Microbiology 1.1 Immunology - Dr. Fontanilla

IMMUNOLOGY
Benida A. Fontanilla, MD, MBA, MSTM

Department of Microbiology and Parasitology
OBJECTIVES
At the end of the 4 hours lecture, the student should be able to:
• Describe the basic principles of immunology, particularly as they relate to response
to infection.
• Define the following terms:
– immune response
– innate immunity
– adaptive immunity
– antigen
– antibody
– major histocompatibility complex
– complement
– cytokines
– hypersensitivity
– Immunodeficiency
• Differentiate humoral and cellular immunity
• Describe the functions of antibodies
• Enumerate and describe the different hypersensitivity reactions
• Describe the more common deficiencies of the immune response
REFERENCE
Jawetz, Melnick & Adelberg’s MEDICAL
MICROBIOLOGY, 26th Edition, 2013,
Chapter 8, pp 123-148.
IMMUNE RESPONSE
Immune response – a response generated against a
potential pathogen
Innate immunity – first line of defense;
non-specific to the pathogen;
rapidly mobilized at the site of infection;
lacks immunologic memory
Adaptive immunity – second line of defense;
specific to the invading pathogen;
can confer protective immunity to reinfection
with that pathogen
IMMUNE RESPONSE
INNATE IMMUNITY
Physiologic Barriers
A. Skin
- intact skin – only few microoganisms can penetrate
- sweat glands and sebaceous glands secretions –
acidic pH is antimicrobial
- Lysozyme in tears, respiratory and cervical secretions
– dissolves bacterial cell walls
- psoriasin – antimicrobial produced by the skin
INNATE IMMUNITY
B. Mucous Membranes
1. in respiratory tract,
- driven outwards by ciliated cells
- surface epithelial cells with IgA
– prevent attachment of piliated bacteria
- phagocytes take up microorganisms and transport
to lymph node
- protective mechanisms in respiratory system like
cough reflex
INNATE IMMUNITY
B. Mucous Membranes
2. in gastrointestinal tract
- saliva – hydrolytic enzymes
- stomach acidity – kills ingested bacteria
- small intestines - proteolytic enzymes
- normal microbial flora – prevent establishment
of pathogenic microorganisms
INNATE IMMUNITY
B. Mucous Membranes
3. Genital tract (vagina) – acid pH by normal
lactobacilli
- to inhibit establishment of yeasts, anaerobes
and gram-negative bacilli
INNATE IMMUNITY
Mechanisms of Innate Immunity
A. Microbial sensors
- macrophages and other phagocytic cells possess
“microbial sensors”
1. Toll-like receptors (TLRs)
2. NOD-like receptors (nucleotide-binding
oligomerization domain-like receptors) (NLRs)
3. RIG-1 like helicases and MDA-5
INNATE IMMUNITY
1. Toll-like receptors (TLRs) – first line of defense
against pathogens
- play a role in initiating the innate immune response
- belong to a family of evolutionary conserved
(PRRs) Pattern Recognition Receptors that recognize
(PAMPs) Pathogen Associated Molecular Patterns
- recognition of microbial patterns lead to signal
transduction cascade that generates a rapid
inflammatory response.
INNATE IMMUNITY
A.Microbial sensors
1. Toll-like receptors (TLRs)
TLR2 – recognizes various ligands (lipoteichoic acid)
expressed by gram-positive bacteria
TLR3 – engages dsRNA in viral replication
TLR1 & TLR6 – recognizes multiple diacyl peptides
(mycoplasma)
TLR4 – gram negative lipopolysaccharides
TLR5 – bacterial flagellin
TLR7 & TLR8 – interact with ssRNA in viral replication
TLR9 – binds bacterial DNA
INNATE IMMUNITY
INNATE IMMUNITY
2. NOD -like receptors (NLRs)
- located in the cytoplasm
- intracellular sensors for microbial products
- activate nuclear factor kappa-light chain-enhancer
of activated B cells (NF-κβ) pathway
- drive inflammatory responses similar to the TLRs.
INNATE IMMUNITY
3. RIG-1 like helicases and MDA-5
- cytoplasmic sensors of viral ssRNA
- trigger type 1 IFN production
- IFNs are highly effective inhibitors of viral
replication
INNATE IMMUNITY
INNATE IMMUNITY
B. Phagocytosis
phagocytes in the immune
system
1. monocytes and
macrophages
2. granulocytes – PMN,
eosinophils and
basophils
3. dendritic cells
INNATE IMMUNITY
B. Phagocytosis
functions of phagocytic
cells
1. chemotaxis
2. migration
3. ingestion
4. microbial killing
hallmark of phagocytic
process
1. rapid
2. nonspecific
3. short duration
INNATE IMMUNITY
B. Phagocytosis
Antimicrobial mechanisms used by phagocytes
1. acidification occurs within the phagosome
pH 3.5 – 4.0 bacteriostatic or bactericidal
2. toxic oxygen derived products are generated
superoxide O2 ; hydrogen peroxide H2O2 and
singlet O2
3. Toxic nitrogen oxides are produced and nitric
oxide is formed
4. antimicrobial peptides participate in killing
macrophage – cathelicidin, macrophage derived peptides
PMN – α-defensins, β-defensins, cathelicidin, lactoferrin
INNATE IMMUNITY
C. Natural Killer Cells (NK cells)
- large, granular lymphocytes
- morphologically related to T-cells
- 10 – 15% of leukocytes in blood
- provide protection against viruses and other intracellular
pathogens
- can recognize virus infected cells
and tumor cells
INNATE IMMUNITY
Have two types of surface receptors
1. lectin-like NK-cell receptors
- bind proteins
2. killer immunoglobulin-like receptor (KIRs)
- recognize major histocompatibility complex (MHC) class I
human leukocyte antigen B (HLA-B)
or HLA-C
- Can lyse target cells – malignant transformation

