RAB4A-DEPENDENT MECHANISTIC TARGET OF RAPAMYCIN ACTIVATION CONTROLS ORGAN-SPECIFIC DISEASE PATHOGENESIS IN SYSTEMIC LUPUS ERYTHEMATOSUS
- Andras Perl, United States of America
Abstract
Background and Aims
Genetic polymorphism and methylation-dependent overexpression of Rab4A influences mechanistic target of rapamycin (mTOR) activation that in turn controls immune cell lineage specification and constitutes an effective treatment target for autoimmunity in systemic lupus erythematosus (SLE).
Methods
To determine the impact of Rab4A during lupus pathogenesis, we generated mice with constitutively active Rab4AQ72Lalleles or lacking expression of Rab4A in T cells (Rab4A-KOCD4Cre) on the C57Bl/6 background and further backcrossed them onto the lupus-prone SLE1.2.3 triple-congenic (B6.TC) line.
Results
Activation of Rab4A accelerated the production of antinuclear antibodies (ANA) and antiphospholipid antibodies (aPL), anti-cardiolipin (ACLA) and anti-β2 glycoprotein I autoantibodies (anti-β2GPI), proteinuria, glomerulonephritis, and neurobehavioral dysfunction, while deletion of Rab4A in T cells abrogated pathogenesis. Dual mTORC1/mTORC2 activation was restrained in CD4 T cells, while mTORC2 was selectively blocked in CD8 T cells of B6.TC/Rab4A-KOCD4Cre mice. By contrast, pristane-inducible ANA, ACLA and anti-β2GPI production and pulmonary vasculitis (PV) were increased in Rab4A-KOCD4Cre mice but blocked in Rab4AQ72L mice relative to age-matched wildtype (WT) controls. However, intrahepatic lymphocytic infiltration and vasculitis were enhanced in Rab4AQ72L but diminished in Rab4A-KOCD4Cre mice. Thymus-derived FoxP3+Helios+ Tregs and mTORC1+/mTORC2+ CD4+CD25+ Tregs were expanded in Rab4AQ72L mice but depleted in Rab4A-KOCD4Cre mice. IL-17-producing CD11b+ pro-inflammatory macrophages were accumulated in the spleen and Gr1+ neutrophils were expanded in the lung of Rab4A-KOCD4Cre mice. Rapamycin completely abrogated nephritis and improved neurobehavioral dysfunction in B6.TC/Rab4AQ72L mice but failed to block PV in WT or Rab4A-KOCD4Cre mice.
Conclusions
The findings suggest that Rab4A impacts organ-specific lupus pathogenesis through modulating mTOR-dependent pro-inflammatory T-cell development and trafficking.