Thyroid eye disease (TED), also known as Graves’ orbitopathy, is an autoimmune disorder characterized by proptosis (protruding or bulging eyes), inflammation, tissue remodeling, fat expansion, and fibrosis in the orbit (eye socket). An autoimmune disease occurs when our body’s immune system turns on itself and attacks self-antigens instead of invading pathogens. Autoimmune diseases are characterized by the presence of autoantibodies against self-antigens. While traditionally TED is viewed in the background of autoantibodies and thyroid autoimmunity, for a more comprehensive view, it is important to examine how both the innate immune system and adaptive immune system collaborate in its pathogenesis. Understanding these mechanisms is crucial for developing therapeutic strategies and predicting disease behavior.
Innate vs. Adaptive Immunity
The immune system consists of the repertoire of our body’s defense mechanisms against invading pathogens and cancers. It is broadly classified into innate and adaptive immune systems.
- Innate immunity is the first line of defense acquired at birth. It is non-specific and acts rapidly (minutes to hours). Innate immunity relies on pattern recognition receptors (PRRs), which are common molecular signatures found on pathogens. The components of the innate immune system include complement proteins, phagocytes (macrophages, neutrophils, dendritic cells), natural killer (NK) cells, etc. Due to its non-specific nature of defense, it does not have immunologic memory.
- Adaptive immunity is slower to engage initially (days), and as the term specifies is adapted towards antigen-specificity. The components of the adaptive immune system include B and T lymphocytes, antigen-presenting cells (APCs) and antibodies. It is highly selective and shows immunologic memory.
Autoimmune disease is initiated with the innate system providing the early inflammatory milieu. It then bridges to adaptive responses and sustains, targets, and “remembers” autoantigens. Hence, autoimmune diseases are rarely the product of only one immune arm but rather, dysregulation in both innate and adaptive immunity subsets, and their cross-talk underpins disease severity and persistence.
Innate Immunity in Thyroid Eye Disease
Early Inflammation and Cytokine Release
In TED, orbital tissues (fibroblasts, adipocytes and extraocular muscles) are infiltrated by immune cells and converted into a proinflammatory environment. In the early phases, the innate immune cells are recruited and take up residence in these tissues and begin to produce pre-inflammatory cytokines (e.g., IL-1, IL-6, TNF, interferons).
These cytokines increase vascular permeability, leading to edema (fluid accumulation) and further infiltration by more adaptive immune cells. They also activate the endothelial cells (which form the linings of the blood vessels) and stimulate orbital fibroblasts, causing them to both express immune ligands and produce further cytokines. This inflammatory phenotype sets the stage for later immune activation and thus, innate inflammation is both an initiator and amplifier of orbital tissue changes.
Antigen Presentation and APC Activation
Dendritic cells (DCs) and macrophages, which are part of the innate arsenal, can also act as APCs. In TED, they start picking up autoantigens from damaged orbital tissues (e.g., thyroid receptor fragments) and ‘present’ them to T cells, thereby triggering adaptive immunity. Interestingly, some of the PRRs of these APCs [e.g., Toll-like receptors (TLRs)] are able to detect tissue damage, which initiates downstream adaptive responses.
Complement Activation
The complement system also undergoes aberrant activation in the autoimmune context. In TED, complement components engage the innate immune cells that have infiltrated into orbital tissues, escalating inflammation and leading to the recruitment of more immune cells.
NK Cells, Neutrophils and Innate Lymphoid Cells
Natural killer (NK) cells and neutrophils may contribute to early tissue injury or immune modulation by recognizing stressed or altered orbital cells. This causes the NK cells to produce IFN-γ and other cytotoxic mediators. Neutrophils, on the other hand, release proteases and reactive oxygen species (ROS), exacerbating tissue damage, which in turn feeds more immune activation.
Adaptive Immunity in TED
As with most autoimmune diseases, the adaptive immune arm is perhaps more classically associated with TED, especially via autoantibodies and T cell responses.
Autoantibodies and B Cells
As mentioned before, one of the classical signs of autoimmune disease is autoantibodies against self-antigens. In TED, patients often have circulating autoantibodies, especially against the thyroid-stimulating hormone receptor (TSHR) and occasionally against the IGF-1 receptor (IGF1R) present in the orbital tissues. B cells differentiate into plasma cells, secreting these pathogenic antibodies to sustain chronic immune activation. These autoantibodies can bind to these receptors and form immune complexes that are recognized by the innate cells. Additionally, B cells themselves express innate sensors (TLRs), which can enhance their activation and cytokine output (a convergence of innate and adaptive functions).
