Functional Significance Of

OVEREXPRESSION OF ERGB/FLI1 GENE IN AUTOIMMUNE DISEASE

Lymphocytes are important components and regulators of immune response. We and have shown that the ETS family of proteins are involved in lymphoid cell development, differentiation, maturation and activation and therefore, they are important regulators of lymphoid gene expression. Inappropriate expression of ETS family of genes may have a detrimental effect on lymphoid cell differentiation, activation and function. T cells in autoimmune diseases are in activated state because they have been shown to express

O ETS2 probe - ETS2

Fig. 3. Expression of ERGB/FLI 1, ETS1 and ETS2 in splenic T cells: ERGB/FLI 1 expression (panel A), and ETS1 and ETS2 expression (panel B), were studied by RNAse protection assay as described in ref. [42], Probes and RNA protected fragments are shown on the right side. Sizes of pBR322 DNA-MspI digest are shown on the left-hand side.

O ETS2 probe - ETS2

Fig. 3. Expression of ERGB/FLI 1, ETS1 and ETS2 in splenic T cells: ERGB/FLI 1 expression (panel A), and ETS1 and ETS2 expression (panel B), were studied by RNAse protection assay as described in ref. [42], Probes and RNA protected fragments are shown on the right side. Sizes of pBR322 DNA-MspI digest are shown on the left-hand side.

interleukin-(IL)-2 receptor (IL-2R) [35-36], MYC, MYB and RAF genes [37^10], T cells are activated by interaction between TCR and antigen in conjunction with the major histocompatibility complex protein recognized on antigen presenting cells. This interaction initiates a cascade of intracellular biochemical events leading to the elevation of intracellular Ca2+ ions and activation of protein kinase C. These signals are conveyed to the nucleus by different effector molecules to initiate or reprogram gene expression. During lymphocyte activation, the activities of a large number of genes involved are changed, including lymphokines and their receptor genes. Activation or repression of T-cell gene expression is facilitated by transcription factors expressed in that cell type. Others and we have shown that several members of the ETS family of transcription factors (ETS1, ETS2, ELF1, ERGB/FLI 1, GABPff and ELK) are expressed in T cells. During T-cell activation, some members of the ETS family of transcription factors are differentially expressed.

In normal T cells, both ETS1 and ERGB genes are expressed at high levels in quiescent state and their expression level decreases to low levels after activation. ETS2 gene expression is induced only after T-cell activation. High expression of ETS2 genes in SLE patients with active disease could thus be contributed by the activated lymphocytes. High levels of ERGB/FLI1 expression observed in lymphoid cells from autoimmune diseases could be due to the development and expansion of special type of autoreactive T cells. On the other hand, it is possible that activation of T cells by autoantigen(s) does not affect the expression of the ERGB/FLI1 gene. Thus, unscheduled expression of ERGB/FLI1 in lymphocytes could contribute to the disease phenotype. This argument is further strengthened by a recent demonstration that transgenic mice overexpressing FLI1 develop high incidence of a progressive immunologic renal disease [41]. Transgenic mice constitutively expressing FLI1 accumulated abnormal T (B220+ CD3+) and B (B220+ CD5+) cells as well as immunocomplexes in the kidney. At late states of the disease, different types of autoantibodies were detected. Inappropriate expression of FLI1 results in an increased number of mature B cells, which have a reduced activation-induced apoptotic response compared to B cells from wild type animals. Splenic B cells from FLI1 transgenic mice had an increased capacity for proliferation and survival. Furthermore, FLI1 gene expression is higher in infiltrated lymphocytes surrounding affected kidney tissue [41], Lymphocytes recognizing these autoantigens may escape the selection process and have enhanced survival because of heightened expression of FLI1 gene. These FLI1-induced alterations in normal maturation of T and B cells suggest that FLI1 play a critical role in normal lymphoid cell function, perhaps through modulation of apoptosis Thus it appears that the unscheduled expression of ERGB/FLI1 gene may perturb lymphoid cell development, differentiation, and function.

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