1 and IFN regulatory factor 4, but lower expression of paired box gene 5 and B-cell lymphoma 6 protein. In addition, CD27, CD95, and HLA-DR were highly expressed on CD19+CD24-CD38hiplasmablasts/plasma cells from patients with IgG4-RD. Furthermore, CD19+CD24-CD38hiplasmablasts/plasma cells secreted more IgG4 than other B-cell populations.


CONCLUSIONS
Circulating CD19+CD24-CD38hiplasmablasts/plasma cells are elevated in active IgG4-RD and decreased after glucocorticoid treatment. This IgG4-secreting plasmablast/plasma cell population might be a potentially useful biomarker for diagnosis and assessing response to treatment.
Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, 100730, China.|Department of Rheumatology, Hebei General Hospital, Shijiazhuang, China.
Wei
W
Lin
Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, 100730, China.
Panpan
P
Zhang
Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, 100730, China.
Hua
H
Chen
Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, 100730, China.
Yu
Y
Chen
Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, 100730, China.
Hongxian
H
Yang
Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, 100730, China.
Wenjie
W
Zheng
Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, 100730, China.
Xuan
X
Zhang
Department of Rheumatology, Hebei General Hospital, Shijiazhuang, China.
Fengxiao
F
Zhang
Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, 100730, China. zhangwen91@sina.com.
Wen
W
Zhang
National Institutes of Health, Bethesda, MD, USA. peterlipsky@comcast.net.
Peter E
PE
Lipsky
D000328:Adult; D015415:Biomarkers / Q000097:blood; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007154:Immune System Diseases / Q000276:immunology*; D007074:Immunoglobulin G / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010950:Plasma Cells / Q000276:immunology*
D015415:Biomarkers; D007074:Immunoglobulin G
Autoimmunity; Biomarker; CD19+CD24−CD38hi plasmablast/plasma cell; IgG4-RD