Epitope Spreading: Mechanisms and Relevance in Immune Diseases

The immune system relies on precise targeting to eliminate pathogens, but sometimes its specificity broadens in ways that contribute to disease. Epitope spreading occurs when the immune response expands beyond an initial target to recognize additional epitopes within the same or different molecules. This process plays a significant role in autoimmune diseases and chronic infections by amplifying immune reactivity over time.

Understanding how epitope spreading occurs provides insight into the progression of immune-mediated conditions and potential therapeutic strategies.

Intramolecular Epitope Spreading

Intramolecular epitope spreading happens when an immune response initially directed at one epitope within a protein extends to other epitopes within the same molecule. This phenomenon is particularly relevant in autoimmune diseases, where the immune system progressively targets additional regions of a self-protein, worsening tissue damage. The process often begins when antigen-presenting cells (APCs) process and present multiple epitopes from a single protein, activating autoreactive lymphocytes that were previously dormant or below the activation threshold.

A well-documented example is multiple sclerosis (MS), where the immune response initially targets a specific region of myelin basic protein (MBP) but later expands to recognize additional MBP epitopes and other myelin-associated proteins. Research in The Journal of Immunology using the experimental autoimmune encephalomyelitis (EAE) model found that T cells initially reactive to a dominant MBP epitope later recognized subdominant epitopes within the same protein, contributing to disease progression. This shift in recognition correlates with increased disease severity and chronicity.

The molecular mechanisms involve antigen processing by dendritic cells and macrophages, which degrade proteins into peptide fragments for presentation on major histocompatibility complex (MHC) molecules. As inflammation persists, additional epitopes become accessible due to increased proteolysis, oxidative modifications, or structural changes in the target protein. Research in Nature Reviews Immunology suggests that post-translational modifications, such as citrullination in rheumatoid arthritis, enhance epitope spreading by altering peptide-MHC binding affinity, making previously ignored epitopes more immunogenic.

Intermolecular Epitope Spreading

Intermolecular epitope spreading occurs when an immune response initially directed at one protein extends to epitopes on distinct but related proteins. This process is significant in autoimmune diseases, where the immune system broadens its reactivity to multiple self-antigens, leading to progressive tissue damage. Unlike intramolecular spreading, which remains confined to different regions of the same protein, intermolecular spreading involves entirely separate molecules, often within the same tissue.

A well-studied example is systemic lupus erythematosus (SLE), where autoantibodies develop against a wide array of nuclear antigens. Research in Arthritis & Rheumatology has shown that immune responses initially targeting one small nuclear ribonucleoprotein (snRNP), such as SmB, later extend to other snRNP components like SmD and U1-RNP. This diversification of autoantibody targets correlates with disease severity.

A similar pattern is observed in pemphigus vulgaris, an autoimmune blistering disorder. Patients often first develop autoantibodies against desmoglein-3 (Dsg3), a cadherin protein critical for epidermal cell adhesion. Over time, the immune response broadens to include desmoglein-1 (Dsg1), leading to more extensive blistering. A study in The Journal of Clinical Investigation found that this spreading is facilitated by epitope mimicry and antigen presentation by B cells, which process and present multiple desmosomal proteins to autoreactive T cells.

In rheumatoid arthritis (RA), intermolecular epitope spreading has been implicated in the progressive targeting of joint-associated proteins. Initial immune responses often begin with citrullinated fibrinogen but later extend to other citrullinated proteins such as vimentin and enolase. Research in Annals of the Rheumatic Diseases has shown that this process is associated with increasing autoantibody titers and more aggressive joint destruction. The presence of anti-citrullinated protein antibodies (ACPAs) serves as both a diagnostic marker and an indicator of disease progression.

T-Cell Mechanisms

T cells facilitate epitope spreading by interacting with antigen-presenting cells (APCs) and B cells, diversifying antigenic targets. Once an immune response is triggered, T cells respond to newly processed peptides presented on MHC molecules. The inflammatory environment enhances antigen presentation, recruiting additional T-cell subsets and sustaining immune activation.

Cytokine signaling plays a key role, particularly through interferon-gamma (IFN-γ), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α). These cytokines amplify dendritic cell activation, enhancing the presentation of cryptic epitopes—peptide sequences that were initially less accessible or poorly immunogenic. Studies on autoimmune disorders such as type 1 diabetes show that the expansion of autoreactive T-cell populations correlates with increased MHC class II expression on pancreatic beta cells, further driving disease progression.

Regulatory T cells (Tregs) ordinarily suppress excessive immune activation and maintain tolerance, but their dysfunction contributes to epitope spreading. In diseases where Treg activity is impaired, unchecked T-cell responses lead to expanding epitope recognition, fueling chronic inflammation. This has been observed in multiple sclerosis, where reduced Treg-mediated suppression allows autoreactive T cells to persist and recognize additional myelin-derived antigens.

B-Cell Mechanisms

B cells contribute to epitope spreading by refining their antibody repertoire through somatic hypermutation and affinity maturation. This process enables recognition of an expanding set of epitopes. When an antigenic target is presented, B cells undergo activation in germinal centers, where mutations in immunoglobulin genes enhance their ability to bind diverse epitopes. As antigen persistence continues, B cells recognizing newly available epitopes gain a selective advantage, leading to an evolving antibody response.

Immune complexes play a significant role, as persistent antigen-antibody interactions facilitate the uptake and presentation of novel epitopes. These complexes are efficiently captured by follicular dendritic cells, which present them to B cells in germinal centers. This prolonged antigen exposure increases the likelihood of B-cell clones recognizing previously unexposed epitopes, broadening the immune response. Autoimmune diseases such as lupus exhibit this pattern, where autoreactive B cells initially targeting a single nuclear antigen later produce antibodies against multiple nuclear components.

Immune-Mediated Conditions

Epitope spreading plays a major role in the progression of immune-mediated diseases, broadening immune recognition and contributing to chronic inflammation and tissue destruction. As the immune system expands its antigenic targets, conditions that initially involved a single epitope evolve into more complex disorders with widespread autoreactivity.

In multiple sclerosis (MS), epitope spreading is linked to the transition from the relapsing-remitting phase to the more severe secondary progressive phase. As the immune response extends to additional myelin proteins, oligodendrocyte destruction accelerates, leading to irreversible neurodegeneration. Longitudinal studies using cerebrospinal fluid samples show that patients with broader autoreactivity against myelin antigens exhibit faster disease progression.

Similarly, in type 1 diabetes, initial immune attacks against insulin-producing beta cells begin with a limited set of epitopes but later expand to include other pancreatic proteins, hastening the complete loss of insulin secretion. Increased autoantibody diversity serves as a predictive marker for disease onset in at-risk individuals.