title: Targeting lymphocyte signaling pathways as a therapeutic approach to systemic lupus erythematosus.
abstract: OBJECTIVE
  Over the past year several key pathways in systemic lupus erythematosus (SLE) lymphocyte signaling have been identified. Pathways that can be exploited for therapy are discussed in this review.
  
  
  RESULTS
  Inhibition of SLE T cell activation by blocking spleen tyrosine kinase (Syk) and SLE T cell migration by blocking CD44 or CXCR4 lead to amelioration of lupus in lupus-prone mice. Similar results can be achieved by boosting CD8+ Treg numbers. Small molecules that block the kinases CaMKIV (calcium and calmodulin dependent kinase IV) and Bruton Tyrosine kinase (Btk) and the phosphatase calcineurin were shown to be effective in treating murine lupus. Finally, gene methylation status determines the expression of several key genes in SLE and strategies to correct it have shown promising results in preclinical studies.
  
  
  CONCLUSIONS
  Molecules that enhance T cell receptor (TCR) signaling or increase lymphocyte migration can be inhibited successfully with significant improvement of disease intensity in lupus-prone mice using small molecules. Manipulation of promoter methylation and histone acetylation represents a novel way to alter gene transcription in SLE.
authors: Division of Rheumatology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA. vkyttari@bidmc.harvard.edu
authors: Vasileios C
authors: VC
authors: Kyttaris
authors: George C
authors: GC
authors: Tsokos
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4 / Q000037:antagonists & inhibitors; D002465:Cell Movement / Q000187:drug effects; D044127:Epigenesis, Genetic; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000628:therapy*; D008213:Lymphocyte Activation / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D000072377:Syk Kinase; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
chemical_list: C514936:CXCR4 protein, mouse; C476399:Cd44 protein, mouse; D018960:Hyaluronan Receptors; D047908:Intracellular Signaling Peptides and Proteins; D011948:Receptors, Antigen, T-Cell; D019718:Receptors, CXCR4; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; C517685:Camk4 protein, mouse