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Phenotypic changes of lymphocyte in a patient with IgG4-related disease after corticosteroid therapy
  1. Shigeru Iwata,
  2. Kazuyoshi Saito,
  3. Shintaro Hirata,
  4. Yoshiya Tanaka
  1. The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan
  1. Correspondence to Yoshiya Tanaka, University of Occupational and Environmental Health, Japan, The First Department of Internal Medicine, School of Medicine, 1-1 Iseigaoka, Yahatanishi Ward, Kitakyushu 807-8555, Fukuoka Prefecture, Japan; tanaka{at}

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Immunoglobulin G4-related disease (IgG4RD) is a novel clinical disease entity characterised by elevated serum IgG4 and tissue infiltration by IgG4-positive plasma cells.1 ,2 Interleukin 4 (IL-4) and IL-10, which were detected with B cells in the salivary gland in this disease,3 direct naive B cells to switch to IgG4 production.4 B cells are therefore considered to be important for the pathogenesis of IgG4RD. However, the phenotype of B cells in patients with IgG4RD remains elusive. In this report we show the phenotypic changes of peripheral blood B cells in a patient with IgG4RD analysed by flow cytometry during treatment with a corticosteroid.

In January 2011 a 53-year-old man presented with symmetrical swelling of the lachrymal glands and a tumour located in the left junction of the renal pelvis and ureter, serum IgG4 >135 mg/dl and IgG4+/IgG+ cells >40% with significant invasion of lymphocytes and plasma cells, typical tissue fibrosis and sclerosis in the salivary gland. He was diagnosed with IgG4RD based on the guidelines for diagnosis.5 Treatment with corticosteroid 40 mg (0.6 mg/kg) was started. One year later the bilateral renal pelvic tumour had disappeared and serum IgG (IgG4) decreased from 1692 (341) mg/dl to 969 (61.5) mg/dl despite tapering of the corticosteroid dose to 2 mg/day.

Meanwhile, before treatment, memory B cells (CD19 gated IgD-CD27 or CD27+ CD38-) and plasmablasts (CD19 gated CD27highCD38high or IgD-CD27high, CD19lowCD38high) increased in a patient with IgG4RD compared with healthy donors in peripheral blood. Moreover, the expression levels of the costimulatory molecules CD80 were upregulated. Spleen tyrosine kinase (Syk) is a tyrosine kinase expressed in various immunocompetent cells including B cells. We have reported that the engagement of immune receptor phosphorylates Syk, resulting in proliferation and cytokine production on B cells.6 It is noteworthy that Syk phosphorylation was also markedly increased in CD19 cells in the patient compared with those in healthy donors.

However, CD27highCD38high plasmablasts in the patient decreased at 1 month and disappeared 6 months after treatment with corticosteroid, whereas the percentage of memory B cells almost did not change. Although he remained in low disease activity after tapering of the corticosteroid dose, the expression levels of CD80 and phospho-Syk on CD19 cells did not change until 1 year later (figure 1).

Figure 1

Phenotypic changes of B cells in a patient with IgG4-related disease before treatment, 1 month and 6 months after treatment with corticosteroid therapy. In the upper 10 contour line graphs, peripheral blood mononuclear cell (PBMCs) were gated on CD19-positive cells and further separated with CD27 and IgD, or CD38 and CD27. In the former, the left quadrant identified plasma cells (IgD-CD27high) and class-switched memory B cells (IgD-CD27+). The right upper quadrant identified IgM memory B cells (IgD+CD27). The right lower quadrant identified naïve B cells (IgD+CD27+). In the latter, CD27−CD38 + identified naïve B cells, CD27+ CD38− identified memory B cells and CD27highCD38high identified plasmablasts and plasma cells. In the lower four line graphs, PBMC were double-stained by CD19 (x-axis) and IgG isotype control, CD38, CD40, CD80 and Syk phosphorylation, respectively (y-axis). CD19lowCD38high identified plasmablasts and plasma cells.

Taken together, although corticosteroid therapy effectively decreased peripheral plasmablasts, activated memory B cells were resistant to treatment in IgG4RD. These results are supported by those of Khosroshahi et al who demonstrated that B cell depletion therapy by rituximab was effective in some patients with IgG4RD refractory to corticosteroid.7 The present data could therefore partly explain why IgG4RD is difficult to maintain in remission after reduction in the dose of corticosteroid. The results also indicate that the combined use of immunosuppressants, B cell-targeted therapies or Syk inhibitors may be considered for the treatment of IgG4RD, as shown in systemic lupus erythematosus, rheumatoid arthritis and idiopathic thrombocytopenic purpura.8,,10 However, further analysis of a large sample of patients is needed.


The authors thank Ms T Adachi, Ms N Sakaguchi and Ms K Noda for the excellent technical assistance. This work was supported in part by a Research Grant-In-Aid for Scientific Research from the Ministry of Health, Labour and Welfare of Japan, the Ministry of Education, Culture, Sports, Science and Technology of Japan and the University of Occupational and Environmental Health, Japan.



  • Competing interests YT has received consulting fees, speaking fees and/or honoraria from Mitsubishi-Tanabe Pharma, Chugai Pharma, Eisai Pharma, Pfizer, Abbott Immunology Pharma, Daiichi-Sankyo, Janssen Pharma, Astra-Zeneca, Takeda Industrial Pharma, Astellas Pharma, Asahi-kasei Pharma and GlaxoSmithKline and has received research grant support from Mitsubishi-Tanabe Pharma, Bristol-Myers Squibb, Takeda Industrial Pharma, MSD, Astellas Pharma, Eisai Pharma, Chugai Pharma, Pfizer and Daiichi-Sankyo. The other authors declare no conflict of interest.

  • Patient consent Obtained.

  • Ethics approval Ethics approval was obtained from the committee in University of Occupational and Environmental Health, Japan.

  • Provenance and peer review Not commissioned; externally peer reviewed.