The RheuMuseum Lecture Series: A Deeper Understanding of the Pathogenesis of axSpA

Professor Iain McInnes of the University of Glasgow delves into the  latest science on the importance of the interleukin-12/17 axis in axial spondyloarthritis. 

Iain McInnes is vice principal and head of the college of medical, veterinary, and life sciences at the University of Glasgow, Scotland.

TRANSCRIPT:

So, one of the most important advances in the last decade has been our appreciation of how the IL-23/IL-17 axis drives pathogenesis in axSpA and, indeed, a whole range of related disorders. [3,7,8,9] Now let's get the basics out there, first of all. There are upstream, or regulatory, cytokines. IL-23 is a classic example. Others include IL-12 and the like, which are, if you like, setting the immunological temperature. [1-8] They determine the kind of immune response that will develop—a type 1 response, a type 17 response, or even a type 2 response. And then there are downstream—or I prefer the term "effector" cytokines—whose job it is, is to actually respond.[1-8] Now, the cytokines that contribute to innate and adaptive immunity overlap to some extent, but they are potentially exclusive, and we're starting to see exclusive responses, particularly for IL-17 family members in axSpA pathogenesis.[1-8]

So let's think a little bit about what we mean by a regulatory cytokine, and I'm going to use IL-23 as a great example. It is released mainly by dendritic cells and myeloid cells upon challenge. [1-8] In host defense, that would be a microbe. In the context of axSpA, it's a little less clear. It might be biomechanical stress. It might be a microbial product on a given genetic background. The consequence is IL-23 release and activation and amplification of type 17 T-cells that release IL-17A, IL-17F, IL-22, and interestingly, TNF, often forgotten. [1-8] Those molecules, in turn, are effector cytokines. Their job is to activate cells in the target tissue, osteoclasts, osteoblasts, stromal cells, and indeed other immune cells—macrophages themselves. [1-8] And so, a vicious cycle of inflammation is initiated and perpetuated.[1-8]

So let's think a little about how elements of the innate and adaptive immune response come together to drive the pathology of axial spondyloarthritis. And particularly how they come together to drive high levels of local IL-17A, IL-17F, and TNF production in the target lesion and bone.[1-8] The classical T cell response, type 17 response, is driven by IL-23.[1-8] But we've come to appreciate in recent years that innate lymphoid cells are also capable of releasing IL-17A, IL-17F, and TNF. And they do so in an IL-23 independent manner.[1-8] So, let's bring all of this together and consider the totality of the cytokine response that we see in axial spondyloarthritis.[1-8]

In axSpA, it would appear to be a predominantly IL-23 independent pathway, comprising mainly innate immune activation, the release of IL-17A, IL-17F, TNF, but also chemokines that bring the vicious cycle of leukocyte recruitment and further amplification of tissue damage.[1-8] The damage is now, I think, well understood to be driven by osteoclast activation, bone loss; osteoblast activation in parallel, leading to bone gain. But that is dysregulated bone gain. In turn, new bone formation and ankylosis. [1-8] And so, at the center of this, the IL-17 superfamily and TNF driving tissue, remodeling, and aberrant function as a result.