The Complement System

The Complement System

• is a major effector of the humoral branch of the immune system representing some 30 proteins of circulating blood plasma which remain inactive until cleaved by a protease in turn making themselves  proteases
• it is so called because it "complements" the action of the antibody → while antibodies provide specificity, the complement system gives actual protection
• comprises mainly of proteolytic enzymes called convertases
• this is heat labile component of blood plasma

Functions

• lysis of cells, bacteria, viruses

Antibody Classes

Immunoglobulins (Ig) in the five classes and subclasses can be expressed either as secreted immunoglobulins (sIg) or as membrane bound immunoglobulins (mIg). sIg has a hydrophillic amino acid sequence of various lengths at the C-terminus whereas the mIg carboxyl terminal domain contains three regions:

1. an extracellular hydrophillic "spacer" sequence composed of 26 amino acid residues
2. a hydrophobic transmembrane sequence
3. a short cytoplasmic tail

The immature pre B-cells express only mIgM on their surfaces. mIgD appears during maturation and is co-expressed with IgM on the surface of the mature B-cell. Even when different classes of immunoglobulins are expressed sequentially on a single cell, the antigenic specificity of all the membrane antibody molecules are identical so that each antibody molecule binds to the same epitope.

Immunoglobulin G (IgG)

IgG (Kuby et al.)

All IgGs are monomers (7S immunoglobulin). Their subclasses differ in the number of disulfide bonds and the length of the hinge region.

Properties

• IgG is the most versatile immunoglobulin because it is capable of carrying out all of the functions of immunoglobulin molecules
• It is the major Ig in serum (75% of serum Ig is IgG) and in extra vascular spaces
• It is the only class of Ig that crosses the placenta. The transfer is mediated by receptors on placental cells for the Fc region of IgG. IgG1, IgG3 and IgG4 readily cross the placenta and protect the developing fetus.
• Complement activation - IgG3 is the most effective followed by IgG1. IgG2 is less efficient while IgG4 does not fix complement at all.
• Binding to cells - Macrophages, monocytes and some lymphocytes have Fc receptors (FcR) for the Fc region of IgG. IgG4 has intermediate affinity and IgG2 has very low affinity. A consequence of binding to the Fc receptors on monocytes and macrophages is that the cells can internalize the antigens better. The term opsonin is used to describe substances that enhance phagocytosis. IgG is a good opsonin (binding of IgG to Fc receptors on other types of cells results in the activation of other functions).

Antibody-Mediated Effector Functions

Opsonization

• promotion of phagocytosis of  the antigen by macrophages, neutrophiles
• FcR present on the surfaces of macrophages, neutrophiles bind the constant region of Ig

                                                                            ↓
                                     secures pathogen to the phagocyte membrane
                                                                            ↓
                                           initiates signal transduction pathways
                                                                            ↓
                                     phagocytosis of Ag═Ab complex takes place

Complement Activation

• IgM, most subclasses of IgG activate collection of serum glycoproteins (complement activators) that perforate cell membranes
• Binding of the Ag═Ab complex to C3b receptors of red blood corpuscles (RBCs)

                                                                           ↓
                                                     RBC delivers to liver/spleen
                                                                           ↓
                       resident macrophages remove complex without destroying the RBC


Antibody-dependent cell-mediated cytotoxicity (ADCC)

                         Infected cell═Ab complex
                                                ║
                                             FcR of NK cells
                                                     ↓
                     activates cytotoxic activity of the effector cells

Antibodies can also cross epithelial layers by a process called transcytosis; for example, transfer of IgG from mother to fetus ("passive immunization")

Structure and Function of Antibodies

Recall:

• B-cells can recognize an antigen via their surface immunoglobulin (Ig) molecules
• T-cells can only recognize an antigen that is associated with a major histocompatibility complex (MHC) molecule

The immunoglobulins (Ig) are glycoprotein molecules that are produced by plasma cells in response to an immunogen and function as antibodies. The immunoglobulins derive their name from the finding that they migrate with globular proteins when antibody-containing serum is placed in an electrical field

Antigens and Antibodies

Immunogenicity → the ability to induce humoral/cell-mediated immune response

B-cell + Antigen → Effector B-cell + memory B-cell
                                           ↓
                                  plasma cell → Antibody


T-cell + Antigen → Effector T-cell + memory T-cell
                                            ↓
                                 CTLs + T_HELPER, etc → cytokines, cytotoxic factors

Antigenicity → the ability to combine specifically with antibodies and surface receptors on T-cells