- Kill virus-infected cells with altered levels of MHC class molecules
INNATE IMMUNITY
- play a role in
antibody-dependent
cellular cytotoxicity (ADCC)
- contains large amounts of
granzyme and perforin
- mediate cytotoxic
action of NK cells
INNATE IMMUNITY
- and the IFN system are both integral parts of innate
immunity that communicate with each other
- primary source of IFN- Υ a potent anti-viral and immuno
regulating cytokine
- lytic activity of NK cells is enhanced by type 1 IFNs
IFN-α and IFN-β – induced by invading virus
- acts through MHC class I molecules which are upregulated
by IFNs
INNATE IMMUNITY
D. Complement
- composed of 30 proteins found in the serum or on
membrane of selected cells.
- complement proteins target pathogens for destruction by
lysis or for engulfment by phagocytes
- 3 pathways : classical, alternative and lectin
- result in lysis of offending invader
INNATE IMMUNITY
INNATE IMMUNITY
E. Mediators of Inflammation: Cytokines
- activated macrophages release
cytokines – IL-1 and TNF-α
prostaglandins
leukotrienes
- effect of mediators:
1. elicit changes in blood vessels -inflammation
2. induce changes in expression of various
adhesion molecules (selectins and integrins)on
endothelial cells and leukocytes – promote
movement across vessel wall to migrate out
toward the irritant
INNATE IMMUNITY
INNATE IMMUNITY
Mechanisms of Innate
Immunity
E. Mediators of Inflammation:
Cytokines
chemokines
– stimulate leukocyte
movement
- recruit monocytes and
neutrophils from
blood into sites of
infection
- synthesized by
macrophages and
endothelial cells
INNATE IMMUNITY
Interferons (IFNs) – role in defense against virus
infection and other intracellular organisms
- 3 groups:
1. Type I – IFN-α and IFN-β
2. Type II – IFN- γ
3. Type III – IFN-λ
INNATE IMMUNITY
Interferons (IFNs)
ADAPTIVE IMMUNITY
ADAPTIVE IMMUNITY
ADAPTIVE IMMUNITY
Stem cells
Lymphoid series
B cells
T cells
Myeloid series
ADAPTIVE IMMUNITY
ADAPTIVE IMMUNITY
Humoral Immunity
ANTIGENS – a substance that can provoke the production of
antibody
Features that determine immunogenicity:
1. foreignness – for immunogenicity to occur,
molecules must be recognized as “non-self”
2. size – most immunogens are usually large proteins
3. chemical and structural complexity –
heteropolymers containing 2-3 different amino acids are more
immunogenic
4. genetic constitution of the host – 2 strains of the same species
of animal may respond differently to the same antigen
5. dosage, route and timing of antigen administration – the
immune response can be optimized by carefully defining the
dosage, route of administration and timing of administration
ADAPTIVE IMMUNITY
Humoral Immunity
ANTIGEN RECOGNITION MOLECULES
Major Histocompatibility Complex
- MHC molecules bind peptide antigens and bind
them to T-cells
- cluster of genes located on chromosome 6
- genes that encode the class I, class II, and
class III MHC proteins
Class I molecules – found on virtually all nucleated
cells in the body; recognized by CD8 cytotoxic T-lymphocytes
Class II molecules – chiefly found on macrophages,
dendritic cells, B-cells and other APC’s;
recognized by CD4 helper T cells
Class III molecules – encodes complement proteins
ADAPTIVE IMMUNITY
ADAPTIVE IMMUNITY
Antigen Processing and Presentation
MHC Class I and endogenous antigens:
- MHC Class I molecules are synthesized in the
endoplasmic reticulum of the infected cell (viral infection)
- Viral proteins in the cytoplasm that have infected
the cell are broken down by proteolytic complex
known as proteasome
- Cytosolic peptides gain access to MHC Class I molecules
in the ER via peptide transporter system (TAPs)
- MHC Class I – peptide antigen complex is formed and
transported to the cell surface for display and
recognition by CD8 cytotoxic T-cells
ADAPTIVE IMMUNITY
MHC Class II and exogenous antigens:
- Class II MHC molecules (membrane glycoprotein) are
synthesized in the RER and proceed out to the Golgi
apparatus and transported out to the cytoplasm via
exocytic
vesicles
- Proteins from exogenous antigens (bacteria) are
taken up by the cell (APCs like dendritic cells and
macrophages) via endocytic vesicles
- proteins are exposed to cellular proteases in intracellular
vesicles producing peptides
- endosomal vesicles with peptides fuse with exocytic vesicles
containing MHC Class II molecules
ADAPTIVE IMMUNITY
ADAPTIVE IMMUNITY
Interference with antigen processing pathways:
Examples
- HIV virus produces a Tat protein that inhibits
expression of Class I MHC molecules
- Herpes virus proteins binds to the TAPs, preventing
transport of viral peptides into the ER where Class I
molecules are being synthesized
* virus infected cells are not recognized by cytotoxic

