Innate mechanisms regulating B cell activation in inflammatory diseases

Generation of powerful and highly specific immune responses against invading pathogens is essential to our survival. However, the immune system can cause disease if activated in an inappropriate manner. Examples include production of IgE antibodies against harmless environmental antigens in allergy and production of IgG antibodies against self-antigens in autoimmunity. Thus, as the antibody-producing cells of the immune system, B cells play a key role in the pathology of both allergic and autoimmune disease.

The aim of the work presented in this thesis was to investigate how B cell activation is regulated by components of the innate immune system in allergy and autoimmunity. In papers I and II, regulation of autoreactive and IgE-producing B cells by the innatelymphocyte subset natural killer T (NKT) cells and the inflammatory cytokine IL-18 was studied in mouse models. In papers III and IV, the interplay between NKT cells and IL-18, as well as the B cell-activating cytokines BAFF and APRIL were studied in vitro and in patients with atopic eczema (AE).

NKT cells were found to regulate activation of autoreactive and IgE-producing B cells by limiting the formation of germinal centers (GCs; papers I and II). In paper I, the regulatory effect of NKT cells was shown to be mediated by interactions with CD1d+ B cells before GC entry. Interestingly, the increased production of self-reactive antibodies in NKT cell-deficient mice could be reduced by injection of NKT cells (paper I), and IgE production could be reduced by injection of the NKT cell-activating ligand α-GalCer (paper II). This indicates a potential for NKT cell-based therapies in autoimmune and IgE-mediated diseases. Several inflammatory conditions have been associated with elevated levels of IL-18, and the effects of this inflammatory cytokine on activation of B cells and NKT cells were studied in papers II and III. In paper II, injections of IL-18 were found to expand the innate marginal zone B cell subset and to induce production of self-reactive natural IgM and IgG antibodies as well as IgE in extrafollicular foci in the spleen. In paper III, IL-18 was found to skew the human invariant (i)NKT cell population towards the pro-inflammatory CD4- subset in vitro. In addition, patients with AE were found to have both elevated levels of IL-18 and a decreased CD4+ iNKT cell population compared to healthy controls. A reduced CD4+ iNKT cell population also coincided with elevated total-IgE levels, suggesting a role for IL-18 and NKT cells in regulation of the IgE response in AE. The regulation of B cell activation in AE was further investigated in paper IV by characterizing the expression of the cytokines BAFF and APRIL in eczema skin and peripheral blood. The levels of neither BAFF nor APRIL were elevated in the circulation compared to healthy controls. In the skin, both BAFF and APRIL were found to be expressed by keratinocytes, macrophages and T cells, and acute lesions had increased levels of BAFF while both acute and chronic lesions had reduced levels of APRIL. This indicates that the expression of these B cell-activating cytokines is altered in the local skin micro-environment in AE.

In conclusion, the work presented here identifies NKT cells and IL-18 as important regulators of B cells that produce IgE and autoreactive antibodies. While NKT cells limit inappropriate B cell activation, IL-18 drives such responses and skews the iNKT cell population towards pro-inflammatory effector functions. Finally, B cell-activating cytokines can be potential targets for new therapeutic strategies in AE.

List of scientific papers

I. Wermeling F, Lind SM, Domange Jordö E, Cardell S, Karlsson MCI. Invariant NKT cells limit activation of autoreactive CD1d-positive B cells. J Exp Med. 2010 May 10;207(5):943-52. (Highlighted in Nat Rev Immunol 2010 Jun;10(6):384).
https://doi.org/10.1084/jem.20091314

II. Lind SM, Domange Jordö E, Hägglöf T, Mattsson N, Gabrielsson S, McGaha TL, Scheynius A, Karlsson MCI. IL-18 induces natural antibody responses regulated by NKT cells. [Manuscript]

III. Lind SM, Kuylenstierna C, Moll M, Domange Jordö E, Winqvist O, Lundeberg L, Karlsson MA, Tengvall Linder M, Johansson C, Scheynius A, Sandberg JK, Karlsson. MCI IL-18 skews the invariant NKT cell population via autoreactive activation in atopic eczema. Eur J Immunol 2009 Aug;39(8):2293-301. Highlighted in News and Views p.1988.
https://doi.org/10.1002/eji.200839195

IV. Chen Y, Lind SM, Johansson C, Karlsson MA, Lundeberg L, Scheynius A, Karlsson MCI. The expression of BAFF, APRIL and TWEAK is altered in eczema skin but not in the circulation of atopic and seborrheic eczema patients. [Submitted]