Immune imbalance in Sjögren's Syndrome, symbolized by a tilted scale representing immune activation and suppression.

Unlocking Sjögren's Syndrome: New Insights into Immune Imbalance and Potential Therapies

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Lena Kashyap in Health & Wellness December 2025 • 5 min read.

"Groundbreaking research sheds light on the complex immune dysregulation in Sjögren's Syndrome, paving the way for targeted treatments and improved patient outcomes."


Sjögren's Syndrome (pSS) is a chronic autoimmune disorder characterized by the immune system mistakenly attacking the body's moisture-producing glands. This primarily affects the salivary and lacrimal glands, leading to dry mouth and dry eyes, hallmark symptoms of the disease. However, pSS can also manifest in a variety of systemic ways, impacting joints, skin, nerves, and other organs, making diagnosis and management complex.

Recent research has significantly advanced our understanding of the intricate immune processes that drive pSS. These studies have illuminated the roles of various immune cells and molecular pathways, offering potential new avenues for targeted therapies. As our knowledge deepens, the possibility of more effective and personalized treatments for pSS comes into sharper focus.

This article explores key findings from recent scientific investigations into the immunological aspects of Sjögren's Syndrome. We will delve into the roles of specific immune cells like T follicular helper cells (Tfh), T follicular regulatory cells (Tfr), regulatory B cells (Breg), and innate lymphoid cells (ILC2), and how imbalances in these populations contribute to the disease. Further, we'll examine the potential therapeutic implications of these discoveries, offering hope for improved management of this challenging condition.

T Follicular Regulatory Cells: Balancing the Immune Response in Sjögren's Syndrome

Immune imbalance in Sjögren's Syndrome, symbolized by a tilted scale representing immune activation and suppression.

Within the intricate network of immune cells, T follicular helper (Tfh) cells play a crucial role in assisting B cells to produce antibodies. In pSS patients, the proportion of circulating Tfh cells is often elevated, correlating with higher disease activity. However, the counterbalance comes from T follicular regulatory (Tfr) cells, which help to control Tfh cell activity and maintain immune homeostasis.

A study by Verstappen et al. (2016) investigated the balance between Tfr and Tfh cells in pSS patients, revealing unexpected insights. While the proportion of Tfr cells was increased in pSS patients compared to healthy controls, the expression of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) on these Tfr cells was significantly decreased. CTLA-4 is a critical molecule for the suppressive function of Tfr cells, suggesting that despite their increased numbers, Tfr cells in pSS patients may have a reduced ability to effectively dampen the immune response.

  • Increased Tfr Cell Numbers: pSS patients exhibit a higher proportion of Tfr cells, seemingly attempting to regulate the overactive immune system.
  • Reduced CTLA-4 Expression: The key suppressive molecule CTLA-4 is significantly reduced on Tfr cells in pSS, impairing their functionality.
  • Implications for B Cell Hyperactivity: The impaired suppressive capacity of Tfr cells may contribute to the expansion of Tfh cells and the subsequent hyperactivity of B cells, driving autoantibody production.
These findings suggest a complex interplay between Tfr and Tfh cells in pSS. The increased number of Tfr cells may represent a compensatory mechanism to control the overactive immune response. However, their reduced suppressive capacity, indicated by lower CTLA-4 expression, suggests a functional defect that contributes to the pathogenesis of pSS. Therapeutic strategies aimed at enhancing Tfr cell function or restoring CTLA-4 expression could potentially help re-establish immune balance and reduce disease activity.

Restoring Immune Harmony: The Future of Sjögren's Syndrome Treatment

The insights gained from these studies highlight the potential for targeted therapies aimed at restoring immune balance in Sjögren's Syndrome. By understanding the specific defects in immune cell function and the dysregulation of key molecular pathways, researchers can develop more effective treatments that address the underlying causes of the disease, rather than merely managing the symptoms. As research continues, there is growing optimism that new and innovative therapies will transform the lives of individuals living with Sjögren's Syndrome.

About this Article -

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Everything You Need To Know

1

What is Sjögren's Syndrome (pSS), and what are its primary symptoms?

Sjögren's Syndrome (pSS) is a chronic autoimmune disorder where the immune system mistakenly attacks the body's moisture-producing glands. The primary symptoms are dry mouth and dry eyes, as the salivary and lacrimal glands are primarily affected. However, pSS can also manifest systemically, impacting joints, skin, nerves, and other organs, leading to complex diagnostic and management challenges.

2

How do T follicular helper (Tfh) cells and T follicular regulatory (Tfr) cells interact in the context of pSS?

Tfh cells assist B cells in producing antibodies, while Tfr cells regulate Tfh cell activity to maintain immune homeostasis. In pSS, the proportion of Tfh cells is often elevated, correlating with increased disease activity. The balance is attempted by Tfr cells. However, the study revealed the expression of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) on these Tfr cells was significantly decreased, impairing their ability to dampen the immune response. This interplay contributes to the pathogenesis of pSS.

3

What is the significance of CTLA-4 in the context of Tfr cells and pSS?

CTLA-4 is a crucial molecule for the suppressive function of Tfr cells. In pSS, even though there are more Tfr cells, the expression of CTLA-4 on these cells is significantly reduced. This reduction impairs their ability to effectively control the overactive immune response, potentially contributing to the expansion of Tfh cells and the subsequent hyperactivity of B cells, leading to autoantibody production. The impaired functionality of Tfr cells due to reduced CTLA-4 expression is a key finding in understanding the immune dysregulation in pSS.

4

What are the potential therapeutic implications of these findings related to Tfr cells and CTLA-4?

The findings suggest that therapeutic strategies aimed at enhancing Tfr cell function or restoring CTLA-4 expression could potentially help re-establish immune balance and reduce disease activity. By understanding the specific defects in immune cell function, such as the reduced CTLA-4 expression on Tfr cells, researchers can develop more effective treatments that address the underlying causes of pSS. This targeted approach offers hope for improved management of this challenging condition.

5

Beyond Tfr and Tfh cells, are there other immune cells or pathways involved in pSS, and what are the goals of future therapies?

Recent research explores other immune cells such as regulatory B cells (Breg) and innate lymphoid cells (ILC2). The overall goal of future therapies is to restore immune balance. Understanding the roles of these immune cells and their molecular pathways is key. Researchers are aiming to develop targeted therapies that address the underlying causes of the disease rather than merely managing the symptoms. As research continues, there is growing optimism that new and innovative therapies will transform the lives of individuals living with Sjögren's Syndrome.

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