Autoimmune Disease Common Cause Hypothesis

More than 22 million Americans (one in thirteen), most of whom (75%) are women are affected by autoimmune disease. Today we know eighty different ways this disease attacks the human body (table 1). Some of most commonly known syndromes are type I diabetes, multiple sclerosis, lupus, and psoriasis. It is estimated that the annual, direct medical costs of these four syndromes alone are between $15 billion and $20 billion in the U.S.

An analysis of the research funding for autoimmune disease illustrates the state of the science. Over the past several decades, government, industry and private philanthropy have supported individual “syndrome” related research overwhelmingly compared to underlying autoimmune disease research. ADRF is not suggesting that this research is irrelevant or unnecessary; on the contrary, much of this research has saved countless lives, has significantly improved the quality of life for countless patients and has greatly contributed to the body of knowledge that now supports the Common Cause Hypothesis.

Aside from the scientific evidence, which will be laid out in this paper, it is increasingly self-evident from personal family accounts that these “syndromes” are connected by one common factor – a defective immune system.

The ADRF web site encourages visitors to share family stories about autoimmune disease, and their unedited stories provide heart-wrenching illustrations of the point. Witness the following accounts:

My daughter and I both have celiac disease (diagnosed after 40 years of suffering for me). My diagnosis helped her find her problem earlier. She was diagnosed first with hypothyroidism and her’s is more severe than mine. Her paternal grandmother had rheumatoid arthritis and hypothyroidism.

Several members of my family of origin have osteoarthritis. A maternal Aunt had lupus. I have Mixed Connective Tissue Disease with thyroid disease and a blood disorder that cannot be diagnosed.

I am a 30-year old woman and was diagnosed with mixed connective tissue disease one year ago. This disease consists of an overlap of lupus, dermatomyositis and Raynaud’s disease. I also have ulcerative colitis. Other members of family also have been diagnosed with diabetes and multiple sclerosis.

A friend of mine has both type I diabetes and myasthenia gravis. She has been struggling with both for about ten years. We both need hope that there is a cure out there and I wonder if there is a link between the two. I’m also interested in the family connections with autoimmune diseases since several of her relatives have similar diseases as well.

Our story is so complex. I have thyroid disease, B12 deficiency and endometriosis. My first-degree relatives have type 1 diabetes, psoriasis, multiple sclerosis, thyroid disease, Crohn’s disease and much more. These brief glimpses into family histories provide a compelling argument for further analysis. A growing body of research suggests that there is more than just coincidence at work. It has been known for years that patients with autoimmune diseases are more likely to have a relative with an autoimmune disease, but they do not necessarily have the same disease. Approximately 15% of all autoimmune patients have two autoimmune diseases and the typical family with one affected adult will have greater than 40% chance of another adult member having an autoimmune affliction.

Large genetic studies repeatedly find that autoimmune diseases can be linked to the same region of a chromosome (MHC Class I) as genes involved in training the immune system to identify “self” tissue. It is common for one identical human twin to have an autoimmune disease and 60 – 70% of the time for their sibling not to have this condition – in fact there are many documented cases in which twins express two different autoimmune diseases, yet they have the same genes!

While much about the human immune system is still not well understood, these family stories, by themselves, create a compelling argument for directing much more funding for basic autoimmune disease research rather than for research addressing autoimmune syndromes.

If people can agree that the:

• 1. Underlying autoimmune malfunction is not well understood;
• 2. Same underlying autoimmune malfunction is present in a number of syndromes; and
• 3. Families with autoimmune disease often have close and extended family members with different autoimmune syndromes, and that this is not by coincidence;

then people can also agree that the solution to curing autoimmune syndromes necessitates understanding and curing the underlying autoimmune disease.

The Science

The science supporting the Common Cause Hypothesis is as compelling as the thousands of available personal accounts, but is more challenging to understand and appreciate. The following will describe the biology that forms the basis of this Hypothesis. There is not consensus regarding all of the underlying mechanisms that cause autoimmune disease, but what is increasing evident is the action of common mechanisms resulting in many autoimmune syndromes.

