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Is autoimmunity like cancer?

The first keynote presentation of this week's Keystone meeting on autoimmunity and transplantation tolerance ended in a rather surprising way -- the speaker was actually heckled during the question answer session for comparing autoimmunity to cancer. When the mechanisms that keep the immune system from attacking itself break down, diseases like diabetes type 1, lupus, and psoriasis can result. Many in the field have focused on how particular inherited mutations change the immunological landsca

By | February 2, 2008

The first keynote presentation of this week's Keystone meeting on autoimmunity and transplantation tolerance ended in a rather surprising way -- the speaker was actually heckled during the question answer session for comparing autoimmunity to cancer. When the mechanisms that keep the immune system from attacking itself break down, diseases like diabetes type 1, lupus, and psoriasis can result. Many in the field have focused on how particular inherited mutations change the immunological landscape and looked for environmental triggers that ultimately initiate the disease. But Christopher Goodnow from Australian National University, one of the leaders in this field, thinks genetics trumps environmental signals in kicking off linkurl:autoimmunity.;http://www.the-scientist.com/supplement/2007-5-1/ He started his keynote talk by describing just how difficult it is to break natural tolerance to self-antigens. In most cases, he pointed out, this doesn't happen all at once - autoimmune diseases develop over many years. He gave the example of the AIRE gene, which, when mutated, causes autoimmune polyglandular syndrome (APS). The different diseases in the syndrome -- hypoparathyroidism, chronic mucocutaneous candidiasis, and type 1 diabetes -- appear one by one, often over the course of decades. The reason, says Goodnow, is that the immune system has many checkpoints to prevent an auto-reactive immune cell from attacking the body. He argued that it is the accumulation of multiple genetic mutations - just as in cancer - that causes autoimmunity rather than a single mutation combined with an environmental stressor. In a recent linkurl:review;http://linkinghub.elsevier.com/retrieve/pii/S0092-8674(07)00838-0 in Cell describing his theory, Goodnow notes that lymphocytes have a higher mutation rate than other cells, which could explain how a single auto-reactive cell could accumulate additional somatic mutations. He admits that there are several genes that initiate autoimmunity immediately, and are usually fatal, like mutations in the Foxp3 gene, but argues that those are the exceptions, not the rule. If he's correct, he writes, clinicians could tailor specific therapies for autoimmune patients based on their somatic and inherited mutations. The audience of immunologists, many of whom helped define the major cellular players in self-tolerance, such as T-regulatory cells, seemed skeptical. Some questioned the idea that a single cell could accumulate so many mutations without other stressors. At the end of the question/answer session, Philippa Marrack from National Jewish Medical and Research Center sauntered up to the microphone and asked Goodnow if he really thought that autoimmunity could be boiled down to a series of genetic mutations. When he said yes, she turned to the audience with a mischievous smile and asked: "With a show of hands, how many of you really believe that this theory is true?" Perhaps five of the several hundred in the room raised their hands. Immunologists hold strongly to their beliefs, Goodnow said, "and I'm probably the worst offender." Time will tell if Goodnow's theory does in fact hold true.
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Avatar of: anonymous poster

anonymous poster

Posts: 5

February 4, 2008

While Goodnow's premise may not hold water (or may, time will tell), the behavior of Philippa Marrack - if she truly behaved as described in this report - was arrogant and juvenile. \n\nWhat an embarassment to all scientists. We need to remember that many now accepted ideas were met, when first presented, with derision. We are supposedly seekers of fact, of truth, whatever it may be, aren't we?\n\nHow about a little real discussion, challenging the speaker to provide solid examples of his or her reasoning, instead of trying to gain useless attention for oneself by being rude. \n\n
Avatar of: Sergio Stagnaro

