OBJETIVOS ESPECÍFICOS

The immune system has evolved to orchestrate two opposing tasks; to protect the body against potentially harmful pathogens while preventing excessive immune reaction leading to tissue destruction. One way the immune system is able to do this is through the interaction between CD200 and its structurally related receptor (CD200R). CD200 is member of the immunoglobulin super family domain (IgSF)-bearing molecules which is

the most abundant molecules found on the cell surface, constituting about one third of the proteins found on the surfaces of leukocytes (332). CD200 has two Ig-like extracellular domains, one transmembrane domain, and a cytoplasmic domain which has no known signaling function. It is expressed on a variety cell types and tissues including: thymocytes, T cells, B cells, kidney glomeruli, tonsil follicles, the placenta, ovary, vascular endothelium and neurons (333-336). CD200 induces an immunosuppressive signal through its structurally related receptor CD200R (337). CD200’s role in negatively regulating the immune system has been shown in spontaneous abortions, prolonging graft survival and tumor rejection (333-336, 338-340). Moreover, CD200 is expressed on many human viruses, such as herpes virus 8 and has been implicated in down regulating T cell and dendritic cell activation as well as modulation of the host- pathogen immune reaction (341, 342). To elucidate the role of CD200 in the immune system, CD200 knockout mice were generated (343). These mice developed normally, but had an increase of macrophages in the spleen and liver and an increase of microglia in the brain. However, these mice were highly susceptible to experimentally-induced autoimmune diseases. In response to nerve damage, induced through facial nerve transaction, CD200 knockout mice had a dramatic increase in microglia activation when compare to wild type mice. To test CD200 function in myeloid linage compartments, CD200 knockout mice were treated to develop both experimental autoimmune encephalomyelitis (EAE) and collage-induced arthritis. CD200 deficient mice were highly susceptible to both conditions when compared to wild type and showed a significant increase of macrophages and self-reactive T cells. These findings suggest that

CD200 controls the induction of an immune response, and lack of CD200 causes an exaggerate immune response leading to autoimmunity (343).

The N-terminal domains of both CD200 and CD200R are critical for their interaction and for the negative immune signal to occur (344). The N-terminal surface of CD200 is highly glycosylated to prevent any cis interactions; however it still displays the binding face which interacts with the CD200R. While the CD200-CD200R interaction is similar to CD80 and CD86 and its interaction with either CD28 (positive) or CTLA4 (negative) the CD200R transmits its single in different ways (345, 346). The CD200R has two Ig like domains, and one cytoplasmic tail which contains a NPXY signaling motif. The CD200R is mainly expressed on myeloid cells such as macrophages, dendritic cells and neutrophils, but it can also be found on T cells. There is little known about how CD200R elicits its downstream signaling; however some research has demonstrated that its NPXY motif binds to a phosphotyrosine domain present in signaling adaptor molecules. It has been demonstrated in mast cells that both Dok1 and Dok2 phosphorylate CD200R and this inhibits downstream activation of the RAS-RAF signaling pathway (347). Moreover, Src family inhibitors such as PP2, repressed the phosphorytalion of CD200R through Dok1, which suggests that the interaction between Dok1 and CD200R is mediated by the Src family of kinases (348).

The skin is highly immunogenic and is one of the first barriers against pathogens; therefore it is not surprising that both CD200 and CD200R are expressed on certain cell types in the skin. Extensive analysis of murine hair follicles, identified CD200 as major contributor it the stem cell behavior of hair follicles and demonstrated that CD200 allowed for the immune-privileged state by attenuating inflammatory immune

reactions (349, 350). CD200R expression was also identified in the skin with rare expression on Langerhans cells, a type of macrophage found in the skin.

CD200-CD200R role in suppressing the immune response has implicated it’s role in cancer, and the ability of cancer to elude the immune reaction. Recently, several Studies have shown an over expression of CD200 in certain cancers, as well as demonstrated a function role of CD200 in the pathogenesis of a variety of cancers. Analysis of cell surface proteins on chronic lymphocytic leukemia identified CD200 as a potential molecule involved CLL (351). Using mixed lymphocytic reactions (MLRs) of dendritic cells, T cells and primary CLL cells, researchers demonstrated that antibodies against CD200 restored Th1 cytokine production (IL2 and IFNγ) from a Th2 response. A switch from a Th1 response to a Th2 response has been seen in cancer progression, which suggests that inhibition of CD200 could restore a Th1 response and help treat certain types of cancers. Using Affymetrix microarrays, CD200 was determined to be upregulated in both multiple myeloma (MM) (352) and acute myeloid leukemia (AML) (353). Furthermore CD200 expression correlated with poor prognosis in both MM and AML, suggesting CD200 could be a potential therapeutic target in MM and AML. In addition to CLL, AML, and MM a gene expression profile array of melanoma cells with different status of ERK activation identified many novel targets of ERK activation in melanoma, including CD200 (264). Moreover, two additional studies of melanoma cell lines demonstrated that CD200 was overexpressed and abrogating CD200 function through monoclonal antibodies or knockdown showed an induction of Th1 cytokine expression (354, 355). Moreover, CD200 expression seemed to correlated with the progression of melanoma. CD200 potent suppression of the immune system not only

Figure 9

The role of CD200 in melanoma. A) The RAS-RAF-MEK-ERK pathway is commonly

upregulated in melanoma; novel ERK targets in melanoma include CD200. B) CD200 interacts with its structurally related receptor which elicits an immune-suppressive signal and potentially allows melanoma to evade an immune response.

prevents autoimmunity but can contribute to the pathogenesis of many different cancers, including melanoma.