Both humans and several animal models have defective “autoreactive” immune cells (bad-cells) that may be responsible for causing several different autoimmune syndromes. The bad-cells, which are erroneously “educated” lymphocytes (immune cells), mistake the body’s normal tissue as a foreign threat and then destroy it. These bad-cells, in a normal person, are destroyed in the thymus gland by a regulatory process called “central deletion” that controls apoptosis (cell death) of young immune cells[1]^,[2]. Although the specifics of this process are not fully understood, the notion that protein expression on bad-cells while in the thymus can lead to cell deletion is well accepted[3]^,[4],[5]. It is a defect in this central deletion system that allows bad-cells to enter the blood stream, and eventually destroy enough normal tissue to manifest as an autoimmune syndrome[6]^{,[7],[8],[9],[10],[11],[12],[13]}. Also present in autoimmune disease is the defect in the immune system T regulatory cells that do not destroy these bad-cells after they enter the blood stream, as they should.[14]
Here is a simplified description of the process: Immune cells, during their early stage of development in the thymus gland, blood marrow and elsewhere in the body, go through an education process that teaches them which tissues are “self” and which are foreign — like bacteria and viruses. Picture the cells like a ball that has suction-cups sticking out all over its surface. Into each suction-cup is placed a piece of protein that is a marker like the ones found within the body. The suction-cups are filled with markers from the heart, kidney, lung, islet cells (diabetes), connective tissue (lupus), thyroid (Graves) and the like as part of their education process. This is done so when the cell circulates through the body, it does not destroy self-tissue.

This education process is not perfect, however, and some cells do not get markers for islet cells, or connective tissue, or thyroid. These cells should be destroyed through a normal central deletion process before they get into the blood stream. Autoimmune disease occurs when these miss educated cells are not destroyed and are allowed to circulate throughout the body. So when the empty suction-cup encounters the protein marker for normal tissue, that marker fills the empty suction-cup, which then activates the immune process that kills the normal-self tissue. It is this faulty system that is at the heart of the Common Cause Hypothesis.

