(PED) 3.04a Immunology - Dr. Foronda

3.
04 Pediatric Immunology I
Dr. Ruby N. Foronda || September 2015 PEDIATRICS
Transcribers:
Editors: Lalican J
OUTLINE 2. Myeloid line: originates from the myeloid stem cell and
Objectives: produces:
• To be familiar with the immune system and its components: innate  Myeloblasts, which forms neutrophils, basophils, mast cells,
and acquired eosinophils, megakaryocytes, monocytes & erythrocytes.
• To discuss the immune response  Monocytes à Macrophages – also antigen presenting cells
• To learn about the pathophysiology, clinical manifestations, and the (APCs) that may differentiate to dendritic cells
diagnosis and management of disorders of the immune system:  Dendritic cells – most potent antigen presenting cells;
descendent of both lymphoid and myeloid stem cells
immunodeficiency, hypersensitivity and rheumatic disorders
 Proerythroblast – precursor erythrocytes (erythropoiesis)

Outline:  Megakaryoblasts – precursor of platelets
I. Introduction to the immune system
II. Elements of the Immune System ELEMENTS OF THE IMMUNE SYSTEM
III. Types of Immunity
IV. Immune Response Types of Immunity
V. Immunodeficiency Innate Immunity Adaptive Immunity
Nonspecific; does not Highly specific response –
Legend: discriminate the different kinds discriminates between various
Remember
Lecturer Book Previous Trans Trans Comm of foreign substances. Ag; unique reaction to each
(Exams)
antigen
G ! & 4 ! Non-‐Adaptive Adaptive
Response does not change with Response changes with
Source: 2016 Trans, Nelson’s repeated exposure repeated encounters with Ag
Initial host response, acts Delayed but strong response
Introduction to the Immune System rapidly Expressed temporally after the
• Immunology is the study of innate immune response
the ways in which the body Inborn Resistance -‐ first time a Resistance that is weak or
defends itself from infectious pathogen is encountered, and is absent on the first exposure, but
agents and other foreign encoded in the germline gene increases dramatically with
substances (control & of the host subsequent exposures
eliminate) ! Fundamentally, they have different mechanisms of action, but
• Self tolerance: still there is synergy between them
o Ability to discrimination
self from non-‐self Sequence of Events in Activation of Innate and Adaptive Immunity
o Essential to permit the
host to eliminate the
pathogen without
excessive damage to its
own tissues

IMMUNE SYSTEM: CELL LINEAGES

ELEMENTS OF IMMUNE RESPONSE
• Host molecules of the human innate immune system sense danger
signal and either recognize pathogen associated molecular patterns
(PAMPs), the common molecular structures shared by many
pathogens, or recognize host cell molecules produced in response to
infection. PAMPs must be conserved structures that are vital to the
pathogen’s virulence and survival

BARRIER MECHANISMS

• Pluripotent hematopoietic stem cell divides into two cell lines: • Epithelium -‐ skin, express tight cell-‐to-‐cell contacts
1. Lymphoid line: originates from the lymphoid stem cell and • Secreted mucus layer -‐ lines the GIT, respiratory system, and GUT
produces: • Epithelial cilia – sweeps away the mucus layer that contains foreign
 B lymphocytes à antibody producing plasma cell organisms
 T lymphocytes
 Natural killer (NK) cells
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[PED] 3.04 IMMUNOLOGY– Dr. Foronda
Soluble Protein and Bioactive Small Molecules
• Naturally present in biological fluids: • Presence of chemoattractants in inflamed tissue à
o Defensins -‐ natural antibiotics which lyse microorganisms circulating cells (neutrophils) expresses selectin ligands on its
directly; secreted by the airways, urogenital tract epithelial cells, surface which are attracted to selectins (adhesion molecules)
skin and lungs. à loose attachment between the endothelial wall and the
o Complement proteins neutrophil à neutrophil loosely rolls along the endothelial
wall à eventually expresses another type of adhesion
• Released from activated cells molecule, integrin à more firm attachment in the
o Cytokines -‐ regulate function of other cells endothelial wall to their receptor, Ig domain CAM à
o Chemokines -‐ recruit inflammatory cells flattening of neutrophil à insinuate itself in between
o Bioactive amines & enzymes such as histamine contribute to endothelial cell into the inflammed tissue à function as
tissue inflammation phagocytes
• Presence of more chemoattractants in the endothelial cell à
• Leukocytes attracts more proinflammatory tissue
o Neutrophils, macrophages, NK cells, mast cells • Aid in transport of different cells
• 3 families of cell adhesion proteins:
• Cell surface receptors − Selectins
o Toll-‐like receptors (TLR) − Integrins
− Ig domain adhesion molecules

