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Thursday, December 13, 2018

A “Nod”vel Approach to Autoimmune Arthritis


Nod2 Deficiency Augments Th17 Responses and Exacerbates Autoimmune Arthritis


As you may know, arthritis is a chronic disorder that causes swelling of the joints and progressive bone and cartilage degeneration. It remains a major public health concern in the United States, as it can be incredibly debilitating.1 While many cases of arthritis are osteoarthritis, which simply involves degeneration of the joints due to wear and tear, what happens when your body’s immune system attacks its own joints? This is a type of arthritis called autoimmune, or rheumatoid arthritis and involves T helper cells that have turned against the body and begun to attack the joints. T helper cells normally recognize invading antigens (invaders that induce an immune response) that are presented to them by other immune cells, and it is up to them to respond accordingly. There is a certain response that sometimes occurs called the Th17 response, where these T helper cells are stimulated to secrete a cytokine called IL-17. Cytokines are signaling molecules that tell other immune cells how to respond to a particular invader, and ILs, or interleukins, form a subgroup of these cytokines. This response causes a lot of inflammation, and is often linked to autoimmunity. In the case of autoimmune arthritis, the IL-17 that is secreted by these Th17 cells tells other immune cells to attack the joint tissues as they would attack an infection-causing invader. When T cells are developing, they go through a selection process that attempts to remove all T cells that are self-reactive. However in autoimmune disorders, this tolerance mechanism has been broken in some way, and the self-reactive T cells are now dangerously roaming around in the body. With all of this in mind, one would think, “Why don’t we just attempt to combat this so-called Th17 response to fight autoimmunity?” This was initially the thought, but previous studies disabling the Th17 response have not been very successful in alleviating autoimmune arthritis. There must be something else going on. This is exactly what researchers at Oregon Health & Science University thought. The Th17 response is part of the adaptive immune system, which involves a specific response to each pathogenic bacteria, virus, etc. that we may come into contact with, and therefore takes a long time to develop after we are infected. However, the researchers chose to focus on the other branch of the immune system: innate immunity. While the adaptive response is specific and slow, innate responses are quick and nonspecific. They work by recognizing certain highly conserved molecules present on the pathogen using their pattern recognition receptors, or PRRs. The highly conserved molecules on the pathogen are known as pathogen-associated molecular patterns, or PAMPs, and their recognition induces a danger response. One of these PRRs is called Nod2, and is the focus of this paper. The researchers picked this one specifically because a previous study showed that a mutation in the Nod2 gene led to ~100% incidence of a form of arthritis called polyarticular arthritis, which is common in younger  people.5  However, the way Nod2 impacts arthritis development has been largely unclear. They sought to explore the regulatory function that Nod2 has within T cells that are self-reactive and arthritis-causing.
Figure 1. Recognition of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs)

The researchers found that Nod2 has a protective role in the development of autoimmune arthritis, and that mutations in the gene that codes for this receptor were found to cause more severe arthritic symptoms in mice. They did this by using a special strain of mice known as SKG mice that were predisposed to arthritis. They took two sets of these SKG mice, introduced a mutation in Nod2 in one set, and kept Nod2 normal in the other. They then injected both sets of mice with a drug called zymosan, which induces arthritis. They found here that the mice with a defective Nod2 receptor had more severe arthritis, which was resembled by greater joint swelling, redness, and paw deformities.
Figure 2. (Left) shows that Nod2-deficient SKG mice that have been injected with the arthritis inducing drug, zymosan, have the most severe arthritic symptoms, denoted by "arthritis score". (Right) the degree of paw swelling is highest in Nod2-deficient SKG mice.
You might be thinking, how did they know that it was not just the arthritis-inducing drug causing the results observed? The researchers wondered the same thing, so they tested the effect of the Nod2 mutation on mice without the SKG mutation and therefore no predisposition to arthritis. They injected mice with no mutations and mice with only the Nod2 mutation with zymosan. They found that neither group showed symptoms of arthritis, indicating that there was something going on with the faulty T cells that were characteristic of the SKG mutation, and not just the drug.
            Interestingly, the Nod2 protein has also been established to have a role in regulating the commensal microbes that live in our guts.7 The researchers then wanted to test if disruptions in the microbiota were responsible for the severe arthritis symptoms in the SKG mice with the Nod2 mutation. They did this by introducing Nod2-mutant mice to the same microbiome as the SKG mice by exposing them to the same bedding and fecal material. To their surprise, they not only found that Nod2 deficiency did not lead to heightened symptoms, but it actually alleviated symptoms of ileitis, a type of inflammatory bowel disease. They could therefore conclude that the arthritic symptoms were independent of autoimmune disorders of the gut.
            Finally, the researchers wanted to find out what was actually going on in the immune system when Nod2 was defective. They focused their attention on the lymph nodes of Nod2-deficient mice, as this is the location where immune cells filter through. They found an increase in T helper cells here; specifically, those detrimental Th17 cells mentioned before. And of course, what were they doing? They were secreting tons of IL-17, which as stated previously, is responsible for inflammation and is linked to autoimmunity. To determine whether IL-17 was actually causing the arthritis they blocked IL-17A, a type of IL-17, in Nod2-deficient SKG mice, and found that joint swelling was significantly reduced.
Figure 3. Shows the numbers of different types of T cells in that have accumulated in the synovial (joint) fluid. CD4+ cells are helper T cells, and they clearly have the highest levels in SKG mice with the Nod2 mutation, indicating that they are contributing to the arthritic symptoms.

