The nationwide experiment will initially include around 100,000 volunteers.
Reviving a decades-old hypothesis of autoimmunity
September 1, 2015|
Generations of in-depth research into human anatomy, histology, and basic physiology have largely explained the physical manifestations of diseases affecting nearly every organ of the body. From cardiology to gastroenterology and pulmonology, form implies function. It is no mystery, for example, why a blood clot between the heart and lungs causes shortness of breath, problems with oxygenation, and strain on the muscles of the heart.
Yet there remains an entire class of illnesses that present systemically, do not respect the boundaries of organ systems, and wreak havoc on quality of life and longevity. And we still have little idea of what starts the vicious cascade in the first place. This category of maladies is called autoimmune disease, and it is our fundamental lack of knowledge about these disorders that so greatly hinders our ability to prevent, diagnose, and treat them.
The scope of the problem is tremendous. The NIH has estimated that more than 23 million Americans suffer from autoimmune diseases—a burden associated with a health-care cost of $100 billion per year. And the morbidity and mortality attributable to autoimmune conditions cannot be ignored. Patients with rheumatoid arthritis have a 60 percent increased risk of death from cardiovascular disease, for example. And patients with systemic sclerosis, an autoimmune disease that causes thickened, tight skin and disruption of the normal structure and function of organs such as the heart, lungs, GI tract, and kidneys, experience a loss of life expectancy of 16 years in men and 34 years in women.
Our fundamental lack of knowledge about autoimmune diseases greatly hinders our ability to prevent, diagnose, and treat them.
There is much we know, or think we know, about the risk factors and manifestations of autoimmune disease, and we even have some diagnostic tests for antibodies that often closely correlate with specific subtypes of disease. However, the fundamental biological mystery remains: What initiates the formation of antibodies that react with the body’s own proteins and result in the destructive processes that define autoimmune disease? Have we simply failed to detect an infectious or environmental exposure that initiates the inflammatory cascade? Is there a benefit accrued via autoantibodies that serves an important biological purpose and helps to explain their existence?
While many theories have been and continue to be posited in answer to these etiological questions, a particularly interesting hypothesis first proposed in the 1960s has been reborn and, if it holds true, could have tremendous implications for the fields of rheumatology, oncology, immunology, neurology, endocrinology, and many others: autoimmune disease may represent collateral damage from the body’s fight against developing cancers. Scientists have long recognized that patients with certain autoimmune diseases are at increased risk of cancer, but only recently has a possible mechanism been identified. Research involving patients with concurrent cancer and scleroderma revealed somatically mutated genes in the patients’ tumors that initiated cellular immunity and cross-reactive humoral immune responses, producing antibodies that reacted to the cancer and are known to play an important role in scleroderma itself (Science, 343:152-57, 2014). The finding implies that the autoimmune disease may arise as an unintended consequence of the body’s own immune response to a developing cancer, which in certain patients will never become clinically evident.
This idea is not far-fetched considering that certain syndromes of this type have been recognized for quite some time. Lambert-Eaton syndrome, in which damage to motor synapses can cause weakness, and limbic encephalitis—inflammation of the brain and resultant confusion and neurologic symptoms—are two examples of conditions known to occur in reaction to a cancer in the body. But the novel findings suggest a much larger possibility that all autoimmune diseases are due to the immune system’s response to cancer. If this is true, detection of specific autoantibodies would help predict which patients will manifest a clinically-apparent cancer. Indeed, researchers have found that specific autoantibodies found in patients with autoimmune myositis—muscle inflammation and symptoms in the joints, skin, lungs, and other body parts—are not only associated with specific subtypes of these diseases, but can also be used to predict which patients will develop the types of myositis associated with cancer (Arthritis Rheum, 67:317-26, 2015).
Such support for the idea that the immune system’s response to cancer cells may trigger autoimmunity has opened a proverbial Pandora’s box of scientific questions. Why do some patients with tumor cells develop autoantibodies while others do not? Can autoimmune diseases be prevented, instead of waiting for them to develop and treating the aftermath? Perhaps most importantly, can we harness the power of the immune system to effectively fight cancer without the resultant production of autoantibodies that cause autoimmune disease? In 2013, the editors of Science named cancer immunotherapy the “Breakthrough of the Year,” foreseeing a new paradigm in medicine. Understanding the origins of autoimmunity is critical to ensuring the safety of these therapies, which represent newfound hope for millions of patients worldwide.
The time is ripe to tackle this most challenging problem of understanding autoimmune etiology. By investing time and effort in these fundamental questions of biology, we can hopefully one day declare with conviction and clarity: body, heal thyself.
Jason Liebowitz is a third-year internal medicine resident at Johns Hopkins Bayview Medical Center in Baltimore, Maryland.
