Microbiology Lecture 1.1 Dra.

Fontanilla
Introduction to Immunology June 17-18, 2013

OUTLINE  resistance that is pre-existing and is not acquired through contact

I. Immune response with a non-self antigen
II. Innate Immunity 2. Adaptive immunity –
a. Physiologic barrier  second line of defense
b. Mechanism of innate immunity  specific to the invading pathogen
1. Microbial sensors  can confer protective immunity to reinfection with that pathogen
2. Phagocytosis
3. Natural Killer Cells INNATE IMMUNITY
4. Complement Physiologic Barriers at the Portal of Entry
5. Mediators of inflammation A. Skin
III. Adaptive Immunity  intact skin -- only few microoganisms can penetrate
a. Antigen Processing and presentation  sweat glands and sebaceous glands secretions -- acidic pH is
b. Antibody Mediated Immunity antimicrobial
a. B cells and antibodies  Lysozyme in tears, respiratory and cervical secretions -- dissolves
b. Immunoglobulin classes bacterial cell walls
c. Primary Response  Psoriasin -- antimicrobial protein produced by the skin
d. Secondary Response
e. Protective function of the antibodies B. Mucous Membranes
f. Strategies to induce antibody prduction  In respiratory tract
c. Cell Mediated Immunity o driven outwards by ciliated cells
d. T Cell Effector Function o surface epithelial cells with IgA
IV. Complement o prevent attachment of piliated bacteria
a. Regulation of Complement System o phagocytes take up microorganisms and transport to lymph node
b. Complement Deficiency o protective mechanisms in respiratory system like cough reflex
c. Pathogen Evasion  In gastrointestinal tract
V. Cytokines o saliva – presence of hydrolytic enzymes
a. Classification and Function o stomach -- acidity kills ingested bacteria
b. Clinical Application o small intestines – presence of proteolytic enzymes
VI. Hypersensitivity o normal microbial flora -- prevent establishment of pathogenic
a. Type 1: Immediate Hypersensitivity microorganisms
b. Type 2 Hypersensitivity  Genital tract (vagina)
c. Type 3: Immune Complex Hypersensitivity o acid pH by normal lactobacilli
d. Type 4: Delayed Hypersensitivity - to inhibit establishment of yeasts, anaerobes
VII. Deficiencies of the Immune Response and gram-negative bacilli

OBJECTIVES Mechanism of Innate Immunity

1. Describe the basic principles of immunology, particularly as they A. Microbial sensors
relate to response to infection.  macrophages and other phagocytic cells possess “microbial sensors”
2. Define the following terms: 1. Toll-like receptors (TLRs)
a. immune response 2. NOD-like receptors (nucleotide-binding oligomerization domain-like
b. innate immunity receptors) (NLRs)
c. adaptive immunity 3. RIG-1 like helicases and MDA-5
d. antigen  When macrophages recognize microbial constituents, they are stimulated
e. antibody to release cytokines that cause the recruitment of more phagocytic cells
f. major histocompatibility complex to the site of infection.
g. complement
h. cytokines 1. Toll-like receptors (TLRs)
i. hypersensitivity o first line of defense against pathogens
j. Immunodeficiency o play a role in initiating the innate immune response
3. Differentiate humoral and cellular immunity o belong to a family of evolutionary conserved (PRRs) Pattern
4. Describe the functions of antibodies Recognition Receptors that recognize(PAMPs) Pathogen Associated
5. Enumerate and describe the different hypersensitivity reactions Molecular Patterns
6. Describe the more common deficiencies of the immune response o recognition of microbial patterns lead to signal transduction cascade
that generates a rapid inflammatory response
IMMUNE RESPONSE
 Immune response – a response generated against a potential pathogen a. TLR2 – recognizes various ligands (lipoteichoic acid) expressed by
o Two types of Immune Response: gram-positive bacteria
1. Innate immunity b. TLR3 – engages dsRNA in viral replication
 first line of defense c. TLR1 & TLR6 – recognizes multiple diacyl peptides (mycoplasma)
 non-specific to the pathogen d. TLR4 – gram negative lipopolysaccharides
 rapidly mobilized at the site of infection e. TLR5 – bacterial flagellin
 lacks immunologic memory f. TLR7 & TLR8 – interact with ssRNA in viral replication
g. TLR9 – binds bacterial DNA

