SPECIFIC IMMUNITYBIOL-261 Microbiology

I. Four Types of Specific Immunity

Definition of specific immunity: The immunochemical process of recognizing and destroying specific foreign cells or substances.

A. NATURALLY ACQUIRED ACTIVE IMMUNITY – produced when foreign antigens enter the body. Two types:

1. Humoral Immunity - elicits the production of antibodies

against antigens.2. Cell Mediated Immunity - triggers

specialized lymphocytes (T- cells)

B. NATURALLY ACQUIRED PASSIVE IMMUNITY

1. Breast Milk – IgA ( a type of antibody) and monocytes.

2. Colostrum – contains bifidus factors, antibodies that protect the newborn gastrointestinal tract.

3. IgG – a type of antibody that is transplacental and protects the infant up to 3 months.

C. ARTIFICIALLY ACQUIRED ACTIVE IMMUNITY

Immunity provided by vaccination.

Examples include: (DTP) Diphtheria Tetanus Pertussis(MMR) Measles Mumps RubellaPolio(HIB) Haemophilus Influenzae type BChicken Pox(HBV) Hepatitus B Virus

D. ARTIFICIALLY ACQUIRED PASSIVE IMMUNITY

The method of collecting IgG from an infected immune

person, and transferring this immunity to an unprotected person. Sometimes given to

infants who are not producing enough antibodies.

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II. THE LYMPHATIC SYSTEM

A. PRIMARY LYMPHATIC ORGANS1. Bone Marrow – hematopoietic stem

cells produce leukocytes, thrombocytes, and erythrocytes.

2. Thymus – specialized lymphocytes called T- cells are made in this glandular structure present in young vertebrates at the base of the neck.

http://www.bartleby.com/107/274.html

Formation of Band T Cells

B. SECONDARY LYMPHATIC ORGANS

1. Lymph nodes –hundreds of small finger tip sized structures that contain lymph. Loaded with T – cells and Follicular Dendritic Cells.

2. Spleen – mostly B – cells. Recovers materials from old erythrocytes.

3. Liver – mostly fixed macrophages (Kupffer cells)

4. Adenoids and Tonsils – mostly B cells

Bovine lymph node

Spleen

Kupffer cells (phagocytes in the liver)

Kupffer cells phagocytizing ink(Rabbit liver)

Central vein

Hepatic orLiver cells

Kupffer cell

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Tonsils / AdenoidsThey in effect act aslymph nodescapturing microbes andprocessing them.

III. Humoral Immunity

A.Definition - the production of

specific antibodies against foreign cells or substances.

B. What is antibody?

Antibody is produced in response to antigens. Antibody (immunoglobulin) protects against bacteria, exotoxins and viruses. Antibody is circulating in blood plasma, lymph or mucus.

C. What is the main function of antibody?

1. To neutralize viruses and toxins2. To agglutinate and prevent

adherance of bacteria3. To enhance phagocytosis

(opsonization)4. To activate complement (most

notably, C3a for inflammation, C3b to enhance phagocytosis and C5a for chemotaxis.

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D. The Five Classes of Antibodies

1. IgG – gamma globulin, 75% of all antibody in blood. Responsible for secondary immune response. Variety of functions.

2. IgM – 10% of antibody in blood. Responsible for primary immune response. Pentamer in structure. Effective at clumping antigen.

3. IgA – 15% of antibody in blood. Effective in secretions with lysozyme. Found in mucus, colostrum, tears and saliva.

4. IgD- < 1% in blood. Found on surface of B cells. Triggers humoral immunity.

5. IgE - <.01% in blood. Mostly in skin tissue. Binds to and triggers mast cell secretions. Involved in allergic reactions. Important in attacking large parasites (worms)

E. Typical Antibody Structure

1. Consists of four polypeptides2. Covalently linked by 4 disulfide

bonds3. 2 heavy chains and 2 light chains4. 2 constant regions (Fc Fragment

crystallizable) and 2 variable regions (Fab Fragment antigen binding).

