Immunoprivilege sites are tissue sites in our body where the appearance of foreign antigen does not cause inflammation. Sounds like a bad thing? Well… Examples of such known regions are eyes, testicles and fetus. It makes sense why lack of inflammation has an important biological role.
Recently, a novel site has been discovered – tunica media of large vessels. Tunica media mainly composed of smooth muscle cells and is surrounded by tunica intima (endothelial cells) from the lumen side and tunica adventitia (fibroblasts) from the other side. Zhang P. et a., recently showed that Allogeneic (cells from a different individual but from the same specie) memory T cells do not get activated by smooth muscle cells. The reason being is that smooth muscle cells lack an essential co-stimulatory molecule called OX40 ligand. As a result, during arterial transplants, such as coronary arteries, smooth muscle cells do not get rejected where as endothelial cells as well as adventitial fibroblasts are proliferated with WBC. Altogether, smooth muscle cells lacking the stimulatory molecule help in transplant medicine. That may be considered as a good side of the coin.
However, in 2001 Dal Canto A. et al., showed y-herpesvirus 68 causes severe chronic vasculitis in mice. The infection with this herpes virus is restricted to only smooth muscle cells and the immune system cannot clear the virus because it fail to get to the smooth muscle cell layer, so the mice die from stroke and/or heart attacks. That obviously does not sound so great anymore.
Can you think of any human virus or infectious agent that can infect smooth muscle cell layer and not be cleared by immune system?
References:
Zhang P., et al., Human Vascular Smooth Muscle Cells Lack Essential Costimulatory Molecules to Activate Allogeneic Memory T Cells. Arteriosclerosis, Thrombosis, and Vascular Biology. 2010; 30:1795-1801
Dal Canto AJ., et al., IFN-g action in the media of the great elastic arteries, a novel immunoprivileged site. The Journal of Clinical Investigation. 2000; 107
This is very interesting, but I do have a couple of questions. Do all smooth muscle cells lack OX40 ligand or just vascular smooth muscle? I would imagine that smooth muscle cells in the gut would need to be as immune competent as possible to prevent against the invasion of ingested pathogens.
ReplyDeleteI agree with the last commenter.. You would think smooth muscle in the gut used for peristalsis would need to be immunoreactive and immunocompetent. If not, how would the gut be able to fight off infection and create an inflammatory cascade in response to to pathogen? Since our small intestines are one of our most permeable membranes and a key sight for absorbtion, they are bound to be exposed to large amounts or foreign particles and pathogens. They would have to be immunocompetent in order to deal with this constant threat. Does cardiac muscle express OX40 (I would think it would)? What is the function of OX40 in normal skeletal muscle function? What happens to skeletal muscle that lacks the OX 40 ligand? Is it not non-immunoreactive like smooth muscle, or it still immunologically able to respond to its environment I love how this issue is not black and white. Although the lack of a immune response in smooth muscle might make its transplantation more successful, It is highly at risk for infection because of its lack of immune function. In my opinion, I would rather have a set of smooth muscle that includes OX40, is not very transplantable, but is secure against immunologic attack. What do you think?
ReplyDeleteIt sounds like smooth muscle in the heart may not be able to successfully activate T-cells themselves (due to lack in this receptor ligand), but wouldn't smooth muscle be just as permeable as epithelial cells when exposed to pro-inflammatory cytokines/chemokines? Also, couldn’t they be damaged as innocent bystanders in a killer T Cell response?
ReplyDeleteDeseases like Chrone’s do not spare the smooth muscle surrounding the GI tract. I found a paper from 2000 that sheds some light on how OX40 ligand pays a role in diseases like Chrone’s. Stüber et al took biopsies of patients with various diseases of the GI and looked for presence of OX40 ligand by IHC. The OX40 interaction turns out to be an important part in the onset of these diseases and OX40 ligand is highly expressed in the cases and not in the controls. To answer the last commenters, not all smooth muscles lack this ligand and are therefore unable to present Ag to T cells.
E. Stüber, et al., The expression of OX40 in immunologically
mediated diseases of the gastrointestinal tract
(celiac disease, Crohn's disease, ulcerative colitis).
Eur J Clin Invest 2000; 30 (7): 594±599
@Rick: Thanks for the additional information. It seems like the study you found, however, raises more questions for me. If OX40 and OX40 ligand are an important part in the onset of Chron's disease, might it be a potential target for treatment or prevention of the disease? If we could locally suppress OX40 or OX40 ligand, it could be beneficial in patients with either arterial transplants or Chron's disease.
ReplyDelete@ KoriW495. The paper that I referred to only speaks for large vessel smooth muscle cells and I bet you not all smooth muscle cells are the same and GI SMCs will be significantly different due to their exposure to pathogens and common bacteria. Also as the gross anatomy of the tracts is different from large vessels SMCs differentiation could be different than those in arteries.
ReplyDeleteSpeaking of treatment for the Chron's disease, there seems to be no animal model for this disease to study further OX40-OX40L interaction.
@AlexE7630. Alex, I agree with you that SMCs of GI must be immunocompetent, at least I want mine to be able to fight off infections. I was trying to fins a good picture online and compare H&E stains of SMCs of GI and SMCs of arteries. I known arterial SMCs are compact and well organized. As you know cardiac muscle cells are highly specialized tissue, and I would speculate that immune infiltrates in cardiac muscles are not safe for heart function. It may be easier to have a highly controlled barrier for pathogens and not worrying about clearing them, kind of like heart-blood barrier, which would to be the job of endocardium. There seem to be no publications on cardiac muscle cells and OX40-OX40L interactions, we could only speculate. Great questions Alex
ReplyDelete@RickH7630. Thanks for the info on Crohn’s disease, new thing for me. Vessels, including large arteries, arterioles, and any artery greater than 60um in diameter have internal elastic lamina, and large vessels also have external elastic lamina (containing elastin), those layers surround smooth muscle cells and I would imagine cytokines may not permeate elastin. Although, then how do nutrients supply SMCs if there is elastin on both sides of the layer?
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