IMMUNE RESPONSES:
INTRODUCTION TO IMMUNOLOGY Innate (non-adaptive; natural)
Dr. M.J. Tendencia
IMMUNOLOGY
Study of the immune system & Immune Reponses
Deals with host defense reactions to foreign (nonself)
entities known as antigens
Deals with antibodies & cell-mediated host defense
functions
WBC of the immune system derive from precursors in
the bone marrow
*Immune System - Considered to be a specific host defense
mechanism (springs into action to defend against a specific
pathogen) that has gained entrance to the body
PRIMARY FUNCTION OF THE IMMUNE SYSTEM
Differentiate between self & non self
Distroy which is non self
Humoral Immunity
Always involves the production of antibodies in
response to antigen
After Production circulating antibodies remain in
blood plasma, lymph, & other body secretions where
they protect against the specific pathogens that
stimulate their production
A person is immune to a particular pathogen because of
the presence of specific protective antibodies that
are effective against that pathogen
Also known as Antibody Mediated Immunity
CELL MEDIATED IMMUNITY
Involves various cell types, w/ antibodies playing
only a minor role
cell mediated immune response
Immune responses significant result is to make
person resistant to certain infectious disease
When resistant one is said to be immune
Preexisting
Not acquired through contact with Ag
Non specific
Includes barriers to infectious agents (skin & mucous
membranes, phagocytic cells, inflammatory mediators
&complement components
st nd
1 and 2 line of defenses
Adaptive (acquired)
After exposure to Ag (infectious agent)
Specific IX
Mediated either by Ab or lymphoid cells
Passive vs Active
rd
*3 line of defense
ADAPTIVE IMMUNITY/ACQUIRED IMMUNITY
A. Passive immunity
Transmitted by Antibodies or lymphocytes preformed in
another host
Excess antitoxin to neutralize the toxins
Limit microorganism multiplication during the
incubation period
rabies, hepatitis A & B, DPT
Advantage: Prompt availability of large amounts of
antibody
Disadvantage: Short life span, hypersensitivity reaction
B. Active immunity
Induced after contact w/ foreign antigens
(microorganisms or their products)
consist clinical/subclinical infection
Immunization w/ live or killed infectious agents or their
antigens
Exposure to microbial products (toxins, toxoids)
Transplantation of foreign cells
Advantage: Long-term protection, capacity to respond
faster
Disadvantage: Slow onset, need for prolonged or
repeated contact w/ the Ag
TYPES OF ACQUIRED IMMUNITY
Active Acquired Immunity
Natural active acquired immunity- Immunity that
is acquired in response to the entry of a live
pathogen into the body (i.e. in response to an
actual infection) protective Abs
Artificial active acquired immunity -
Immunity that is acquired in response to
vaccines
Passive Acquired Immunity
Natural passive acquired immunity - Immunity that
is acquired by a fetus when it receives maternal
Abs in utero or by an infant when it receives
maternal Abs contained in colostrum
Artificial passive acquired immunity - Immunity
that is acquired when a person receives Abs
contained in antiserum or gamma globulin
VACCINE
Material that can artificially include immunity to an
infectious disease, usually after injection or ingestion
of the material
A person is deliberately exposed to a harmless version
of a pathogen (toxin), w/c will stimulate the persons
immune system to produce protective antibodies &
memory cells, but will not cause disease in the person
The persons immune system is primed to mount a
strong protective response should the actual
pathogen be encountered in the future
IDEAL VACCINE
Contains enough antigenic determinants to stimulate
the immune system to produce protective antibodies
Contains antigenic determinants from all the strains of
the pathogen that cause the disease (Multivalent or
Polyvalent)
Few or no side effects
Does not cause disease in the vaccinated person
TYPES OF VACCINE
1. Live attenuated vaccines
2. Inactivated vaccines
3. Subunit vaccines
4.Conjugate vaccines
HiB
meningococcal meningitis
pneumococcal vaccine
5. Toxoid vaccines
Diphtheria
tetanus
6. DNA vaccines or gene vaccines lab animals
7. Autogenous vaccines Staphylococcus
LIVE ATTENUATED VACCINES
avirulent (non-pathogenic) mutant strains of pathogens
that have been derived from the virulent (pathogenic)
organisms
growing the org. for many generations under various
conditions or by exposing them to mutagenic
