The Biology of Spondyloarthritis: Studies of the Host Immune Response in Experimental Chlamydia Infection and in Patients with Ankylosing Spondylitis.

Spondyloarthritis (SpA) refers to a family of related inflammatory diseases affecting axial and peripheral joints. Reactive arthritis (ReA) and ankylosing spondylitis (AS) are both subsets of SpA. Despite the important role of HLA-B27 in conferring risk for SpA, a multitude of environmental and other genetic factors contribute to these diseases. This thesis contains two distinct halves that examine unique aspects of the SpA family of disease. The general aim of this thesis is to better understand host immunity in the context of the SpA family of diseases. The first half, comprised of Chapters 1-5, examines immune alterations in patients with AS. The second half, comprised of Chapters 6-9, examines how macrophages control host immunity to the ReA-associated bacteria, Chlamydia. Each half contains a comprehensive literature review in addition to peer-reviewed, primary scientific publications. The thesis is tied off by chapter 10, which provides future directions and conclusions. AS, the most common subset of SpA and the subset with the strongest HLA-B27 link, typically affects males in young adulthood. The TNF-inhibitors (TNFi) have proven to be effective at controlling the symptoms of AS but are not curative. Genetic and immunological studies have implicated the Th17 axis of inflammation in the pathogenesis of AS. The first half of this thesis discusses potential non-canonical roles of HLA-B27, documents an abnormal expansion of T cells associated with prolonged TNFi use, details a male sex bias in the Th17-axis, and examines the role of novel factors in driving the Th17-axis in AS patients. ReA is triggered by a prior infection with bacteria such as Chlamydia. How Chlamydia infection causes sequelae like ReA is unknown as the basic biology of host-pathogen interactions is not well understood. The second half of this thesis dissects the interaction of Chlamydia with the host immune system, focusing on the specific role of the macrophage in murine models of infection. In conclusion, a better understanding of environmental and genetic factors that contribute to the chronic inflammation of SpA will aid in understanding and treating these common, disabling diseases.Ph.D