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 MICROBIOLOGY 1.1

 do not express antigen specific receptors; however, have two types of

surface receptors:
1. Lectin-like NK-cell receptors - bind proteins not carbohydrates
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
 play a role in antibody-dependentcellular cytotoxicity (ADCC)
 contains large amounts ofgranzyme and perforin -- mediate
cytotoxicaction of NK cells
 the IFN system are both integral parts of innateimmunity that
communicate with each other
 primary source of IFN- Υ a potent anti-viral and immunoregulating
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 IFN
Figure 1. Different Human Toll-like Receptors (TLRs).
D. Complement System
2. NOD -like receptors (NLRs)  composed of 30 proteins found in the serum or on membrane of
o located in the cytoplasm selected cells.
o intracellular sensors for microbial products  A set of proteins that enhance the function of both the adaptive and
o activate nuclear factor kappa-light chain-enhancerof activated B cells innate responses to infection
(NF-κβ) pathway  complement proteins target pathogens for destruction by lysis or for
o drive inflammatory responses similar to the TLRs. engulfment by phagocytes
 3 pathways for activation : classical, alternative and lectin
3. RIG-1 like helicases and MDA-5  result in lysis of offending invader
o cytoplasmic sensors of viral ssRNA
o trigger type 1 IFN production E. Mediators of inflammation: Cytokines
o IFNs are highly effective inhibitors of viral replication  Activated macrophages release:
a. cytokines – IL-1 and TNF-α
B. Phagocytosis b. prostaglandins
 Phagocytes in the immune system c. leukotrienes
1. monocytes and macrophages  Effect of mediators:
2. granulocytes – Polymorphonuclears (PMN), eosinophils and basophils a. elicit changes in local blood vessels
3. dendritic cells o Begins with local vasodilation, from which plasma escapes.
 Functions of phagocytic cells: o Edema fluid accumulates in the area of injury, and fibrin forms a
1. chemotaxis network and occludes the lymphatic channels, limiting the spread of
2. migration organisms
3. ingestion b. induce changes in expression of various adhesion molecules
4. microbial killing (selectins and integrins) on endothelial cells and leukocytes
 Hallmark of phagocytic process o promote movement across vessel wall to migrate out toward the
1. rapid irritant
2. nonspecific
3. short duration Chemokines
 stimulate leukocyte movement
 Antimicrobial mechanisms used by phagocytes:  recruit monocytes and neutrophils from blood into sites of
1. Acidification occurs within the phagosome infection
- pH 3.5 – 4.0 bacteriostatic or bactericidal  synthesized by macrophages and endothelial cells
2. Toxic oxygen derived products are generated superoxide O2; hydrogen
peroxide H2O2 and singlet O2 Interferons (IFNs)
3. Toxic nitrogen oxides are produced and nitric oxide is formed  role in defense against virus infection and other intracellular
4. Antimicrobial peptides participate in killing: organisms
macrophage – cathelicidin, macrophage derived peptides  3 groups:
PMN – α-defensins, β-defensins, cathelicidin, lactoferrin 1. Type I – IFN-α and IFN-β
2. Type II – IFN- γ
C. Natural Killer Cells (NK cells) 3. Type III – IFN-λ
 large, granular lymphocytes  Antiviral proteins, IFN-α and IFN-β, are distinct from the IFN- γ
 morphologically related to T-cells produced by activated T-lymphocytes. IFN-α and IFN-β help control
 10 – 15% of leukocytes in blood viral replication by inhibiting protein synthesis in cells.
 provide protection against viruses and other intracellular pathogens
 can recognize virus infected cells and tumor cells

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 MICROBIOLOGY 1.1

ADAPTIVE IMMUNITY MHC Class II and Exogenous antigens:

Overview of Adaptive Immune Response: (this could help to
understand the sequence of following topic under Adaptive immunity.)
 Upon entry of potential pathogen and after interaction with the
Innate immune response, it or its major antigens are taken up by
antigen-presenting cells (APC).
 With various Antigen processing and presentation steps, the MHC-
Antigen complexes in the surface of APC are recognized by T-cells.
 Concurrently, 2 types of adaptive immune response develop,
o Antibody-mediated response: CD4 Helper T-lymphocytes recognize
MHC II-Antigen complex; and causes the activation of B-
lymphocyte to differentiate into plasma cells, which then produce
specific immunoglobulins (antibodies).
o Cell-mediated response: CD8 Cytotoxic T-lymphocytes recognize
MHC I-Antigen complex. This activity is aimed mainly at the
destruction of cells.
 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
 MHC Class II – peptide antigen complex is transported to the cell
surface for display and recognition by a CD4 T-helper cell.

ANTIGEN – 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, because of a
different composition of genes involved in the immune response
5. Dosage, route and timing of antigen administration – the immune Figure 2. Endogenous and Exogenous Antigen processing.
response can be optimized by carefully defining the dosage, route of
administration and timing of administration
o It is possible to enhance the immunogenicity of a substance by
mixing it with an adjuvant. Adjuvants are substances that
stimulate the immune response – eg. By facilitating uptake into
antigen-presenting cells.