chemicals or radiation
should not be administered to immunosuppressed
individual
even weakened pathogens can cause disease in these
persons
adenovirus, chicken pox (varicella), measles, mumps,
German measles, polio, rotavirus, smallpox, yellow
fever
BCG, cholera, typhoid fever (oral vaccine)
INACTIVATED VACCINES
made from pathogens that have been killed by heat or
chemicals
can be produced faster and more easily
less effective than live vaccines
o the antigens on the dead cells are usually
less effective and produce a shorter period
of immunity
Hep A, flu, Jap B, polio, rabies
anthrax, typhoid fever (subcutaneous vaccine)
SUBUNIT VACCINE (or acellular vaccine)
uses antigenic (antibody-stimulating) portions of a
pathogen
pili of N. gonorrheae
genes that code for hep B surface protein intro into
yeast cells yeast produced large quantities of that
protein proteins are injected into people
Hep B, whooping cough
CONJUGATE VACCINES
conjugate bacterial capsular antigens (by themselves
are not antigenic) to molecules that stimulate the
immune system to produce Abs against the less
antigenic capsular antigens
Hib, meningococcal meningitis, pneumococcal
pneumonia
TOXOID VACCINES
(toxoid) exotoxin that has been inactivated by heat or
chemicals
injected safely to stimulate the production of antigens
that are capable of neutralizing the exotoxin of
pathogens
antitoxins antibodies that neutralize toxins
antiserum serum containing antitoxins
Diptheria, tetanus, botulism
DNA OR GENE VACCINE
experimental, using lab animals
particular gene from a pathogen inserted into
plasmids plasmids injected ID or IM inside the
host cells, genes direct the synthesis of a particular
microbial protein (Ag) copies produced body
produces Abs directed against the protein Abs
protect the person from infection w/ the pathogen
malarial parasite antigen
AUTOGENOUS VACCINE prepared from bacteria isolated
from a localized infection, a staph boil pathogens are killed
& then injected into the same person to induce production of
more antibodies.
NONADAPTIVE (INNATE) IMMUNITY
Mechanisms of Nonspecific Host Defense:
INNATE, NON-SPECIFIC IMMUNITY
Infectious agents must overcome innate host defense
to establish a focus of infection
Characterized by physiologic barriers to entry of
pathogenic organisms
Very fast host defense responses
 Skin & mucous membranes, phagocytic cells, Oral mucositis Mouth but Viridans strep,
inflammatory mediators, & complement 2 to cancer also entire Capnocytophagiagingivalis
components. Chemo GI tract
Response may vary with age & w/ hormonal or
metabolic activity
INNATE IMMUNOLOGIC MECHANISM
Second Line of defense
INNATE IMMUNOLOGIC MECHANISMS A. Reticuloendothelial cells
1. Physiologic barrier at the portal of entry Phagocytosis - engulfment of
2. Innate immunologic mechanism microorganisms by macrophages
B. Activation of complement by the alternative pathway
First line of defense C. Inflammatory response
Epithelial tissues that cover the whole surface of the release of cytokines from macrophages
body: serves to hold the spread of pathogen until specific
1. Skin adaptive response is initiated
- sweat & sebaceous secretions Fever
- contain lysozyme dissolves bacterial cell walls D. Interferons critical cytokines that play a key role in
- tears, respiratory & cervical secretions defense against viral infection
2. Mucous Membranes E. NK cells large granular lymphocutes, morphology
- Respiratory mucus / cilia / phagocytes related to T Cells, which make up 10 -15 % of leukocytes in
- GIT saliva /acid pH / enzymes / phagocytes the blood
- Normal Flora oppose the establishment of pathogenic
microorganisms A. ALTERNATIVE PATHWAY OF COMPLEMENT ACTIVATION
- After entering tissues, many pathogens are recognized, Important first line of defense
ingested, & killed by phagocytes Activated by microbial surfaces
Proceeds in the absence of antibodies
INTRINSIC EPITHELIAL BARRIERS TO INFECTION Antimicrobial properties: opsonization, lysis of
Mechanical bacteria & amplification of IR
Epithelial cells joined by tight junctions
Longitudinal flow of air or fluid across epithelium
Movement of mucus by cilia
Chemical
Fatty acids (skin)
Enzymes: lysozyme (saliva, sweat, tears), pepsin (gut)
Low pH (stomach)
Antibacterial peptides; defensins (skin, gut), cryptidins
(intestine)
Microbiological
Normal flora compete for nutrients and attachment to
epithelium and can produce antibacterial substances.