lymphocytes.
ADAPTIVE IMMUNITY
- superantigens like staphylococcal enterotoxin, toxic
shock syndrome toxin, group A streptococcal
pyrogenic exotoxin
- superantigens bind to “outside” portion of the MHC
protein-T-cell receptor complex
- cause T-cells to be stimulated and to release large
amounts of cytokines (IL-1, TNF) – pathogenesis of
disease
ADAPTIVE IMMUNITY
ADAPTIVE IMMUNITY
B cells and Antibodies
Humoral immunity is mediated by antibodies, which are
produced by B-cells
- large pool of different B lymphocytes that have a
life span of days or weeks
-B cells are found in the bone marrow, lymph nodes
and gut-associated lymphoid tissues (appendix,
Peyer’s patches, tonsils)
ADAPTIVE IMMUNITY
B-Cell Receptor for Antigen
- display a single immunoglobulin molecule on the
surface which serve as receptors (B-cell receptor )
BCR for a specific antigen
- each B-cell can respond to only one antigen or
closely related groups of antigens
- all immature B-cells carry IgM immunoglobulins on
their surface and most carry IgD
ADAPTIVE IMMUNITY
B-Cell Receptor for Antigen
- an antigen interacts with the B lymphocytes that
shows the best “fit” and binds to the BCR
- there is an antigen-binding site on a B-cell to fit
almost any antigenic determinant
- the B cell is stimulated to divide and form a clone
(clonal selection)
- this selected B-cell differentiate to become plasma
cells and secrete antibody
- each person can make approximately
1,000,000,000,000 different antibody molecules
ADAPTIVE IMMUNITY
Steps in Antibody Formation
1. Binding of antigen to the surface immunoglobulin via
BCR
2. The BCR with the bound antigen is internalized by the B
cell
- the antigen is degraded to yield peptides that are
then returned to the cell surface bound to MHC
class II molecules
3. MHC class II-peptide complex on B cells is recognized by
antigen-specific helper CD4 T-cells
- these T-cells have already interacted with APC
dendritic cells and have differentiated in response to
the same antigen
ADAPTIVE IMMUNITY
4. Chemokines, such as CXCL13 and its receptor CXCR5,
play an important role in this migration process
5. CD40 ligand on T-cells binds to CD40 on B cells
- T-cell produces cytokines such as IL-4, IL-5 and IL-6
which induce B-cell proliferation
6. Finally, the activated B cells migrate into follicles and
proliferate to form germinal centers
- germinal center B cells that survive this process now
differentiate into either antibody-producing plasma
cells or memory B cells.
ADAPTIVE IMMUNITY
ADAPTIVE IMMUNITY
* some bacterial antigens can directly stimulate antibody
production
- thymus independent antigens
- induce B-cell responses with limited class switching
- do not induce memory B cells
- eg. bacterial polysaccharides and lipopolysaccharides
ADAPTIVE IMMUNITY
Fab fragment
Fc fragment
ADAPTIVE IMMUNITY
ADAPTIVE IMMUNITY
Immunoglobulin Classes
1. IgG
- made up of four subclasses – based on amino acid
sequence differences in the H chain constant region
IgG1 - 65 % of total IgG
IgG2 - directed against polysaccharide antigens
- against encapsulated bacteria
IgG3 - effective activator of complement due to
rigid hinge region
IgG4 - does not activate complement due to
compact structure
ADAPTIVE IMMUNITY
1. IgG
- predominant antibody in
secondary immune responses
- important defense against
encapsulated bacteria
- readily crosses the placenta;
most abundant Ig among
newborns
- mediates opsonization of
antigen through antigen-
antibody complexes to Fc