ANTIGEN RECOGNITION MOLECULES

Major Histocompatibility Complex (MHC)
 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
 3 classes of MHC:
1. Class I molecules
– found on virtually all nucleated cells in the body; recognized by
CD8 cytotoxic T-lymphocytes
Figure 3. Antigen-presenting cell with Antigen (Peptide) complex with MHC
2. Class II molecules
molecule in its surface.
– chiefly found on macrophages, dendritic cells, B-cells and other
APC’s; recognized by CD4 helper T cells
Interference with antigen processing pathways:
3. Class III molecules
Examples
– encodes complement proteins
 HIV virus produces a Tat protein that inhibits expression of Class I
MHC molecules
Antigen Processing and Presentation
 Herpes virus proteins binds to the TAPs, preventing transport of viral
MHC Class I and Endogenous antigens: peptides into the ER where Class I molecules are being synthesized
o virus infected cells are not recognized by cytotoxiclymphocytes
 MHC Class I molecules are synthesized in the endoplasmic reticulum of
the infected cell (viral infection)  Superantigens like staphylococcal enterotoxin, toxic shock syndrome
toxin, group A streptococcal pyrogenic exotoxin
 Viral proteins in the cytoplasm that have infected the cell are broken
o bind to “outside” portion of the MHC protein-T-cell receptor
down by proteolytic complex known as proteasome
complex
 Cytosolic viral peptides gain access to MHC Class I moleculesin the ER
o cause up to 10% of T-cells to be nonspecifically activated
via peptide transporter system (TAPs)
o cause T-cells to be stimulated and to release large amounts of
 MHC Class I – peptide antigen complex is formed and transported to
cytokines (IL-1, TNF) – pathogenesis of disease
the cell surface for display and recognition by CD8 cytotoxic T-cells
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 MICROBIOLOGY 1.1
Antibody-mediated (Humoral response) Immunity
B-cell 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)
B-Cell Receptor for Antigen
 display a single immunoglobulin molecule on thesurface 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
 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
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
o 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
o these T-cells have already interacted with APC dendritic cells and
have differentiated in response to the same antigen
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
o T-cell produces cytokines such as IL-4, IL-5 and IL-6which induce
B-cell proliferation
6. Finally, the activated B cells migrate into follicles and proliferate to
form germinal centers.
o germinal center B cells that survive this process now
differentiate into either antibody-producing plasma cells or
memory B cells
Figure 4. Antibody formation by B-cells
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 some bacterial antigens can directly stimulate antibody production
o thymus independent antigens
o induce B-cell responses with limited class switching
o do not induce memory B cells
o eg. bacterial polysaccharides and lipopolysaccharides
Immunoglobulin Classes
1. IgG
 made up of four subclasses based on amino acid sequence
differences in the H chain constant region
 4 subclasses:
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
 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
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
evidence of intrauterine infection
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 a 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
4. IgE
 the Fc region of IgE binds to its high affinity receptoron 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 through the release of mediators.
5. IgD
 acts an antigen receptor when present on the surface on certain B
lymphocytes
 trace amounts in serum
 function is unclear
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 MICROBIOLOGY 1.1
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
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
Protective Function 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.
2. Virus Neutralization
 viruses need to invade the cell; an 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
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
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
B. Passive Immunity
 generated by administration of preformed antibodies
 prompt availability of large amounts of antibody
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 eg. After needle stick injury vs Hepatitis B virus
 Hypersensitivity reaction if preformed antibody is produced from
other species – horse, sheep
Cell-Mediated 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
Figure 5. Differentiation of T-cells
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
T-Cell Proliferation and Differentiation
 With MHC class II presentation, 2 signals needed to activate naïve CD4 T-
cell:
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
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 MICROBIOLOGY 1.1

 With MHC Class I presentation, CD8 is fully activated.
 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; does not use co-stimulatory molecule
 virus-infected cell is destroyed through cytotoxic granules released
from the CD8 T-cells
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
surface 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 cel ldeath)

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
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
c. Th17 cells Figure 7. CD8 Effector cells
 produced when TGF-β and IL-6 come together
 produce IL-17 and IL-22 COMPLEMENT SYSTEM
 IL-17 – cytokine that induces stromal and epithelial cells to  Major Pathways that activate complement:
produce IL-8 1. Classical Pathway
 IL-8 – a potent chemokine that recruits neutrophils and 2. Alternative Pathway
macrophages to infected tissues 3. Mannan-binding Lectin (MBL) Pathway
d. Regulatory T (Treg) cells  All three pathways lead to release of C5 convertase which breaks down C5
 CD4 T cells become Treg when exposed to TGF-β into C5a and C5b
 function by suppressing T-cell responses  C5a is an anaphylatoxin as well as a chemotactic factor
 produce TGF-β and IL-10 which suppress immune  C5b binds to C6 and C7 to form a complex that inserts into the membrane
responses bilayer
 C8 then binds to the C5b-C6-C7 complex followed by polymerization of up
to 16 C9 molecules to produce Membrane Attack Complex (MAC)
 The MAC generates a channel pore in the membrane cytolysis by allowing
free passage of water across the cell membrane

