Regulation of autoimmune disease by chemokines and chemokine receptors

Murine experimental autoimmune encephalomyelitis (EAE) is a CD4 + Th1 mediated demyelinating disease of the central nervous system (CNS) that serves as a model for the human disease multiple sclerosis. This autoimmune disease is characterized by the infiltration of antigen-specific T cells as well as macrophages into the CNS resulting in demyelination and progressive paralysis. An essential step during the progression of autoimmunity is the migration of destructive cells into tissue sites. Chemokines have been demonstrated to play a critical role in CNS cellular trafficking during the induction and progression of EAE. Understanding the role chemokines and the specific interactions they have with chemokine receptors in regulating the accumulation of autoreactive cells in the target organ is important for the understanding of disease progression.; The differential chemokine production along with temporal and spatial expression serves as an important regulatory mechanism during the progression of EAE by directing mononuclear cell trafficking within the CNS. The requirement for specific chemokine production for disease pathogenesis was demonstrated by antibody depletion studies. Specifically, in vivo neutralization of CCL2 (monocyte chemotactic protein-1 (MCP-1)) and CXCL10 (interferon-γ-inducible protein-10 (IP-10)) decreased clinical and histological disease, severity, and CNS infiltration of mononuclear cells. These results suggest an important role for MCP-1 and IP-10 in the recruitment and accumulation of inflammatory mononuclear cells during EAE pathogenesis.; Infiltrating mononuclear cells would require chemokine receptor expression for chemokine induced CNS trafficking and accumulation. Chemokine receptor expression during acute EAE was performed by flow cytometric analysis and revealed CCR1 and CXCR3 expression on CNS derived CD4+ T cells. Functional studies for chemokine receptors were examined using CCR2-deficient mice. CCR2-deficient mice did not develop severe clinical EAE, exhibited decreased disease incidence, and demonstrated no CNS lesions suggesting the necessity for CCR2 in disease progression. Together, the temporal and spatial expression of chemokines, especially MIP-1α, IP-10, and MCP-1 govern the trafficking and retention of autoreactive inflammatory cells in the CNS through interactions of chemokine receptors, especially CCR1, CCR2, and CXCR3 resulting in tissue destruction and clinical disease and open the possibility of using receptor antagonists for organ-specific autoimmune disease therapy.