Immune Complexes and Inflammation

• Immune complexes are soluble entities circulating in the blood, potentially causing infection, tissue damage, or hypersensitivity reactions.
• The complement system, a protein surveillance system, targets these complexes by attaching a protein biomarker for later removal.
• Complement proteins, produced in the liver, bind to immune complexes, like bacterial or viral particles, facilitating their binding to host cells for elimination in a process called opsonization.

Inflammation Caused by Immune Complexes

• Immune complexes trigger inflammation by activating the body's defense mechanisms, mainly the complement system and phagocytic cells.
• Immune complexes activate the complement system when deposited in tissues.
• C1q complement proteins bind to the immune complex, starting a cascade of reactions.
• This cascade produces molecules like C3a and C5a, which attract and activate immune cells (neutrophils and macrophages).
• Complement activation leads to the formation of the membrane attack complex (MAC), which directly damages cell membranes.
• Anaphylatoxins (C3a, C5a) stimulate the release of pro-inflammatory cytokines from immune cells.
• Cytokines increase blood vessel permeability, enabling more immune cells and proteins to enter the tissue.
• Neutrophils and macrophages phagocytose immune complexes but release reactive oxygen species (ROS) and enzymes, causing extra tissue damage.
• Inflammation is marked by increased blood flow, swelling, redness, and pain.
• Inflammation causes vasodilation and vascular permeability, resulting in edema (swelling).
• Unresolved immune complexes lead to chronic inflammation, causing tissue destruction and organ dysfunction.
• The deposition of immune complexes in kidneys leads to glomerulonephritis, in joints leads to to rheumatoid arthritis and in blood vessels to vasculitis.
• Circulating C3b binds to antigen-antibody complexes; red blood cells carry these complexes to the liver and spleen for degradation.
• Red blood cells use CR1 receptors to bind immune complexes delivering them to the spleen or liver, preventing tissue damage/inflammation.

Opsonization

• Opsonization involves coating pathogens or antigen-antibody complexes with molecules to enhance recognition and ingestion by phagocytes.
• Opsonization facilitates the immune system's clearance of foreign or harmful entities.

Key Features of Opsonization

• Pathogens are tagged with complement proteins (C3b) or antibodies (IgG) on their surface to mark them for phagocytosis.
• Antigen-antibody complexes are tagged by C3b or IgG to facilitate removal by phagocytic cells.
• Infected/apoptotic host cells are opsonized for removal to prevent further damage.
• Complement proteins like C3b and C4b serve as opsonins.
• IgG is a primary opsonizing antibody, binding to Fc receptors on phagocytes via its Fc region.
• Mannose-binding lectin (MBL) functions as an opsonin.
• Opsonins bind to specific receptors on phagocytes to trigger engulfment and destruction.
• C3b binds to complement receptors (CR1), and IgG binds to Fc gamma receptors (FcγRs) on phagocytes.
• Opsonization involves tagging infected cells, pathogens, and antigen-antibody complexes.
• Pathogens marked with C3b or antibodies enable phagocytosis.
• Antigen-antibody complexes tagged with C3b facilitate clearance from circulation, preventing tissue deposition.
• Apoptotic or infected host cells can be opsonized for safe removal.
• Complement proteins facilitate the removal of immune complexes and infected cells via opsonization.
• Opsonins tag immune complexes and cells for removal.
• Complement fragment C3b is a major opsonin; C3b activation of phagocytic cells enhances phagocytosis.
• Immune/phagocytic cells express complement receptors (CR1, CR3, CR4) that bind complement fragments.
• Complement fragments (C5b, C6-C9) attach to soluble complexes/pathogens and form pores on the microbial surface.
• The MAC embeds in the microbial lipid bilayer, disrupting the membrane and causing cell death.

