what does this mean exactly?
So all tissues are held together by a mixture of collagen and elastic fibres. In muscle, for instance, you have fibres forming networks like the net bags they sell citrus fruit in at various levels of structure - around bundles of a few muscle cells, around larger fascicles and around entire muscles - endomysium, perimysium and so on. Collagen fibres provide tear-resistant strength and elastic fibres stretch with movement and keep everything neat - like lycra.
In the past my group studied elastic fibres mostly and I know less about the collagen fibres. Both may be relevant but it is the elastic fibres that showed up things that were of interest to us, including TGF beta binding proteins, complement inhibitor proteins and free forms of immunoglobulin receptor.
I forget the details after thirty years but elastin protein itself forms crimpable fibres bound together with other proteins such as fibrillin (1 and 2 at least). These proteins form overlapping chains a bit like tiles on a roof and under electronmicroscopy you see banding. It seems that in association with this banding you have regular binding sites for immune signalling or regulatory proteins. It is a bit like the carriages in a train that each have a slot on the side where you can put boards saying 'First class' or 'Manhasset only' or 'Dining Car'. When you stain tissues to pick out the regulatory proteins with a fluorescent marker you see the fibres light up like LED Christmas light strings.
The really interesting thing is that each tissue stains up quite differently. Complement regulatory proteins like CD55, for instance, are painted on to the fibres supporting muscle and joint lining. TGF beta binding proteins are painted on to fibrillin chains almost everywhere I think but since fibrillin is predominantly found in stretchy tissues this will have more ability to bind TGF beta.
The reason why we were interested was to explain why certain immune disorders attacked specific tissues. We had already realised that in rheumatoid arthritis immune complexes produced inflammation in joints because of the specific presence of an immunoglobulin receptor on the macrophages of joint lining. But there is another disease called polymyalgia rheumatic where immune complexes seem to cause trouble in elastic ligaments and around muscles. The story was never sorted out but the strange thing about these structures is that they carry the same receptor we blamed in RA but not on macrophages as such - painted on to the fibres instead. That would mean complexes would stick but maybe activate complement rather than cytokines.
The other story is that ankylosing spondylitis is a condition specifically affecting the stretchiest parts of the body with the most elastin - spinal ligaments, wall of the aorta, ligaments around joints, lining of the cauda equine nerves at the base of the spinal cord, the ligaments that support the lens in the eye and the top ends of the lungs. (We know that these are the places most dependent on elastin because the genetic disease of fibrillin, Marfan syndrome, specifically affects these places as well.) And ank spond is almost certainly a disorder of non-specific T cell activation. Why should T cells get activated where there is elastin being stretched a lot? The answer that seemed likely to us is that TGF beta is the most powerful off signal for T cells. So if elastic fibres normally paint themselves with TGF beta it ought to be that T cells are supposed to be turned off where a lot of stretching is going on. If that turning off was interfered with then you would get a disease specifically causing inflammation in these tissues.
Another thing that may be relevant is that if you have musculoskeletal problems like back or joint pain you are almost bound to have more pain when you have a viral infection. It seems that the 'malaise' signals of cytokine activation light up tissues already primed.
And more generally, we probably forget that a huge amount of information must be painted on to tissue matrix in order for it to know how to heal correctly. A surgical wound will repair to an almost invisible scar despite going through a phase a being red and swollen. The tissue knows exactly how it should join itself up. That knowledge is partly in the cells but they have to be guided by feeling around in the matrix.
