Systematic analysis of immune cell populations in muscles and tissues throughout the lifespan of dysferlin-deficient BLAJ mice
Dysferlinopathies are strongly associated with infiltration of immune cells and inflammation, likely driven by impaired membrane function and increasing levels of damage-associated molecular patterns. However, it is not clear whether factors associated with the myofibres or an altered microenvironment may directly activate the immune response, compared with the extent that altered dysferlin-deficient immune cells may exacerbate and distort the immune response. Therefore, the aim of this project was to thoroughly investigate differences in key immune cell populations from many tissues of dysferlin deficient BLA/J compared with control wild-type C57BL/6J mice, in the context of both age and sex, throughout their lifespan. Our analysis of key immune sites involved in the generation of an immune response and supplying immune cells to dysferlinopathy-affected muscles suggested that the early immune response is driven by the local/proximal lymph nodes and bone marrow. Whilst the spleen appeared to play a role later in disease progression. Interestingly, many immune cells in dysferlinopathy displayed altered metabolic function early in disease with production of both pro-/anti-inflammatory molecules, suggesting a mixed inflammatory profile (rather than a classic pro-inflammatory or anti-inflammatory function). Our data also suggested some of these changes to immune cells and cytokines could potentially be candidate immune-related biomarkers for dysferlinopathy disease progression. Understanding these cellular changes related to the immune response will help to establish the impact of inflammatory dysfunction in dysferlinopathies. This new insight will also help inform decisions for selecting appropriate candidate drugs for therapy and potentially identify immune-related biomarkers of dysferlinopathic changes.