Oral tolerance is defined as the induction of antigen specific immunological tolerance brought about by ingesting protein antigens(1). Ingested foods have unique antigenic characteristics the immune system is programmed to ignore, thereby allowing the body to tolerate the antigens found in food. In order to properly maintain immunologic homeostasis, oral tolerance is essential. Recently evidence has been published that identified a role for retinoic acid in oral tolerance(2-4). Retinoic acid is the physiologically active metabolite of vitamin A, retinol, and beta carotene found in the diet.
Two major players in oral tolerance are dendritic cells (DC) and T regulatory cells (T reg)(5). DC are responsible for antigen presentation, T reg cells are responsible for suppression of Th1, Th2, and Th17 (6) and thus are anti-inflammatory (the voice of reason in an otherwise reactionary society). Because of their function as immune suppressors, it stands to reason that T reg cells should play a pivotal role in any process of tolerization, including oral tolerance. Here are a few other details about T reg cells that are important for the rest of this summary to make sense: they need Transforming growth factor beta (TGF-b) to become a T reg cell from a naïve T cell, they primarily come from the thymus but they can also be produced peripherally, including the Gut Associated Lymphoid Tissue (GALT), and there is an integrin called a4b7 that helps them home to the GALT(5).
So here is what scientists have recently found: there is a specific population of DC (CD103+) in the GALT that makes TGF-b so that the naïve T cell that binds the antigens that it found in the intestinal lumen is stimulated to become a T-reg cell. The same DC’s also make retinoic acid and when these cells are treated such that they can no longer make retinoic acid, their capacity to induce differentiation into a T reg cell is diminished (3;4). In addition, a4b7 expression in T reg cells that were made in the thymus is dependent upon retinoic acid so it plays a role in the efficient trafficking to the GALT(2). Both of these findings, when taken together provide evidence that retinoic acid could play an important role in oral tolerance. What remains to be defined is whether it is necessary (meaning oral tolerance can not proceed in its absence); we know it is not sufficient (it alone can not induce oral tolerance).
Now to the part about why I care: disturbances in oral tolerance have been implicated as a possible mechanism in the pathogenesis of type 1 diabetes (T1D).* Some scientists have postulated that there are proteins in common foods that share antigenic determinants with the beta cells (bovine insulin is regularly vilified in the court of scientific opinion) and, when the very important process of oral tolerance is disturbed, the immune system becomes ‘confused’ and starts attacking beta cells(7). So could retinoic acid play a role? Before we can answer this question there are a number others that need to be answered first, I will introduce a few of them. First: is abnormal oral tolerance really the pathogenic mechanism in the auto-immune process that leads to T1D? Second: is retinoic acid necessary to the process of oral tolerance? Third: how are people with beta cell autoimmunity different with respect to their cells’ ability to utilize the dietary precursors of retinoic acid?
What other questions do you think are important when piecing this puzzle together?
* Type 1 diabetes is an absolute lack of insulin due to the immune mediated destruction of the beta cells (the insulin producers) in the pancreas.
Reference List
(1) Faria AM, Weiner HL, Faria AMC, Weiner HL. Oral tolerance. [Review] [321 refs]. Immunological Reviews 2005; 206:232-259.
(2) Benson MJ, Pino-Lagos K, Rosemblatt M, Noelle RJ, Benson MJ, Pino-Lagos K et al. All-trans retinoic acid mediates enhanced T reg cell growth, differentiation, and gut homing in the face of high levels of co-stimulation.[see comment]. Journal of Experimental Medicine 2007; 204(8):1765-1774.
(3) Coombes JL, Siddiqui KR, rancibia-Carcamo CV, Hall J, Sun CM, Belkaid Y et al. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism.[see comment]. Journal of Experimental Medicine 2007; 204(8):1757-1764.
(4) Sun CM, Hall JA, Blank RB, Bouladoux N, Oukka M, Mora JR et al. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid.[see comment]. Journal of Experimental Medicine 2007; 204(8):1775-1785.
(5) von BH, von Boehmer H. Oral tolerance: is it all retinoic acid?[comment]. Journal of Experimental Medicine 2007; 204(8):1737-1739.
(6) Cohen JJ. JJ Cohen's IMMU 7630 Class Notes. Ref Type: Generic
(7) Vaarala O, Vaarala O. Is it dietary insulin?. [Review] [50 refs]. Annals of the New York Academy of Sciences 2006; 1079:350-359.
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5 comments:
Nice article, but I believe you mean "transforming growth factor beta", not "tumor like growth factor beta".
Right, thanks. I will correct that
I'm confused by how exactly the immune system becomes confused by bovine insulin. If I understand this correctly, immune tolerance allows the immune system to ignore food antigens. So how instead, does the immune system start to target one food antigen specifically (bovine insulin), and a self-antigen (beta cells) that is similar to it also?? Does your reference #7 mention a possible mechanism for this? (I suppose I could read it to find out, but thought maybe you have a quick answer for me!)
The kicker with type 1 diabetes is that it is thought (maybe)to be the result of a disruption in oral tolerance. Instead of ignoring the antigens seen in food, the body mounts an immune response to them. Keep in mind, this is just one theory among many, and to identify a mechanism would mean joining Al Gore's ilk.
Identification of a dietary antigen has practical appeal, think if we could identify the bad guy from food that starts the auto immune process, we could just have kids at risk avoid that food and prevent type 1 diabetes. This is a similar idea to celiac disease except that in the case of celiac disease you are not preventing disease, only clinical symptoms of the disease.
mds7630: what an intriguing article you've posted, and an interesting proposition. My main interest/clinical focus is T2DM, but this is an interesting twist to the T1DM story. Your discussion of tolerance made me think about insulin resistance. As I said, my main focus is on more of a T2DM context, but the other day I was reviewing some physiology material and was reminded that "insulin resistance" actually was first recognized in T1DM. Patients, essentially, developed resistance to bovine/porcine (animal) insulin preparations and over time required larger and larger doses. The reason was that the patients developed antibodies to the insulin due to impurities in the preparations (1). So then I thought, why, then, could they tolerate ANY insulin injected, if their immune system reacts to it? Why could they continue to take it? I just did some searching and read a very OLD (i.e. 1944!) case report of a woman with...it must have been T2DM (check it out...PDF is available from the JCI!) She had a severe allergy to insulin, mainly bovine/porcine. They hospitalized her and administered unfathomable amounts of insulin (i.e. up to 2,500 units in a ~2wk admission). She was observed to have a severe Type I hypersensitivity to the injections and was ketotic much of the time...even anaphalactic in one episode (2). A more recent (but still older) report identified that IgE binding is used to test if patients are allergic to insulin. And in the present day, of course, there are human preparations of insulin that are made from recombinant DNA (3). So nowadays, allergies to insulin are rare. This doesn't fully clarify my original question: why was it possible for them to take increasing doses of insulin? I wonder if the impurities were slightly different with every vial, and this would allow for some antigenic variability? Maybe a good question for Dr. C. Just to focus back on your discussion, I wonder if the oral tolerance theory could somehow be at play in people who develop T2DM later in life? Perhaps these are the people whose beta cells fail sooner? Thanks for the ear, TLH
refs:
1)Frayn K. Metabolic regulation: A human perspective. 2nd ed. Oxford, UK: Blackwell Science, 2003.
2)Lowell,FC. Immunologic studies in insulin resistance: I.Report of a case exhibiting variations in resistance and allergy to insulin. JCI, 1944.
3)DeeLeeuw, I. et al. Insulin allergy treated with human insulin (recombinant DNA). Diabetes Care, Nov.-Dec, suppl, 1982.
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