Autoimmune Disease Common Cause Research Initiative
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An Autoimmune Disease Research Foundation Proposal to the US Congress
The Autoimmune Disease Research Foundation (ADRF) promotes the argument that autoimmune disease should be regarded as one disease that is manifested as many distinct syndromes, and that research funding from government and the philanthropic sectors should direct more resources to basic research and clinical interventions addressing the root cause of autoimmune disease rather than the syndromes known today as “autoimmune diseases” such as Type I Diabetes, Multiple Sclerosis, Crohn’s Disease and Lupus.
The Common Cause Hypothesis assumes that many, if not all of these “syndromes”, have a single cause — a defective aspect of the immune system. Therefore, in order to cure many of these “syndromes” it is essential that the defective aspect be corrected. Any medical intervention such as tissue transplantation or inflammation control, that does not address the underlying immune system defect, will not lead to a cure or to long-term quality of life improvement. The current emphasis on treating symptoms is unlikely to lead to a lasting cure.
At the center of the Common Cause Hypothesis is the scientific analysis and conclusion that “mis-educated” autoreactive lymphocytes destroy healthy tissue in the human body, leading to different expressions of the disease based on the organ or cells that are being destroyed. In addition, therapies that replace damaged or destroyed tissue without first stopping the autoimmune assault, will ultimately fail.
Autoimmune Disease Common Cause Research Initiative
Breakthrough research advancements during the past five years have compelled ADRF to call for the creation of an “Autoimmune Disease Common Cause Research Initiative”. ADRF is currently recruiting allied autoimmune disease research organizations to sign on to supporting this Initiative so that a successful effort for Initiative funding can be proposed to Congressional advocates.
This Initiative will provide funding to test the medication-intervention protocol has been successfully used to reverse Type I Diabetes[i],[ii],[iii],[iv],[v]and Sjogren’s Syndrome[vi] in laboratory animals. The same immune system defect that was reversed in these research successes for is also considered to be active in intestinal inflammatory disorders including Celiac and Crohn’s disease [vii], [viii], [ix], [x],[xi], scleroderma[xii], lupus[xiii], autoimmune thyroid disease[xiv]. This intervention strikes at the common underlying defect causing autoimmune disease.
Through the leadership and funding of the National Institutes of Health, which recently confirmed the reversal of Type I Diabetes and Sjogren’s Syndrome in 100% of test animals[xv], as well as funding support from philanthropic foundations concerned with specific autoimmune syndromes, the Initiative will test the medication-intervention protocol that reversed Type I Diabetes and Sjogren’s Syndrome test in animal models addressing other autoimmune syndromes. Syndromes that may be tested include: Multiple Sclerosis, Rheumatoid Arthritis, Inflammatory Bowel Disease, Crohn’s Disease and Lupus.
Success in different autoimmune disease animal models will lead to testing related interventions in humans. There is increasing evidence that changes in the structure of the NF-kB1 gene, which is at the root of the immune system defect causing autoimmune disease, makes people more susceptible to type I diabetes[xvi],[xvii], multiple sclerosis[xviii], lupus and Sjorgren’s syndrome [xix].
Both humans with autoimmune disease and several animal models have what appear to be the same defective “autoreactive” immune cells (bad-cells) that may be responsible for causing several different autoimmune syndrome. 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[xx],[xxi]. 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[xxii],[xxiii],[xxiv]. 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[xxv],[xxvi],[xxvii],[xxviii],[xxix],[xxx],[xxxi],[xxxii]. 
[i] Treatment success and regenerative mechanisms influenced by age of NOD mice and target organ of autoimmune attack
S. Tran, et al., Diabetes 55, 283 (June, 2006). (1) McGill University, Montreal, QC (2) Brigham and Women’s Hospital,
Boston, MA (3) National Institutes of Health, Bethesda, MD
[ii] Islet Recovery and Reversal of Type 1 Diabetes in Mice in the Absence of Infused Spleen Cell Contribution
Junko Nishio, Jason L. Gaglia, Stuart E. Turvey, Christopher Campbell, Christophe Benoist, Diane Mathis
www.sciencemag.org, Science Vol 000 2006
[iii] 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.
[iv] Islet Regeneration During the Reversal of Autoimmune Diabetes in NOD Mice
Shohta Kodama, Willem Ku¨htreiber, Satoshi Fujimura, Elizabeth A. Dale, Denise L. Faustman
Science Vol 302 14 November2003
[v] Y. Okubo, et al., Diabetes 55, 281 (June, 2006).
