Will Jill come tumbling after? The case for a JAK2-type mutation as a prequel to the connective tissue disorders.

Med Hypotheses. 2009 Nov;73(5):651-4
Authors: McQueen FM, Dalbeth N

The JAK2 [V617F] mutation has recently been recognised as critical to the pathogenesis of the myeloproliferative disorders (MPDs). Thus, a common mutation affecting a haematopoietic precursor stem cell is capable of giving rise to diverse clinical phenotypes. In this hypothesis paper, we propose that a similar mutation affecting a stem cell precursor, most likely of the B cell lineage, could underlie the development of the connective tissue disorders which could be regarded as “lymphoproliferative” disorders. Consistent with this hypothesis is the observation that there are similarities between the myeloproliferative disorders and the connective tissue disorders in terms of their biological behaviour. Diseases within each family can transform into each other and sometimes into haematological malignancies (most often B cell origin non-Hodgkins lymphoma for the connective tissue disorders and acute myeloid leukemia for the myeloproliferative disorders). The timecourse for development of the connective tissue disorders involves a long latent period when autoantibodies are present (anti-CCP and ANA) possibly reflecting production by a B cell clone. A similar time-dependent increase in clonal dominance has been described in erythroblastic clones taken from the bone marrow of polycythemia vera patients, long before the onset of clinical disease. Evidence of B cell clonality has been described in bone marrow samples from rheumatoid arthritis patients and from glandular biopsies from those with Sjogren’s syndrome. Moreover, pseudofollicles containing activated B cells are features of rheumatoid synovial membrane and have also recently been described in subchondral bone where they are associated with macrophages, T cells and osteoclasts. The success of B cell depletion therapy in rheumatoid arthritis and systemic lupus erythematosus is also strong circumstantial evidence for this hypothesis.

PMID: 19482442 [PubMed – indexed for MEDLINE]