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.
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.
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/.
3.
“Th17 Cells Overview.” Thermo Fisher Scientific, Thermo Fisher
Scientific, www.thermofisher.com/us/en/home/life-science/cell-analysis/cell-analysis-learning-center/cell-analysis-resource-library/ebioscience-resources/th17-cells-overview.html.
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.
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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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