GENERAL IMMUNOLOGY PHT 324 Dr. Rasheeda Hamid Abdalla Assistant Professor E-mail rasheedahamed12@hotmail.com

ANTIBODIES

OBJECTIVES HOW ANTIBODIES DEFEND OUR BODY????

How Antibodies Defend Our Body Opsonization: The attachment of microbes to phagocytes or phagocytes to cells recognized as non-self. MAC Cytolysis: The lysis of gram-negative bacteria and cells recognized as non-self by the membrane attack complex (MAC) of the complement system. Antibody-dependent Cellular Cytotoxicity (ADCC) by NK Cells.

How Antibodies Defend Our Body Neutralization of Exotoxins. Neutralization of Viruses. Preventing Bacterial Adherence to host Cells. Agglutination of Microorganisms. Immobilization of Bacteria and Protozoa.

Opsonization Opsonization or Enhanced Attachment, refers to the antibody molecules IgG and the complement proteins C3b and C4b attaching antigens to phagocytes. This results in much more efficient Phagocytosis.

Opsonization (cont’d) The process starts with IgG or IgM being made against a surface antigen of the organism or cell to be phagocytosed. The Fab portion of the antibody reacts with epitopes of the antigen. The Fc portion of IgG can then bind to neutrophils and macrophages thus sticking the antigen to the phagocyte.

Opsonization (cont’d) Alternatively, IgG and IgM can activate the classical complement pathway and C3b or C4b can stick the antigen to phagocytes. One portion of the C3b binds to proteins and polysaccharides on microbial surfaces; another portion attaches to CR1 receptors on phagocytes, B-lymphocytes, and dendritic cells for Enhanced phagocytosis

Opsonization (cont’d) Attachment then promotes destruction of the antigen. Microorganisms are placed in phagosomes.

Where they are ultimately digested by lysosomes.

If the antigen and the cell is too large to be ingested (such as virus-infected host cells, transplant cells, cancer cells, etc.), phagocyte empties the contents of its lysosomes directly on the cell.

Opsonization is especially important against microorganisms with antiphagocytic structures such as capsules

Some bacteria are able to resist phagocytic engulfment. Some capsules prevent the formation of C3 convertase, an early enzyme in the complement pathways. Without this enzyme, Opsonins C3b and C4b, as well as the other beneficial proteins are not produced.

Some capsules simply cover the C3b that does bind to the bacterial surface and prevent the C3b receptor on phagocytes from making contact with C3b.(Streptococcus pneumoniae).

Membrane Attack Complex (MAC) Cytolysis The process starts with IgG or IgM being made against Epitopes on membranes. The Fab portion of IgG or IgM reacts with the epitopes on the membrane and Fc portion of the antibody then activates the classical complement pathway. C5b6789n (membrane attack complex or MAC) then puts holes in the membrane

Membrane Attack Complex (MAC) Cytolysis In the case of bacteria, MAC can put holes in the outer membrane and possibly the cytoplasmic membrane of Gram-negative cell wall.

With Enveloped Viruses, MAC can damage the viral envelope

Causing lysis

In the case of "foreign" human cells (virus-infected cells, transplanted cells, cancer cells), MAC causes Direct Cell Lysis.

Some bacteria are more resistant to MAC Some gram-negative bacteria attach Sialic acid to the LPS antigen and this prevents the formation of the complement enzyme C3 Convertase that is needed for the formation of all the beneficial complement proteins such as C3b, C5a, and MAC. Neisseria gonorrhoeae as well as Bordetella pertussis and Hemophilus influenzae are examples which alter their LPS in this manner.

Neisseria meningitidis and Group B Streptococcus, produces capsular polysaccharides composed of Sialic acid which prevents MAC lysis.

Antibody-Dependent Cellular Cytotoxicity (ADCC) by NK cells NK cells are capable of antibody-dependent cellular cytotoxicity or ADCC. NK cells have receptors on their surface for the Fc portion of antibodies. When antibodies are made against epitopes on "foreign" membrane-bound cells, (e.g., virus-infected cells, transplant cells, cancer cells), Fab portions of the antibodies react with “Foreign" Cell.

The NK cells then bind to the Fc portion of the antibody. The NK cell is then able to cause its lysis by inducing membrane lesions with pore-forming perforins and Cytotoxic granzymes.

Neutralization of Exotoxins Antitoxin antibodies (mainly IgG) are made against protein Exotoxins. They combine with the exotoxin molecules before they can interact with host target cells and thus Neutralize the exotoxin .

Neutralization of Viruses Antibodies are made against viral Capsids or envelope glycoproteins where they bind to and cover the viral surface. This prevents viral adsorption to host cells.

However, some viruses are able to overcome this antibody defense. The influenza viruses undergo what is called Antigenic Drift and Antigenic Shift. Antibodies made against the original human influenza virus can no longer bind to the new strain of virus or stick the virus to phagocytes

HIV, because of its high rate of mutation produces altered gp120 to which antibodies made against the earlier strains of HIV can no longer bind. The hepatitis C virus (HCV) through mutation, produces viral variants ("escape mutants") to resist antibodies

Preventing Bacterial Adherence Antibodies are made against Pili, Capsules, and Adhesins to prevent bacteria from adhering to and colonizing host cells.

Some bacteria are able to overcome this antibody defense. Some bacteria can produce immunoglobulin proteases which can degrade the protective IgA found in mucus. Examples include bacteria that colonize mucous membranes such as Streptococcus pneumoniae , Hemophilus influenzae , Neisseria gonorrhoeae, Neisseria meningitidis.

Another way certain bacteria can evade antibodies is by changing the adhesive tips of their pili as seen with Neisseria gonorrhoeae.

Agglutination of Microorganisms This is especially function of antibodies with multiple reactive Fab sites such as IgM and IgA. The antibodies Link microorganisms together (cause them to agglutinate) so they can be Filtered out of the lymph and blood and be phagocytosed more effectively by fixed macrophages.

Immobilization of Bacteria and Protozoa Antibodies made against flagella of motile bacteria or flagella or cilia of motile protozoa arrest their movement and block their ability to spread.

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