blood lecture

At first, it was a mystery how few genes code for the millions of different specificities of antibody or T cells produced by the lymphoid tissue

escape a single gene is usually necessary for the formation of each different type of protein.

Whole gene for forming each type of T cell or B cell is never present in the original stem cells.

There are only “gene segments”—actually, hundreds of such segments—but not whole genes.

During preprocessing, these gene segments become mixed with one another .

B/c there are several hundred types of gene segments,& millions of different combinations in which the segments can be arranged in single cells, the millions of different cell gene types that can occur.

Role of Macrophages in the Activation Process.

In lymphoid tissue, millions of macrophages are present line the sinusoids of the lymph nodes, spleen,& other lymphoid tissue.

Invading organisms are first phagocytized & partially digested by the macrophages antigenic products are liberated into the macrophage cytosol.

Macrophages pass these antigens by cell-to-cell contact directly to the lymphocytes activation of the specified lymphocytic clones.

Secrete Interleukin-1 promotes growth and reproduction of specific lymphocytes.

Role of the T Cells in Activation of the B Lymphocytes Most antigens activate both T & B

lymphocytes at the same time.

T cells, called helper T cells, secrete specific substances called lymphokines activate the specific B lymphocytes.

Mechanism for Activating a Clone of B Lymphocytes

B lymphocytes, each of these has on the surface about 100,000 antibody moleculesreact highly specifically with only one specific type of antigen.

On entry of a foreign antigen, macrophages phagocytize the antigen present it to adjacentB lymphocytes. Antigen is also presented toTcells

activated helper T cells formed.

• B lymphocytes specific for the antigen immediatelyenlarge and take on the appearance of lymphoblasts.• lymphoblasts further differentiate to form plasmablasts,

• In plasmablasts, the cytoplasm expands and the rough endoplasmic reticulum vastly proliferates. •Plasmablasts then begin to divide at a rapid rate ,giving in 4 days a total population of about 500cells for each original plasmablast.

Mature plasma cell then produces gamma globulin antibodies about 2000 molecules per second for each plasma cell

Formation of “Memory” Cells— Few lymphoblasts do not form plasma cells but form new B lymphocytes similar to those of the original clone.

B cell population of the specifically activated clonebecomes greatly enhanced, and the new B lymphocytesare added to the original lymphocytes of theSame clone.

Immunologically, remain dormant until activated onceagain by a new quantity of the same antigen. These lymphocytes are called memory cells.

Differences b/w theprimary response for forming antibodies that occurs onfirst exposure to a specific antigen and the secondaryresponse that occurs after second exposure to the sameantigen.Primary response• 1-week delay in the appearance of the primary response,• weak potency• shortlifeSecondary response, •begins rapidly after exposure to the antigen (often within hours)• more potent• forms antibodies for many months rather than for only a few weeks.

1. Immunocompetent B cellsexposed to antigen. AntigenBinds to B cells withcomplementary receptors.

2. B cell displays processedantigen fragments. HelperT cell binds to B cell andSecretes lymphokines.

3. Lymphokines stimulateB cell to divide repeatedlyand form a clone.

4. Some cells of the clonebecome memory B cells.Most differentiate intoplasma cells.

5. Plasma cells synthesizeand secrete antibody

Helper T cellB cell

B cell Plasma cell

Nature of the Antibodies

Antibodies are gamma globulins called immunoglobulins

They usually constitute about 20% of all the plasma proteins.

All the immunoglobulins are composed of combinations of light and heavy polypeptide chains.

Structure of immunoglobulins

• Combination of two light and two heavy chains,

• Some have combinations of as many as 10 heavy and 10 light chains.

• Each heavy chain is paralleled by a light chain at one of its ends, thus forming a heavy-light pair.

• There are at least 2 and as many as 10 such pairs in each immunoglobulin molecule.

Each light and heavy chain, contains

variable portion

Constant portion.

The variable portion is different for each specificity of antibody.

It is this portion that attaches specifically to a particular type of antigen..

CONSTANT PORTION OF IMMUNOGLOBULIN

Constant portion of the antibody determines other properties of the antibody:

Diffusivity of the antibody in the tissues,

Adherence of the antibody to specific structures within the tissues,

Attachment to the complement complex,

The ease with which the antibodies pass through membranes,

Specificity of Antibodies Each antibody is specific for a particular

antigen; This is caused by its unique structural

organization of amino acids in the variable portions of both the light and heavy chains.

The amino acid organization has a different steric shape for each antigen specificity,

When an antigen comes in contact with itmultiple prosthetic groups of the antigen fit as a mirror image with the antibody.