Complement in B Cell Activation

• B cells require a second signal for activation via the lectin or alternative pathways.
• C3b is deposited on the microbe's surface, and B cells recognize this complement fragment, providing an activating signal.
• B lymphocytes recognize antigens and differentiate into plasma cells, which secrete antibodies.
• B cell activation requires CD4+ T cells, cytokines (IL-4, interferon gamma), toll-like receptors, and complement.

B Cell Receptor (BCR)

• The BCR is a transmembrane receptor protein on B cells, composed of an immunoglobulin molecule (IgM) and an heterodimer (Igalpha and Igbeta/CD 79).
• B cells express CR1, CR2/CD21, CD19, and CD20 on their surface.
• When the BCR recognizes antigens, the Igalpha and Igbeta subunits (CD79) activate signaling cascades.
• B cell activation leads to differentiation into a plasma cell and antibody production.
• C3b, deposited on the pathogen surface, binds to the CR1 protein on the B lymphocyte. Factor I cleaves C3b, generating IC3b, which Factor I cleaves again, generating C3dg.
• C3dg binds to CR2/CD21 on the B cell surface, activating B cells to produce antibodies.

Inflammation and Complement

• Complement activation results in inflammatory outcomes, like MAC formation, opsonization and anaphylatoxin release.
• Anaphylatoxins are proinflammatory mediators which recruit/activate immune cells.
• The main anaphylatoxins, C3a, C4a, and C5a attract leukocytes and amplify inflammation.
• Opsonization enhances the recognition/ingestion of pathogens by phagocytes.
• Complement system (C3b) promotes opsonization by marking pathogens for destruction.
• The MAC forms a pore in the pathogen's membrane, causing cell lysis and death.
• C5b initiates MAC formation, binding to the pathogen membrane.
• C6 and C7 bind to C5b, forming the C5b67 complex, and C8 binds to C5b67, inserting into the membrane.
• C9 molecules polymerize to form the MAC pore, disrupting membrane integrity.
• MAC-induced osmotic imbalance causes cell rupture (lysis).
• Lysing pathogens neutralize and clear pathogens from the bloodstream, promoting immune defense.

Complement-Mediated Recruitment of Anaphylatoxins

• Complement activation cleaves C3 into C3a and C3b.
• C3a and C5a are released during the cleavage of C3 and C5 to promote inflammation.
• Anaphylatoxins bind to receptors on immune cells, triggering intracellular signaling cascades.
• Binding of C3a and C5a to their receptors (C3aR and C5aR/CD88) induces cellular responses, leading to chemotaxis.
• Anaphylatoxins increase vascular permeability and enhance phagocytosis.
• C3a, C5a, and C4a are all anaphylatoxins that induce inflammatory responses upon binding to receptors on immune cells.

Complement-Mediated Opsonization of Pathogens

• Complement activation cleaves C3 into C3a and C3b.
• C3b, iC3b, and C3dg function as opsonins.
• C3b binds covalently to the pathogen, forming the C3b convertase complex.
• Phagocytes recognize and bind to C3b and its breakdown products via complement receptors (CR1/CD35 and CR3/CD11b/CD18).
• Binding of opsonins to phagocyte receptors triggers the engulfment and destruction of the opsonized pathogen.
• C5 convertase cleaves C5 into C5a and C5b.
• C5b binds to the target surface, initiating the assembly of the MAC.
• C6, C7, and C8 bind to C5b to form C5b-C8, which inserts into the membrane.
• C9 molecules polymerize, forming the MAC pore which disrupts the cell, causing lysis and death.

Role of Complement in T Cell-Independent B Cell Activation

• T cell-independent antigens activate B cells directly without T cell assistance.
• Binding of these antigens to B cell receptors (BCRs) activates the complement system.
• Complement activation leads to C3b deposition on the antigen surface which acts as a co-stimulatory.
• B cells express complement receptor 2 (CR2/CD21).
• Binding of C3d to CR2 enhances antigen recognition and signaling by the BCR, amplifying B cell activation.