A few years ago, a reader of the New York Times blog “Consults – Experts on the Front Lines of Medicine” (now replaced by Ask Well) posed the question “How does someone get scleroderma?” Leading expert Dr. John Varga responded “The cause of scleroderma is unknown. Viruses and exposure to certain chemicals and occupational toxins have been suspected, but nothing has been firmly proven to cause the disease.”
Since then, more research has been done and, a few days ago, results from a study published in the journal Science (December 5, 2013) provided evidence for a mechanism that may likely lead to the development of scleroderma – in an attempt to control cancer cells, the immune system attacks healthy tissues. The study, titled “Association of the Autoimmune Disease Scleroderma with an Immunologic Response to Cancer” was carried out by John Hopkins scientists.
Scleroderma is a group of diseases that affect the connective tissue – the tissue that supports the skin and the internal organs. In people with scleroderma, the affected tissue becomes hard or thick.
There are two main types of scleroderma. One is the localized type – this type often affects only the skin and does not harm major organs. The other one is the systemic type, which affects the skin, tissues under the skin, blood vessels, and major organs.
Paul Klee, one of the most inventive painters of the 20th century, was notoriously affected by the systemic scleroderma type. The somber tone of his late work is ascribed to the progression of the disease and chronic suffering. He wrote “If only the enigma of death were not so ambiguous! No less so is the enigma of life, for one has to wonder what beauty and splendor can be found in the torments of recent times.”
At the time, scleroderma was considered a mysterious disease. Now, we know that scleroderma is an autoimmune disease.
Patients with scleroderma produce autoantibodies – antibodies that cause tissue damage because they’re directed toward the patients’ tissues instead than toward foreign invaders. In scleroderma patients, the autoantibodies that cause tissue damage bind a protein called RPC1.
The John Hopkins scientists found that cancer cells from a majority of patients with severe scleroderma produce a mutated or “foreign” form of the RPC1 protein. This mutated form triggers production of antibodies able to bind the mutated RPC1 protein present in cancer cells. However, these antibodies are also able to bind the normal RPC1, which is present on healthy cells. In other words, in scleroderma patients, antibodies are produced to combat cancer but, in addition to destroying cancer cells, they also destroy healthy tissues.
“As early cancers grow, the body is exposed to novel proteins caused by the mutations in the cancer and potentially opens a window to development of autoimmune disease,” said Bert Vogelstein, Clayton Professor of Oncology at the Johns Hopkins Kimmel Cancer Center and a Howard Hughes Medical Institute investigator.
It is reasonable to speculate that, as more research is done, similar mechanisms will be identified for other types of autoimmune diseases.
Copyright © 2014 Immunity Tales.
I’m curious as to why these “autoantibodies” are not destroyed during positive and negative selection of B cells and T cells. During the production and maturation of these lymphocytes, the immune system ensures that B/T cells do not contain receptors that allow tight binding to the host cells. If binding does occur, it could lead to the death of our own cells and can cause autoimmune diseases. With all this in mind, how do these B cells and T cells escape the “weeding out” mechanism of the immune system?
I wondered the same thing, but after reading Chapter 13 in our textbook, I found out that during clonal selection, some autoreactive T cells and B cells can escape deletion, and continue to circulate in the peripheral system. The book suggested that the negative selection process may not be completely functional. For example, some proteins responsible for eliminating these autoreactive lymphocytes may not be functioning properly, so that can lead to those T cells and B cells being able to escape deletion. There’s also the possibility that some self antigens are not processed and presented to the lymphocytes. Self antigens can actually be confined to a specific organ outside the primary lymphoid organs (where clonal selection takes place), and only after a traumatic injury are these antigens released. After being released, they stimulate an immune response that can lead to an autoimmune disease. Basically, there’s some sort of mechanistic failure responsible for these self-reactive T and B cells being able to escape.
Another important cause behind autoimmune diseases is the breakdown of tolerance to self antigens, but the mechanism behind this is not fully known. Scientists also believe that some individuals have a genetic predisposition for autoimmune diseases. If you combine genetics and possible failure during lymphocyte selection to effectively eliminate autoreactive T and B cells, it’s easy to see how the immune response can go wrong. I hope this answers your question!
Parham, P. (2009). The Immune System (3rd ed.). New York, NY: Garland Science.
