M4

• The immune system

  • Composed of the phylogenetically oldest, highly diversified innate immune system and the adaptive immune system
• Regulatory mechanisms of complement

  1. Activation of complement is focused on the surface of invading microorganisms

  2. Limited complement deposited on normal cells and tissues

  3. Malfunctioning regulatory mechanisms may cause injury to cells, tissues, and organs
• Complement system

  • Group of more than 30 circulating and membrane-bound regulatory and constitutive component glycoproteins
  • Promotes host defense against infectious agents
  • Promotes the clearance of apoptotic cell debris and immune complexes
  • Regulates the immune response
• The complement system was inferred late in the 19th century
• Complement is phylogenetically older than immunoglobulins and is present in primitive organisms that lack immunoglobulins
• Complement provides innate or natural immunity and host defense, even in the absence of an antibody response
• Three complement pathways in human serum

  • The Classical Pathway
  • The Alternative Pathway
  • The MBL Pathway (MBLectin Pathway)
• Classical Pathway proteins

  • Designed by the uppercase letter C followed by the number relating to their order of appearance in the reaction sequence
• Complement pathways

  • Classical pathway
  • Alternative pathway
  • MBL pathway
• Classical pathway proteins


  • Designed by uppercase letter C followed by a number indicating their order of appearance in the reaction sequence. Exception: C4 acts before C2. Components of C1 complex are termed C1q, C1r, and C1s
• Alternative pathway proteins

  • Referred to as factors with uppercase letters (e.g., factor B, factor D). Fragments of complement proteins from proteolytic cleavage are designated by appended lowercase letters (e.g., C4a, C4b)
• MBL pathway proteins

  • Designated by abbreviations of the names of the proteins (e.g., MBL for mannan-binding lectin, MASP for MBL-associated serine protease)
• The complement system can be activated in three different ways: classical pathway triggered by antigen-antibody combination, alternative pathway discovered in the 1950s as a natural defense system, and lectin pathway, an antibody-independent means of activating complement proteins
• Properdin's major function is to stabilize a key enzyme complex in the alternative pathway
• Lectin pathway is another antibody-independent means of activating complement proteins
• Most plasma complement proteins are synthesized in the liver except for C1 components and Factor D
• Complement activation

  Can be divided into three main stages: recognition unit, activation unit of the classical pathway (and the lectin pathway), formation of membrane attack complex
• C3 is the central molecule of complement activation pathways
• Complement activation

  1. Recognition unit

  2. Activation unit

  3. Formation of membrane attack complex
• C3


  Central molecule of complement activation pathways
• C3 is the central convergence point for the three complement activation pathways, which all proceed to lysis, phagocytosis, or regulation of the inflammatory response farther down the cascade
• C3 is a molecule synthesized in many cells, particularly hepatocytes and is released into the circulation, where it binds to foreign target surfaces
• Complement Proteins


  • C3
• The activation and conversion of C3 to C3b lead to covalent binding of C3b to the surface of a target such as a microorganism
• The target becomes coated with C3b capable of interacting with cells expressing C3b receptors, including all phagocytes, all B lymphocytes, and a subset of T lymphocytes
• The classical pathway of complement activation, described around 1900, was the first to be studied, and for this reason is called classical
• The classical pathway is responsible for complement activation on most antibody-sensitized cells
• Immunoglobulins that can activate the Classical Pathway

  • IgM
  • IgG1
  • IgG2
  • IgG3
• Immunoglobulins that can't activate the Classical Pathway

  • IgG4
  • IgA
  • IgE
  • IgD
• Molecules that can activate the Classical Pathway

  • C-reactive protein
  • Serum amyloid P component
  • β-amyloid
  • Some gram-negative bacteria
  • Certain viruses
  • Mycoplasmas
  • Protozoa
  • Intracellular components such as DNA, mitochondrial membranes, cytoskeletal filaments, and apoptotic cells
• The first complement component of the classical pathway to bind is C1, consisting of three subunits—C1q, C1r, and C1s, which require the presence of calcium to maintain structure
• Recognition Unit

  1. C1q, C1r, and C1s subunits require the presence of calcium to maintain structure

  2. C1q binds to antibody molecules, C1r and C1s subunits generate enzyme activity to begin the cascade

  3. When two or more globular heads of C1q attach to bound immunoglobulin molecules, the collagen-like stalks change their configuration, causing C1r to become a serine protease, which cleaves a small fragment of C1s, uncovering the C1s protease, whose only targets are C4 and C2
• Activation Unit

  1. Formation of the activation unit begins when C1s cleaves C4 and ends with the production of the enzyme C5 convertase

  2. C4 is cleaved by C1s to split off a fragment called C4a, opening a thioester containing active site on the remaining part, C4b, which must bind to protein or carbohydrate within a few seconds or it will react with water molecules to form iC4b, which is rapidly degraded
• First amplification step in the cascade

  For every C1 attached, approximately 30 molecules of C4 are split and attached in clusters within a 40-nm radius of C1
• Complement proteins


  • Named as they were isolated before the sequence of activation was known, hence the irregularity in the numbering system
• C2 activation


  When combined with C4b in the presence of magnesium ions, C2 is cleaved by C1s to form C2a and C2b
• C3 convertase


  The combination of C4b and C2a, known as C3 convertase, written as C4b2a to indicate that the complex is an active enzyme
• The C3 convertase complex (C4b2a) is not very stable with a half-life estimated to be between 15 seconds and 3 minutes
• If binding of C3 occurs

  C3 is cleaved into two parts, C3a and C3b
• C3


  The major and central constituent of the complement system, serving as the pivotal point for all three pathways