Allowing rapid and tight bonding between the antibody and the antigen.

When the antibody is highly specific many bonding sites between the antibody-antigen.

They held together by

(1) hydrophobic bonding, (2) hydrogen bonding, (3) ionic attractions, (4) van der Waals forces.

It also obeys the thermodynamic mass action

Ka= Conc. of bound antibody-antigen Conc. of antibody x Conc. of

antigen

Ka is called the affinity constant measure of how tightly the antibody binds with the antigen.

The Five Classes of Antibodies Class Structure Location and Function IgA Plasma IgA is found in blood plasma; Secretory IgA is found in mucus, saliva, tears,

milk, and intestinal secretions. IgA prevents pathogens from adhering to epithelia

and penetrating the underlying tissues.

IgD An integral protein of the B cell memb; acts as an

antigen receptor.

IgE Found mainly in tonsils, skin, and mucous

membranes. Stimulates mast cells and basophils release

histamine & other chemical mediators of inflammation & allergy;

Attracts eosinophils to sites of parasitic infection.

IgG Constitutes 75% to 85% of circulating antibodies in

plasma.

Crosses placenta and confers temporary immunity on the fetus. Includes the anti-D antibodies of the Rh blood group.

The predominant antibody secreted in the secondary immune response.

IgG and IgM are the only antibodies able to bind complement

IgM Bivalent is an antigen receptor of the B cell memb; Pentavalent occurs in blood plasma.

Predominant antibody secreted in the primary immune response;

very strong agglutinating ability;

includes the anti-A and anti-B agglutinins of the ABO blood group.

Mechanisms of Action of Antibodies (1) By direct attack on the Invader

(2)By activation of the complement system

Direct action of antibodies on invading agents: 1. Agglutination, multiple large particles with antigens on their surfaces,such as

bacteria or red cells, are bound together into a clump

2. Precipitation, molecular complex of soluble antigen

(such as tetanus toxin) & antibody become so large that it is insoluble and precipitates

3. Neutralization, Antibodies cover the toxic sites of the antigenic agent

4. Lysis, Potent antibodies directly cause rupture

of the agent

Complement System for Antibody Action-: “Complement” is a system of about 20 proteins, many of which are enzyme precursors. Most important are 11proteins designated C1 through C9, B, and D Present among plasma proteins in the blood& proteins that leak out of the capillaries into the tissue spaces.Enzyme precursors are normally inactive activated mainly by classic pathway.

Classic Pathway.

Initiated by an antigen-antibody reaction antibody binds with an antigen, specific reactive site on the “constant” portion of the antibody becomes “activated,”

Binds directly with the C1 molecule of the complement system.

The C1 enzymes that are formed then -->activate increasing quantities of enzymes.

Multiple end products are formed that prevent damage to the body’s tissues caused by the invading organism or toxin

Classic Pathway

Opsonization

1. Opsonization and phagocytosis: activated by C3b by both neutrophils and macrophages.

2. Lysis: Lytic complex C5b789

3. Agglutination

4. Neutralization of viruses.

5. Chemotaxis: C5a causing chemotaxis of neutrophils and macroophages

6.Activation of mast cells and basophils:Fragment C3a,C4a and C5a

7. Inflammatory effects.

Several other complement products contribute to local inflammation. These products cause

(1) Already increased blood flow to increase still further

(2) the capillary leakage of proteins to be increased,

(3) the interstitial fluid proteins to coagulate in the tissue spaces.

ALLETERNATET PATHWAY

It is due to protien in circulation called factor-1.

it binds with polysaccharides present in the cell membrane of the invading organism.

This binding activates C3 &C5 which attack the antigenic products of invading organism.

ActivatedT Cells and Cell-Mediated Immunity On exposure to an antigen A: activated T lymphocytes are formed.

B: T- Lymphocyte memory cells are formed and spread to lymphatic tissue of whole body.

Antigen-Presenting Cells, MHC Proteins, and Antigen Receptors on the T Lymphocytes.

T lymphocytes respond to antigens only when they are bound to specific molecules called MHC proteins on the surface of antigen-presenting cells in the lymphoid tissues .

The three major types of antigen-presenting cells are

macrophages, B lymphocytes, dendritic cells. The dendritic cells,are located throughout

the body, their only known function is to present antigen to T cells.

The MHC proteins are encoded by a large group of genes called the major histocompatibility complex (MHC).

The MHC proteins bind peptide fragments of

antigen proteins degraded inside antigen presenting cells transport them to the cell surface.

There are two types of MHC proteins:

(1)MHC I proteins, which present antigens to cytotoxic T cells,

(2) MHC II proteins, which present antigens to T helper cells.