I would like to expand on what you stated about negative selection not being completely functional. As we learned in class, both B and T cells develop in primary lymphoid organs, undergoing negative selection to eliminate self-reactive antigens. B cells develop in the bone marrow and are therefore exposed to antigens limited to the blood during negative selection. This means that there are many tissue-specific antigens that developing B cells are not screened for. In the case of T cells, which develop in the thymus, a transcription factor called the autoimmune regulator (AIRE) found only in the medullary epithelial cells of the thymus, expresses cell and tissue-specific antigens that are used to screen for self-reactive T cells. The blood and AIRE cannot possibly contain or encode for every antigen expressed in the human body, and consequently autoimmune diseases occur.
Greer, S. (Oct 2013). Positive and Negative Selection of T Cells. BIOL 4278 Immunology. Lecture conducted at Gerogia State University, Atlanta, GA.
Autoimmune diseases all involve the reduction of T cell tolerance. This leads to the adaptive immunity attacking its own tissues because T cells become autoreactive and inflammatory. Furthermore, T cells aid B cells in antibody production (1). In this case, an autoantibody is produced which binds both mutated and normal forms of RPC1, causing an autoimmune response.
This disease is the result of a biological trade-off with severe consequences. Unlike the hypersensitivity disorder of allergies, which seem to be caused by the body’s immune system reacting to a normally harmless substance, scleroderma is an autoimmune disease that results from an attempt to control cancer cells. This is a great example of how deleterious alleles can remain in populations regardless of their harmful phenotypes. From an evolutionary standpoint, fitness costs associated with cancer cells seem to be higher than fitness costs caused by the autoimmune disease.
The specific genes responsible for scleroderma have not yet been identified (2). Discovering these genes is important, as it could open up opportunities to study the specific mechanisms responsible for producing the autoantibodies. After identifying the genes, further studies can identify the timing and intensity of the gene expression, and give potential to identify what exactly is causing these antibodies to bind RPC1 of healthy cells.
1) The Immune System, Peter Parkham, Third Edition (Chapter 13, pgs 417, 433).
2) Gabrielli A, Avvedimento EV, Krieg T (2009). “Scleroderma”. N. Engl. J. Med.360 (19): 1989–2003. doi:10.1056/NEJMra0806188
This article reminds me of the one on molecular mimicry since the antibodies bind to the mutated RPC1 protein of cancer cells and the normal RPC1 proteins present in the immune system. It seems like another case of “mistaken identity”. Even so, I find it strange that the antibodies can bind to the mutated form and the self form. If it’s mutated, doesn’t that mean there’s a difference in protein sequence? Considering the fact that the adaptive immune system is known for being highly specific in its attack of foreign substances in the body, it’s rather surprising that it can’t distinguish between a mutated and a self protein. Are mutated RPC1 proteins that similar to normal ones? Judging from the article, the proteins must be similar enough to confuse antibodies. Seeing how they bind to the same receptors on the autoantibodies, it can be inferred that they share a similar, recognizable sequence. If so, what are the differences between these proteins that led scientists to refer to the ones from cancer cells as “mutated” in the first place?
RPC1 proteins are encoded by the POLR3A gene. The gene are usually encoded for proteins that acts as a sensor to detect foreign DNA and trigger an innate immune response (1). Most cell in the innate immune system has receptors that can recognize what is foreign and once binded to the receptor, has the ability to destroy the antigen, or send signals to the adaptive immune system. The component of the protein is probably a common receptor that every cell in the body has, and that are needed for the activation of the innate immune system. However, what if the innate immune system is the one that is not working correctly? The adaptive immune system are then directed towards the cells that are usually part of the innate immune system. This will include signal proteins that triggers the innate immune response, like the RPC1 protein. The mutation of the RPC1 proteins triggers an innate immune response that once presented to the adaptive immune system recognizes as the receptor of cells part of the innate immune system. This will cause the binding of antibodies to the RPC1 proteins and the binding of the RPC1 proteins in any cells that is a part of the innate immune system. I wonder if the cause of cancer which leads to scleroderma was actually the responsibility of the immune system.
Would it be effective to target the RPC1 protein rather than the antibodies themselves? If research has concluded that this protein does in fact alter the binding that occurs with the antibodies, then steps should be taken to control the production, or site of production, of these proteins. One would not think of suppressing the immune system antibodies because the body thrives off of the protection of the bodily system. Thus suppressing T and B cell production that carries out the adaptive immune response would bring more harm than good.
In addition to that, the vital differences between systemic and localized scleroderma must be considered. In this case one implements a much more severe result than the other. Is it possible that other factors contribute to such a stark difference in the two forms? Nontheless, systemic scleroderma is an extremely detrimental form of cancer. And with all of the increased research on cancer that is currently underway, hopefully there will be a break in not only this form of cancer, but in all forms.