What is an antigen?

What is an Antigen?

An antigen is a substance—typically a protein, carbohydrate, or lipid—that can be recognized and bound by components of the immune system, specifically antibodies or T cell receptors, thereby exhibiting antigenicity. 1

Core Definition and Molecular Characteristics

An antigen is fundamentally defined by its ability to bind to immune system components, though not all antigens trigger an immune response. 1, 2 The key molecular features include:

• Biochemical nature: Antigens can be proteins, carbohydrates, lipids, or combinations thereof, with proteins being the most common and immunogenic 2
• Size requirements: Surface epitopes (the specific binding sites on antigens) are typically 880-3,300 Da in size, while the smallest complete immunogens are approximately 4,000-10,000 Da 2
• Structural complexity: Greater structural complexity increases antigenicity due to the presence of more numerous and varied epitopes 2

Critical Distinction: Antigenicity vs. Immunogenicity

Not all antigens are immunogenic—antigenicity refers only to the ability to bind immune components, while immunogenicity refers to the ability to actually trigger an immune response. 1, 2 This is a crucial clinical distinction:

• Antigenic substances can bind to antibodies or T cell receptors but may not activate immunity 1
• Immunogenic substances are a subset of antigens that can induce innate or adaptive immune responses, leading to humoral or cell-mediated immunity 2
• Some antigens may even induce anergy (unresponsiveness) rather than activation 2

Classification by Origin

Antigens are classified based on their source relative to the host: 3

• Autoantigens: Self-antigens normally present in the body; relevant to autoimmune disease 3, 4
• Alloantigens: Antigens from genetically different individuals of the same species; critical in transplantation and blood transfusions 3, 4
• Xenoantigens: Antigens from different species 3
• Neoantigens: Newly formed antigens, particularly those arising from somatic mutations in cancer cells 1

Antigenicity in the Context of Immune Recognition

Antigenicity is conferred by the expression and presentation of epitopes that can be recognized by naïve T cell clones in a specific host, meaning the host must not have undergone clonal deletion against those epitopes during central tolerance. 1

Key principles of antigen recognition:

• Central tolerance: Healthy cells have limited antigenicity because their antigens are typically expressed in the thymus during T cell development, leading to deletion of reactive T cell clones 1
• Foreignness: The more phylogenetically distant an antigen is from the recipient, the greater its immunogenicity 2
• Post-translational modifications (PTMs): Can create antigenic epitopes not covered by central tolerance, as these modifications may not occur similarly in the thymus versus peripheral tissues 1

Clinical Relevance in Cancer Immunotherapy

In the oncology context, understanding antigenicity is essential for personalized immunotherapy: 1, 5

• Tumor neoantigens (TNAs): Arise from non-synonymous mutations and frameshift mutations; highly immunogenic because they are not covered by central tolerance 1
• Tumor-associated antigens (TAAs): Self-antigens expressed by cancer cells (e.g., tissue differentiation antigens like CD19, CD20, or ectopically expressed proteins like CEA); weaker immunogenicity than TNAs but clinically relevant 1
• Only 1-2% of somatic mutations are actually processed, presented, and recognized by T cells, necessitating computational prediction methods for neoantigen identification 5

Common Pitfalls in Understanding Antigens

• Confusing antigenicity with immunogenicity: An antigen may bind immune receptors without triggering a response 1, 2
• Assuming all foreign substances are immunogenic: Size, complexity, solubility, and presentation context all matter 2
• Overlooking the role of adjuvanticity: Even highly antigenic substances require danger signals (DAMPs) to drive robust immune responses 1
• Ignoring host-specific factors: The same antigen may be immunogenic in one host but tolerogenic in another, depending on the T cell receptor repertoire 1