We will use the human herpesvirus, Epstein-Barr virus (EBV), to probe immune dysfunction in systemic lupus erythematosus (SLE) by studying changes in EBV latent infection in these patients. EBV establishes lifelong infection in >90% of humans. In healthy individuals this is a tightly regulated process, which is evident in the blood, where: the virus is only carried by memory B cells; the viral load is stable over long periods of time; and there is little or no viral gene expression. We have preliminary data that indicates EBV latent infection is disrupted in patients with SLE. First, there are very high viral loads in the blood of these patients. Previous work by our laboratory showed that treating organ transplant recipients with immunosuppressive medications leads to similarly elevated viral loads. However, analysis of the preliminary data indicates that these high loads of EBV in the blood of patients with SLE cannot be accounted for by treatment with immunosuppressive agents. Furthermore, the increase in the viral load is related to the presence of flares of SLE; when patients are symptomatic and immune deregulation is at its maximum, the viral load increases. Second, a latency gene of the virus, LMP1, is atypically expressed in the blood of these patients. We hypothesize that there are two aspects of the immune dysfunction in SLE that could disrupt EBV infection. First, defects in cytotoxic lymphocyte (CTL) function can result in increases in viral load, but not affect other aspects of the infection. Second, defects in the cells that harbor the virus, memory B cells, could lead to the appearance of atypical states of viral infection in the blood and/or result in an increase in viral loads in the blood. In this proposal we will assess the relative contributions of these two mechanisms. We will evaluate 1) whether there are defects in CTL function in patients with SLE; 2) whether there are alterations in EBV infection in the blood of patients with SLE, such as infection of other B cell types and expression of EBV genes; and 3) changes in CTL function and EBV infection are affected by SLE disease activity. These studies will provide new insight into the immune dysfunction in SLE and shed light on the cause of this disease.
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| Gross, Andrew J; Proekt, Irina; DeFranco, Anthony L (2011) Elevated BCR signaling and decreased survival of Lyn-deficient transitional and follicular B cells. Eur J Immunol 41:3645-55 |
| Gross, Andrew J; Lyandres, Julia R; Panigrahi, Anil K et al. (2009) Developmental acquisition of the Lyn-CD22-SHP-1 inhibitory pathway promotes B cell tolerance. J Immunol 182:5382-92 |
| Gross, Andrew J; Hochberg, Donna; Rand, William M et al. (2005) EBV and systemic lupus erythematosus: a new perspective. J Immunol 174:6599-607 |
