Kickas.org Forums Ankylosing Spondylitis General Discussion #1 AS Web Support Group NIH scientists discover secrets of helper T cells

Press Release (reprint) October 20, 2010Recent NIH scientific findings

Scientists at the National Institutes of Health have redefined the roles of several cytokines involved in the generation of immune cells implicated in severe autoimmune diseases. The study in mice showed that development of Th17 immune cells can occur without the presence of transforming growth factor (TGF)-beta, a mediator thought to be required for Th17 cell development. The study demonstrates that the interaction of three inflammatory cytokines (proteins that influence the behavior of cells) – interleukin-6 (IL-6), IL-1-beta and IL-23 – is responsible for the creation of Th17 cells that are more active in promoting autoimmunity than Th17 cells generated with IL-6, IL-1-beta and TGF-beta. These findings reemphasize the separate roles of IL-23 and TGF-beta in immunity and autoimmunity, and open up possibilities for the development of new therapies. The study appears in the current issue of the journal Nature.

The immune systems of mice and humans mainly consist of B cells and T cells. While B cells fight infections and can induce autoimmunity by producing antibodies that directly target foreign antigens or a person’s own tissue, T cells are involved in overall cell-mediated immunity. Importantly, how a T helper (Th) cell differentiates (develops from an immature, unspecialized cell into a mature, specialized cell) determines how it mediates immune responses. Th17 cells produce IL-17, a powerful inflammatory cytokine, and have been implicated in multiple autoimmune diseases, including rheumatoid arthritis, psoriasis and multiple sclerosis. The established belief has been that Th17 cells initially differentiate in response to activation by IL-6 and TGF-beta. However, previous research has shown that TGF-beta is primarily associated with suppressing immune functions and promoting regulatory T cells (Treg), which can produce inhibitory cytokines that dampen inflammatory immune responses.

In the present study, the NIH scientists first looked at the conditions to differentiate Th17 cells from naïve T cells outside of the mouse (in vitro) and tried several different cocktails of cytokines to see which combinations would promote Th17 development. They found two combinations that efficiently induced Th17 differentiation. As previously described, IL-6, IL-1-beta, and TGF-beta-1 together created Th17 cells. Surprisingly, IL-6, IL-1-beta, and IL-23 without TGF-beta also created Th17 cells. Most interestingly, the action of Th17 cells generated with IL-23, designated Th17(23), was different from the action of Th17 cells generated with TGF-beta (Th17(beta)). The researchers compared transcription factors, receptors and mediators of the two Th17 subtypes and looked at the pathogenic activity of both Th17 subtypes in mice during experimental autoimmune encephalomyelitis (EAE), a common model of autoimmunity that mimics some aspects of multiple sclerosis. They found that Th17(23) cells provoked significantly more severe disease than did Th17(beta) cells.

These findings suggest a new model for Th17 generation and the existence of functionally different subtypes of Th17 cells. This study also provides a better understanding of the array of immune components involved in autoimmunity and suggests possibilities for new targeted therapies.

NIH scientists contributing to this study are affiliated with the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Institute of Dental and Craniofacial Research (NIDCR), and the National Institute of Allergy and Infectious Diseases (NIAID). Additional support was provided by Merck Research Laboratories (Schering-Plough Biopharma), Palo Alto, Calif.
Reference
Ghoreschi K, Laurence A, Yang XP, Tato CM, McGeachy MJ, Konkel J, Ramos HL, Wei L, Davidson T, Bouladoux N, Grainger J, Chen Q, Kanno Y, Watford WT, Sun HW, Eberl G, Shevach E, Belkaid Y, Cua DJ, Chen W, O’Shea JJ. Enhanced Pathogenicity of Th17 cells Generated in the Absence of Transforming Growth Factor-ß Signaling. Nature. 2010 October 21;467(7318): 967-971.

Who
John J. O’Shea, M.D. Scientific Director, National Institute of Arthritis and Musculoskeletal and Skin Diseases, is available to comment on this article.

Contact
To schedule interviews, please contact Trish Reynolds, 301-496-8190, reynoldsp2@mail.nih.gov.

Very cool! Thanks for posting this. I am curious to know where this research is going to take us next. It seems the deeper they go, the more intricate it becomes1

Warm hugs,

Hi Kat,
I think they're making great progress in figuring out how the immune cascade really works in all of the complexity. I think they're on a path that will lead good places for autoimmune diseases in general, especially AS, RA, PS, Type 1 Diabetes, Alzheimers, most of the enchilada. The more complex syndromes that don't seem to follow a set behavior pattern, like Lupus and MS, I hope will also greatly benefit. It's good stuff.
Jess

Yah, I see the same potential. And the deeper they go, the more specifically targetted the treatments will become. I wonder what the longterm effects of tweaking things that deeply embedded in the genome will be, admittedly. Still, I see the potential (in the future) for medications tailored to the individual patient based on the patient's own DNA. Fascinates the hell out of me. Even if it does give me a brain twitch.

Warm hugs,

I am too old to benefit from any of the new stuff that will be coming up in the future, this should give hope to all the younger people here. I am grateful that I lived to see the TNF's. There might be some real progress that will help them.

This is sure interesting. It looks like there is a lot going on in the immunology/autoimmune studies.

Donna