receptors on macrophages
and other cells.
ADAPTIVE IMMUNITY
2. IgM
- the main immunoglobulin produced early in the primary
immune response
- present on the surface of all uncommitted B cells
- composed of five H2L2 units and one molecule of J chain
= pentamer with 10 identical antigen-binding sites
- most efficient immunoglobulin in agglutination,
complement fixation and other Ag-Ab reactions
- has the highest binding capacity and cross linking of all Igs
- evaluation of the presence of serum IgM is useful in the
diagnosis of certain infectious diseases
- does not cross the placenta; presence of IgM in the newborn is
ADAPTIVE IMMUNITY
ADAPTIVE IMMUNITY
3. IgA
- main immunoglobulin responsible for mucosal
immunity
- found in secretions such as milk, saliva and tears;
respiratory, intestinal and genital tract secretions
- each secretory IgA molecule consists of two H2L2 and
one molecule of J chain and secretory component
- a receptor binds IgA dimers and facilitates transport
across mucosal epithelial cells
- two subclasses IgA1 and IgA2
- some bacteria (Neisseria spp) can destroy IgA1 by
producing a protease
ADAPTIVE IMMUNITY
4. IgE
- the Fc region of IgE binds to
its high affinity receptor
on the surface of mast cells,
basophils and eosinophils
- the bound IgE acts as a
receptor for the antigen that
stimulates its production
- resulting Ag-Ab complex
triggers allergic responses
of the immediate
(anaphylactic) type
ADAPTIVE IMMUNITY
5. IgD
- acts an antigen receptor when present on the surface
on certain B lymphocytes
- trace amounts in serum
- function is unclear
ADAPTIVE IMMUNITY
Primary Response
Primary Response
- an individual encounters an antigen for the first
time
- antibody produced against that antigen will be
detectable in the serum within days or weeks
- serum antibody concentration continues to rise for
several weeks and then declines
- first antibodies formed are IgM, followed by IgG,
IgA or both
- IgM levels then decline sooner than IgG levels
ADAPTIVE IMMUNITY
Primary Response
ADAPTIVE IMMUNITY
Secondary Response
Secondary Response
- second encounter with the same antigen or a
closely related “cross-reacting” antigen months or
years after the primary response
- produce qualitatively similar IgM
- much more IgG is produced; persists longer than
the primary response
- antibody produced tends to bind antigen more
firmly, have higher affinity and dissociate less easily
ADAPTIVE IMMUNITY
Protective Functions of Antibodies
1. Enhanced phagocytosis
- antibodies coat organisms (opsonizing); more
readily ingested by phagocytes
- antibody-mediated immunity against bacteria is
most effective in bacterial infections in which
virulence is related to polysaccharide capsules
eg: Streptococcus pneumoniae,
Haemophilus spp.
Neisseria spp.
ADAPTIVE IMMUNITY
2. Virus Neutralization
- viruses need to invade the cell; obligate intracellular
pathogens
- antibodies directed against specific viral proteins bind to
the virus and block the ability of the virus particle to
attach to cell membrane receptor
3. Neutralization of Toxins
- antibodies can neutralize toxins of bacteria
eg: Corynebacterium diphtheriae – diphtheria toxin
Clostridium tetani – tetanus toxin
Clostridium botulinum - botulism
ADAPTIVE IMMUNITY
4. Complement-Mediated Lysis
- attachment of antibodies to viral proteins on virus
infected cells or to a microbial cell can activate
complement system leading to cell lysis
5. Antibody-Dependent Cell Cytotoxicity (ADCC)