5. Variable regions contain hypervariable amino acid sequences.

6. Hypervariable regions bind antigen (specific immunity!)

Antibodies - Immunoglobulin

F ab

Fc

Antibodies - Immunoglobulin

Hinge

Immunoglobulin M

Pentamer structure

F. Antigens – from the prefix of anti-body gen-erators

1. Antibody is produced in response to antigens.

2. Antigens are also referred to as foreign, immunogen or nonself.

3. Have minimal size, minimal complexity limits.

4. Usually large proteins or sugars imbedded in proteins like “O’ polysaccharide in Gram –,teichoic acid in Gram + bacteria. Spikes of viruses, pollen (allergens), blood cell surface molecules, transplanted tissue cells, or exotoxins.

G. How are antibodies produced?

Humoral Immunity is normally triggered by antigen and requires clonal selection of specific T and B cells Five leukocytes are involved:

1. Macrophage (or Dendritic cells)/ Antigen Presenting Cell (A.P.C.)

2.T Helper Cell Clone (TH2 cell)3.B Cell Clone 4.Plasma B Cell5.Memory B cell

H. Key Steps in Humoral Immunity?1.Macrophage (MP) ingests, digests and

presents all microbial antigens.The MP is called an Antigen Presenting Cell (A.P.C.). It presents to a TH2 cell. The APC also secretes IL-1 (interleukin I) which signals the hypothalamus to reset temp (fever).

2. A specific TH2 cell clone has receptors that recognize one specific antigen on the APC. This TH2 cell clone proliferates in response to IL-1, and secretes IL-2 which signals other TH2 cells of that clone to proliferate. IL-2 also activates specific T cells in cell mediated immunity to proliferate in response to specific antigen.

3.A specific B cell clone binds specific antigen on a microbe with IgD receptor. The B cell ingests and digests the microbe, and presents one specific antigen on it’s surface.

4. The TH2 cell clone recognizes the one specific antigen on the B cell. The TH2 cell secretes IL-4 which signals the specific B cell clone to proliferate, and differentiate into two new types of cells.

5.The B cell differentiates into a Plasma cell and secretes 2,000 IgM molecules per second for 5 days. This is the Primary Immune Response Objective disease symptoms,and potential mortality.

6. If the host survives the infection, a pool of Memory Cells develop which seed the entire lymphatic system.

7.Memory Cells display IgD on their surface. If host is exposed to the pathogen again, a secondary response takes place immediately.

8. Memory Cells are triggered to secrete 2,000 IgG per second immediately for 25 days. There are NO DISEASE SYMPTOMS this time!

MHC = major histocompatibility complex

I. Effects of vaccination, transplants & HIV on Humoral Immunity?

1. Vaccination is an example of artificially acquired active immunity designed to trigger a specific pool of memory cells.

2. Transplanted cells possess antigens that trigger humoral and cell mediate immunity. Cyclosporin is a drug given to transplant patients in order to block immunological rejection (blocks synthesis of IL-2).

3. HIV slowly kills all TH cell clones. Memory cells are still intact.

4. SCIDS (Severe Combined Immunodeficiency Syndrome) David in the Bubble. No T or B cell functionality.

IV. TOLERANCE

A.The inability to react immunologically to the body’s own molecules or sometimes foreign antigens.

B. Begins with fetal development, and is maintained by the thymus. A defect results in an autoimmune disorder.

C. What are two ways that tolerance is maintained?

1.Clonal deselection (deletion) – The physical elimination of lymphocytes in the thymus via programmed cell death (apoptosis). Thymus has highest rate of cell production in the body, but only 10% of all lymphocytes entering the thymus survive.

2.T Suppressor Cell (TS) variant T cell prevents other T cells from proliferating with IL-10.

