Impaired intracellular pathogen clearance and inflammatory joint disease: Is Whipple's disease a guiding light?

Whipple's disease can mimic spondyloarthritis (SpA) or rheumatoid arthritis (RA) for many years and, in a few cases, induces the development of antibodies to cyclic citrullinated peptides. The causative agent Tropheryma whipplei can smolder within cells, including macrophages, by suppressing the xenophagic process, a type of selective autophagy that targets pathogens. Other inflammatory joint diseases may also stem from impaired xenophagy with persistence of bacteria or viruses that can eventually migrate from the mucous membranes to the joints and entheses, where they may exert adverse effects on immune responses, even if they fail to replicate. Xenophagy interferes with the loading of peptides (including self-peptides) onto major histocompatibility complex proteins. Another effect of xenophagy is the induction of citrullination, which accelerates pathogen clearance but can also contribute to loss of self-tolerance. Pathogens react to citrullination by becoming dormant. These facts suggest a role in SpA and RA for impaired xenophagy with migration of pathogens to joints and entheses, where they may remain dormant. Studies of fibroblast-like synoviocytes showed alterations in autophagy that correlated with citrullination of vimentin, alpha-enolase, and filaggrin, which are targets of RA-specific autoantibodies. Compared to autoimmune responses (T-cell or B-cell clones, autoantibodies) alone, metastatic spread of pathogens initially located in the mucous membranes as the event inducing inflammatory joint disease would constitute a better explanation to the heterogeneous distribution of the joint involvement, palindromic onset in some cases (as seen in Whipple's disease), occurrence of flares, and possible development of escape phenomenon to immunomodulating drugs in a manner reminiscent of delayed antibiotic resistance.