Decreased Expression of Innate Immunity-Related Genes in Peripheral Blood Mononuclear Cells from Patients with IgG4-Related Disease.

Abstract

BACKGROUND:

IgG4-related disease (IgG4-RD) is a new clinical entity of unknown etiology characterized by elevated serum IgG4 and tissue infiltration by IgG4-positive plasma cells. Although aberrancies in acquired immune system functions, including increases in Th2 and Treg cytokines observed in patients with IgG4-RD, its true etiology remains unclear. To investigate the pathogenesis of IgG4-RD, this study compared the expression of genes related to innate immunity in patients with IgG4-RD and healthy controls.

MATERIALS AND METHODS:

Peripheral blood mononuclear cells (PBMCs) were obtained from patients with IgG4-RD before and after steroid therapy and from healthy controls. Total RNA was extracted and DNA microarray analysis was performed in two IgG4-RD patients to screen for genes showing changes in expression. Candidate genes were validated by real-time RT-PCR in 27 patients with IgG4-RD and 13 healthy controls.

RESULTS:

DNA microarray analysis identified 21 genes that showed a greater than 3-fold difference in expression between IgG4-RD patients and healthy controls and 30 genes that showed a greater than 3-fold change in IgG4-RD patients following steroid therapy. Candidate genes related to innate immunity, including those encoding Charcot-Leyden crystal protein (CLC), membrane-spanning 4-domain subfamily A member 3 (MS4A3), defensin alpha (DEFA) 3 and 4, and interleukin-8 receptors (IL8R), were validated by real-time RT-PCR. Expression of all genes was significantly lower in IgG4-RD patients than in healthy controls. Steroid therapy significantly increased the expression of DEFA3, DEFA4 and MS4A3, but had no effect on the expression of CLC, IL8RA and IL8RB.

CONCLUSIONS:

The expression of genes related to allergy or innate immunity, including CLC, MS4A3, DEFA3, DEFA4, IL8RA and IL8RB, was lower in PBMCs from patients with IgG4-RD than from healthy controls. Although there is the limitation in the number of patients applied in DNA microarray, impaired expression of genes related to innate immunity may be involved in the pathogenesis of IgG4-RD as well as in abnormalities of acquired immunity.

• Authors: Akio Nakajima, Yasufumi Masaki, Takuji Nakamura, Takafumi Kawanami, Yasuhito Ishigaki, Tsutomu Takegami, Mitsuhiro Kawano, Kazunori Yamada, Norifumi Tsukamoto, Shoko Matsui, Takako Saeki, Kazuichi Okazaki, Terumi Kamisawa, Taiichiro Miyashita, Yoshihiro Yakushijin, Keita Fujikawa, Motohisa Yamamoto, Hideaki Hamano, Tomoki Origuchi, Shintaro Hirata, Hiroto Tsuboi, Takayuki Sumida, Hisanori Morimoto, Tomomi Sato, Haruka Iwao, Miyuki Miki, Tomoyuki Sakai, Yoshimasa Fujita, Masao Tanaka, Toshihiro Fukushima, Toshiro Okazaki, Hisanori Umehara
• Journal: PloS one (PLoS One) Vol. 10 Issue 5 Pg. e0126582 ( 2015) ISSN: 1932-6203 [Electronic] United States
• PMID: 25973893 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cell Cycle Proteins
• Glycoproteins
• Immunoglobulin G
• MS4A3 protein, human
• Membrane Proteins
• Receptors, Interleukin-8
• alpha-Defensins
• human neutrophil peptide 3
• human neutrophil peptide 4
• Lysophospholipase
• lysolecithin acylhydrolase

Topics

• Adult
• Aged
• Aged, 80 and over
• Autoimmune Diseases (immunology, pathology)
• Case-Control Studies
• Cell Cycle Proteins (genetics, metabolism)
• Down-Regulation
• Female
• Glycoproteins (genetics, metabolism)
• Humans
• Immunity, Innate (genetics)
• Immunoglobulin G (blood)
• Leukocytes, Mononuclear (cytology, immunology, metabolism)
• Lysophospholipase (genetics, metabolism)
• Male
• Membrane Proteins (genetics, metabolism)
• Middle Aged
• Oligonucleotide Array Sequence Analysis
• Real-Time Polymerase Chain Reaction
• Receptors, Interleukin-8 (genetics, metabolism)
• Th2 Cells (cytology, immunology)
• Up-Regulation
• alpha-Defensins (genetics, metabolism)