Transcript specific immunity - GG Andersen Consulting

SPECIFIC IMMUNITY
BIOL-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 Rubella
Polio
(HIB) Haemophilus Influenzae type B
Chicken 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 ORGANS
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.
1.
Formation of B
and 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)
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Kupffer cells phagocytizing ink
(Rabbit liver)
Central
vein
Kupffer cell
Hepatic or
Liver cells
Tonsils / Adenoids
They in effect act as
lymph nodes
capturing microbes and
processing 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 toxins
2. To agglutinate and prevent
adherance of bacteria
3. 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 polypeptides
2. Covalently linked by 4 disulfide bonds
3. 2 heavy chains and 2 light chains
4. 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 Cell
5.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 cell
6. 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) cell
a. 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
an overproduction 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. AIDS
A. 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 continued
1. 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 TRANSMISSION
FOR 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)
IVDU (shooting galleries)
MSM + IVDU
Heterosexual
PERINATAL AND POSTNATAL
TRANSFUSION
 UNKNOWN
48%
26%
10%
10%
1%
1%
(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 HIV
1. 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.