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Published on: June 7, 2017
Autoimmune Th2-mediated dacryoadenitis in MRL/MpJ mice becomes Th1-mediated in IL-4 deficient MRL/MpJ mice
Douglas A Jabs1, Robert A Prendergast, Adam L Campbell
1Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. douglas.jabs@mssm.edu
Purpose:
MRL/MpJ mice of substrains MRL/MpJ-fas(+)/fas(+) (MRL/+) and MRL/MpJ-fas(lpr)/fas(lpr) (MRL/lpr) spontaneously develop autoimmune dacryoadenitis and sialadenitis and are a model for the human disorder Sjögren syndrome. The dacryoadenitis in both substrains appears to be Th2 in nature, with little IFN-gamma and substantial IL-4 at the site of lacrimal gland inflammation.
Methods:
MRL/MpJ mice with a defective IL-4 gene-both MRL/+-IL-4(tm)/IL-4(tm) (MRL/+/IL-4(tm)) and MRL/lpr-IL-4(tm)/IL-4(tm) (MRL/lpr-IL-4(tm))-that resulted in a loss of IL-4 production were bred and evaluated for dacryoadenitis.
Results:
MRL/+/IL-4(tm) and MRL/lpr/IL-4(tm) mice developed dacryoadenitis of similar onset, appearance, and severity as found in MRL/MpJ mice with an intact IL-4 gene. Immunohistochemistry examination revealed a substantially greater number of inflammatory cells staining for IFN-gamma than for IL-13 in the dacryoadenitis of IL-4-deficient MRL/MpJ mice (MRL/+/IL-4(tm), 66% vs. 0.8%, P = 0.001; MRL/lpr/IL-4(tm), 67% vs. 1.2%, P = 0.002). Real-time PCR demonstrated greater amounts of IFN-gamma than IL-13 mRNA relative transcripts in lacrimal glands of MRL/lpr/IL-4(tm) mice (mean difference, 28.6; P = 0.035). Greater CD86 (B7-2) than CD80 (B7-1) expression was present in MRL/+/IL-4(tm) mice (11% vs. 3%, P = 0.003) and MRL/lpr/IL-4(tm) mice (10% vs. 3%, P = 0.002).
Conclusions:
These results suggest that a Th2 autoimmune process can be converted to a Th1 process in the absence of IL-4.
Insights
Removing interleukin-4 (IL-4) from MRL/MpJ mice converted their autoimmune dacryoadenitis from a Th2 to a Th1 process. This suggests that Th2 autoimmune responses can be shifted to Th1 in the absence of IL-4.
Area of Science:
- Immunology
- Autoimmunity
- Molecular Biology
Background:
- MRL/MpJ mice spontaneously develop autoimmune dacryoadenitis and sialadenitis, serving as a model for Sjögren syndrome.
- The lacrimal gland inflammation in these mice is characterized by a Th2-dominant immune response, with low interferon-gamma (IFN-γ) and high interleukin-4 (IL-4).
Purpose of the Study:
- To investigate the role of IL-4 in the development of autoimmune dacryoadenitis in MRL/MpJ mice.
- To determine if the absence of IL-4 could alter the immune response profile from Th2 to Th1.
Main Methods:
- MRL/MpJ mice with a defective IL-4 gene (MRL/+/IL-4(tm) and MRL/lpr-IL-4(tm)) were generated to eliminate IL-4 production.
- These IL-4-deficient mice were evaluated for the development of dacryoadenitis.
- Immunohistochemistry and real-time PCR were used to analyze inflammatory cell populations and cytokine mRNA expression (IFN-γ vs. IL-13).
- Flow cytometry was employed to assess the expression of co-stimulatory molecules CD86 (B7-2) and CD80 (B7-1).
Main Results:
- IL-4-deficient MRL/MpJ mice developed dacryoadenitis with similar onset, appearance, and severity compared to controls.
- Immunohistochemistry revealed a significant increase in IFN-γ-producing cells and a decrease in IL-13-producing cells in the lacrimal glands of IL-4-deficient mice.
- Real-time PCR confirmed higher relative transcript levels of IFN-γ compared to IL-13 mRNA in these mice.
- Expression of CD86 was significantly greater than CD80 in both IL-4-deficient substrains.
Conclusions:
- The absence of IL-4 in MRL/MpJ mice leads to a shift in the autoimmune response from Th2 to Th1.
- These findings suggest that IL-4 is critical for maintaining the Th2-mediated autoimmune process in this model of Sjögren syndrome.
- Modulating IL-4 pathways could be a potential therapeutic strategy for autoimmune diseases characterized by Th2 responses.