Regulation of Complement System

 C1 inhibitor binds to and inactivates the serine protease activity of C1r

and C1s
 Factor I cleaves C3b and c4b – reducing amount of C5 convertase
available
 Factor H enhances the effect of factor I on C3b
 Factor P (Properdin) protects C3b and stabilizes the C3 convertase of the
alternative pathway
 Decay-accelerating factor – a membrane ound protein found on most
blood cell surfaces – accelerate the dissociation of C3 convertase on all 3
pathways

Major Biologic Effects of Complement

 Opsonization – to phagocytose much more efficiently

 Chemotaxis – to stimulate movement of neutrophils and monocytes to
sites of antigen depositions
Figure 6. CD4 effector cells

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 MICROBIOLOGY 1.1

 Anaphylotoxins – C3a and C5a produce increased vascular permeability
and smooth muscle contraction; it also stimulate mast cell to release
histamine
 Cytolysis – MAC leads to killing or lysis of many types of cells.
Complement Deficiencies
 C2 deficiency –serious pyogenic infections
 MAC components deficiency – enhances susceptibility to Neisserial
infection
 Properdin deficiency – susceptibility to meningococcal disease
 C1 inhibitor protein deficiency – hereditary angioedema
Pathogen Evasion
 Some microbes have developed surfaces that interfere with opsonization
by C3b or interfere with insertion of the MAC
 Complement activation inhibited by presence of microbial generated
proteins
- Protein A and Protein C bind IgG Fc
 Microbes can generate enzymes that degrade complement component
CYTOKINES
 multifunctional potent low-molecular-weight protein cell regulators
 produced transiently and locally by numerous cell types
 functions involved in hematopoiesis, immunity, infectious diseases
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
 in the second contact, a hypersensitivity reaction can occur
Type 1: Immediate Hypersensitivity (Allergy)
 occurs within seconds after antigen combines with the specific IgE
 antigen’s fixation to cellbound IgE, cross-linking of IgE molecules, and
release of pharmacologically active molecules from cells
 may take place as a systemic anaphylaxis ( eg. In intravenous
administration of heterologous proteins) or as local reaction (atopic
allergy)
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
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. Atopic hypersensitivity
 strong familial predispositon; elevated IgE levels
 symptoms induced by exposure to specific allergens such as pollen,
house dust, food (shellfish)
 common clinical manifestations include hay fever, asthma, eczema, and
urticarial

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

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
Type 2 Hypersensitivity
the sera of patients withseptic shock
 involves binding of IgG antibodies to cell surface antigens or extracellular
2. Measurement of cytokine production in vitro to monitor of immune
matrix molecules
status
 antibodies directed at cell surface antigens can activate complement to
- T-cell function can be monitored by the ability of T-cells to produce
damage cells
IFN-γ
 example:
3. Recombinant cytokines – key therapeutic agents
o hemolytic anemias, ABO transfusion reactions andRh hemolytic disease
- INF-α – hepatitis C infection
o autoimmune antibodies can combine with cell surfacewith resulting
- INF-β – multiple sclerosis
hemolysis
4. Targets of therapeutics – cytokine receptor antagonists and anti-cytokine
o penicillin on surface of RBC, Goodpasture Syndrome, Grave’s disease
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
 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
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 MICROBIOLOGY 1.1

Type 3: Immune Complex Hypersensitivity 2. Tuberculin-type Hypersensitivity

 formation of immune complexes (antibody combined 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)
 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
o little immediate reaction after small amount of tuberculin is
injected into the epidermis of a patient previously exposed to
Mycobacterium tuberculosis
o duration and redness develop and reach a peak in 24-72 hrs
o Mononuclear cells accumulate in the subcutaneous tissue, and
there are CD4 Th1 cells in abundance.
o that person has been infected with the agent but does not imply
the presence of current disease
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
 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

Type 4: 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 wit antigen and lasts for
days
 Two types:
1. Contact hypersensitivity
o sensitization with simple chemical (formaldehyde)
o plant materials (poison ivy) topically applied drugs(sulfonamides)
o some cosmetics
o small molecules enter the skin and attach to body proteins to
serve as complete antigen
o Langerhans cell in the epidermis is probably the APC with interacts
with CD4 Th1 cells.

Nitro Blue – Tetrazolium Test

 Semiquantitative assay
 Tests for the phagocytic function of polymorphonuclear
leukocytes (PML)
 Cells reduce a colorless NBT into a blue-black deposit within
the cell
 In CGD, the PMNLs will not turn blue

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)

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 MICROBIOLOGY 1.1

 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)

Group 5 | Macuha. Madrid. Malazarte. Mallari. Manabat Edited by: Mae Mangila Page 9 of 9