The lack of some suppressor T cells (including TCD4+CD25+(high) positively selected first in thymic medulla) specific to a restricted set of
autoantigens may be the common link between all patterns of
rheumatoid arthritis. In other words, instead of a 'peak' of TCD4+ effector T cells common to all patients with
rheumatoid arthritis (which has so far never been demonstrated), a 'hole' in TCD4+CD25+(high) responses towards a limited set of
autoantigens responsible for the normal maintenance of tolerance within the joints may be shared by many patients with
rheumatoid arthritis. The hallmark of this disorder is the involvement of tissues subjected to friction stress bathed in a lubricating fluid (
rheumatoid nodules and bursae, tendinous sheaths, pleura, pericardium, sclera, and joints covered by hyaline cartilage). Consequently,
autoantigens shared by all forementioned places may be better candidates than
autoantigens restricted to the hyaline cartilage (like
collagen II).
Tenosynovitis,
bursitis and
rheumatoid nodules can herald
rheumatoid arthritis, and rheumatoid
pericarditis is very frequent at the histological level.
Lubricin and superficial zone
protein (SZP), which are closely related products of the megacaryocyte stimulating factor (MSF) gene, are among the best candidate
autoantigens for such a positive selection of suppressor T cells.
Lubricin is responsible for most of the lubricating properties of synovial fluid, and SZP (expressed by the superficial articular chondrocytes from diarthrodial cartilages and lining cells of synovial villi) also shares lubricating and cytoprotective properties. Moreover, the expression of
lubricin is very probable in pericardium and pleura, and can be induced by friction stress. Although this mucinous
glycoprotein may already share close similarities at the antigenic levels with
mucins previously demonstrated in Hassall's corpuscles of the thymus, evidence for the ectopic expression of
lubricin/SZP within normal human thymus may further support this hypothesis. The prenatal positive selection within the thymus of a functional pool of TCD4+CD25+(high) clones specific for most peripheral tissues is critical (at least in mice) for the quality of tolerance for the rest of the organism's lifespan. Therefore, a poor expression of
lubricin/SZP early in life within the human thymus may also favour a lack of suppressor T cells specific to tissues bathed with synovial fluid, i.e. the onset of
rheumatoid arthritis later on in life. As studies of human thymus long before the onset of
rheumatoid arthritis are hampered for obvious reasons, studies of murine thymus could be a first step. In as much as the human counterpart of
lubricin is expressed in the thymic medulla of mice, the generation of knocked-out mice for its expression within the thymus could be one of the best models to test the above hypothesis. The stimulation of TCD4+CD25+(high) clones specific for
immunodominant epitopes from the joints/synovial fluid (belonging perhaps to
lubricin or SZP) could help restore a normal balance between effector T cells and suppressor T cells in
rheumatoid arthritis patients.