Alpha-enolase antibodies are autoantibodies that target the enzyme alpha-enolase. This enzyme is critical in the glycolytic pathway, converting 2-phosphoglycerate to phosphoenolpyruvate. Alpha-enolase antibodies are considered biomarkers in several autoimmune and inflammatory diseases. Their presence is often associated with disease severity and progression, particularly in conditions where immune dysregulation plays a central role.
Enolases are dimeric enzymes composed of different combinations of three subunits: alpha (α), beta (β), and gamma (γ). These subunits form active enzyme isoforms that are tissue-specific and play roles in glycolysis and various non-glycolytic functions, including cellular regulation and stress responses.
Alpha-enolase (gene ENO1): The alpha subunit is ubiquitous in nearly all tissues. When both subunits in the dimer are alpha, the enzyme is referred to as αα-enolase. Alpha-enolase is involved in glycolysis but also acts as a plasminogen receptor on the cell surface, playing a role in tissue remodeling and immune responses. Its non-glycolytic role makes it significant in pathological conditions such as cancer and autoimmune diseases.
Beta-enolase (gene ENO3): Beta subunits are primarily found in muscle tissue, where ββ-enolase isoforms predominate. This isoform is essential for energy production in muscle cells, particularly during high-demand states such as exercise. Mutations in beta-enolase can lead to metabolic myopathies.
Gamma-enolase (gene ENO2 or NSE): Gamma subunits are found mainly in neurons and neuroendocrine tissues. The dimer formed by gamma subunits is known as γγ-enolase. Gamma-enolase plays a crucial role in neuronal metabolism and survival. It is also known as neuron-specific enolase (NSE) and is commonly used as a biomarker for neuronal injury (such as in stroke or trauma) and neuroendocrine tumors.
Mixed isoforms: In some tissues, mixed dimers, such as αγ-enolase, are found. These dimers may combine the functions of different subunits based on the tissue’s metabolic needs, allowing enzyme activity and regulation flexibility.
While alpha-enolase primarily functions in energy metabolism, it is also involved in other processes, such as cell proliferation, differentiation, and response to cellular stress. Its presence on the surface of cells, where it can act as a plasminogen receptor, further links it to processes like fibrinolysis and tissue remodeling. When alpha-enolase becomes an immune system target, the resulting autoantibodies have been implicated in various autoimmune and inflammatory diseases.
Alpha-enolase can become immunogenic due to oxidative stress, post-translational modifications, or exposure to cryptic epitopes. These alterations can trigger an autoimmune response, leading to the production of autoantibodies that target alpha-enolase. Once these antibodies form, they can contribute to chronic inflammation and tissue damage, especially in diseases characterized by autoimmunity or chronic inflammation.
Anti-enolase antibodies have been described in many diseases. They can be directed against subtypes, such as the ubiquitous α-subunit or the neuron-specific β-subunit. Autoantibodies against muscle-specific β-enolase also react with the ubiquitous α subunit. There are also cross-reactions between the α and c subunits.
In patients with lymphocytic hypophysitis (also in the context of autoimmune polyglandular syndrome, APS [APECED]), autoantibodies against α-enolase and/or γ-enolase are found (58%). γ-enolase is expressed in the healthy pituitary gland, pituitary tumors, and the placenta. There may be immunopathogenic relationships between this placental expression and the pituitary autoantibodies in Sheehan syndrome. However, anti-α- and/or γ-enolase antibodies in lymphocytic hypophysitis are not specific to the disease. These antibodies were found not only in lymphocytic hypophysitis (41.2%) but also very frequently in silent pituitary adenomas (46.2%), other pituitary diseases (23.5%), various autoimmune diseases (20%) and in healthy subjects (4.3%). There is a tendency to attribute to these antibodies the role of a prognostic marker of an ongoing autoimmune process rather than the role of a diagnostic marker. Antibodies against the α-subunit or α-dimer of α-enolase have been described in many diseases. Found in retinitis pigmentosa and carcinoma-associated retinopathy (CAR), glaucoma, collagen vascular disease, cystoid macular edema, primary and secondary (in systemic lupus erythematosus and rheumatoid arthritis) membranous nephropathy (69% and 58% respectively), systemic nephropathy, lupus erythematosus (27%), cryoglobulinemic nephritis (32%), scleroderma (30%) and especially in severe forms with pulmonary manifestations, Raynaud's phenomenon, mixed connective tissue disease, ANCA-positive and negative vasculitis, paraneoplastic retinopathy (69%), Crohn's disease, ulcerative colitis (with or without detectable ANCA), acute and chronic viral hepatitis (B, C), autoimmune hepatitis (up to 60%), primary sclerosing cholangitis (27%), severe forms of primary biliary cirrhosis (29%), autoimmune polyglandular syndrome type 1 (APS I), alcoholism, senile dementia, Alzheimer's disease, paranoia, psychoses, schizophrenia, endometriosis, hyperthyroidism.