4 Stages of Cellular Movement to Site of Inflammation
• First stage: attachment and rolling occurs when lymphocytes leave
the stream of flowing blood cells in a post capillary venule and roll
along venule endothelial cells, mediated by L-‐selectin molecules.
• Second stage: firm adhesion with activation-‐dependent stable arrest
occurs with stimulation of lymphocytes by chemoattractants or by
endothelial cell-‐derived cytokines. Adhesion molecules selectin and
integrin are used in this stage.
• Third stage: sticking and arrest.
• Fourth stage: transendothelial migration, wherein lymphocytes are
able to move to the site of the antigen.

THE COMPLEMENT SYSTEM
• Complement proteins participate in a biochemical cascade that acts
to eliminate pathogens and foreign materials from an organism
 Numbered from 1-‐10 – each recognizes their own unique cell • There are 3 pathways: Classical pathway, Alternative pathway and
wall pattern (specific for a ligand – ie. LPS in g (-‐) recognized Mannose-‐binding lectin pathway
by TL6) • These pathways utilize different signals to activate the complement
 Attached to a cell surface system
 Found in macrophages, dendritic cells, neutrophils,
• These 3 pathways converge on Factor 3 to form protein fragments
eosinophils, epithelial cell, keratinocytes
C3a and C3b
 Able to recognize pathogen associated with pathogen-‐
associated molecular patterns (PAMPs): LPS peptidoglycans,
lipoteichoic acid, lipoarabinomannan, and unmethylated DNA
with CpG motif (from viruses)
 Activation of TLRs triggers cells to produces substances (i.e.
pro-‐inflammatory cytokines) that will produce inflammation
− Receptor à signal goes in cell and its nucleus à production
of pro-‐inflammatory cytokines

o Adhesion molecules
Figure 1. Complement System

A. CLASSICAL PATHWAY
• Uses of antigen and antibody complexes to initiate the cascade
! This Ag-‐Ab complex attach to C1 à activate C4 and C2 à C1, C4,
C2 turns into C3 Convertase à Activates C3 à Produce C3a