Sergio Stagnaro

Posts: 59

February 4, 2008

I described formerly a lot of biophysical-semeiotic constitutions, recognized bedside with a stethoscope (www.semeioticabiofisica.it, including Bibliography). All these predispositions to most common, human disorders, such as diabetes, autoimmunity, cancer,as well as relative Inherited Real Risk, are characterized by local microcirculatory remodelling, wherein are typical newborn-pathological, type I, subtype a) oncological, and b) aspecific Endoarteriolar Blocking Devices (EBD), according to my theory of Angiobiopathy (for instance, see Bibliography NĀ° 140. Stagnaro Sergio. Newborn-pathological Endoarteriolar Blocking Devices in Diabetic and Dislipidaemic Constitution and Diabetes Primary Prevention. The Lancet. March 06 2007. http://www.thelancet.com/journals/lancet/article/\nPIIS0140673607603316/comments?totalcomments=1).\nAs regards autimmunity/allergic constitution, in all BALT, GALT, CALT(= Cerebral Associated Lymphatic Tissue, I discovered a lot of years ago), mamma, urinary bladder, vermiform appendix, a.s.o., doctors can bedside observe typical signs of inherited remodelling, indicating parenchimal cell congenital alterations. In conclusions, in my opinion, Biophysical-Semeiotics data corroborate in some extence the theory of Christopher Goodnow, who thinks genetics trumps environmental signals in kicking off autoimmunity. Interestingly, cancer can occur exclusively in individuals involved by both Oncological Terrain and Oncological Real Risk, whose microcirculatory remodelling is characterized by subtype a), oncological EBD (171. Stagnaro Sergio. Overloking Oncological Terrain and oncological Real Risk, no paper is up-dated! 18 January 2008 Ann. Intern Med. http://www.annals.org/cgi/eletters/147/11/775). Finally, my 51 year-long clinical experience allows me to state that Oncological Terrain and autoimmune/Allergic constitutions may be associated, BUT rather rearly.
Avatar of: anonymous poster

anonymous poster

Posts: 1

February 6, 2008

I have first hand experience of currently several autoimmune conditions...I am literally dying for a cure...or for effective treatment.\n\nMy take on this articlle is clear..any thought provoking expressions made by leaders in the field is all good for finding the answers to why Im like I am now...sick to death.\n\nPersonally I suffered an unknown gastro bug at age eleven ..then continually suffered IBS symptoms..then for the last 2 years..(fastforward to age 40) infections of camplybacter \nand then severe chicken pox (nearly died) and now 2 years on I find myself with multiple untreatable uncurable autoimmune diseases.\n\nWheres the genetic link..well my mother had Graves..thats it..brothers and sisters are fine and ten years older.\n\nSo for me..its clear that Genetics and also obvious environmental triggers were present..\nSo from my personal perspective I see a mix of geneteic and environmental..\nHowever not to say that Chris is wrong..perhaps the immune system just gets more messed up at each infection.\n\nWhat is clear also to me and to the many autoimmune sufferers is that we need some progress..not just in theory but in practical treatments or cures.\n\nSeveral papers have recently highlighted tbreakthroughs in transplant rejection being overcome by blending or having effectively an immune system transplant.\n\nWhy can this not be tried now in people dying from autoimmune conditions ? to my knowledge not one effective immune system transplant has occured for an autoimmune patient...why ?\n\nI urge the medical community for the sake of the sick and the dying to consider this option where no other option exists..we must move forward.\n\n\nthanks for letting me provide my point of view.\nGood luck and best wishes to all researchers worldwide..keep working hard,...we need you !\n\nJon
Avatar of: Frank Conrad

Frank Conrad

Posts: 1

February 6, 2008

I?ve been on the receiving end of Dr. Marrack?s scrutiny, after a research in progress talk at National Jewish. She has a keen scientific mind and her questions and comments are always relevant, always insightful, and often very amusing.\n\nThe article did not imply arrogance or derision. The scientific process requires that new ideas are subject to peer review and challenge, to make certain those ideas are sound.\n\nDr. Marrack was not disputing that autoimmunity is a combination of genetics and environmental influence. Her comments to Dr Goodnow simply challenged the idea that autoimmunity occurs predominantly as a consequence of acquired somatic mutations (as cancer does), rather than underlying genetic predispositions already present at birth.

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