- attachment of antibodies to viral proteins on virus
infected cells --- antibody-coated cells interact with
killer cells = lysis
ADAPTIVE IMMUNITY
Strategies to Induce Antibody Production
A. Active Immunity
- induced after contact with foreign antigens
(microorganisms and their products)
- clinical infection, subclinical infection, immunization
with live or killed infectious agents or their antigens,
exposure to microbial products (toxins, toxoids) or
transplantation of foreign cells
- the host actively produces antibodies
- protection is delayed until antibody production reaches
an effective level
*binding of antibodies to antigens leads to the formation of
circulating immune complexes – kidneys, heart valves – organ
dysfunction
ADAPTIVE IMMUNITY
Strategies to Induce Antibody Production
B. Passive Immunity
- generated by administration of preformed antibodies
- prompt availability of large amounts of antibody
- eg. After needle stick injury vs Hepatitis B virus
* Hypersensitivity reaction if preformed antibody is

produced from other species – horse, sheep
ADAPTIVE IMMUNITY
Cell-mediated Immunity
BREAK
To be continued next lecture session
IMMUNOLOGY
continuation
Jawetz, Melnick & Adelberg’s MEDICAL
MICROBIOLOGY, 26th Edition, 2013,
Chapter 8, pp 123-148
ADAPTIVE IMMUNITY
Cell-Mediated Immunity
Review:
Humoral Immunity / Antibody-Mediated Immunity:
- toxin-induced disorders
- microbial infections – polysaccharide capsule virulence
- viral infections
- T-cell subsets and APC’s recognize and respond to the
pathogen
ADAPTIVE IMMUNITY
Development of T-cells
- T-cell progenitor cells undergo differentiation in the
thymus
- under the influence of thymic hormones T-cells
differentiate into committed cells expressing a specific
T-cell receptor (TCR)
- most T-cells with TCR become positive for both CD4
and CD8 (co-receptor molecules)
- T-cells undergo selection process that result in the
retention only of those cells with antigen receptors for
nonself or foreign antigens – 99% die in the thymus
- those that survive undergo final maturation process
which express either CD4 or CD8
- exit into the periphery to mature into effector cells
ADAPTIVE IMMUNITY
T-Cell receptor for Antigen
- T-cell receptor proteins have variable and constant
regions similar to antibodies
- variable regions are located at the amino terminals of
the polypeptide chain farthest away from the cell
membrane
- both chains contribute to the variable domain that
interact with antigen presented by MHC complex
- CD4 and CD8 function as co-receptors
- during recognition of antigen, the CD4 and CD8
molecules interact with T-cell receptor complex and
MHC molecules on the APC
- CD4 binds to MHC class II and CD8 binds to MHC class I
ADAPTIVE IMMUNITY
T-Cell Proliferation and Differentiation
MHC Class II presentation: 2 signals needed to activate
naïve CD4 T-cells
1. T-cell receptor interacting with the MHC-peptide complex
presented on the APC; CD4 glycoprotein on the naïve T-cell
acts as co-receptor = ensures stability between T-cell and
APC.
2. interaction of B7 costimulatory molecules on the APC
with CD28 on the T-cell.
- T-cell secretes cytokines IL-2 and IFN-γ