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(inflammation) and C3b (Opsonin – coats microbes to facilitate CELLULAR ELEMENTS
phagocytosis, marks target cell for destruction, attracts membrane A. Natural Killer Cells (NK Cells)
attack complex-‐ C5,6,7,8,9) • Represents a third lineage of lymphoid
• Initiated by IgM or IgG antibody binding to antigens on the outer
cells but does not recognize specific
surface of invading bacterial cells, protozoa or tumor cells
antigen.
• C1a hydrolyzes a peptide bond in C2 and C4, which is then
• Potent killers of virally-‐infected cells and
associated on the cell surface -‐> C1-‐C2a-‐C4b complex, a.k.a C3 cancer cells.
convertase
• Part of the lymphoid cell line but it does
• C3 is normally present in serum
not recognize specific antigen.
• C3 convertase hydrolyzes C3 and cleaves off to C3a and C3b
& From Harrisons: Share features
o C3a -‐> when combined with c5a à an anaphylatoxin
with both monocytes-‐macrophage and
facilitating inflammatory cell recruitment
neutrophils in that they mediate both
o C3b -‐> is the active component of the complement cascade
antibody-‐dependent cellular cytotoxicity
and serves as an opsonin (coats microbes to facilitate
and NK cell activity
phagocytosis, marks target cell for destruction, calls
B. Mast Cells
membrane attack complex)
• Attaches to C3b and makes the target cell. • Tissue-‐based inflammatory cell of bone marrow origin that
responds to danger signals with immediate and delayed release of
• C5 then initiates the formation of the membrane attack complex
inflammatory mediators.
(MAC-‐C5, C6, C7, C8, and C9)
• Normally puts a defense against parasites, but is also implicated in
the pathology of allergic diseases because of the presence of IgE
B. ALTERNATIVE PATHWAY
receptors along its cell surface.
• Acts on C3 present in the serum
• Respond to danger signals by releasing: histamine, leukotrienes,
• Activated by polysaccharides of invading
chemokines and cytokines
microorganisms/microbial structures, in the ABSENCE of a specific
• Matures in the tissue and it usually present along the skin and
antibody, or by IgA.
blood vessels.
• Involves Properdin and factor D

• Factor D cleaves B -‐> Ba and Bb -‐> acts on C3 -‐>increased
C. Phagocytes
production of C3a and C3b
• Engulf pathogenic microbes and use intracellular vacuoles to
• Properdin – stabilizes C3bBb
focus toxic effector molecules (nitric oxide, superoxide, and

degradative enzymes) in an effort to destroy the organism.
C. MANNOSE-‐BINDING LECTIN PATHWAY
• Use Fc receptors (Ab) and C receptors along the membrane to
• Activated by the opsonin, mannan-‐binding lectin (MBL) -‐> binds enhance uptake of particles marked by the immune system for
mannose polysaccharides on the invading microorganism surface
destruction.
• MBL activates the plasma proteases MBL-‐associated serine • Neutrophils
proteases 1 and 2 (MASP 1 and 2). This is similar to the activated o Granulocyte – cytoplasmic granules; polymorphonuclear
C1 complex of the classical pathway that then cleaves C4 in the C2 o Phagocytosis
– C4 complex -‐> C4b -‐> converts C3 -‐> C3a and C3b
o Short life span (hours)
• Triggered by microbes with terminal mannose groups but follows o Very important in “clearing” bacterial infections
the other pathways down to C3-‐convertase cleaving C3 into C3a o Innate immunity
and C3b o CD66 membrane marker

Figure 3. Neutrophil

• Eosinophils
Figure 2. Punctured Shigella wall by complement o Kills antibody-‐coated parasites through degranulation.
o Involved in allergic inflammation
Ag-‐Ab complexes provide the activating signal. There is sequential o Granulocyte; double-‐lobed nucleus
activation of the C complexes, C1, C4, C2, which provides the key o Orange granules contain toxic compounds.
enzyme in the pathway, the C3 convertase. C3 convertase acts to • Monocyte
cleave and activate C3. Cleavage results in the release of the C3a o Young macrophage in the blood; there are tissue specific
segment, a potent anaphylatoxin that induces mast cell degranulation, macrophages.
creates edema, and recruits phagocytic cells. The larger C3b fragment
attaches to the activating agent, marking it for destruction. C3b serves
as a site for attack of the C membrane attack complex and serves as an
opsonin.

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! Q: How have T cells been designed to fight intracellular

organisms?
A: The immune system has evolved to permit the T cell to
recognize both a self-‐ component and a microbial structure
through the MHC molecules. MHC is recognized as “self” and
therefore is not attacked. Microbial structure is recognized as
Figure 4. Monocyte. Phagocytic cells of the monocyte/macrophage foreign.
lineage also act as Antigen-‐Presenting Cells (APCs)

TYPES OF MHC:
• Dendritic cells
o Activation of T cells and initiate adaptive immunity
o Found mainly in lymphoid tissue.
o Function as APC and is the most potent stimulator of T-‐cell
response.
o Present in most tissues and concentrated in secondary
lymphoid tissues.

