Considering its fund-hindering prevalence, it is unlikely that few reading this have ever heard of Systemic Sclerosis, or Scleroderma (SSc) so here’s a brief description…I stress “brief”: Scleroderma is a chronic connective tissue autoimmune disease characterized by systemic tissue fibrosis (i.e. too much collagen in places it shouldn’t be) with symptoms that can range from mild to life threatening (1).
“So where do the antibodies come into play, and what’s all this stimulatory jazz,” you might be asking? Rightly so. Stimulatory antibodies, until recently a curiosity associated mainly with Graves’ disease and hyperthyroidism, are immunoglobulins with the unusual ability to bind to a cell’s receptor and stimulate some form of physiological function or process not originally thought to be associated with the immune system. In the case of Graves’ disease, stimulatory antibodies bind (in excess) to thyrotropin receptors on the thyroid and stimulate the release of thyroid hormone (2). Since the body can regulate Thyroid Stimulating Hormone production but not, apparently, autoantibody production the result is chronic thyroid over-stimulation with hyperthyroidism ensuing. It is important to remember that until recently Graves’ disease was the only condition in which this stimulatory autoantibody phenomenon was known to occur. Enter Scleroderma. In a recent study by Baroni et al., 46 SSc patients (all that were in the study) were shown to have elevated serum stimulatory IgG levels (3). These IgG autoantibodies bound to, and stimulated, Platelet-Derived Growth Factor Receptors (PDGFR) resulting in excess collagen production. More importantly, none of the 75 controls, who displayed other autoimmune diseases such as Raynauds’s Phenomenon, Systemic Lupus Erythematosus, Rheumatoid Arthritis, and Idopathic Pulmonary Fibrosis, displayed elevated PDGFR stimulatory IgG levels. With additional experiments Baroni et al. was able to tease out the pathways resulting in increased fibroblast (cells that make collagen) activity: 1) SSc autoantibody IgGs bind to PDGFR, 2) This binding increases Reactive Oxygen Species (ROS) production, 3) Long term accumulation of ROS stimulates collagen-gene expression, 4) Too much collagen equals thick skin and crunchy-stiff blood vessels. …Okay, so step 4 was not in their original paper, but you can see how it is a logical corollary.
Hopefully by now you are thinking, “So what?” Well, Gleicher et al. realized the importance immediately and discusses it in his recent paper published last June (4). Basically, the finding by Baroni et al. (stimulatory IgGs in SSc patients) changes the way we must view the role of autoantibodies in human physiology and autoimmune disease. It has been known for some time that even healthy people occasionally harbor low levels of autoantibodies in their system. It is only when these concentrations rise excessively that they become problematic. That there is a stimulatory (Gleicher uses the term “functional”) role for autoantibodies in Graves’ disease and Scleroderma, and that there might be similar undiscovered autoantibodies with similar functions in other diseases, brings with it a new paradigm in which to view autoimmune function and future research.
1. LeRoy EC, Black C, Fleischmajer R, Jablonska S, Krieg T, Medsger TA, Jr., Rowell N, Wollheim F. Scleroderma (systemic sclerosis): classification, sub-sets and pathogenesis. J. Rheumatol 1988; 15:202-5.
2. Morgenthaler NG, Hodak K, Seissler J, Steinbrenner H, Pampel I, Gupta M, McGregor AM, Scherbaum WA, Banga JP. Direct binding of thyrotropin receptor autoantibody to in vitro translated thyrotropin receptor: a comparison to radioreceptor assay and thyroid stimulating bioassay. Thyroid 1999 May; 9(5):466-75.
3. Baroni SS, Olivieri A, Campelli N, Luchetti M, Poloni A, Trappolini S, Moroncini G, Bacigalupo A, Leoni P, Avvedimento EV, Gabrielli A. Stimulatory autoantibodies to PDGF receptor in patients with extensive chronic graft-versus-host disease. Blood 2007 Jul 1;110(1):237-41.
4. Gleicher N, Barad D, Weghofer A. Functional autoantibodies, a new paradigm in autoimmunity? Autoimmun Rev 2007 Nov;7(1):42-5.
4 comments:
I've never heard of scleroderma before! Very interesting to learn about how this diseases' mechanism relates to that of Graves' disease we learned about in lecture.
SethW7630...a most interesting article about scleroderma. I've taken care of people in the hospital with this disease, and I remember noticing that the condition of their skin makes them very self-conscious about their body image (among other problems). This is surely a relevant comparison to Grave's disease as a form of Type II immunopathology, and I hope the data you've cited will help promote a new way of viewing antibody levels. TLH
An interesting post, for sure. I wonder if testing for autoantibodies to PDGF receptor in the scleroderma patients was just a lucky shot in the dark for this group? More likely, the PDGF receptor - ROS - Collagen pathway must be well developed, and therefore a logical pathway for which to check for autoimmune stimulation if you are getting an excess of collagen buildup? Still, very cool.
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