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					The Complement System and the Integration of Innate and Acquired Immunity
David J. Kusner, M.D., Ph.D.

The Integrated Immune Response
Objectives 1. To understand the mechanisms by which the distinctive characteristics of innate and acquired immunity are integrated into a diverse and multifunctional immune system 2. To understand the complement system as the primary soluble component of innate immunity and characterize its interaction with phagocytes and the adaptive immune system.

The Diversity of Microbial Challenges
Classes of Microbes: Viruses, Bacteria, Fungi, Parasites (Protozoa, Helminths)

Size -

20 nm (Parvoviruses) 25 meters (Tapeworms)

Composition - Protein (Prions), Nucleic acid + protein (Viruses)  Eukaryotes

The Diversity of Microbial Challenges
Presence/Absence of reservoirs/vectors –Tuberculosis, Malaria, Lyme disease,

Mode of Transmission: aerosol (Measles), blood and body fluids (HIV) Extracellular / Intracellular Pathogenesis: Staph. aureus, M. tuberculosis

The Diversity of Microbial Challenges
Rapidity of disease onset: Meningococcal meningitis, Prion-induced neurodegenerative disease
Severity of disease: Localized vs. Systemic inflammation

Epithelial barrier defenses
Epithelial barriers - Skin and mucous membranes (GI, Respiratory, Urogenital tracts)

- Physical barrier: inhibit establishment of infection, block spread through tissues - Clearance mechanisms – mucus, cilia

Epithelial barrier defenses
- Secretions Acid, enzymes – stomach Antimicrobial peptides – Defensins

- Normal (non-pathogenic) flora Competition for nutrients Production of antimicrobial compounds - Epithelial turnover and cell sloughing

Disruption of epithelial defenses
- Extremely common feature of infection.

- Provides microbes with access to tissues, blood and lymphatic vessels  potential for systemic spread of pathogen/ products – wounds, burns - The consequences of disruption of epithelial barrier defenses can often be prevented or minimized.

Infection of an Epithelial Surface and the Integrated Immune Response

The Complement System
A group of > 30 plasma proteins which comprise the primary soluble component of innate immunity.

Rapidly activated in response to infection, without induction or recall of adaptive immunity.

The Complement System
However, in the presence of an adaptive immune response, complement proteins interact with both its soluble and cellular components (antibodies, lymphocytes, activated macrophages, dendritic cells).

Complement proteins circulate in plasma as inactive precursors.

The Complement System
Infection results in activation of complement proteins via a series of proteolytic reactions that yield biologically active fragments.

These coupled proteolytic reactions result in an amplification cascade, in which limited stimulation of proximal complement components results in massive activation of distal complement proteins.

Complement System: Overview

Complement proteins opsonize microbes and promote their phagocytosis.

Complement receptors on the surface of leukocytes bind complement proteins
Phagocytic receptors: CR1, CR3, CR4 present on neutrophils, monocytes, macrophages, dendritic cells.
- Bind C3b / C3bi that are attached to microbial surfaces (as opsonins)  phagocytosis

Complement receptors on the surface of leukocytes bind complement proteins
CR2: surface of B cells and dendritic cells. Binding of activated complement fragments to CR2 amplifies antigen-induced cellular activation - provides a link between the innate and acquired immune systems.

The Complement System kills microbes via the Membrane Attack Complex (MAC).

Activation of the Complement System
2 activation pathways are components of innate immunity : Alternative pathway, Lectin pathway

The Classical pathway of complement activation is part of the adaptive immune response - dependent on Abs.

Activation of the Complement System
All 3 activation pathways result in generation of an enzyme complex which can cleave C3, called the C3 convertase. C3  C3a + C3b - Integration point of the complement system (Innate and Adaptive immunity)

- Major amplification point

Activation of the Classical Pathway
Requires Antigen - Antibody complexes

Complement component C1 binds to the Fc region of the Ab (IgM- most potent activator) C1 is a protease that cleaves C2 and C4 to form the C3 convertase of the classical path.

Activation of the Alternative Pathway
Soluble proteins of the Alternative Pathway (B,D,P) bind to repetitive structures on microbial surfaces, such as components of the cell wall.

The complex of B, D and P forms the C3 convertase of the Alternative Pathway. Recognition is selective for microbes, but not highly specific (pattern recognition).

Activation of the Lectin Pathway
The soluble plasma protein, Mannan-Binding Protein (MBP or MBL) binds to the sugar mannan which is restricted to the surface of certain microbes (not on vertebrate cells)
This leads to attachment of other complement proteins (C4,C2) to form the C3 convertase of the Lectin Pathway.

Regulation of Complement System
Due to its potential for rapid amplification, and the ability of activated complement proteins to damage host tissue as well as microbes, strict regulation is needed.

Soluble Inhibitors of Complement
C1 inhibitor (C1 INH, C1 esterase inhibitor) binds and inactivates C1  inhibition of Classical Pathway.

Lack of C1 INH (hereditary angioneurotic edema) - spontaneous activation of complement and kinin systems, inflammation of the skin and critical organs. - Symptoms are completely reversed by administration of C1 INH.

Cellular Inhibitors of Complement
Decay accelerating factor (DAF) and CD59 are proteins present on mammalian cells, inhibit the assembly of the MAC on host cells.

Deficiencies of DAF and CD59 occur in the disease Paroxysmal Nocturnal Hemoglobinuria (PNH) - intermittent hemolysis of RBCs due to unregulated deposition of activated complement components on the cell surface.

Complement Deficiencies
Congenital: Deficiencies of C7, C8, C9 “terminal complement components”. Markedly increased incidence of Neisserial infections. - N. meningitidis: meningitis, bacteremia - N. gonorrhoeae: STDs, bacteremia

Acquired: consumption of complement proteins during extensive activation of the complement system.

Complement System - Summary
Plasma proteins + Complement Receptors on leukocytes + Regulatory proteins

Integral to innate immunity, also functions with the adaptive immune system. Amplification cascade that proceeds via coupled proteolytic reactions.

Complement System - Summary
Functions: Recruit inflammatory cells: C3a, C5a

Opsonizes pathogens: C3b, C3bi Directly microbicidal: MAC

General Biomedical Principles
In addition to its intrinsic biochemical beauty and physiologic importance, the complement system illustrates several principles which are fundamental to the biomedical sciences. 1. Amplification - coagulation, fibrinolytic, kinin systems 2. Multiple levels of compensatory regulation 3. Receptor - ligand interactions determine specificity 4. Inflammation - both beneficial / deleterious

Cytokines
Cytokines are essential soluble mediators of both the innate and adaptive immune systems. In fact, cytokines are one of the major integrators which bridge these complementary systems. 1. recruitment of leukocytes (chemokines) 2. activation of phagocytes augment innate immunity 3. absolutely required for the maturation and activation of lymphocytes

Activated Macrophages Secrete Cytokines that Stimulate both Innate and Acquired Immunity

Cytokines Exhibit Both Immunoprotective and TissueDamaging Effects

Integrators of Immunity
Components which are responsible for the interdependence of innate and acquired immunity

1. 2. 3. 4. 5.

Complement system Cytokines/chemokines Macrophages Dendritic cells Antibodies

The Integrated Immune Response


				
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