More and more researchers are documenting that the defect that allows these bad-cells to escape destruction and attack normal tissue is present and active in different autoimmune syndromes. Autoimmune diseases are defined and named because the bad-cell destroys different tissues. In the case of type I diabetes, the immune system destroys insulin producing beta cells. In lupus the immune system destroys connective tissue. In multiple sclerosis nerve covering is destroyed. In Graves’s disease, thyroid tissue is destroyed.
Autoimmune disease is often referred to as a genetic disease, because it runs in families. At issue, however, is the phenomenon seen in twins where it is common for one identical human twin to have an autoimmune disease and 60 – 70% of the time for the sibling does not have the disease. The twins have the same genes but the genes do not behave the same way in each twin.
This is likely the result of transcription factors (TF) that transcribe the genetic instructions through the creation of proteins that then go on to serve mechanical metabolic functions in the body. It appears the different patterns of TF activity may account for the differences between autoimmune and non-autoimmune cells[15]^{, [16]}.
A key transcription factor protein is called “nuclear factor kappa Beta” (NF-kB). It has a central role in maintaining and, in autoimmune disease, upsetting the body’s central deletion process as well as the basic immune response that kills foreign bacteria and viruses[17]^{, [18]}. Cells die and are created continuously in the body, and this requires a highly complex regulatory system. Cells are killed through the dispatch of a variety of cytokines, (substances that kill cells), and NF-kB plays a pivotal role in regulating this cytokine balance.
A primary cytokine that is implicated in many autoimmune syndromes is “tumor necrosis factor” (TNF-alpha). In the bad-cell, a defective NF-Kb activation leads to the suppression of the cytokine effect of TNF-alpha and preserves the life of the bad-cell (central deletion does not occur) — leading to its release into the blood and normal tissue destruction. This defective NF-kB activation has been shown to be strongly functionally linked to intestinal inflammatory disorders including Celiac and Crohn’s disease [19]^{, [20], [21], [22],[23]}, scleroderma[24], lupus[25], autoimmune thyroid disease[26] as well as type I diabetes[27]^{, [28], [29]}. Supporting this phenomenon further in humans, there is increasing evidence that changes in the structure of the NF-kB1 gene makes people more susceptible to type I diabetes[30]^,[31], multiple sclerosis[32], lupus and Sjorgren’s syndrome [33].
The defect in the bad-cell that leads to the NF-kB defective activation that preserves the life of the bad-cell by reducing TNF-alpha, also makes the bad-cell vulnerable. As the bad-cell matures while circulating in the blood and attacking normal tissue, the level of NF-kB activity decreases. This makes the bad-cell vulnerable to being killed by an increase in the level of the TNF-alpha cytokine. In a normal cell, NF-kB suppresses the killing effect of TNF-alpha, but as the bad-cell matures, it can be killed by increasing the level of TNF-alpha in the cell[34]^{, [35]}.
A proposed cure for autoimmune disease that proved effective in the autoimmune animal model, is to increase the level of TNF-alpha through medication so the matured bad-cells will be killed, stopping the destruction of normal tissue[36]^,[37]. Ironically, it is TNF-alpha that causes the inflammatory response in many autoimmune diseases and the drugs used to treat the inflammation and pain attempt to decrease TNF-alpha. Anticytokine therapies that decrease TNF-alpha have demonstrated effectiveness in the clinic and have led to their approval for the treatment of rheumatoid arthritis (RA), Crohn’s disease (CD), juvenile arthritis and psoriatic arthritis[38].
There is evidence, however, that some patients using TNF-alpha decreasing drugs for rheumatoid arthritis show higher levels of auto (self) antigens to other tissues and show increased rates of contracting other autoimmune syndromes[39]. There are studies that demonstrate at least 10% of rheumatoid arthritis patients develop lupus antibodies while receiving TNF-alpha decreasing drugs[40]^,[41],[42].
This would be expected if the model of increasing TNF-alpha to kill the bad-cells is indeed valid.

Conclusion

I have had insulin dependent diabetes for 50 years and I can’t begin to tell you what stress I have been under my whole life. On my mother’s side of the family, autoimmune disease is paramount – 4 cases of diabetes, one has multiple sclerosis, an aunt had scleraderma, another with Raynauds phenomena, thyroid problems, and rheumatoid arthritis.
The Autoimmune Disease Research Foundation recognizes the invaluable contributions that have been made over decades by researchers, philanthropists, government funders and patients who have focused attention and funds on understanding and conquering specific autoimmune syndromes. This has resulted in an explosion in the body of knowledge about the immune system and the autoimmune malfunction, and has been fundamental to the realization that in order to cure many autoimmune syndromes the autoimmune malfunction must be reversed.
There has been some progress made through Congressional resolutions[43]^,[44] and the creation of the National Institutes of Health’s Autoimmune Disease Research Plan. We also commend the awarding of $51 million to nine research centers over five years, and the creation of the Autoimmunity Centers of Excellence (ACE) program that is a response to the Autoimmune Disease Research Plan and is to conduct clinical trials and basic research on new immune-based therapies for autoimmune diseases. This program will enhance interactions between scientists and clinicians in order to accelerate the translation of scientific research findings into medical applications.
According to NIH, however, less than 50% of NIH autoimmune disease funding is directed for the study of the pathogenesis and immune dysfunction of autoimmune disease, and these funds are spread over more than 25 different disease syndrome areas.[45]
It is now time to recognize the convergence of this body of knowledge, and to reconsider and refocus attention to the underlying core biology that appears to be the Common Cause of many autoimmune diseases. In doing so, it will be possible to dramatically accelerate progress toward curing many devastating syndromes through a unified, rather than a fragmented effort.