DAMAGE TO SKIN & MUCOUS MEMBRANES PREDISPOSES TO

INFECTION
PREDISPOSING SITE OF BACTERIA COMMONLY
FACTOR INFECTION CAUSING INFECTION

IV catheters Skin S. epidermidis, S. aureus

Diabetes Skin S. aureus

Burns Skin P. aeruginosa

Trauma to jaw Gingival Actinomycesisraelii

crevice

Dental Oropharynx Viridans strep

extraction

B. RETICULOENDOTHELIAL SYSTEM
Mononuclear phagocytic cells
Blood, lymphoid tissues, liver, spleen, BM, lungs
Kupffer cells, macrophages
Filtering microorganisms from the blood
Phagocytosis are enhanced by opsonins
Release cytokines
C. PHAGOCYTOSIS
Migration, chemotaxis, ingestion & microbial killing
PMN (granulocytes), phagocytic monocytes
(macrophages), fixed macrophages
Enhanced by opsonins
Stimulated to release cytokines that cause the
recruitment of more phagocytic cells to the site of
infection.
OUTCOME: kill ingested microorganisms
permit their prolonged survival
permit intracellular multiplication
Circulating phagocytic monocytes
Activated macrophages have increased no of lysosomes
Produce and release IL-1
Factors Affecting Phagocytosis
Presence of opsonins coat the surface of bacteria &
facilitate ingestion by phagocytes.
Mechanisms:
1. Antibody alone can act as opsonin
2. Antibody plus antigen can activate complement via
the classic pathway to yield opsonin
3. Opsonin may be produced by heat-labile system in
immunoglobulin or other factors activate C3 via the
alternative pathway
Receptors on the membrane of macrophages for Fc
portion of antibody and for the C3 component of
complement
Aid the phagocytosis of antibody-coated particles
Effects of ingestion of foreign particles on phagocytic
granulocytes:
1) Oxygen consumption increases generation
of superoxide anion (O2 ) & increased release of H2O2
2) Glycolysis increases via the HMP shunt
3) Degranulation of lysosomes w/ release of hydrolytic
enzymes into the phagocytic vacuole to form
"phagolysosome
REDUCED PHAGOCYTOSIS PREDISPOSES TO INFECTION
CAUSED BY CERTAIN BACTERIA
Decreased number of PMNs
Cancer chemotherapy, total body irradiation
Staph aureus. P aeruginosa
Decreased function of PMNs
Chronic granulomatous disease
S. aureus
Decreased function of spleen
Splenectomy, sickle cell anemia
Strep pneumoniae, N. meningitidis, H. influenza
C.INFLAMMATION
3 essential roles:
1. Deliver additional effector molecules &cells to
sites of infection
2. Provide a physical barrier
3. Promte the repair of injured tissue
Is initiated by the response of macrophages to
pathogens
Any injury to tissue elicits In R
Serves to hold the spread of pathogen until adaptive
response is initiated
Pain, redness, heat, swelling
First cells attracted are the neutrophils then monocyte
(macrophages)
 Phagocytes engulf the microorganisms intracellular BACTERICIDAL AGENTS PRODUCED OR RELEASED BY
PHAGOCYTES ON INGESTION OF MICROORGANISMS

