Granzyme B: evidence for a role in the origin of myasthenia gravis.
OBJECTIVE
Although the pathogenesis of myasthenia gravis (MG) as an antibody mediated disorder of acetylcholine receptors (AChRs) at neuromuscular junctions is well understood, the origin of the autoimmune response is unclear. The thymus is intimately involved in initiation of the autoimmune response; the antigen, AChR, is present in the thymus, but how the autoimmune response is triggered is not known. Granzyme B (GrB), a proteolytic enzyme present in cytolytic T cells and natural killer (NK) cells, selectively cleaves many potential autoantigens (but few non-autoantigens), generating novel fragments that trigger autoreactive responses. This protease has been strongly implicated in the pathogenesis of several autoimmune diseases including lupus, rheumatoid arthritis, dermatomyositis, and others. In the studies described in this manuscript, we examined the ability of GrB to cleave the AChR subunits, and performed biochemical, immunohistochemical and molecular studies on thymus glands from myasthenic patients and controls to assess GrB expression.


RESULTS
GrB efficiently and specifically cleaves subunits of AChR, especially the epsilon subunit. GrB is present in thymus glands from myasthenia patients, but is absent in control thymuses.


CONCLUSIONS
Our results provide evidence supporting a potential role for GrB in the process of initiation of MG, and are consistent with the concept of an immunodominant epsilon epitope.
Casciola-Rosen
L
L
Department of Medicine, Johns Hopkins University, Baltimore, MD, USA. lcr@jhmi.edu
Miagkov
A
A
Nagaraju
K
K
Askin
F
F
Jacobson
L
L
Rosen
A
A
Drachman
D B
DB
D015551:Autoimmunity; D002460:Cell Line; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D053804:Granzymes / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D006801:Humans; D008715:Methionine / Q000378:metabolism; D009157:Myasthenia Gravis / Q000473:pathology*; D011950:Receptors, Cholinergic / Q000145:classification / Q000235:genetics / Q000378:metabolism; D011978:Receptors, Nicotinic; D013460:Sulfur Isotopes / Q000378:metabolism; D013950:Thymus Gland / Q000187:drug effects* / Q000378:metabolism*; D014162:Transfection
C504423:CHRNE protein, human; D011950:Receptors, Cholinergic; D011978:Receptors, Nicotinic; D013460:Sulfur Isotopes; D008715:Methionine; D053804:Granzymes