V. CELL MEDIATED IMMUNITY

The 6 cells of Cell Mediated Immunity

1. T helper 2 cell (TH2) 2. T helper 1 cell (TH1)3. T suppressor cell (TS)4. T cytotoxic cell (TC)5. Natural Killer cell (NK) –

considered a type of T cell6. Macrophage (MP)

1. The T Helper Cell (TH2)

a. In response to antigens found on the A.P.C., the TH2 cell secretes Interleukin – 2 (IL-2) starts Cell Mediated Immunity

b. IL-2 signals other T cells specific for antigen to proliferate and become active.

2. The T Helper 1 cell (TH1)

a.Involved with fighting intracellular pathogens like Mycobacteria tuberculosis.

b.Triggered by intracellular antigens.c.Secretes lymphokines that signal

macrophage chemotaxis, inhibition from leaving the site of antigen, and aggregation factors (MCF macrophage cytotoxicity factor, MIF migration inhibitory factor, MAF macrophage aggregation factor).

d. Secretes gamma IFN which activates Natural Killer cells.

3. T Suppressor (TS) cella. Maintains tolerance during

pregnancy, after severe burns, trauma,and surgery.

b. Fibroblasts produce beta IFN which activates the TS to terminate inflammation during the healing phase of the inflammatory response. TS cell secretes IL-10 ending T cell proliferation.

4. T Cytotoxic Cell (TC cell)a. The so called Killer T cell.

Activated by TH2 cells.b. Directly kills cells that display

antigen on their surface by firing a lethal protein (perforin). TC cell targets virus-infected, cancer, and transplant cells.

c. Kills abnormal cells that arise by mutations. Part of an anti-cancer cell strategic defense system known as immunological surveilance.

5. The Natural Killer Cell (NK)a. large granular lymphocyte.

derived from T cells. Kills with perforin. Activated by gamma interferon secreted by TH1 cell, and IL-2 secreted by the TH2 cell.

b. Kills cells with antibody on the surface. Major role in immunological surveilance.

c. Carcinogens and psychological stress depress NK cells, while exercise and humor stimulate proliferation.

6. Macrophage (MP)

a. Secretes Tumor Necrosis Factor (TNF) in response to antigens found on abnormal cells. Part of immunological surveilance.

b.TNF is chemotactic for neutrophils.

c. The MP can be armed with IgG.

VI. IMMUNOLOGICAL DISORDERS

A. TYPE I HYPERSENSITIVITY (HPS) – immediate or anaphylactic type.

1. Anaphylaxis -sudden fluid build up. 2. Occurs within 30 minutes to allergen 3. Wheal and flare reaction on the skin.

A fluid-filled, itchy, bump. Ex. hives, rhinitis, and reactions to cat dander and house mites.

4. Systemic anaphylaxis (ex. bee stings, penicillin)

5. 10% of U.S. has severe allergies.due to anoverproduction of IgE.

6.The Fc of IgE binds to mast cells or basophils. When IgE binds to allergens, fluid phase mediators are released.

7.Treatment - hyper-immunize the allergen injected 5-7 days. Works 80% of the time to trigger switch from IgE to IgG stops symptoms.

8. Diagnosis: RAST (radioimmunoassay test) uses patients serum to measure specific IgE,

B. TYPE II HPS – CYTOTOXIC

1. Takes 5-12 hours.2. Involves TC cell or antibody +

complement lysis.3. Examples: Incompatible blood

transfusion, erythroblastosis fetalis, thrombocytopenic purpura.

C. Type III HPS – IMMUNE COMPLEX

1. Occurs in 3-8 hours.2. Requires antibody + slight excess

of solublized antigen.3. Activation of complement.4. Precipitation of immune complex in

sensitive tissues. 5. Ex. of autoimmune disorders:

glomerulonephritis, rheumatoid arthritis, and rheumatic fever due to precipitation of M-protein (of Strep. pyogenes) in the basement membrane of sensitive tissues.