intracellular digestion

pH of the inflamed area becomes acid

cellular proteases induce lysis of leukocytes

macrophages engulf debris & microorganisms

D.Natural Killer Cells

role in antibody-dependent cellular cytotoxicity
(ADCC)
Resemble large, granular lymphocytes
do not express antigen-specific receptors ADAPTIVE IMMUNITY
lyse target cells that have undergone malignant Acquired
transformation innate immune response sets the scene for the
role in immune surveillance against tumor induction of an adaptive IR essential prerequisite
establishment for the adaptive immune response
kill certain virus-infected cells with altered levels consists of cells displaying antigen
of MHC class I molecules recognition molecules
lytic activity is enhanced by high levels of alpha & has the capacity for long-term memory
beta interferons. Key features: specificity & memory
Cells involved: B lymphocytes
E. FEVER T lymphocytes CTL, TH
macrophages
Fever most common systemic manifestation of Primary vs Secondary immune response
IR; cardinal symptom of infectious disease Humoralvs cellular immune response
Stimulation of hypothalamus by
pyrogens(endotoxin, IL 1) ANTIGEN
Beneficial Effects of Fever:enhance antibody Features that determine immunogenicity:
production and T cell proliferation are more Foreignness (difference from self)
efficient at higher body temperatures Molecular size: MW less than 10,000 are weakly
immunogenic
F. INTERFERONS Chemical & structural complexity
Antigenic determinants (epitope) smallest unit that is
Antiviral capable of binding an Ab
proteins Dosage, route & timing of Ag administration
Control viral
replication A. B Lymphocytes
by inhibiting Lymphocytes produced in the BM
protein Display Ig molecules on their surface serve as
synthesis in receptors for a specific Ag
cells Surface receptors for the Fc portion of Ig& for
several complement components
Activated by an encounter w/ Ag to become Ab-
secreting plasma cells

