Attenuated immune control of Epstein–Barr virus in humanized mice is associated with the multiple sclerosis risk factor HLA‐DR15

Abstract

Immune responses to Epstein–Barr virus (EBV) infection synergize with the main genetic risk factor HLA‐DRB1*15:01 (HLA‐DR15) to increase the likelihood to develop the autoimmune disease multiple sclerosis (MS) at least sevenfold. In order to gain insights into this synergy, we investigated HLA‐DR15 positive human immune compartments after reconstitution in immune‐compromised mice (humanized mice) with and without EBV infection. We detected elevated activation of both CD4+ and CD8+ T cells in HLA‐DR15 donor‐reconstituted humanized mice at steady state, even when compared to immune compartments carrying HLA‐DRB1*04:01 (HLA‐DR4), which is associated with other autoimmune diseases. Increased CD8+ T cell expansion and activation was also observed in HLA‐DR15 donor‐reconstituted humanized mice after EBV infection. Despite this higher immune activation, EBV viral loads were less well controlled in the context of HLA‐DR15. Indeed, HLA‐DR15‐restricted CD4+ T cell clones recognized EBV‐transformed B cell lines less efficiently and demonstrated cross‐reactivity toward allogeneic target cells and one MS autoantigen. These findings suggest that EBV as one of the main environmental risk factors and HLA‐DR15 as the main genetic risk factor for MS synergize by priming hyperreactive T‐cell compartments, which then control the viral infection less efficiently and contain cross‐reactive CD4+ T cell clones.

Epstein Barr virus infection and immune defense related to HLA‐DR15: consequences for multiple sclerosis

“…All these factors together lead to a substantially increased risk for MS, which in all combinations give an increased risk on top of a baseline risk, reviewed in detail here [18]. EBV has a special role, in that the infection seems to be a prerequisite to develop MS. Also, there should be a peripheral antigenic drive of autoreactive T cell responses, and EBV is a candidate for this, once again supported by the study of Zdimerova et al [5]. The synergy, and interactions, between environmental factors and gene variants tell us about common etiological and pathogenic pathways.…”

“…The study by Zdimerova et al [5] mainly supports the concept of molecular mimicry in which parts of the virus induce cross‐reactive T cell response to CNS antigens. Clearly, T cells reactive with CNS components arise upon EBV infection in humans [19].…”

“…I here discuss MS with regard to its genetic epidemiology and immunology, the associations to HLA class II variant and EBV in MS, and the gaps in our knowledge that the experimental study by Zdimerova et al. [5] fills in.…”

“…MBP is known to be able to induce CNS neuroinflammation in rodents. In total, the study [5] gives a basis for a hypothesis that a poor class II‐mediated immune control of EBV may ultimately lead to MS. These results question the previous arguments for a role of EBV in MS.…”

“…This is the case for aspects of EBV infection and HLA‐DR15. A limitation of the Zdimerova et al study [5], is that the basic mechanisms for the HLA‐DR15 mediated less well‐controlled EBV infection remain to be explained. One can consider that specific antigens/parts of EBV, crucial for the immune defense against the virus, are less well presented by the HLA‐DR15 allelic molecule which then would allow a higher viral load.…”