- T-cells are able to proliferate and differentiate into
effector cells
ADAPTIVE IMMUNITY
ADAPTIVE IMMUNITY
T-Cell Proliferation and Differentiation
MHC Class I presentation: CD8 activation
- T-cell receptor interacts with MHC class I – peptide
complex on the infected cell
- CD8 glycoprotein acts as a co-receptor
-once activated the cytotoxic T-cell produces IL-2 and
IFN-γ, growth and differentiation factors for T-cells
- independent of co-stimulation
- virus-infected cell is destroyed through cytotoxic
granules released from the CD8 T-cells
ADAPTIVE IMMUNITY
T-cell Effector Functions
1. CD4 Effector cells
a. Th1 cells – differentiate in the presence of IFN-γ
- activate macrophages
- cause B cells to switch to produce different
subclasses of IgG
- promote clearance of bacteria by direct
destruction in the IFN-γ activated macrophage
or by destruction after phagocytosis of
opsonized particles
- produce IL-2 and IFN-γ
ADAPTIVE IMMUNITY
b. Th2 cells – predominate in the presence of IL-4
- activate mast cells and eosinophils and cause B
cells to synthesize IgE
- respond to helminthic infections
- secrete IL-4, IL-5, IL-9 and IL-13
ADAPTIVE IMMUNITY
c. Th17 cells – produced when TGF-β and IL-6 come
together
- produce IL-17 and IL-22
- IL-17 – cytokine that induces stromal and
epithelial cells to produce IL-8
- IL-8 – a potent chemokine that recruits
neutrophils and macrophages to infected
tissues
ADAPTIVE IMMUNITY
d. Regulatory T (Treg) cells –
- CD4 T cells become Treg when exposed to
TGF-β
- function by suppressing T-cell responses
- produce TGF-β and IL-10 which suppress
immune responses
ADAPTIVE IMMUNITY
2. CD8 Effector Cells
- CD8 cells differentiate into effector cytotoxic cells by
engagement of their TCR and recognition of
class I MHC – peptide complex on the surfce of an infected
cell
- CD8 T-cells kills infected cells
- cytotoxic granules containing perforin,
granzymes and granulysin
- releases perforin that helps granzyme and
granulysin to enter the infected cell
- granzyme initiates apoptosis (programmed cell
death)
ADAPTIVE IMMUNITY
COMPLEMENT
Major Pathways that activate complement
1. Classical Pathway
2. Alternative Pathway
3. Mannan-binding Lectin (MBL) Pathway
- All three pathways lead to release of C5 convertase which breaks