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[14] Shevach, E.M. Regulatory/suppressor T cells. Fundamental Immunology 2003

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[19] E . Breese, C. P. Braegger, C. J. Corrigan , J. A. Walker-Smith, T.T. MacDonald, Interleukin-2- and interferon-g -secreting T cells in normal and diseased human intestinal mucosa, Immunology 78 (1993) 127 – 131

[20] F. Powrie, M.W. Leach, S. Mauze, S. Menon, L.B. Caddle, R.L. Coffman, Inhibition of Th1 responses prevents inflammatory bowel disease in scid mice reconstituted with CD45RBhi CD4+ T cells, Immunity 1 (1994) 553 – 562

[21] I.J. Fuss, M. Neurath, M. Boirivant, J.S. Klein, C. de la Motte, S.A. Strong, C. Fiocchi, W. Strober, Disparate CD4+ lamina propria (LP) lymphokine secretion profiles in inflammatory bowel disease. Crohn ‘s disease L P cells manifest increased secretion of IFN-g, whereas ulcerative colitis LP cells manifest increased secretion of IL-5, J. Immunol. 157 (1996) 1261 – 1270.

[22] R. Targan, S.B. Hanauer, S.J. van Deventer, L. Mayer, D.H. Present, T. Braakman, K.L. DeWoody, T.F. Schaible, P.J. Rutgeerts A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor a for Crohn’s disease. Crohn’s Disease cA2 Study Group, N. Engl. J. Med. 337 (1997) 1029 – 1035

[23] Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature 2001 May 31;411(6837):599-603 Hugot JP; Chamaillard M; Zouali H; Lesage S; Cezard JP; Belaiche J; Almer S; Tysk C; O’Morain CA; Gassull M; Binder V; Finkel Y; Cortot A; Modigliani R; Laurent-Puig P; Gower-Rousseau C; Macry J; Colombel JF; Sahbatou M; Thomas G Fondation Jean Dausset CEPH, 27 rue J. Dodu 75010 Paris, France

[24] Increased CD8C T Cell Apoptosis in Scleroderma Is Associated With Low Levels of NF-·B Journal of Clinical Immunology, Vol. 24, No. 1, January 2004, Aharon Kessel, Itzhak Rosner, Michael Rozenbaum, Devy Zisman,3 Anca Sagiv, Zehava Shmuel, Edmond Sabo,1 And Elias Toubi

[25] Abnormal NF-kappa B activity in T lymphocytes from patients with systemic lupus erythematosus is associated with decreased p65-RelA protein expression J Immunol 1999 Aug 1;163(3):1682-9 (ISSN: 0022-1767) Wong HK; Kammer GM; Dennis G; Tsokos GC Department of Cellular Injury, Walter Reed Army Institute of Research, Washington, DC 20307, USA.

[26] Autoimmune thyroid disease induced by thyroglobulin and lipopolysaccharide is inhibited by soluble TNF receptor type I. Eur J Immunol 2002 Apr;32(4):1021-8 (ISSN: 0014-2980) Zaccone P; Fehervari Z; Blanchard L; Nicoletti F; Edwards CK; Cooke A Department of Pathology, Immunology Division, Cambridge University, Cambridge, GB.

[27] Reversal of established autoimmune diabetes by restoration of endogenous B-cell function. J Clin. Invest. 2001: 108: 63-72 Ryu S, Kodama S, Ryu K, Schoenfeld, Faustman D. Diabetes Unit, Massachusetts General Hospital, Harvard Medical School, Boston 02129.