T Cells: CD4⁺ Helper, CD8⁺ Cytotoxic and Regulatory (Treg) Subsets
Helper T cells (CD4⁺) are central in autoimmune orchestration by producing pro-inflammatory cytokines such as IFN-γ, IL-2, and IL-17. These cytokines promote inflammation, fibroblast activation, and recruitment of further immune cells into orbital tissue. Cytotoxic CD8⁺ T cells, on the other hand, directly attack orbital cells expressing the autoantigens, contributing to cell damage and release of antigens. Regulatory T cells (Tregs) are a subset of T cells whose function is to restrain or regulate the destructive activity of the innate and adaptive immune systems. Deficiency, dysfunction, or imbalance in Tregs is a known phenomenon in autoimmune diseases, including TED, and fails to suppress autoreactive responses.
Memory & Amplification
Adaptive immunity brings memory, and once B and T cells “learn” the autoantigen, they respond more vigorously upon re-encounter. This explains both chronic and/or relapsing phases of TED. Moreover, adaptive responses also display epitope spreading, whereby immune reactivity against one antigen may expand to target nearby or related self-antigens, worsening disease.
Innate and Adaptive Immunity Crosstalk in TED
As mentioned before, the innate and adaptive immune systems feed off each other, self-propagate inflammation and tissue destruction in autoimmune disease. In TED, this begins with the innate cells recognizing self-antigens and creating feedback loops of cytokine production and adaptive immune cell activation. Once inflammation begins, cytokines from innate and adaptive cells (IL-6, TNF, IFNs) recruit more immune cells, perpetuate activation, and stimulate fibroblasts to produce extracellular matrix, chemokines, and more antigens. In TED specifically, this cross-talk results in a kind of “vicious cycle” escalating orbital remodeling and fibrosis.
Evidence in TED Models and Human Studies
While much of our mechanistic understanding is inferred from autoimmune paradigms, there is specific supporting evidence in TED from human and animal studies. These include:
- Orbital tissues from TED patients show infiltration by macrophages, dendritic cells, T and B cells
- Orbital fibroblasts express TSHR and can respond to TSHR antibodies or IGF1R antibodies by secreting cytokines and adipogenesis, amplifying inflammation.
- Pro-inflammatory environment in the orbital tissues due to the expression of cytokines (e.g., IL-1β, IL-6, TNF, IFN-γ).
- In some experimental models, blocking certain cytokines (e.g., IL-6, TNF) or interfering with T cell responses reduces orbital inflammation.
- Correlative studies find associations between higher antibody titers, inflammatory markers, and more severe TED activity.
Therapeutic Insights on How The Immune System Affects TED
Understanding how the immune system drives TED sheds light on why certain therapies work and opens doors for newer strategies.
Some of these are:
- Targeting adaptive immunity: Many current and emerging therapies (e.g, anti-CD20 B cell depleting agents, anti-CD3 antibodies, T cell co-stimulation blockers) target the adaptive arm.
- Modulating innate inflammation: Drugs that block cytokines (e.g., anti-IL6, TNF inhibitors) or inhibit innate sensors (e.g., TLR antagonists) could suppress the early inflammatory milieu.
- Interrupting cross-talk: Therapies that block cytokine signaling or complement, or interfere with APC co-stimulation, may break the feedback loops between innate and adaptive arms.
Since innate activation often precedes full adaptive responses, early intervention during the “active” phase of TED may yield better outcomes than later fibrotic phases. Also being explored are precision medicine-based strategies, where patients with distinct immune profiles (e.g., high innate cytokines, particular T cell subsets) are given tailored immunomodulatory regimens.
Get Trusted Diagnosis and Treatment for Thyroid Eye Disease
TED at its core is a disorder of immune dysregulation involving both the innate and adaptive arms of the immune system, and their cross-talk. The innate system initiates inflammation and shapes the adaptive response, which then produces autoantibodies and cytokines that recall and amplify innate effectors. The interaction between those arms creates a self-sustaining cycle that leads to orbital inflammation, remodeling, and fibrosis.
Effective treatment and management focus on controlling inflammation, restoring eye comfort and appearance, and preventing long-term tissue damage through personalized care plans. If you suspect or are having signs and symptoms of TED (bulging eyes, inflammation), do not hesitate to schedule an appointment with Dr. Raymond Douglas.
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