down C5 into C5a and C5b
- C5a is an anaphylatoxin as well as a chemotactic factor
- C5b binds to C6 and C7 to form a complex that inserts into the
membrane bilayer
- C8 then binds to the C5b-C6-C7 complex followed by
polymerization of up to 16 C9 molecules to produce MAC
- The MAC generates a channel pore in the membrane cytolysis by
allowing free passage of water across the cell membrane
COMPLEMENT
COMPLEMENT
Regulation of Complement System
1. C1 inhibitor binds to and inactivates the serine protease
activity of C1r and C1s
2. Factor I cleaves C3b and c4b – reducing amount of C5
convertase available
3. Factor H enhances the effect of factor I on C3b
4. Factor P (properdin) protects C3b and stabilizes the C3
convertase of the alternative pathway
5. Decay-accelerating factor – a membrane ound protein
found on most blood cell surfaces – accelerate the
dissociation of C3 convertase on all 3 pathways
COMPLEMENT
Complement Deficiencies
1. C2 deficiency –serious pyogenic infections
2. MAC components deficiency – enhances
susceptibility to Neisserial infection
3. Properdin deficiency – susceptibility to
meningococcal disease
4. C1 inhibitor protein deficiency – hereditary
angioedema
COMPLEMENT
Pathogen Evasion
1. Some microbes have developed surfaces that
interfere with opsonization by C3b or interfere with
insertion of the MAC
2. Complement activation inhibited by presence of
microbial generated proteins
- Protein A bind IgG Fc
- Protein C
3. Microbes can generate enzymes that degrade
complement component
CYTOKINES
Cytokines
- potent low-molecular-weight protein cell
regulators
- produced transiently and locally by numerous cell
types
- multifunctional proteins
- hematopoiesis, immunity, infectious disease
tumorigenesis, homeostasis, tissue repair and
cellular development and growth
-act as signaling molecules by binding to their own
glycoprotein receptors on cell membranes
- followed by a relay of the signal to the cell nucleus
CYTOKINES
Classification and Functions
1. Immunoregulatory
- IFN-γ – role in antigen presentation
2. Proinflammatory – seen in infectious diseases
- IL-11, IL-6, TNF-α and IFNs
3. Anti-inflammatory – down regulate an overactive
inflammatory response
- TGF-β, IL-10, IL-11 and IFN-β
4. Growth and Differentiation
- colony stimulation factor (CSFs) and stem cell factor
CYTOKINES
Clinical Application
1. Biomarkers of disease – provide clues for
mechanisms of disease
- proinflammatory cytokines TNF-α, Il-1 and IL-6
can be detected in the sera of patients with
septic shock
2. Measurement of cytokine production in vitro – useful
monitor of immune status
- T-cell function can be monitored by the ability of
T-cells to produce IFN-γ
- eg. Identify TB reactivity
CYTOKINES
Clinical Application
3. Recombinant cytokines – key therapeutic agents
- INF-α – hepatitis C infection
- INF-β – multiple sclerosis
4. Targets of therapeutics – cytokine receptor
antagonists and anti-cytokine monoclonal antibodies
- downgrade pathogenic responses to
exaggerated
cytokine production
- eg. Inhibitors of TNF-α - used to manage
rheumatoid arthritis
inhibitors of IL-2 and IL-15 – used in
transplantation and cancer
HYPERSENSITIVITY
Hypersensitivity – a condition in which a immune
response results in exaggerated or
inappropriate reactions that are harmful to the
host
- the first contact with an antigen induces a
necessary preliminary event that induces
sensitization to that allergen
- the second contact, a hypersensitivity reaction
can occur
HYPERSENSITIVITY
Type I: Immediate Hypersensitivity (Allergy)
- occurs within seconds after antigen combines with
the specific IgE
- intravenous administration – systemic
- atopic allergy – local reaction
HYPERSENSITIVITY
A. Mediators:
1. Histamine – causes vasodilation, increased capillary
permeability, smooth muscle contraction (bronchospasm)
- primary mediator
2. Prostaglandins and leukotrienes – derived from arachidonic
acid via the cyclooxygenase pathway
- secondary mediators
- PG cause bronchoconstriction
- Leukotrienes – increased permeability of capillaries
HYPERSENSITIVITY
B. Treatment and Prevention
- reverse action of mediators by maintaining airway,
artificial ventilation, supporting cardiac function
- give epinephrine, antihistamines, and corticosteroids
- prevention by identification of allergen and avoidance
C. Atopy – strong familial predispositon; elevated IgE levels