September 5, 2015
There has been interesting reasearch into the Heat shock proteins formed after impacts to joint cartileges, and its relationship to rheumatoid arthritis:
The following are exerpts from a paper I wrote about cetyl myristoleate:
In Rheumatoid arthritis there are many different actions taking place. The synovial membrane becomes inflamed because B cells produce antibodies that attack a protein in the cartilage of the synovial joint. Also joint tissues are destroyed by gamma-delta T cells that mistake the existence of stress proteins produced when cells are injured for mycobacterium antigens and attack.i These cell wall mounted stress proteins called p65 also called “heat shock proteins” have the exact same size protein as Mycobacterium antigens, 65 kilodaltons.ii These proteins are present in rheumatoid tissue as well as the ‘scavenger’ macrophages near the diseased tissue and on the cartilage forming cells called chondroblasts.iii When any of these cells show the p65 cell surface protein antigen, they are marked for destruction by T cells and trigger an immune response stimulating more T cells to come to the site and do more destruction.iv When the destruction of the cartilage begins the body also initiates an immune response which causes the release of inflammatory chemicals that cause further tissue damage. The synovial membrane hypertrophies and becomes locally invasive to a depth of 10 cells where it meets the bones. It forms a “pannus” tissue which produces messenger RNA encoded for producing destructive proteins called matrix metalloproteinases.v This ‘positive feedback system’ progresses until the all of the remaining cartilage has been destroyed in the joint and often the bone surfaces as well. This results in deformities in the hands, feet, and other joints and can eventually cause fusing of the joint completely.
i Clayton, Julie(1991) New Scientist, May 04, 1991, http://www.newscientist.com/article/mg13017675.700-confusion-in-the-joints-if-the-immune-system-becomesconfused-it-can-turn-against-the-bodys-own-tissues-causing-destructivediseases-such-as-rheumatoid-arthritis-are-bacteria-to-blame.html
ii Clayton, (1991) Ibid.
iii Clayton (1991) Ibid.
iv Clayton(1991) Ibid.
v Buch M, Emery P, The aetiology and pathogenesis of rheumatoid arthritis. Hospital Pharmacist 2002;9:5-9. http://www.pjonline.com/pdf/hp/200201/hp_200201_aetiology.pdf
September 15, 2015
Even more fundamental may be that both autoimmunity and cancer may result from alterations in one's microbiome, a view opened by the recent linking of early antibiotics with the later development of Juvenile Idiopathic Arthrits.
September 15, 2015
I have a science degree but have never practived as a scientist. That said, I have experimented on my own body with a lot of stuff. For example, I got rid of the asthma that I acquired at age 52. Oh --- I also no longer get colds, and my allergies went mostly (75% or so) away.
You folks might want to examine how and why hyperimmune egg works
September 17, 2015
An excellent review which lucidly explains the currecnt developments in a vastly unknown field. How little we know?
September 17, 2015
An excellent review which lucidly explains the current developments in a vastly unknown field. How little we know?
September 24, 2015
Arch Dermatol Res. 2002 May;294(3):103-8. Epub 2002 Apr 10.Minocycline does not alter collagen type I metabolism of dermal fibroblasts in culture. Author information Abstract
Minocycline has been used successfully for the treatment of dermal fibrosis in patients suffering from systemic sclerosis. However, little is known of the mechanism of the antifibrotic action of minocycline. We studied the in vitro effects of minocycline by analysing the influence of various amounts of minocycline on cell proliferation and synthesis and degradation of collagen I in cultured human dermal fibroblasts from healthy donors and two patients with systemic sclerosis. Collagen I metabolism of cultured dermal fibroblasts from two- and three-dimensional culture systems was studied by Northern hybridization and real-time RT-PCR. Messenger RNA of collagen I, proline-4-hydroxylase, lysyl-hydroxylase, matrix metalloproteinase I, and protein of MMP-1 (ELISA) and collagen I in culture supernatants were determined. Minocycline did not alter the expression of the investigated mRNAs, irrespective of the dosage, the culture system and the incubation times used. Similarly, the amounts of collagen I and MMP-1 protein were not affected. Consequently, direct antifibrotic effects of minocycline on untreated human dermal fibroblasts in vitro seem unlikely. Therefore, other mechanisms are probably responsible for the clinical effect observed in the treatment of systemic sclerosis.
But there ara convenient denials... obviously:Arthritis Rheum. 2004 Feb;50(2):553-7. Minocycline is not effective in systemic sclerosis: results of an open-label multicenter trial. Mayes MD1, O'Donnell D, Rothfield NF, Csuka ME. http://www.ncbi.nlm.nih.gov/pubmed/14872498