Humoral Immunity and Antibody Function

• Humoral immunity uses antibodies in the extracellular space to neutralize pathogens and isolate antigens.
• Antibodies mainly protect by acting on the extracellular surface.
• Pathogens that enter the intracellular space can evade the immune system and cause disease.
• Key components of humoral immunity are B cells (T cell dependent or independent), antibody-producing plasma cells, and the complement system.

Antibody Function

• B cells interact with antigens and differentiate into antibody-secreting plasma cells.
• Antibody-antigen interactions are specific, non-covalent biochemical reactions that are the foundation for several humoral functions.
• Neutralization involves IgG and/or IgA antibodies binding to pathogen regions to prevent host cell surface binding.
• Agglutination involves IgM and or IgA antibodies binding to pathogens/particles by forming cross-linked networks to trap pathogens.
• Antibodies bind directly to pathogens, and this attachment changes the antibody molecule shape, which helps phagocytic cells attach and get involved.
• IgG, IgE, or IgA tagged pathogens are bound to corresponding receptors on NK cells and eosinophils.
• Instead of phagocytosis, NK and eosinophil cells use cytolytic mechanisms to destroy infected cells in a process called antibody-dependent cell-mediated cytotoxicity, or ADCC.
• The classical pathway of complement activates when IgM and IgG antibody isotypes bind to antigens, inducing a shape change on the antibody's Fc portion.
• The antibody conformational change makes an antibody-antigen complement complex, producing C3b and complement fragments to assemble the membrane attack complex, or MAC.
• Humoral immunity is effective against microbes outside host cells.
• Microbes use tactics like intracellular invasion to avoid antibodies and complement.
• Cell-mediated immune responses can mitigate infection, even when pathogens are inside cells.

Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC)

• ADCC is where antibodies bind to antigens on a target cell's surface (e.g., infected or cancerous cells), marking it for destruction by immune cells.
• ADCC bridges the adaptive (antibody production) and innate (effector cell activity) immune systems.
• Steps in ADCC include antibody binding, effector cell recognition, effector cell activation, and target cell killing.
• Antibodies (typically IgG, sometimes IgE) recognize and bind specific antigens on the target cell surface.
• Immune cells with Fc receptors (specific for the antibody's Fc region) bind to the antibodies coating the target cell.
• Binding triggers activation of the effector cell, causing it to release cytotoxic molecules.
• Effector cells release cytolytic substances such as perforin (creating pores) and granzymes (inducing apoptosis), or secrete cytokines to kill the target cell.
• Cells that use ADCC include natural killer (NK) cells, eosinophils, macrophages, and neutrophils.
• NK cells are major ADCC players.
• NK cells express FcγRIII (CD16), a receptor that binds to IgG-coated cells, which prompts the release of perforin and granzymes to induce apoptosis in the target cell.
• Eosinophils participate in ADCC against large parasitic organisms (e.g., helminths).
• Eosinophils bind to IgE-coated parasites via FcεR and release toxic granules like major basic protein.
• Macrophages bind to antibodies via Fc receptors and can phagocytose smaller targets or release inflammatory mediators.
• Neutrophils bind antibody-coated targets and release reactive oxygen species and lytic enzymes.
• ADCC is essential for removing infected cells, tumor cells, and parasites that are too large for phagocytosis.
• The interaction of antibodies and effector cells boosts the immune system’s ability to destroy targets that have evaded other immune mechanisms.

Cell-Mediated Immunity

• Cell-mediated immunity is like cell-to-cell combat, divided into delayed-type hypersensitivity, or DTH, and cell-mediated lysis.

DTH and CTLs

• DTH is mediated by CD4+ Th1 cells, and cell-mediated lysis is mediated by CD8+ cytotoxic T lymphocytes, or CTLs.
• DTH depends on previously activated CD4+ cells encountering the appropriate antigen peptide, MHC class II complex displayed on excited cells at the infection site.
• Antigen-presenting cells, such as tissue macrophages, reactivate the CD4+ cells, which then activate macrophages to destroy infected cells.
• Activated cells will also destroy non-infected cells.
• CTLs circulate to sample cytoplasmic-derived peptides that match initial activation.
• Reactivation occurs when CTLs bind to a peptide, MHC class I complex on the surface of host cells, such as infected epithelial cells and other immune cells.
• Once activated, CTLs bind directly to the MHC class I complex on the host cell surface and destroy the infected or damaged cell from the inside out.
• DTH uses CD4+ T cells, resulting in activated macrophages that kill infected cells.
• Cell destruction is achieved via cell-to-cell contact from CD8+ cytotoxic T lymphocytes or CTLs that bind the infected cell and secrete perforins and pre-enzymes to induce cell death.
• CTLs can bind the surface ligand FasL to the receptor Fas on the target cell, resulting in apoptotic death.
• Humoral immunity uses antibodies that attach to the surface of invading microbes in mechanisms that neutralize, trap, and tag the pathogen, resulting in destruction, and further complement activation.
• Humoral and cell-mediated immunity are used by the body to temper both intracellular and extracellular pathogens.

Humoral immunity uses antibodies to neutralize pathogens. Antibodies protect by acting on the extracellular surface. Key components are B cells, plasma cells and the complement system.