1. Dental Microbiology #211 IMMUNOLOGY 2006 Lecture 4 The Antibodies and the Complement System

2. Antibodies are also called Immunoglobulins

3. Topics The structure of Immunoglobulins Classes of Immunoglobulins Biological properties of Immunoglobulins The Complement system and its functions

4. The Antibodies Antibodies are synthesized by B lymphocytes in 2 forms: soluble and cell bound. The cell-bound form is the BCR. The soluble form is released into the circulation as antibodies Each B cell produces Ab of a single specificity and expresses on the cell surface only one BCR specificity The specificity of the Ab produced by a B cell is the same as of its BCR

5. The Antibodies Fig 1

6. Antibodies are also called Immunoglobulins Immunoglobulins (Ig) are divided into 5 classes: IgG IgM IgA IgD IgE Ig are glycoproteins They differ in size, amount of CHO and biologic functions

7. Ig structure Fig 2 The prototypic Ig molecule is IgG. It is made up of 4 polypeptide chains held together by disulfide bonds Two Light (L) and two Heavy (H) chains form the letter Y in which the two arms and the stem are linked by a Hinge region L chain 212-213 amino acids long H chain 440 amino acids The chains are held together by disulfide bonds S-S Hinge

8. Variable and Constant regions Fig 3 VL CL CH The first 110 amino acids in each chain are variable (V regions) blue and purple The remaining 110 aa in the L chain and the remaining 330 aa in the H chain are constant (C regions) (green and yellow) The V regions contact the antigen. The C regions are involved in biological functions V V C CC C

9. Ig Domains Each segment of about 110 amino acids is tightly packed and forms a domain. Each Ab molecule has therefore 4 V domains (one in each H and one in each L chain), one C domain in each L chain and either 3 or 4 C domains in each H chain. Each IgG H chain has 3 C domains but IgM and IgE H chains each has 4 C domains.

10. Ig Fragments Fig 4 The IgG molecule can be dissected by proteolytic enzymes: Papain  2 Fab and 1 Fc fragment. Pepsin  1 large F(ab) 2 and several small fragments from the Fc segment

11. The function of the Ig segments The distinct Ig segments are involved in different functions: The Fab binds Ag The Fc is involved in: Transplacental passage of Ab Enhanced phagocytosis by macrophages and PMN (opsonization) Activation of Complement: Kills foreign cells, triggers inflammatory reactions. Enhances phagocytosis

12. Ag-binding function Fig 5 Antibodies bind Ag in pockets or grooves defined by the V regions of the H and L chains.

13. Ig Classes Structure Fig 6

14. Ig classes and their functions All Ig classes bind Ag in the same way via their Variable regions Distinct classes have different Fc segments and thus perform distinct biologic functions: IgG: Neutralizes toxins and prevents viral entry into cells Crosses the placenta from mother to fetus. Activates the Complement cascade. Enhances phagocytosis (opsonization)

15. IgM: Neutralizes toxins and viruses Activates the Complement cascade IgA: Crosses secretory epithelia. Neutralizes toxins and viruses Clears pathogens in secretions: saliva, nasal, bronchial secretions, seminal fluid, etc. IgE: Releases pharmacologic mediators from basophils and mast cells and triggers allergic reactions (Hay fever) IgD: Function unknown

16. Polymeric Ig (Fig. 7) In order to form the polymers, both IgM and IgA have an additional polypeptide chain, called the J chain, that helps to hold the subunits together All immunoglobulins are constructed from a basic unit of two H and two L chains, but IgM and IgA form polymers

17. sIgA Fig 8

18. The Complement System The complement system (Abbr. C): A group of proteins present in the plasma of all individuals. Part of the innate immune system. A major biological effector system of both the innate and the adaptive immune responses. The C components are present in the plasma in an inactive state. Upon activation most C components become proteolytic enzymes and act in sequence to cleave the next C component into active fragments.

19. There are 9 complement proteins (C1 to C9) The C facilitates and amplifies inflammatory responses in several ways: 1.Increases vascular permeability 2. Destroys cell membranes of pathogens and thus induce cell death through lysis 3.Enhances phagocytosis (opsonization).

20. The three C activation pathways Fig 9 Adaptive Innate Innate

21. In the adaptive immune response, the classical C pathway becomes activated when either IgM or IgG Ab binds to specific Ag. The binding of Ab to Ag exposes a site on the Fc segment of the Ig H chain which in turn binds to and triggers the activation of the first C component (C1).

22. Activation of the C cascade Fig 10

23. Activation of the C cascade. Fig 11

24. The Membrane Attack Complex The activation of the first C component called C1 starts the sequential enzymatic activity that becomes progressively amplified (C cascade). Each component splits the next one into a large and a small fragment. The large fragments become attached to the target cell membrane and end up by forming the Membrane Attack Complex (MAC).

25. MAC Fig 12 The MAC terminates with multiple copies of the last C component called C9 which generate pores in the target cell membrane thus inducing cell lysis

26. Role of the small C fragments Fig 13 The small fragments called anaphylatoxins induce powerful inflammatory reactions, by increasing vascular permeability and thus allowing passage of inflammatory cells from the blood vessels into the surrounding tissue (diapedesis).

27. END