[28] In vivo apoptosis of diabetogenic T cells in NOD mice by IFN-c/TNF-a International Immunology 2004; 1 of 10 Hui-Yu Qin, Pratibha Chaturvedi and Bhagirath Singh Department of Microbiology and Immunology, University of Western Ontario, Robarts Research Institute and Canadian Institutes of Health Research, Institute of Infection & Immunity, London, Ontario, Canada

[29] Multiple roles for tumor necrosis factor-alpha and lymphotoxin alpha/beta in immunity and autoimmunity. Arthritis Res 2002;4 Suppl 3:S141-52 (ISSN: 1465-9905) McDevitt H; Munson S; Ettinger R; Wu A

[30] D.M. Hegazy, D.A. O’Reilly, B.M. Yang, A.D. Hodgkinson, B.A. Millward, A.G. Demaine, NFn B polymorphisms and susceptibility to type 1 diabetes, Genes Immun. 2 (2001) 304 – 308.

[31] T. Gylvin, R. Bergholdt, J. Nerup, F. Pociot, Characterization of a nuclear-factor- nB (NFnB) genetic marker in type 1 diabetes (T1DM) families, Genes Immun. 3 (2002) 430 – 432

[32] B . Miterski, S . Bohringer, W. Klein , E . Sindern, M. Haupts, S. Schimrigk, J.T. Epplen, Inhibitors in the NFn B cascade comprise prime candidate genes predisposing to multiple sclerosis, especially in selected combinations, Genes Immun. 3 (2002) 211 – 219

[33] S. Vallabhapurapu, R.P. Ryseck, M. Malewicz, D.S. Weih, F. Weih, Inhibition of NF- nB in T cells blocks lymphoproliferation and partially rescues autoimmune disease in gld/gld mice, Eur. J. Immunol. 31 (2001) 2612 – 2622

[34] NOD mice are defective in proteasome production and activation of NF-kappaB Mol Cell Biol 1999 Dec;19(12):8646-59 Hayashi T; Faustman D

[35] In vivo apoptosis of diabetogenic T cells in NOD mice by IFN-c/TNF-a International Immunology 2004; 1 of 10 Hui-Yu Qin, Pratibha Chaturvedi and Bhagirath Singh

[36] Reversal of established autoimmune diabetes by restoration of endogenous B-cell function J. Clin. Invest. 2001: 108: 63-72 Ryu S, Kodama S, Ryu K, Schoenfeld, Faustman D.

[37] In Vivo Apoptosis Of Diabetogenic T Cells In Nod Mice By IFN-c/TNF-a International Immunology 2004; 1 of 10 Hui-Yu Qin, Pratibha Chaturvedi and Bhagirath Singh

[38] Targeting cytokines in autoimmunity: new approaches, new promise. Expert Opin Biol Ther 2003 Jun;3(3):435-47 (ISSN: 1471-2598)Andreakos E

[39] Enbrel, Side Effects & Drug Interactions ADVERSE REACTIONS http://www.healthscout.com/rxdetail/68/116/2/main.html

[40] Shakoor N, Michalska M, Harris CA, Block JA. Drug-induced systemic lupus erythematosus associated with etanercept therapy. Lancet 2002; 359(9306): 579-80.

[41] Feldmann M, Brennan FM, Maini RN. Role of cytokines in rheumatoid arthritis. Ann Rev Immun 1996; 14: 397-440.

[42] FDA Briefing Document. March 4, 2003 Meeting of Arthritis Advisory Committee.

[43] Representative Patrick Kennedy (RI) and Representative Fred Upton (MI) introduced H.R. 3359, also known as the Prevention, Awareness and Research Autoimmune Disease Act, to Congress on October 21, 2003

[44] 108th CONGRESS 2d Session H. RES. 610 Expressing the sense of the House of Representatives with respect to the level of funding provided to the National Institutes of Health for carrying out the Autoimmune Diseases Research Plan. IN THE HOUSE OF REPRESENTATIVES April 28, 2004 by Congressman Stephen Lynch and Congressman Tiahrt

[45] Autoimmune Disease Research Plan http://www.niaid.nih.gov/dait/pdf/ADCC_Report.pdf

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