Altered cell-cell and cell-matrix interactions in the development of systemic autoimmunity

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by immune system dysregulation.
• Macrophages (MPhi) play a critical role in immune responses and are implicated in SLE pathogenesis.
• Aberrant Rho protein activity has been observed in MPhi from SLE-prone mice.

Purpose of the Study:

• To investigate the impact of apoptotic cells on Rho activity in MPhi from SLE-prone mice.
• To identify adhesion-related genes differentially expressed by MPhi in the presence of serum lipids mimicking apoptotic cells (SL-Apo).
• To explore the potential role of these gene expression changes in the development of autoimmunity.

Main Methods:

• Gene array analysis of MPhi from prediseased MRL mice (an SLE model).
• Culture of MPhi in the presence and absence of SL-Apo.
• Assessment of Rho activity in MPhi.

Main Results:

• MPhi from major inbred SLE models share a defect in Rho activity, triggered by apoptotic cells.
• SLE-prone MPhi display normal Rho activity when cultured without apoptotic cells.
• Gene arrays revealed differential expression of 42 adhesion-related genes in MPhi exposed to SL-Apo, with 32 showing normal expression without SL-Apo.

Conclusions:

• Apoptotic cells induce a specific defect in Rho activity in MPhi from SLE-prone mice.
• The identified dysregulation of adhesion-related genes suggests a potential mechanism predisposing to autoimmunity.
• Adhesion molecules and their altered expression may be critical in the pathogenesis of chronic autoimmune diseases like SLE.