Cell trafficking through tissues depends on cell-cell and cell-matrix contacts mediated by integrins and other specialized adhesion molecules. The observed downregulation of molecules mediating the interactions between leukocytes and endothelial cells in the LN tissues of susceptible LEW rats, specifically
Sele and
Sell, could facilitate recruitment of effector cells into the retina. Cell recruitment is reported to be guided by chemotactic signals through the CCL2/CCR2 axis.
27 In our study, important variations of gene expression rates between strains and during the course of time was observed for the
Scya2 gene coding for CCL2 (MCP-1), its ligand CCR2, and VTN. It is noteworthy that the
Scya2 and
Vtn genes are located within the same QTL region (
Eau3) on rat chromosome 10.
2 The role of the CCL2/CCR2 axis in regulating the development of a Th1 response has been suggested.
28 In a pulmonary
Cryptococcus neoformans infection model, neutralization of CCL2 or deletion of CCR2 resulted in comparable macrophage and T-cell recruitment deficits, as well as a switch from Th1- to Th2-type cytokine production within the infected lung. However,
Scya2 neutralization does not result in pulmonary eosinophilia, nor does it produce an IFNγ defect within the draining LNs, as does CCR2 deletion, suggesting that the adaptive phase of cell-mediated immunity (mononuclear cell recruitment) uses the CCL2/CCR2 signaling axis, whereas the innate phase (Th1 polarization) involves a
Scya2 (CCL2)-independent, CCR2 signaling pathway.
28 It has been proposed that, if antigen-presenting cells (APCs) promoting Th1 differentiation express CCR2, the loss of CCR2 may prevent Th1 polarization because Th1-APCs do not appear in the draining LNs. A similar scenario may apply in our case, in which the absence of CCR2
+ APCs in the draining LNs, suggested by the significant downregulation of CCR2 gene expression at day 3 pi in the resistant F344 strain might fail the activation of Th1-polarized T cells to be able to trigger the adaptive response to the retinal antigen(s) responsible for the disease.
29 Furthermore, upregulation of
SCYA2 was shown in patients with rheumatoid arthritis,
30 and in a relapsing autoimmune encephalomyelitis model
31 and its receptor gene
Ccr2 is located on rat chromosome 8q32, which has been found to regulate susceptibility to EAU.
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