Type I interferons: beneficial in Th1 and detrimental in Th17 autoimmunity

Abstract

In relapsing remitting multiple sclerosis (RRMS), type I interferon (IFN) is considered immuno-modulatory, and recombinant forms of IFN-β are the most prescribed treatment for this disease. However, within the RRMS population, 30-50% of MS patients are nonresponsive to this treatment, and it consistently worsens neuromyelitis optica (NMO), a disease once considered to be a form of RRMS. In contrast to RRMS, type I IFNs have been shown to have properties that drive the inflammatory pathologies in many other autoimmune diseases. These diseases include Sjögren's syndrome, system lupus erythematosus (SLE), neuromyelitis optica (NMO), rheumatoid arthritis (RA) and psoriasis. Historically, autoimmune diseases were thought to be driven by a TH1 response to auto-antigens. However, since the discovery of the TH17 in experimental autoimmune encephalomyelitis (EAE), it is now generally thought that TH17 plays an important role in MS and all other autoimmune diseases. In this article, we will discuss recent clinical and basic research advances in the field of autoimmunity and argue that IFN-β and other type I IFNs are immuno-modulatory in diseases driven predominantly by TH1 but in contrast are inflammatory in diseases that have a predominant Th17 response.

Figure 1

Autoimmune diseases initiated with the IL-23/TH17 response secrete high levels of IL17A and IL-17F. IL-17A and F initiates granulocyte infiltration to the site of inflammation as well as orchestrates germinal center formation and B-cell maturation in lymphoid tissues. Endogenously expressed or therapeutically administered IFN-β could exacerbate TH17 diseases by directly stimulating granulocytes to release tissue destructive proteases and cytokines or by elevating BAFF to enhance the production of auto-reactive antibodies and memory B-cells.

Figure 2

Autoimmune diseases initiated by TH1 cells have high levels of IFN-γ that drive lymphocytic and macrophage infiltration in to sites of inflammation. IFN-γ upregulates IL-7 expression in lymphoid tissue stromal cells during T-cell differentiation and provides signals to expand and maintain the TH1 population. IFN-β treatment synergizes with both IFN-γ and IL-7 to attenuate inflammation by up-regulating the anti-inflammatory cytokines IL-27 and IL-10 and decrease chemokine production from macrophages/microglial cells.