Decoding Sjögren’s disease: The role of IFN-γ–producing TH1 cells and dysfunctional Tregs in disease pathogenesis
Sjögren's disease (SjD) is a
fairly common autoimmune condition, affecting about 0.5 to 1% of people. It’s
known for causing dryness in the eyes and mouth, a condition called sicca
syndrome, due to problems with the tear and saliva glands. But SjD can be more
than just dryness; it can also affect other parts of the body, such as the
joints, blood vessels, nerves, and lungs. In some serious cases, it can even be
life-threatening, with complications like lung problems, kidney failure, and a
higher risk of lymphoma. Unfortunately, we don’t fully understand what causes
SjD, and treatments that work for other autoimmune diseases haven't been very
effective for SjD.
Recent research has focused on a
particular type of immune cell called regulatory T cells (Tregs), which
normally help to control inflammation. This study, published in ScienceTranslational Medicine, used mice to explore what happens when these Tregs
don't work properly. The researchers specifically looked at two genes, Stim1
and Stim2, which are important for calcium signaling within cells. They found
that when these genes are removed from Tregs in mice, it leads to a condition
that looks a lot like SjD.
The mice with the faulty Tregs
developed several key symptoms of SjD. Their tear and saliva glands became
inflamed, with immune cells invading the tissues. This inflammation led to
reduced saliva production and dry eyes, just like in human SjD. Moreover, the
researchers observed that the tear glands were damaged, and the mice had
increased levels of certain autoantibodies, which are frequently found in
patients with SjD. These autoantibodies are directed against the Ro/SSA and
La/SSB antigens, which are characteristic of the disease. The mice also
developed lung inflammation, which is another common problem in people with
SjD.
A key part of the study was
understanding how the faulty Tregs were causing these problems. They
discovered that the loss of Stim1 and Stim2 in Tregs disrupts a process called
Store-Operated Calcium Entry (SOCE). This disruption in calcium signaling
prevents the Tregs from working properly. Interestingly, the researchers found
that the inflammation in the salivary glands was not caused by destruction of
the gland structures, but rather by the immune system attacking the glands. The
issue wasn't that the glands were physically damaged, but that they weren't
working well because of the inflammation.
To understand the inflammatory
response better, the team analyzed the genes that were switched on in the
inflamed salivary glands of the mice. They discovered that the pathways related
to the activation of T cells were prominent, especially TH1 and TH2 related
pathways, and the production of type I interferon, which is also observed in
human SjD. These findings suggest that the lack of working Treg cells leads to
an imbalance in the immune system, with an overactive TH1 and TH2 response
causing inflammation. Further analysis identified key molecules like IFN-γ,
IL-4, and STAT1 as drivers of this inflammation. In particular, the researchers
noted that IFN-γ, a TH1 cytokine, was increased in the salivary glands and
correlated with the severity of the inflammation.
The study also looked at how
these findings in mice relate to human SjD. They analyzed blood samples from
patients with SjD and found that, similar to the mice, there were signs of an
overactive TH1 response. Also, a subset of Tregs, called memory Tregs, were
less functional in patients with SjD. The researchers noted that in patients
with SjD, memory Treg cells showed a depletion of genes associated with their
normal function, which could contribute to exocrine gland autoimmunity. This
suggests that the problems with Treg cells might be a critical factor in the
development of human SjD, and similar to the mouse model, may have reduced
expression of genes related to T cell function and the maintenance of tissue
homeostasis.
To explore the role of specific T
cells further, the researchers transferred CD4+ T cells (a type of immune cell)
from the sick mice into healthy mice. This transfer was sufficient to cause
SjD-like disease in the healthy mice, demonstrating the critical role of these
T cells in the disease. Importantly, when they blocked the production of IFN-γ
in the transferred T cells, the recipient mice experienced significantly less
severe symptoms of SjD, including improved saliva and tear production. This
demonstrated that IFN-γ produced by CD4+ T cells is critical in causing the
dysfunction of salivary and tear glands.
Following this, they tested if
blocking the JAK1/2 signaling pathway could reduce inflammation and improve
gland function in mice. This pathway is involved in the response to IFN-γ. They
found that mice treated with a JAK inhibitor called baricitinib had less
inflammation in the salivary glands, increased saliva production, and reduced
dry eyes. Even though immune cells were still present in the tear glands, the
JAK inhibitor improved their function, suggesting that this inhibitor reduces
the impact of inflammatory molecules on these glands. This highlights the role
of IFN-γ signaling in exocrine gland cells and suggests that targeting this
pathway could help treat SjD. The researchers also discovered that the JAK
inhibitor suppressed the production of IFN-stimulated genes (ISGs), including
Stat1, Gbp1, Isg15, Mx1, Cxcl9, and Cxcl10, in salivary gland cells, indicating
how the drug worked to protect the glands.
In conclusion, this study
provides valuable insights into the mechanisms underlying Sjögren's disease.
The findings highlight the importance of functional Tregs and the detrimental
role of overactive TH1 cells and the inflammatory cytokine IFN-γ in the development
of SjD. The research also suggests that drugs like JAK inhibitors, may be
useful in treating this disease by disrupting the inflammatory processes and
restoring gland function. Further research is required to investigate why
memory Treg cells are dysfunctional in SjD and to explore the role of type I
interferon in the development of the condition. The mouse model developed in
this study will be an important tool for future investigations into this
complex condition.
Additional information: IFN-γ–producing TH1 cells and dysfunctional regulatory T cells contribute to the pathogenesis of Sjögren’s disease. Sci. Transl. Med. (2024). https://www.science.org/doi/10.1126/scitranslmed.ado4856
Journal information: https://www.science.org/journal/stm
This article is really interesting. The researchers built the mouse model for Sjögren's disease by knocking out Stim1 and Stim2. They found removing the 2 genes leads to Treg dysfunction, overactive Th1 response and increased IFN-γ. They confirmed those findings by examining patients' examples and by transferring CD4+ T cells from the sick mice into healthy mice. Finally, they targeted at JAK1/2 signaling pathway to block IFN-γ. It is very comprehensive and thought-provoking. I will read the article in detail.
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