Background/Purpose:

IgG4-related disease (IgG4-RD) is a new disease entity characterized by high serum IgG4 levels, IgG4-positive plasmacytic infiltration and fibrosis in various organs. Although the clinical features including serum abnormalities, organ involvement, diagnosis, and the therapeutic approach have been reported recently, the molecular mechanism of this disease remains unclear. The purpose of this study was to determine the mechanism of up-regulation of IgG4 class switch recombination in IgG4-RD.

Methods:

1)    We extracted RNA from PBMC of patients with IgG4-RD (n=6), Sjögren’s syndrome (SS) (n=6), and healthy control (HC) (n=8), from CD3 positive T cells and CD20 positive B cell sorted from PBMC of patients with IgG4-RD (n=3), SS (n=4), and HC (n=4). The RNAs were also prepared from labial salivary glands (LSG) of patients with IgG4-RD (n=11), SS (n=13), and HC (n=3).

2)    The mRNA expression levels of IgG4-specific class switch-related molecules such as Th2 cytokines (IL-4 and IL-13), Treg cytokines (IL-10 and TGFβ), transcriptional factors (GATA3 and Foxp3) were examined by quantitative PCR assay.

3)    IgG4-non-specific class switch related molecules such as CD40, CD154, BAFF, APRIL, IRF4, and AID were also examined by quantitative PCR assay.

Results:

1)    IgG4-specific class switch-related molecules. The mRNA expression level of IL-4 was significantly higher in LSG of IgG4-RD than HC (P<0.05). Treg cytokines (IL-10 and TGFβ) were significantly higher in LSG of IgG4-RD than SS and HC (P<0.05, each). There were no significant differences in the PBMC expression levels of various cytokines, among the three groups. In LSG, the expression of GATA3 was significantly lower in IgG4-RD than in SS, Foxp3 was significantly higher in IgG4-RD and SS than in HC (P<0.05, each).

2)    IgG4-non-specific class switch-related molecules. The mRNA expression levels of CD40 and CD154 were significantly lower in PBMC of IgG4-RD than SS (P<0.05, each). However, the expression of CD40 in CD20 positive B cells and that of CD154 in CD3 positive T cells were comparable in the three groups. The expression of BAFF was significantly higher in LSG of IgG4-RD than HC (P<0.05). The expression of APRIL was significantly lower in PBMC of IgG4-RD than HC (P<0.05). The expression of AID was significantly higher in LSG of IgG4-RD than SS and HC (P<0.05, each).

Conclusion:

In LSG of IgG4-RD, increased Treg cytokines (IL-10 and TGFβ) might play important roles in IgG4-specific class switch recombination and fibrosis, which are characteristic features of IgG4-RD. High expression of AID could also contribute to up-regulation of IgG4-specific class switch recombination along with IL-10 in LSG of IgG4-RD. Thus overexpression of IL-10, TGFβ, and AID in LSG might play important pathogenic roles in IgG4-RD. This study showed different expression levels of IgG4 class switch-related molecules in LSG than in PBMC of IgG4-RD, which suggested that IgG4 class switch recombination seem be mainly up-regulated in affected organs.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/molecular-mechanism-of-igg4-class-switch-recombination-in-igg4-related-disease/