[vi] Treatment success and regenerative mechanisms influenced by age of NOD mice and target organ of autoimmune attack
S. Tran, et al., Diabetes 55, 283 (June, 2006) (1) McGill University, Montreal, QC (2) Brigham and Women’s Hospital, Boston, MA (3) National Institutes of Health, Bethesda, MD
[vii] 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
[viii] 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
[ix] 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.
[x] 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 – 103
[xi] 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
[xii] 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
[xiii] 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.
[xiv] 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.
[xv] Treatment success and regenerative mechanisms influenced by age of NOD mice and target organ of autoimmune attack
S. Tran, et al., Diabetes 55, 283 (June, 2006) (1) McGill University, Montreal, QC (2) Brigham and Women’s Hospital, Boston, MA (3) National Institutes of Health, Bethesda, MD
[xvi] 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.
[xvii] 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
[xviii] 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
[xix] 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
[xx] Klinman, N. R. The “clonal selection hypothesis” and current concepts of B cell tolerance. Immunity 5, 189-195 (1996).
[xxi] Stockinger, B. T lymphocyte tolerance: from thymic deletion to peripheral control mechanisms. Adv Immunol 71, 229-265 (1999).
[xxii] Pitkanen, J. & Peterson, P. Autoimmune regulator: from loss of function to autoimmunity. Genes Immun 4, 12-21 (2003).
[xxiii] Venanzi, E. S., Benoist, C. & Mathis, D. Good riddance: Thymocyte clonal deletion prevents autoimmunity. Curr Opin Immunol 16, 197-202 (2004).
[xxiv] Miller, J.F. Discovering the origins of immunological competence. Annu.Rev. Immunol. 17:1 1999
[xxv] Hayashi T; Faustman DL Role of defective apoptosis in type 1 diabetes and other autoimmune diseases.
Recent Prog Horm Res 2003;58:131-53
[xxvi] Hayashi T; Faustman DL Involvement of apoptotic cell death in autoimmune diseases.
Med Electron Microsc 2002 Mar;35(1):1-8 Kawakami A; Eguchi K
[xxvii] Perniok A, Wedekind F, Herrmann M, Specker C, Schneider M. High levels of circulating early apoptic peripheral blood mononuclear cells in systemic lupus erythematosus. Lupus. 1998;7(2):113-8.
[xxviii] Emlen W, Niebur J, Kadera R. Accelerated in vitro apoptosis of lymphocytes from patients with systemic lupus erythematosus. J Immunol. 1994 Apr 1;152(7):3685-92.
[xxix] Rose LM, Latchman DS, Isenberg DA. Apoptosis in peripheral lymphocytes in systemic lupus erythematosus: a review. Br J Rheumatol. 1997 Feb;36(2):158-63.
[xxx] Lorenz HM, Grunke M, Hieronymus T, et al. In vitro apoptosis and expression of apoptosis-related molecules in lymphocytes from patients with systemic lupus erythematosus and other autoimmune diseases. [see comments]. Arthritis Rheum. 1997 Feb;40(2):306-17.
[xxxi] Zeher M, Gyimesi E, Szodoray P, Szondy Z. Expression of apoptosis-related Fas antigen and in vitro apoptosis of lymphocyte subsets from patients with primary Sjogren’s syndrome: comment on the article by Lorenz et al. Arthritis Rheum. 1997 Oct;40(10):1912.
[xxxii] Van Houten N, Budd RC. Accelerated programmed cell death of MRL-lpr/lpr T lymphocytes. J Immunol. 1992 Oct 1;149(7):2513-7
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I have autoimmune thyroid (Hashimoto’s). During this journey to finding out what’s wrong with me I found one very interesting bit of information. I have a dysfunction with my innate immune system.
My immunologist tested me for mannose-binding lectin and it came back deficient. He only did the test because he just learned about it at a seminar. My 2 endo’s have never even heard of it. How hard is it to just do all the testing of an individuals immune system?????
There have been a number of conference presentations and peer-reviewed papers presented in the last several months outlining a common-cause for Autoimmune disease.
At the 6th International Congress on Autoimmunity in Portugal last September, I co-chaired a session where a number of presentations were made describing the common cause.
Unfortunately, I tried to leave the URLS of these presentations and transcripts but this comment system told me my message “seemed a little bit spammy.” So I guess you will have to find the other presentations manually, they are all linked from the following conference video:
http://vimeo.com/1787405
“Autoimmunity Reviews” has just published two papers which describe the ‘common cause’ in detail. A fulltext pre-print is available from:
http://AutoimmunityResearch.org/transcripts/AR-Proal-Metagenome.pdf
There are three other peer-reviewed papers “in press” at the Annals of NY Academy of Sciences.
Please do not hesitate to contact me at any time (there is an email link at the top of my webpage) if I can be of any further assistance in thsi initiative.
Trevor