We have discovered mice with a genetic mutation that predisposes to rheumatoid arthritis. The trait is autosomal dominant and fully penetrant. The affected mice present with a severe symmetrical, erosive chronic poly-arthritis, similar to human rheumatoid arthritis (RA). It mostly affects the peripheral joints (the ankles, metatarsal and inter-phalangeal joints) with less severe damage in the central joints (knees and shoulders). Inter-vertebral joints, especially between T9 and T13, are also affected. The bone marrow shows unusual B lymphoid aggregates, associated with osteolytic lesions, and bronchus associated lymphoid tissue is present in all affected mice. Homozygozity dramatically increases the severity of the disease. The phenotype is independent of T and B cells, and still develops in the absence of Myd88 or GM-CSF.
We found that the mutation is a spontaneous insertion of a transposon in the 3’UTR of the TNF gene, and causes a dramatic increase in the expression of this cytokine. Accordingly, loss of TNFR1 completely prevents all aspects of the phenotype.
We are presently in the process of identifying new regulators of TNF expression.