To put the pieces of the puzzle together, The researchers found that the Nod2 mutation was contributing to arthritis, and that T helper cells of the Th17 type were producing copious amounts of IL-17. They even found that when they put autoreactive T cells from Nod2-deficient SKG mice into mice that had been wiped of their immune cells, they experienced severe arthritic symptoms. This overall indicates that Nod2 has a protective role in the development of autoimmune arthritis, in that it keeps Th17 cells low and lessens their production of the IL-17 signal. This then prevents the attack of joint tissues.

Implications for the future of autoimmune arthritis treatment?
This study suggests that our innate immune system may have much more to do with the development of autoimmune diseases than we might think. The way our body quickly and nonspecifically combats everyday pathogens that enter our bodies may influence the development of our T cells. Studies of more of these types of receptors may give us more information about autoimmunity, or even studies of the effects of Nod2 on other types of autoimmune diseases. However, these results suggest that the role of Nod2 is case-dependent, as its deficiency actually helped symptoms of inflammatory bowel disease! The understanding and appreciation of this one receptor is just one small step towards figuring out the vast black box of autoimmune disease!

References
1.     Barbour, K. E., C. G. Helmick, M. Boring, X. Zhang, H. Lu, and J. B. Holt. 2016. Prevalence of doctor-diagnosed arthritis at state and count
2.     Designs, Jedz. “Beginners Guide to T Cells.” Helper T Cells, www.tcells.org/beginners/tcells/.
4.     Boundless. “Boundless Anatomy and Physiology.” Lumen Learning, Lumen, courses.lumenlearning.com/boundless-ap/chapter/adaptive-immunity/.
5.     “Polyarticular Arthritis.” AboutKidsHealth, www.aboutkidshealth.ca/Article?contentid=1053&language=English.
6.     Miceli-Richard, C., S. Lesage, M. Rybojad, A. M. Prieur, S. Manouvrier-Hanu, R. Ha¨fner, M. Chamaillard, H. Zouali, G. Thomas, and J. P. Hugot. 2001. CARD15 mutations in Blau syndrome. Nat. Genet. 29: 19–20.
7.     Al Nabhani, Z., G. Dietrich, J. P. Hugot, and F. Barreau. 2017. Nod2: the intestinal gate keeper. PLoS Pathog. 13: e1006177
8.     What Is Crohn’s Ileitis? | Crohn’s Disease | IBDrelief. www.ibdrelief.com/learn/what-is-ibd/what-is-crohns-disease/crohns-ileitis.
9.     N, Varun C. “Viral DNA? Lets Do a STING Operation.” Medical Microbiology, varuncnmicro.blogspot.com/2013/08/viral-dna-lets-do-sting-operation.html.
10.  Napier, Ruth J., et al. “Nod2 Deficiency Augments Th17 Responses and Exacerbates Autoimmune Arthritis.” The Journal of Immunology, 2018, doi:10.4049/jimmunol.1700507.

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