B. T Lymphocytes
Lymphocytes that require maturation in the thymus
Utilized to activate B cells & to cope w/ intracellular
pathogens
 a. CTL (Cytotoxic T cells)
destruction of cells in tissue grafts, tumor cells, or
cells infected by some viruses
mainly utilized to activate B cell responses and to
cope with intracellular pathogens.
b. TH (Helper T cells)
stimulating B cells to produce antibodies
delayed hypersensitivity
defense against intracellular agents
T lymphocytes or T cells
2 major categories:
1. Helper T cells
2. Cytotoxic T cells
Helper T cells
also known as T-helper cells, TH cells and CD4+
Primary function is secretion of cytokines (proteins
w/c facilitate chemical messages among various cells
in the body)
Cytotoxic T cells
also known as T cytotoxic cells , Tc cells & CD8+ cells
Primary function: to destroy virally infected host
cells,foreign cells and tumor cells
Antigen Recognition Molecule
In order for the immune system to respond to nonself
(antigen), a recognition system capable of precisely
distinguishing self from nonself had to evolve
ANTIBODY
Immunoglobulins
Formed by clonal selection
Fab Ag binding sites
Fc involved in placental transfer, CF, &phagocytosis
IgG, IgA, IgM, IgE&IgD
IgG- predominant antibody in secondary response
IgM- main immunoglobulin in early primary response
IgA main immunoglobulin in secretions
IgE allergies and helminth infections
IgD- acts as an antigen receptor when present on
surface of B lymphocyte
Fab fragment antigen binding
Fc fragment crystallizable
CELL SURFACE RECEPTORS FOR ANTIGEN
1. B cell receptor for antigen
2. T cell receptor for antigen
3. products of the major histocompatibility complex
(MHC).
1. B CELL RECEPTOR FOR ANTIGEN
- membrane-bound receptor
- IgM or IgD
- interacts with other cell surface molecules, known as
Ig&Ig
- transduce signals after antigen binding
- signals result in biochemical events leading to cell
activation.
2. ANTIGEN-SPECIFIC T CELL RECEPTOR
- Transmembraneheterodimeric protein
- Linked to CD3 complex do not bind Ags
- Transduction of signal into the T cell
- CD4 expressed on 60% of mature CD3+ TC
- CD8 30% of T cells
- Serve as co-receptors in T cell activation
- CD4 bind to class II MCH expressed on APC
- CD8 bind to class I MHC
3. MAJOR HISTOCOMPATIBILITY COMPLEX
- Series of genes that code for cell surface proteins
(chromosome 6)
- Called Human Leukocyte Antigen (HLA)
- Responsible for rapid rejection of tissue grafts
- Bind peptide Ag & present them to T cells
- TCR only recognizes Ag presented by MHC on the APC
Upon entry of pathogen into the host major antigens
are taken up by APCs (macrophages) antigens
reappear on the macrophage surface complexed with
proteins encoded by MHC presented to clones of T
lymphocytes produce cytokines that induce
lymphocyte proliferation
2 arms of the immune response
a. cell-mediated
b. antibody-mediated
Antibody-mediated arm
- CD4 THC recognize the pathogen's antigens complexed
with class II MHC proteins on the surface of APC
- produce cytokines that activate B cells expressing Ab
that specifically match the Ag
- B cells differentiate to form plasma cells which produce
Ig
Antibody-mediated arm (Humoral)- CD4 THC recognize the
pathogen's antigens complexed with class II MHC proteins on
the surface of APC
- produce cytokines that activate B cells expressing Ab that
specifically match the Ag
- B cells differentiate to form plasma cells w/c produce Ig
Features of Some Human MHC Gene Products
The Secondary Response
Class I Class II Second encounter with the same antigen
Antibody response more rapid and rises to
Genetic loci HLA-A, -B, HLA-DP, -DQ, and DR higher levels than during the primary response
(partial list) and C Persistence of antigen-sensitive "memory
cells
Polypeptide MW 45,000 a chain (MW 33,000), b chain Amount of IgM produced is qualitatively
composition + 2M (MW (MW 29,000), Ii chain (MW similar to that produced after the first contact with
12,000) 30,000) the antigen
Much more IgG is produced tends to persist
much longer
Cell distribution All nucleated Antigen-
somatic cells presenting cells
(macrophages, B
cells, etc),
activated human
T cells
Present peptide antigens to CD8 T cells CD4 T cells

Size of peptide bound 811 1030 or more

residues residues

THE COMPLEMENT SYSTEM

Serum & membrane-bound proteins
Innate and acquired host defense
Augment the effects of other components of the
immune system
Numbered C1 to C9
reaction sequence C1-C4-C2-C3-C5-C6-C7-C8-C9.
Up to C5 activation involves proteolytic cleavage
liberating smaller fragments from C2 through C5
smaller fragments = a; larger fragments = b
Activation can be initiated either by Ab-Ag complexes or
by a variety of nonimmunologic molecules.

Main effects:
1. Opsonization: organisms, Ag-AB complexes (C3b)
2. Chemotaxis: C5a stimulates movement of PMNs
ANTIBODY MEDIATED HUMORAL IMMUNITY 3. Anaphylatoxins: C3a, C4a & C5a degranulation of
mass cells w/ release of mediators inflammation
The Primary Response 4. Cytolysis: insertion of the C5b6789 complex (MAC)
First encounter killing/ lysis of bacteria, tumor cells RBCs
Ab to Ag is detectable in serum within days or weeks
depending on the nature and dose of Ag and the route
of administration
Serum Ab concentration continues to rise for several
weeks & then declines drop to low levels
First Ab formed - IgM followed by IgG, IgA, or both
 macrophages present antigen to T lymphocytesvia
their cell surface-situated MHC proteins
antigen-MHC class II complex is recognized by helper
(CD4) T lymphocytes
antigen-MHC class I complex recognized by cytotoxic
(CD8) T lymphocytes
T cells produces cytokines becomes activated,
expands by clonal proliferation

