Antibody Basics: Part 7 - Functions in the human body: Understanding the key roles of antibodies

Welcome back to Antibody Basics by Biointron, Part 7. In this episode, we’ll go back to basics on antibodies in the human body and understand how they became the basis of life-saving therapeutics.

Importance in the Immune System

• Antibodies play a crucial role in the immune system's defense against pathogens such as bacteria, viruses, and other harmful invaders.

• They are specialized proteins produced by B cells, a type of white blood cell, in response to the presence of antigens, which are molecules on the surface of pathogens or foreign substances.

• Antibodies have a unique structure to recognize and bind specifically to antigens. 

• The incredible diversity of antibodies allows our immune system to recognize and combat a vast array of pathogens.

Neutralization

A process by which antibodies bind to pathogens, such as viruses or toxins, preventing them from infecting host cells or exerting their harmful effects.

Mechanism:

• Antibodies recognize specific antigens on the surface of pathogens.

• Binding of antibodies to antigens neutralizes the pathogen by:

• Blocking its ability to attach to host cells.

• Inhibiting its entry into host cells.

• Disrupting its ability to cause harm.

Relevance:

• Prevents infection and disease by stopping the spread of pathogens.

• Plays a crucial role in vaccine development and therapeutic antibody treatments.

Examples:

• Influenza virus neutralization by antibodies targeting hemagglutinin.

• Neutralization of bacterial toxins, such as tetanus toxin or diphtheria toxin, by specific antibodies.

Opsonization

A process in which antibodies coat pathogens, facilitating their recognition and phagocytosis by immune cells.

Mechanism:

• Coating of pathogens enhances their recognition by phagocytic cells, such as macrophages and neutrophils.

• Phagocytic cells engulf and destroy opsonized pathogens through phagocytosis.

Relevance:

• Increases efficiency of pathogen clearance by promoting recognition and uptake by immune cells.

• Plays a critical role in the innate immune response against bacterial and fungal infections.

• Deficiencies in opsonization mechanisms can lead to increased susceptibility to infections.

• Opsonization is exploited in the development of vaccines and therapeutic strategies targeting infectious diseases.

Examples:

• Antibody-mediated opsonization of bacteria, facilitating their recognition and elimination by macrophages.

• Complement-mediated opsonization of pathogens through the deposition of complement proteins on their surface.

Agglutination

The clumping together of particles, such as pathogens or foreign cells, due to the binding of antibodies to multiple antigens on their surface.

Mechanism:

• Antibodies recognize and bind to multiple antigens present on the surface of pathogens or foreign cells.

• Cross-linking of antigens by antibodies leads to the formation of large aggregates or clumps, allowing phagocytic cells to recognize and engulf them.

Relevance:

• Enhances immune response by immobilizing and trapping pathogens, preventing spread and facilitating clearance.

• Agglutination assays are commonly used in diagnostic tests for infectious diseases and blood typing.

• Agglutination-based vaccines exploit this mechanism to induce a stronger immune response against pathogens.

Examples:

• Agglutination of bacteria by antibodies, aiding in their clearance from the bloodstream.

• Blood typing tests use agglutination reactions to determine an individual's blood type based on the reaction of antibodies with specific antigens on red blood cells.

Complement Activation

A process by a group of proteins in the blood and tissues is triggered to initiate a cascade of immune responses against pathogens.

Mechanism:

• The 3 main pathways (classical, lectin, alternative) involves specific recognition molecules and activation steps leading to formation of key complement proteins, e.g. C3 and C5.

• Results in several effector functions, including opsonization, inflammation, and cell lysis.

Relevance:

• Acts as a bridge between the innate and adaptive immune responses.

• Dysregulation of complement activation is associated with various diseases, e.g. autoimmune/inflammatory disorders.

• Complement-based therapies are being developed for the treatment of complement-mediated diseases and as adjuvants for vaccines.

Examples:

• Classical pathway activation triggered by antigen-antibody complexes, leading to the formation of the C3 convertase enzyme.

Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC)

A mechanism by which certain immune cells, particularly natural killer (NK) cells, recognize and destroy target cells coated with antibodies.

• Antibodies bind to specific antigens present on the surface of target cells, such as infected or cancerous cells.

• NK cells express Fc receptors (FcγRIIIa) that recognize the Fc region of antibodies bound to target cells.

• Engagement of Fc receptors on NK cells by antibody-coated target cells triggers the release of cytotoxic granules containing perforin and granzyme, leading to the death of the target cell.

Relevance:

• ADCC is a key mechanism underlying the efficacy of antibody-based therapies, including monoclonal antibodies and antibody-drug conjugates.

• Understanding and enhancing ADCC activity is important for optimizing the therapeutic outcomes of antibody-based treatments.

Examples:

• ADCC-mediated destruction of virus-infected cells coated with specific antibodies, such as in HIV or influenza infections.

• Use of monoclonal antibodies in cancer treatment, where ADCC contributes to tumor cell killing.

Memory Response

The ability of the immune system to generate a rapid and robust antibody-mediated defense upon re-exposure to a previously encountered antigen.

• During the initial encounter with an antigen, B cells specific to that antigen undergo activation and differentiation into plasma cells, which produce large quantities of antigen-specific antibodies.

• Some activated B cells differentiate into memory B cells, which persist in the body for an extended period and can rapidly proliferate upon re-exposure to the same antigen, leading to a faster and stronger antibody response.

Relevance:

• Provides long-term immunity against specific pathogens.

• Understanding the memory response is essential for the development of vaccines and immunotherapies.

• Defects in the memory response, such as immunodeficiencies, can impair the body's ability to generate long-lasting immunity.

Examples:

• Vaccination induces the formation of memory B cells specific to vaccine antigens, conferring immunity against diseases like measles.

• Secondary immune responses to infections are better protected upon re-exposure due to the presence of memory B cells.

Clinical Relevance

Drug Development: Antibodies are valuable tools in drug development, serving as therapeutic agents, diagnostic reagents, and targets for drug discovery. Monoclonal antibodies, antibody-drug conjugates, and bispecific antibodies are used in targeted therapies for various diseases, including cancer, inflammatory disorders, and infectious diseases. Antibody-based platforms also enable the development of novel biologics and precision medicine approaches.

ADCC: Understanding and enhancing ADCC activity is important for optimizing the therapeutic outcomes of antibody-based treatments. The binding between Fc and Fc-γ receptor is significantly influenced by N-glycans in the CH2 structural domain. Importantly, in therapeutic antibodies such as CD20, Her2, and EGFR, absence of core fucose on the Fc N-glycan enhances that binding affinity, resulting in increased ADCC activity and improved therapeutic efficacy.

Beyond Fighting Infections

Blood typing: Antibodies in our blood plasma recognize specific antigens on red blood cells, determining our ABO blood group and ensuring compatible blood transfusions. The Rh (Rhesus) factor is a protein antigen present on the surface of red blood cells, and individuals are classified as Rh-positive or Rh-negative.

Allergy: When the immune system overreacts to harmless antigens like pollen, antibodies can trigger allergic reactions. IgE antibodies are produced to neutralize them by binding to mast cells and basophils, triggering the release of inflammatory mediators such as histamine.