- symptoms induced by exposure to specific allergens
- pollen, house dust, food (shellfish)
- hay fever, asthma, eczema, and urticaria
HYPERSENSITIVITY
Type II Hypersensitivity
- involves binding of IgG antibodies to cell surface
antigens or extracellular matrix molecules
- antibodies directed at cell surface antigens can activate
complement to damage cells
ex: hemolytic anemias, ABO transfusion reactions and
Rh hemolytic disease
- autoimmune antibodies can combine with cell surface

with resulting hemolysis
ex: penicillin on surface of RBC, Goodpasture Syndrome
Graves disease
HYPERSENSITIVITY
HYPERSENSITIVITY
Type III: Immune Complex Hypersensitivity
- formation of immune complexes
- antibody combines with its specific antigen
- deposited in tissues
- in persistent microbial or viral infections, immune
complexes deposited in organs (kidneys)
- autoimmune disorders – self antigens elicit antibodies
that bind to organs and tissues (joints, kidneys, blood
vessels)
HYPERSENSITIVITY
Type III: Immune Complex Hypersensitivity
Two major forms:
1. Arthus reaction – local, typically elicited on skin when a
low dose of antigen is injected and immune complex
form locally; occurs within 12 hours
- IgG is formed; activation of complement leads to
activation of mast cells and neutrophils, mediator
release and vascular permeability
2. Systemic Immune Complex disease
- ex: Acute Poststreptococcal glomerulonephritis
HYPERSENSITIVITY
HYPERSENSITIVITY
Type IV: Cell-Mediated (Delayed) Hypersensitivity
- a function of specifically sensitized T-lymphocytes
that activate macrophages to cause an
inflammatory response
- response is delayed – starts days after contact with
antigen and lasts for days
HYPERSENSITIVITY
HYPERSENSITIVITY
Type IV: Cell-Mediated
(Delayed) Hypersensitivity
Two types:
1. Contact hypersensitivity
- sensitization with simple
chemical
(formaldehyde)
plant materials (poison
ivy) topically applied
drugs(sulfonamides)
some cosmetics
HYPERSENSITIVITY
Type IV: Cell-Mediated (Delayed)
Hypersensitivity
Two types:
2. Tyberculin-type Hypersensitivity
- little immediate reaction after small
amount of tuberculin is injected into
the epidermis of a patient previously
exposed to Mycobacterium
tuberculosis
- induration and redness develop and
reach a peak in
24-72 hrs
- that person has been infected with
the agent but does not imply the
presence of current disease
HYPERSENSITIVITY
DEFICIENCIES OF THE IMMUNE RESPONSE
A. Primary Immunodeficiency
- disorders of the immune system in which the
defect is intrinsic to the cells of the immune system
- have a genetic basis
- loss of number or function of B cells, T cells or
phagocytic cells, complement components,
cytokines or TLRs
- leads to increased susceptibility to infections
A. Primary Immunodeficiency
Example: Chronic Granulomatous Disease (CGD)
- impaired phagocytic function
- normal levels of Igs, T- and B- cells and
phagocytic cells
- genetic defect in cytochrome b-558
- defect in the ability of phagocytes to
produce peroxide and superoxide
B. Secondary Immunodeficiency
- disorders of immune system in which the defect is
induced by external factors such as viruses, malignancy
and drugs
C. Infections
- Viral infections : Measles (Rubeola) and Ebstein Barr Virus (EBV)
- HIV – uses CD4 molecules as the virus receptor and chemokine
receptor; progressive loss of CD4 T-cells
- develop multiple oppostunistic infections
D. Malignancy
- leukemias – deficiency in neutrophils: loss of phagocytosis
- increased infections with bacteria and fungi
- lymphomas and multiple myeloma
- some tumors secrete high levels of TGF-β that suppress a
variety of responses including Th1 responses
E. Drugs
-cytotoxic drugs used to treat cancer (cisplatin)
- immunosuppressive drugs (cyclosporine) –transplantation
- treatment of autoimmune diseases (RA)
THE END

Microbiology 1.1 Immunology - Dr. Fontanilla

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Microbiology 1.1 Immunology - Dr. Fontanilla

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IMMUNOLOGY

Benida A. Fontanilla, MD, MBA, MSTM

- Can lyse target cells – malignant transformation

* virus infected cells are not recognized by cytotoxic

5. Antibody-Dependent Cell Cytotoxicity (ADCC)

* Hypersensitivity reaction if preformed antibody is

- T-cell secretes cytokines IL-2 and IFN-γ

- All three pathways lead to release of C5 convertase which breaks

C. Atopy – strong familial predispositon; elevated IgE levels

- autoimmune antibodies can combine with cell surface

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