Impact of Epstein-Barr Virus infection in SLE.

International context and working hypothesis

SLE is a chronic autoimmune disorder. The course of the disease is unpredictable, with peak periods of illness (active SLE) alternating with periods of remission (inactive SLE). SLE-related autoimmune symptoms can be triggered by environmental factors, such as ultraviolet light, drugs and viruses, such as EBV. The apparent lack of EBV control in SLE patients raised three questions: 1) Do SLE patients mount insufficient or defective EBV-specific T cell responses? 2) Is the lack of viral control unique to EBV? and 3) Is EBV reactivation cause or consequence of SLE disease flares?

Objective

Determine the association between SLE immunopathology and EBV replication.

Results

To answer these questions I established a large bio-bank of SLE patients and controls (n = 144), requesting a direct collaboration with medical doctors and acquisition of ethical approval (CPP), consent forms and clinical data. I assessed quantitative and qualitative attributes of EBV-specific CD8⁺ T cells, showing that polyfunctionality of EBV-specific CD8⁺ T cells upon antigen stimulation is diminished in SLE patients compared to healthy controls. I finally associated the dysfunctional T cell phenotype with the up-regulation of the inhibitory receptor programmed death 1 (PD-1), and strengthened this association by reversing the dysfunctional T cell phenotype through specific blockade of the PD-1 signaling pathway. Of note, the above findings were not observed in the context of another herpes virus infection, cytomegalovirus (CMV).Interestingly, longitudinal monitoring revealed that bursts of viral load always occurred in a delayed manner with respect to disease flare onset. The latter result suggested that frequent EBV reactivation is an aggravating consequence, rather than a cause, of SLE immunopathology. I propose that activation of EBV-infected self-specific B cells in autoimmune patients drive EBV reactivation and T cell exhaustion. Based on my previous work and these findings I was recently proposed to review the PD-1 signaling pathway.

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