T CELL PROLIFERATION & DIFFERENTIATION

BIOLOGICAL ACTIVITIES PROMOTED BY C5a

CELL-MEDIATED IMMUNITY

important in toxin-induced disorders, infections

with capsulated bacteria, and defense response to
infections
imparts resistance and aids in recovery
cooperation of antibodies required
Important in combating tumor cells
T CELL FUNCTIONS formation of IgE binds to receptors on mast cells and
A. Effector functions eosinophils
In response to tumors/allografts CD4+ Mediators Histamine; Prostaglandins; thromboxanes
cells recognized Class II MHC & become
activated prodn of IL-2 Type II hypersensitivity
CD8+ cytotoxic cells recognized class I MHC binding of IgG to cell surface antigens or extracellular
on the foreign cells destruction of these matrix molecules
cells activate complement to damage the cells
B. Regulatory functions complement-mediatedlysis - hemolytic anemias, ABO
Antibody production by B cells requires transfusion reactions, HDN.
participation of T helper cells
Both B and T cells must have the same class Type III: Immune Complex Hypersensitivity
II MHC specificity immune complexes are formed are deposited in tissues
autoimmune disorders
T CELL-DEPENDENT RESPONSE Activation of complement system
Arthus reaction local
Antigen systemic immune complex disease APSGN

IgM on the B cell surface Type IV: Cell-Mediated (Delayed) Hypersensitivity

specifically sensitized T lymphocytes that activate
Internalized & processed macrophages to cause an inflammatory response
response is delayedie, it usually starts 23 days after
Returned to B cell surface contact with the antigen and often lasts for days
w/ class II MHC
COURSE OF A TYPICAL ACUTE INFECTION
Interact with TCR on THC

Produce cytokines

Enhance division of B cells, differentiate into Ab producing

plasma cells

CONDITIONS THAT PREDISPOSE TO INFECTION

PREDISPOSING CONDITION ORGANISMS COMMONLY
CAUSING INFECTION
HYPERSENSITIVITY REACTION IMMUNOCOMPROMISED
immune response results in exaggerated or STATE
inappropriate reactions Low Ab Pyogenic bacteria (S aureus, S
harmful to the host pneumonia)
typically occur after the second contact with a specific
Low complement (c3b) Pyogenic bacteria (S aureus, S
antigen (allergen)
pneumoniae)
first contact induces sensitization to allergen.
Low complement Neisseria meningitis
4 types of hypersensitivity reactions. Types I, II, and III -
(C6,7,8,9)
antibody-mediated; type IV - T-cellmediated.
Low CD4 cells (AIDS) Various bacteria (MTB)
Type I: Immediate Hypersensitivity (Allergy)
within seconds
systemic anaphylaxis or local reaction
PREDISPOSING CONDITION ORGANISMS COMMONLY
CAUSING INFECTION
PRESENCE OF FOREIGN
BODIES
Urinary catheters E. coli

IV catheters Staph epidermidis, Candida

albicans
Prosthetic heart valves S. epidermidis, C albicans

Vascular grafts S. epidermidis, S. aureus,

Salmonella enterica
Prosthetic joints S epidermidis

Deficiencies of the Immune Response

Immundeficiency diseases
A. Primary Immunodeficiences - genetic defect results in
the loss of number or function of B cells, T cells, or
phagocytic cells, complement components, cytokines
loss of functional elements leads to increased
susceptibility to infections
chronic granulomatous disease
severe combined immunodeficiency
B. Secondary Immunodeficiencies
- associated with infections, malignancy and drugs
Infections - HIV infection
Malignancy leukemias, lymphomas, multiple myeloma,
other cancers
Drugs cytotoxic drugs (cisplatin), immunosuppressive
drugs (cyclosporine)

CLINICAL IMMUNOLOGY LABORATORY(diagnostic testing)

ANTIBODY EVALUATION ASSAYS
A. Enzyme-Linked Immunosorbent Assay
B. Immunofluorescence
C. Immunoblotting
D. Other Laboratory assays
- Protein electrophoresis
- Immunofixation electrophoresis
- nephelometry