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Overview

Introduction
  • Humoral immunity is based upon the production and activity of antibodies that
    • defend against extracellular threats such as bacteria via
      • opsonization of the surface of the pathogen leading to
        • phagocytosis by innate immune cells like macrophages
        • cytotoxicity by triggering release of toxic compounds by innate immune cells
      • neutralization of pathogens and viruses by
        • blocking interaction of pathogenic proteins with host receptors
        • inactivating virulence factors expressed by pathogens
      • activation of the complement cascade through the classical pathway
  • The main effector cell of humoral immunity B-cell that
    • is activated by displaying peptides to helper T-cells
    • undergoes affinity maturation to make higher affinity antibodies
    • undergoes class switching to develop new classes of antibodies
    • differentiates into plasma cells that are specialized to produce antibodies
  • Humoral immunity occurs in multiple phases including
    • the primary response that occurs immediately after B-cell activation
    • the secondary response after further differentiation of B-cells
Activation of Humoral-Mediated Immunity
  • Humoral immunity can be activated by two classes of antigens including
    • thymus independent antigens that do not require T-cell help
    • thymus dependent antigens that require T-cell help
Activation of Humoral Mediated Immunity
Feature Thymus Independent
Thymus Dependent
Function
  • Detect conserved non-peptide antigens
  • Identify pathogens that are missed by T-cells
  • Detect peptide antigens
  • Cooperate with T-cells to clear pathogens
Activation steps
  • Crosslinking of B-cell receptors by polymeric antigens
  • Examples include bacterial cell wall or lipopolysaccharide
  • Activation by mitogens to promote general B-cell activity
  • Endocytosis of protein antigens that are detected by the B-cell receptor
  • Processing of these antigens in endosomes and presentation on MHC class 2
  • Recognition of MHC complexes by activated helper T-cells
  • Interaction of costimulatory CD40 on B-cells with CD40 ligand
  • Differentiation after cytokine stimulation
Limitations
  • Does not lead to class switching or affinity maturation
  • Does not produce immunological memory (require adjuvent)     
  • Requires peptide antigen
  • Must have functional helper T-cells
 
Affinity Maturation and Isotype Switching
  • After B-cells are activated they can undergo two main processes including
    • affinity maturation to increase receptor affinity
    • isotype switching to produce different antibody isotypes
  • Affinity maturation is a coordinated process with distinct stages including
    • migration of B-cells to secondary lymphoid organs where
      • B-cells proliferate in germinal centers to form a colony
      • the B-cell receptor is randomly mutated in different cells
    • selection of the cells with the highest affinity receptors within the colony by
      • providing a limited number of survival signals
      • allowing mutated B-cells to compete for these signals
      • pruning less effective B-cells through apoptosis
  • Isotype switching is stimulated after activation and
    • occurs in germinal centers of secondary lymphoid organs
    • is the process of irreversibly switching constant regions by DNA rearrangement with 
      • removal of μ (IgM) and δ (IgD) type constant regions
      • addition of other constant regions making IgG, IgE, and IgA
    • is controlled by stimulation with specific cytokines
      • no specific IL required for IgG production
      • IL-4 produces IgE  
      • IL-5 produces IgA
Primary and Secondary Responses
  • Upon activation distinct populations of B-cells will develop including
    • effector B-cells that mediate the primary response by
      • secreting antibodies
      • secreting cytokines
    • proliferating B-cells that mediate the secondary response after
      • undergoing affinity maturation and class switching
      • differentiating into plasma cells
  • These responses differ in a variety of key aspects
Primary versus Secondary Responses
Feature Primary Response
Secondary Response
Function
  • Immediately secrete antibodies
  • Contain infection while secondary response develops
  • Develop into a more effective response with higher affinity
  • Clear infection after development
Antibody type
  • Low affinity IgM
  • High affinity IgG
  • IgA in mucosal infections
  • IgE in parasitic infections
Timing
  • Early in infection
  • Late in infection
 

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