D. TYPE IV HPS – DELAYED TYPE HYPERSENSITIVITY

1. Occurs in 24-48 hours.2. Indurated hard bump consisting of

macrohages signaled by the TH1 cell to migrate to the site of specific antigen.

3. Examples include: Allergic contact dermatitis to gold and other metals, and poison ivy.

4. Examples of autoimmune diseases: IDDM (juvenile onset diabetes), XLE (systemic lupus erythematosis) and MS (multiple sclerosis).

Tuberculosis is a classic example of Type IV HPS. Mycobacteria tuberculosis is slowly phagocytized due to Wax D. Wax D induces TH1 cell to signal MP chemotaxis, inhibition,and aggregation at site of lung infection. A lesion forms around the invading bacilli. Lesion consists of dead cells. Macrophage fill up with Mycobacteria and become Giant Epitheloid cells. Collagen is laid down by fibroblasts. This collective mass is called a tubercle.

V. AIDSA. AIDS was first described in June

1981 in Los Angeles. The etiological agent, HIV, was discovered in February 1983 at the Pasteur Institute by Francois Barre’ Sinoussi.

B. The structure consists of 2 identical strand of RNA each containing 10 identical genes. It is a 100 nanometer virus with an enveloped bar shaped capsid.

B. Structure of HIV continued1. gp120-viral envelope glycoprotein

attaches to T-H CD-4 receptor.2. gp160-viral envelope glycoprotein

mutates frequently causes antigenic drift.

3. p66 - reverse transcriptase makes DNA from RNA. The basis for Retrovirus Family classification.

3. p24 - capsid protein used in the ELISA test for detecting HIV antibodies.

4. p51 - capsid protein used to make reverse transcriptase. Protease inhibitors stop this enzyme.

Th cell

C. EPIDEMIOLOGY OF HIV INFECTION

1. 40 million estimated HIV+ globally. 2 million estimated in the U.S.A.

2. Only 5-10% of all cases globally are homosexual MOT.

3. There are 40,000 new HIV infections every year in the U.S. mostly among young females.

D. MODE OF TRANSMISSIONFOR HIV in the U.S.A.

Highest rate of infection is 1st year. Blood contains the most HIV, then semen,& vaginal secretions. Saliva and tears have few viruses. 6-99 CDC Report:

MSM (fisting) 48% IVDU (shooting galleries) 26% MSM + IVDU 10% Heterosexual 10% PERINATAL AND POSTNATAL 1% TRANSFUSION 1% UNKNOWN (toothbrush & razor?) 9%

E. STAGES OF HIV INFECTION

1. Early acute symptoms – 6 days to 6 wks.skin rashes, oral ulcers, lymphadenopathy. The TH count above 500 mm3. The period from infection until HIV + on the ELISA test is window of seroconversion.

2. Late chronic symptoms – TH count 200-500 mm3, night sweats, thrush, diarrhea, vomiting and anorexia.

3. Full Blown AIDS – TH count less than 200 mm3. Many O.I.’s start. In the U.S.; Pneumocystis carinii, Herpes Viruses, and Strep pneumoniae.

F. PATHOLOGY OF HIV1. Persistent slow wasting insidious

infection.2. HIV infects & kills TH clones over

a period of ~ 10 years. HIV activates TC cells. TC’s destroy all TH with HIV antigen on the surface, and also kills by signaling TH cell apoptosis.

3. Destroys humoral & cell mediated immunity.

G. THERAPY, PREVENTION, VACCINE PROMISE and ORIGIN OF HIV

1. HAART – Highly Active Antiretroviral Therapy with protease inhibitors.

2. A live attenuated HIV holds the most promise for vaccine. (KU-Dr. Bill Narayan).

3. Prevention is best accomplished with risk education, social abstinence, condoms, and clean needles.

4. The origin is controversial, but may have started in central Africa.