Innate and adaptive immune responses in viral and chronic inflammatory diseases

In this thesis I address some important questions regarding innate and adaptiveimmune responses in different human diseases. We analysed two distinctconditions: chronic autoimmune inflammation, specifically SLE, and chronic viralinfection, represented by herpes simplex virus (HSV). The role of differentcomponents of the immune system were addressed, ranging from innate factors,such as IFN-alpha and NK cells, to the adaptive immune system, represented by Tcells.The results are discussed with respect to the various possible levels ofinteraction between the innate and the adaptive immune systems.

We first focused on a specific subset of NK cells, CD56bright NK cells, which isnormally found in lymphoid tissue and at sites of inflammation and which, uponactivation, has the capacity to produce large amounts of cytokines. CD56bright NKcells are often discussed in relation to their possible role in shaping adaptiveimmune responses. The proportion of CD56bright NK cells was significantlyincreased in blood in subjects affected by SLE. This finding was not dependent ondisease activity and may be due to increased levels of IFN-alpha, a typical hallmarkof SLE patients.

We then investigated several aspects of herpes virus infections. We describe apossible role for the activating NK cell receptor NKG2D in the immune responseagainst HSV1 infection. We determined that HSV1 has the ability to downregulatethe cell surface expression of NKG2D ligands of infected cells. We also observedthat NK cells from patients affected by recurrent HSV1 manifestations haveslightly increased levels of expression of NKG2D on blood NK cells during theacute phase of viral reactivation. In a prospective clinical study of patients withHSV genital infection, we observed that low specific T-cell responses against HSV-antigens during primary HSV1 and 2 infection predict a high frequency of clinicalrecurrences. Finally we examined the immune response of patients affected byrecurrent meningitis caused by HSV2 infection. During asymptomatic periods,these patients showed elevated expression of TLR3 and TLR9, elevated IFN-alphaproduction to certain stimuli and elevated specific T-cell responses when comparedto patients with recurrent genital infection and to healthy seropositive donors. Inaddition, there were qualitative differences in their T-cell cytokine profile. Weconclude that HSV2 meningitis is likely not a consequence of an impaired antiviralinnate or adaptive immune sponse at the systemic level.

List of scientific papers

I. Schepis D, Gunnarsson I, Eloranta ML, Lampa J, Jacobson SH, Kärre K, Berg L (2009). "Increased proportion of CD56bright natural killer cells in active and inactive systemic lupus erythematosus." Immunology 126(1): 140-6. Epub 2008 Jun 18
https://doi.org/10.1111/j.1365-2567.2008.02887.x

II. Schepis D, DAmato M, Studahl M, Bergström T, Kärre K, Berg L (2009). "Herpes simplex virus infection downmodulates NKG2D ligand expression". [Accepted]
https://doi.org/10.1111/j.1365-3083.2009.02241.x

III. Franzen-Röhl E, Schepis D, Atterfelt F, Franck K, Vikström A, Liljeqvist JÅ, Bergström T, Aurelius E, Kärre K, Berg L, Gaines H (2009). "Herpes simplex virus specific T-cell response in primary infection correlate inversely with frequency of subsequent recurrences". [Manuscript]

IV. Franzen-Röhl E, Schepis D, Lagrelius M, Franck K, Jones P, Liljeqvist JÅ, Bergström T, Aurelius E, Kärre K, Berg L, Gaines H (2009). "Increased cell mediated immune responses in patients with recurrent herpes simplex virus type 2 meningitis". [Manuscript]