Systemic lupus erythematosus (SLE) is a chronic, idiopathic autoimmune disease characterized by episodic flares and progression of disease, substantial morbidity and mortality(l, 2). It is a multisystern rheumatic disease with a wide variety of associated clinical neurological and psychiatric syndromes including cognitive, behavioral, affective, and/or motor manifestations that may effect up to 75 percent of SLE patients(3). Both morbidity and mortality remain high because of lack of understanding of the underlying mechanisms related to abnormal central nervous system (CNS) function. In addition, progress has been hampered by the lack of specific diagnostic methods and therapeutic regimens. A long-standing challenge has been to discover drugs that can halt the progression of disease by inhibiting the ongoing pathologic immune responses while maintaining physiologic immune surveillance. An ideal therapeutic approach would be to modify the expression of the genes that contribute to immunopathogenesis of neuropsychiatric lupus (NPLE). Although the genes responsible for neurological disturbances in SLE is not finely dissected out, preliminary studies in mouse models of lupus suggests aberrant cytokine genes expression in hippocampus and cerebellum are responsible for the neurological deficit(3-5). Our laboratory has recently demonstrated that the histone deacetylase (HDI) inhibitor Trichostatin A (TSA) reverses the skewed expression of several genes implicated in the immunopathogenesis of SLE(6). TSA significantly down-regulated CD154 (CD40-ligand) and IL-10 mRNA and protein, while simultaneously up-regulating IFN-g message and protein levels in human SLE PBMC/T cells. Furthermore, our preliminary data in MRlJIpr mouse model of lupus demonstrates that this inhibitor down-regulates IL-10, IL-6, IL-12p30, IL-12p40 and IFN-g mRNA and protein secretion in MRL/Ipr splenocytes. Since IL-6, IL-10 and IFN-g genes are over expressed in cerebellum and hippocampus in MR/Ipr lupus, we propose the concept that HDIs may be useful for the prevention or treatment of neuropshychiatric lupus.
| Mishra, Nilamadhab; Reilly, Christopher M; Brown, Doris R et al. (2003) Histone deacetylase inhibitors modulate renal disease in the MRL-lpr/lpr mouse. J Clin Invest 111:539-52 |
