Chapter 15. COMPLEMENT, INTERFERON AND INFLAMMATORY RESPONSE P.G. REDDY

 

15.1 SUMMARY OF MAJOR OBJECTIVES

After studying this chapter one should be able to answer the following questions:

15.2 Complement

Complement is the name given to a complex series of some 20 serum proteins and is the principal effector system of the inflammatory response. Some components are labeled numerically with prefix C (C1, C2, C3 etc.) and others with alphabets (B, D, P etc.) They complement the antibody system in an immune response against an invading organism. Complement comprises approximately 10% of the plasma globulin fraction. C3 component is the most abaundant and very important component.

Complement reaction is a casacade process, i.e. a series of enzymatic reactions in which the product of one reaction is the catalyst for the next. This is an advantage to the host because uncontrolled activation may lead to cellular destruction and tissue damage. Complement reaction is non-specific and thus belongs to innate immune mechanisms.

The 20 proteins of the complement system are synthesized in the liver and the following extrahepatic sites: monocytes, tissue macrophages, epithelial cells of the gastrointestinal and genito-urinary systems and fibroblasts. some of the complement components ( C1, C2, C4) are coded for by class III genes in the major histocompatibility complex (MHC). 

15.2.1 Complement Reaction

Consists of 3 distinct pathways. The first two are (classical and alternate) pathways that result in the activation of C3 component. The third pathway (terminal pathway) results in the generation of membrane attack complex (MAC) from C3. (Please refer to pages 117-119 of Veterinary Immunology by Tizard for a more detailed description of these pathways). 

Clasical Pathway: Function in the immune host

Pathway by which antigen-antibody complexes can activate the complement system. These complexes activate first component of complement (C1) starting a cascade reaction resulting in the formation of C42 (also known as C3 convertase). C42 acts on C3 to form C3a and C3b.

Alternate Pathway: Functions in the non-immune host

C3 convertase activity is generated in the absence of antibody.

1. Activation factors: C3, B, D and P (properdin)

2. Inhibiting factors: H and I

In the presence of activator surfaces (bacterial and fungal cell walls, helminth cuticles, tumor cell membranes etc.) factor H is strongly inhibited. 

Biological Properties of Complement

C3a - anaphylatoxin

C5a - anaphylatoxin

Anaphylatoxins have powerful effects; increased vascular permeability, smooth muscle contraction, mast cell degranulation etc. 

C5a: an important mediator of inflammatory response. Following activities are associated with C5a activation:

Smooth muscle contraction;

mast cell degranulation;

neutrophil activation;

chemotaxis etc. 

15.3 Summary of Actions

Membrane attack complex (C5-C9) is responsible for the lysis of bacteria and other foreign cells.

C3 facilitates localization of complexes in germinal centers and the opsonization and phagocytosis of microorganisms.

neutrophil activation and chemotaxis. 

15.3.1 Activation of complement in infection 

 15.4 Interferon

Interferons (IFN) are proteins produced in vivo by a variety of cell types. Upon activation, IFN can affect viral replication, the immmune response and cellular growth. When cells are infected by virus they may produce interferon which induces a state of antiviral resistance in uninfected tissue cells. 

Name Cell Antigenic types derivation (human)

alpha leukocytes 14

beta fibroblasts 4

gamma B/T lymphocytes 4

15.4.1 Effects of IFN on Cytotoxic Cells

a) IFN aids in the generation of alloantigen-specific cytotoxic T lymphocytes (CTL).

b) IFN enhances the effects of lymphocytes participating in antibody-dependent cell-mediated cytotoxicity (ADCC).

c) IFN enhances spontaneous natural killer cell (NK) cytotoxicty.

Nk cells are large granular lymphocytes, grow in response to IFN and/or interleukin-2 and are suggested to be the first line of defense against tumor cells and viral infections. They are not gentically restricted with respect to the effect and the target cell. 

15.5 Inflammatory Response

The inflammatory response functions to permit the host defenses to neutralize the source of infection by diluting, destroying, containing or compartmentalizing the agent. The following indicates some of the effects of the inflammatory response:

Acute inflammatory response: capillary dilatation (redness), exudation of plasma proteins and fluid (edema) and accumulation of PMN's are collectively termed as acute inflammatory response.

1.increased PMN populations by chemotactic response

2.enhances the opportunity for surface phagocytosis

3.Stabilizes the infectious process by mast cells and macrophages. Mast cells and macrophages secrete several preformed (histamine, platelet activating factor, interleukins etc.) and newly synthesized (leukotrienes, prostaglandins, thromboxanes) chemotactic factors and vascular permeability mediators.

4.dramatic increase in acute phase proteins (synthesized and secreted by liver) which include C-reactive protein (CRP), serum amyloid A protein etc. These inturn activate complement, enhance opsonization and adherence. Also sequester iron.

 

STUDY QUESTIONS 1. What is the major difference in the activation of complement by classical pathway and alternate pathway? 2. Describe the functions of the activated C5a. 3. Write TRUE or FALSE. a. Complement activation always requires a specific immunological memory. b. Activation of complement in some cases contributes to pathological consequences of an infection. c. Gamma interferon is secreted by polymorphonuclear leukocytes.   4. Write the major known functions of interferon. 5. Name the three different interferon's and the cell types that produce them. 6. Explain the role of mast cells in acute inflammatory reaction. 7. What are acute phase proteins.