Antigen

Antigens are central to the functioning of the immune system, serving as the molecular signatures that allow immune cells to distinguish between self and non-self. Their interactions with antibodies and T-cell receptors are fundamental to the processes of immune recognition, activation and memory within both innate and adaptive immunity.
Antigens may be derived from a wide range of biological substances, including proteins, polysaccharides, lipids and nucleic acids. They can originate from microorganisms, environmental allergens or from within the body itself. Depending on their nature and how the immune system encounters them, antigens may elicit immune activation, tolerance or, in pathological circumstances, autoimmune reactions.

Molecular Characteristics and Recognition

Antigens are defined by their ability to bind selectively to antibodies or T-cell receptors. This binding occurs through highly specific interactions, with antibodies recognising distinct molecular regions known as epitopes. A single antigen may contain multiple epitopes, each capable of stimulating a different lymphocyte population. These interactions underpin the clonal selection process, whereby only lymphocytes with receptors specific to the encountered antigen proliferate.
Antibodies are typically antigen-specific, though in certain cases they may exhibit cross-reactivity, binding structurally similar antigens. The antigen–antibody reaction represents a cornerstone of humoral immunity. T-cell receptors, by contrast, do not bind whole antigens; they recognise short peptide fragments presented on major histocompatibility complex (MHC) molecules displayed on the surfaces of antigen-presenting cells.
Antigens vary widely in structure. Many are large biological polymers, while others, such as haptens, are small molecules that become immunogenic only when attached to a larger carrier protein. Immunoglobulin-binding proteins, including protein A and protein G, can bind antibodies at non-antigen sites, allowing them to influence immune interactions without acting as classical antigens.

Immunogenicity and Immune Activation

An antigen that can elicit an immune response is termed an immunogen. Immunogenicity depends on molecular size, structural complexity and the presence of adjuvants—substances that enhance innate immune activation and facilitate subsequent adaptive responses. Immunogens stimulate B-cell receptors or T-cell receptors, initiating cascades that culminate in antibody generation, cytotoxic T-cell responses or both.
Some antigens require the assistance of T cells for antibody production (T-dependent antigens), whereas others can stimulate B cells directly (T-independent antigens). The immune system selectively responds to antigens considered non-self; central tolerance processes in the thymus and bone marrow prevent reaction against self molecules by eliminating self-reactive lymphocyte clones.
Vaccines provide controlled exposure to immunogenic antigens, activating memory lymphocytes so that future encounters with the pathogen elicit faster and more effective immune responses.

Historical Development of the Concept

The term “antigen” emerged in the late nineteenth and early twentieth centuries. Paul Ehrlich’s side-chain theory provided an early conceptual framework for antibody generation. Microbiologist Lászlo Detre introduced the notion of antigenic substances, initially believed to be precursors of antibodies. By 1903 the concept evolved to refer to molecules capable of inducing antibody formation. The modern definition—an antibody generator—reflects this historical development.

Terminology and Structural Features

Antigens contain specific regions known as antigenic determinants, or epitopes, which serve as binding sites for antibodies. These determinants provide the molecular basis for specificity. Using a lock-and-key comparison, the antigen may be seen as presenting multiple keys (epitopes), each recognised by a corresponding antibody.
Certain specialised antigen categories include:

• Allergens – antigens that trigger allergic responses through inappropriate immune activation.
• Superantigens – potent antigens that cause non-specific activation of T cells and excessive cytokine release.
• Tolerogens – antigens that induce immunological non-responsiveness; structural changes can convert them into immunogens.
• Immunodominant antigens – epitopes that elicit stronger immune responses than others within the same pathogen.

Antigen Processing and Presentation

Antigen-presenting cells such as dendritic cells, macrophages and B cells process antigens into peptide fragments and display them on MHC molecules. MHC class II presents peptides to helper T cells, typically derived from exogenous antigens, whereas MHC class I presents endogenous peptides to cytotoxic T cells. Activation requires precise molecular compatibility between the peptide, MHC molecule and T-cell receptor.
Adjuvants enhance antigen processing and presentation by promoting innate immune activation, making them essential components of many vaccines.

Types of Antigens Based on Source

Exogenous Antigens

Exogenous antigens originate outside the body and enter through inhalation, ingestion or injection. After uptake by antigen-presenting cells via phagocytosis or endocytosis, they are processed and presented to helper T cells using MHC class II. Cytokines released by activated helper T cells stimulate B cells, cytotoxic T lymphocytes and other immune cells. Some exogenous antigens, such as those from intracellular pathogens, may later become endogenous.

Endogenous Antigens

Endogenous antigens arise within cells due to normal metabolic processes or intracellular infection by viruses or bacteria. They are presented on MHC class I and recognised by cytotoxic T cells. Central tolerance mechanisms eliminate T cells reactive to normal self-antigens to prevent autoimmune destruction.
Endogenous antigens include:

• Autologous antigens – self molecules.
• Xenogenic and heterologous antigens – derived from different species.
• Idiotype or immunoglobulin allotype antigens – unique antigenic determinants on antibodies.

Autoantigens and Autoimmunity

Autoantigens are self-proteins or nucleic acids that, in autoimmune diseases, become targets of the immune system. Failures in tolerance mechanisms allow autoreactive T cells or antibodies to persist, leading to tissue damage. Examples occur across many autoimmune conditions, including systemic lupus erythematosus and type 1 diabetes.

Neoantigens and Tumour Immunology

Neoantigens are novel peptides absent from the normal human genome. They typically arise from mutations in cancer cells and can provoke strong T-cell responses because they bypass central tolerance. Advances in sequencing technology allow systematic identification of neoantigens, enabling personalised immunotherapies. Viral antigens also contribute to tumour neoantigen profiles in virus-associated cancers such as cervical cancer and certain head and neck malignancies.

Sources and Biological Diversity

Antigens may be derived from a wide variety of microbial and non-microbial sources. Microbial antigens include bacterial cell wall components, flagella, capsules, fimbriae and toxins, as well as viral proteins. Non-microbial examples encompass pollen, egg white proteins, transfused blood cells and transplanted tissues.