Mechanisms of Tissue Injury in Autoimmune Diseases such as Lupus; Autoimmune Disease and Atherosclerosis

Interviews with Experts

Jane E. Salmon, MD
Jane E. Salmon, MD
Attending Physician, Hospital for Special Surgery
Senior Scientist, Hospital for Special Surgery

Stephen Paget, MD: It is a pleasure today to introduce Dr. Jane Salmon, who is a Professor of Medicine at the Weill College of Medicine at Cornell University and an attending physician here at the Hospital for Special Surgery. Her interest is in mechanisms of tissue injury in autoimmune diseases, most specifically systemic lupus erythematosus. Obviously, it is very important that in people with autoimmune diseases of various types -- rheumatoid arthritis with regard to the joints, lupus with regard to the kidneys and other tissues -- that the inflammatory process leads to damage of the tissues. First, could you tell us how that occurs? What are the actual mechanisms that lead to tissue damage?

Jane Salmon, MD: Well, lupus is an immune complex disease. So a critical mediator in tissue injury is deposition of immune complexes. IgG activates complement. So complement receptors and receptors for immunoglobulin trigger most damage. Those are really the areas of interest at my laboratory.

Stephen Paget, MD: Do those areas have specific therapeutic significance?

Jane Salmon, MD: Certainly. There are clinical trials now with inhibitors of complement in lupus and rheumatoid arthritis, and we are very interested in those. In terms of immunoglobulin receptors, they are inherited polymorphisms in these receptors, and they are used as predictors for injury; at least we are hoping to be able to use them to predict severity of disease and who will get different manifestations of disease. There are small proteins that conceivably block immunoglobulin receptors and inhibit inflammation in areas of tissue deposition like in the kidney. So there is a lot of potential. In addition, intravenous gamma globulin may act by blocking inflammation triggered by immune complexes, at least at some level, by lowering autoantibody levels. So there are many therapies directed specifically at limiting effector function in organs in lupus.

Stephen Paget, MD: So, before that, before these new medications, we have kind of used shotguns to control or inhibit or suppress many parts of the immune system. These would be more focus-targeted types of therapies?

Jane Salmon, MD: That's the goal. Before we could really target immunoglobulin receptors and complement components and complement receptors. Again, we can't do that yet, we can do it in mouse models. We would just stop autoantibody production, but we would also paralyze the entire immune system so the patient would be at risk of microbial infections and cancer perhaps. Rather than shutting off immune responses, what we are trying to do is prevent damage from pathogenic antibodies.

Stephen Paget, MD: You mentioned the term polymorphisms a few minutes ago, and those are genetic variations that occur. Could you tell us how they could be employed in predicting who might develop certain manifestations in lupus?

Jane Salmon, MD: Sure. In receptors for immunoglobulin, for example, there are very subtle differences in the structures of receptors among healthy, normal people. What I believe is very important in terms of risk to individuals for either microbial infection or immune complex mediated damage -- or anything that has to do immunoglobulin -- are these subtle variations in the structure of the receptor that affect how the receptor works. So you can have a three plus receptor or a two plus receptor in terms of potency of triggering inflammation via white blood cells, for example, macrophage or neutrophils. And, for example, patients who have highly effective responses may be much better at protecting themselves against pneumococcal pneumonia. They have very trivial disease, whereas, if they have very potent responses, they may have much worse rheumatoid arthritis, for example. They have much more inflammation in the joint and much more damage. So if we understand subtle polymorphisms in this class of receptors and learn more about polymorphisms in receptors for complement or in complement components or levels of production, all these little variants create a single person with a specific profile when they get environmental information that triggers autoimmunity.

If we understood how effectively they would handle their immune complexes, so they won't get severe sepsis or they will get severe lupus, we could predict whom to treat and with which therapy; whom to treat more aggressively and whom to treat less aggressively; whom to follow much more closely for the potential development of renal disease or for joint erosions in rheumatoid arthritis or for sepsis when they have a mild bacterial infection, say a skin infection in a rheumatoid patient, for example. So, subtle genetic variations can determine the manifestations of a rheumatic disease and, if we understand them, we can make predictions and design better therapy or prevent complications.

Stephen Paget, MD: You have been particularly interested in the fact that patients with systemic lupus develop premature atherosclerosis. Can you tell us how that relates to lupus or whether it is due to cholesterol or blood pressure or other predisposing factors that we have all read about?

Jane Salmon, MD: Now that lupus patients are living fairly normal lives and their longevity is similar to healthy young women, what we are finding is, as a consequence of our excellent treatment, patients are not getting renal disease but they are getting atherosclerosis. That is manifested by early myocardial infarctions and by evidence of atherosclerosis when we do tests looking for plaque in the carotid, which are arteries in the neck. And plaque in the carotid is a marker for plaque in coronary vasculature.

Initially the thought was that our treatments were causing these problems. Steroids cause high blood pressure and high cholesterol. But we've done a study looking at blood pressure and cholesterol in lupus patients to see whether and why they are getting carotid plaque and, in fact, that is not why. The conventional risk factors that one thinks about in men and women with typical atherosclerosis are not the main problems in lupus patients. There is something about lupus. There is something about total vascular inflammation that is pro-atherogenic. What that is we are not sure, but certainly even in non-autoimmune patients, inflammatory mediators play an enormous role in provoking atherosclerosis. Lupus patients may be the most interesting group of patients in the study because they don't have so many of the other risk factors, and if we take care of them well -- correct the potential risk factors -- and if we can understand why they get atherosclerosis early, we may be able to apply that globally to understand mechanisms of inflammation in atherosclerosis.

Stephen Paget, MD: Thank you very much, Dr. Salmon.

Dr. Salmon was interviewed by Dr. Stephen A. Paget, Physician-in-Chief, Hospital for Special Surgery


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