The Rheuma-Nomades

1. February 2010

Until recently, rheumatoid arthritis was considered a pure autoimmune disease. Cytocine seemed to lure B- and T-lymphocytes to the joints. Researchers now show that the disease is rather similar to a metastasizing tumor.

In the beginning it is a small inflammation. It makes the joint swell and it hurts. But instead of being decent and recede and heal after a few weeks, the inflammation keeps seeking new targets. At the end, nearly all joints are affected. Worst case scenario: Moving becomes nearly impossible.

RASF – new main players on the RA-stage

Rheumatoid arthritis (RA) affects about one percent of the world’s population, in Europe this rate is a bit lower. The one bothered with it seems to have a body not having a grip any more on the own immune system. The inner layer of the synovium shows an abnormal cell growth. There, also activated immune cells immigrate which cause the inflammation. Next to activated B- and T-cells and bone-destroying osteoclasts, mainly a large number of fibroblasts, the so-called RASF (Rheumatoid Arthritis Synovial Fibroblasts) are active there. And those are not just contributors in the background but “key players” taking care of the disintegration of bones and connective tissue.

The present theory: Primarily RA is an autoimmune disease where B- and T-cells attack the tissue. Fibroplasts are those cells activated on-site and helping with the lesions. And how does this disease expand to more and more joints? Perhaps by cellular or humoral factors? Elena Neumann at the Kerckhoff-Klinik, a specialized hospital in Bad Nauheim/Germany and her working group appear to create a new picture now. In an article published in the renowned “Nature Medicine“ several weeks ago, she showed that the inflammation keeps wandering, very similar to another uncontrolled proliferation i. e. a metastasizing tumor.

Fibroblasts on the tramp

The scientists showed in an elegant demonstration with an animal model without an own immune system – the SCID-mouse – that RASF fills the role of the wandering tumor cells. SCID mice accept human tissue without objections respectively rejection reaction. Elena Neumann and her team now transplanted joint cartilage of RA patients into those mice, namely into their opposite sides. However, only one of the samples contained the fibroblasts the researchers were interested in. Indeed, the examined cells had wandered to the second implant after two months – without additional stimuli of the murine or human immune system. In control experiments with fibroblasts of osteoarthritis patients or normal skin-fibroblasts, the connective tissue cells remained in place.

Which way now do those cell-nomads take to infect other joints? Apparently they succeed to wander into blood vessels and back out at the goal. Adhesion molecules like VCAM-1 and integrine help with the access and provide for an on-time stop at the destination station. In between the cells are found in the milt, the body’s own filtering system. Particularly attractive for the fibroblast attack is an exposed, unprotected bone matrix. Healthy tissue leaves the aggressors indifferent though.

New therapies gaining ground?

Not only in animal experiments but also in human beings, the working group has already shown that fibroblasts in RA go hiking. But the new results in the SCID mouse model are now supposed to be the basis to stop the fire in the joints from spreading. Thus a block of the adhesion or also of the matrix degradation enzymes of the fibroblasts might stop the continuous process. Over the past years, more and more so-called “biologicals” were added to the DMARD-agents formerly used like Methotrexat and Sulfasalazin for RA therapy. Now antibodies and molecules blocking e.g. the message flow by cytokines consort with anti-inflammatory drugs and cytostatics. For example Anakinra competes with the IL-1 receptor, Tocilizumab works against the IL-6 receptor, Abatacept is a recombinant CTLA4 molecule designed to prevent stimulation of the T-cells.

Like Ronald van Vollenhoven of the Swedish Karolinska Institute stated in a review – there are still many unanswered questions regarding rheumatoid arthritis: Why do only such a few patients react to the many new opportunities for therapy. “Healing” is one goal that we might not be able to reach with the current possibilities yet. But the results in Bad Nauheim have still been another step in decoding the secrets about the spreading of rheumatic inflammations.

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