In studies of mice with the HLA-B27 gene, researchers saw the usual clinical signs of AS, but if the mice “are housed in a germ-free condition, no clinical manifestations develop. So an environmental trigger for the development of spondyloarthritis is likely, with the gut being a prime source,” says Dr. Haroon.
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Explore This IssueDecember 2017
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Intestinal bugs, such as Heliobacter pylori, have been shown to trigger MIF release in past studies, so the researchers suspected “the gut could be where the disease process begins in SpA,” says Dr. Haroon.7 “A gut-related factor could be a clue to onset, severity or certain clinical features of the disease. Fecal and serum calprotectin levels have been used for predicting irritable bowel syndrome presence and activity, but a similar marker for AS has yet to be conclusively proved.”
The researchers enrolled 147 AS patients who satisfied the modified New York diagnostic criteria and 61 healthy volunteers used as controls.8 They collected baseline serum samples, annually recorded clinical variables and took radiographs every two years. The AS patients were classified as either progressors or nonprogressors based on the annual rate of increase in their modified Stoke AS Spinal Score (mSASSS), with 56 progressors and 91 nonprogressors. The AS patients stayed on their regular, daily doses of standard therapy: non-steroidal anti-inflammatory drugs (NSAIDs) and/or tumor necrosis factor (TNF) inhibitors.
The researchers also analyzed the patients’ ileal tissue to identify MIF-producing cells in the gut. Using flow cytometry, they identified MIF-producing subsets, expression patterns of the MIF receptor CD74, and MIF-induced TNF production in the patients’ peripheral blood samples. They analyzed MIF-induced mineralization of osteoblast cells, and measured β-catenin levels.
The study’s results show MIF plays important roles in AS disease progression. In the AS patients, MIF serum levels measured higher at baseline compared with levels in healthy controls. This factor independently predicted radiographic disease progression in these patients, says Dr. Haroon.
MIF levels measured higher in their synovial fluid, and MIF expression was elevated in their peripheral joints and ileum tissue, as well. MIF-producing macrophages and Paneth cells were enriched in their guts. MIF also induced TNF production in the AS patients’ monocytes. MIF activated β-catenin in their osteoblasts and promoted osteoblast mineralization, which suggests it possibly stimulates the pathogenic bone growth seen in AS.
AS patients in the study also featured lower levels of the protein CD74 in their monocytes, which could be a sign of disease progression that must be explored further, says Dr. Haroon. CD74 is a high-affinity receptor for MIF. When MIF binds to CD74’s surface, its intracellular domain (ICD) cleaves or splits open.