Figure 5. Dendritic cells. Present in most tissues and concentrated in
secondary lymphoid tissues. Most potent APC.

Figure 6. MHC I vs MHC II
• Macrophage

o Affect lymphocytes by secreting cytokines that control
lymphocyte proliferation, differentiation and effector
function.
o Acts as APCs that process, display foreign antigens àpresent
to lymphocytes à have the ability to initiate and coordinate
adaptive immune responses.
o Able to control the action of lymphocytes, the principal cells
of acquired immunity.
o Secrete cytokines that control lymphocyte proliferation and
effector function.
o Display foreign substances in a form that can be recognized
Figure 7. Topview Class II MHC binding site
by lymphocytes and therefore have the ability to initiate

and coordinate adaptive immunity.
G Serves as a link between innate and adaptive immunity.

MAJOR HISTOCOMPATIBILITY COMPLEX/HUMAN LEUKOCYTE
ANTIGEN
• Surface glycoproteins that bind peptide fragments of proteins and
presented to T cells.
• Encoded by genes in chromosome 6.

! Q: Why does the adaptive immune system need both T

and B lymphocytes?
A: B lymphocytes are very efficient weapons against
“loose” extracellular microbes. T lymphocytes are
designed to fight intracellular microbes

Figure 8. Antigen processing Peptide + MHC

! MHC 1-‐Virus à enters the cell à occupies MHC 1 molecules à
golgi àpeptides carry to surface of the cell à interact with CD 8

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! MHC 2-‐Antigen à endocytosed à undergoes proteolysis à Selected Cytokines and Their Effects
occupies MHC 2 molecules à Golgi à peptide carry to the
surface of the cell à INTERACT with CD 4

CYTOKINES AND CHEMOKINES
A.CYTOKINES
• Diverse and redundant group of intercellular signaling peptides and
glycoproteins.
• Most are genetically and structurally unrelated to one another.
• Several hundred have been identified.
• Each is secreted by particular cell types in response to a variety of
stimuli.
• Cytokines produced in response to an immune insult determine
whether the response is cytotoxic (kill another cell), humoral
(produce antibodies), cell-‐mediated or allergic responses.
• Regulate also wound healing, hematopoiesis, angiogenesis, and other
biologic processes.
• Many are pleiotropic in which they are capable of acting on many
different cell types. This results from the expression on multiple cell
types of receptors for the same cytokine, leading to the formation of
"cytokine networks." Its action may be autocrine, paracrine, and
endocrine. CELLS OF ADAPTIVE IMMUNITY
• Recognized based on the antigen specific receptor on the surface T
Classification of Cytokines & B lymphocytes (T-‐Cell Receptor/B-‐Cell Receptor).
• Normally composed of small number of cells that proliferate after
Produced by Function Example encountering the pathogen
Mediators & Macrophage Induce early TNF Mediator of • LYMPHOCYTES ONTOGENY:
regulators of inflammatory toxic shock and
innate immunity reactions (Pyrexia) sepsis
Type I IFNs,
IL 1, 6, 10, 12, 15
chemokines
Mediators & Activated T a) Act primarily on IL 2, 4, 5
regulators of lymphocyte other lymphocyte IL 13
adaptive populations, (lymphotoxin)
immunity regulating growth & TGF β
differentiation IFN γ
b) Affect nonlymphoid
effector cells
(macrophage,
inflammatory
leukocytes)
Cytokines that Bone Growth & Ckit ligand (stem
stimulate marrow differentiation factors cell factor)
hematopoiesis stromal cells, of leukocyte IL 3, 7, 9, 11
leukocytes precursors of various GM CSF
lineages (granulocyte-‐ Figure 9. 2 Types of Lymphocytes
monocyte colony • Natural Killer Cells
stimulating • T-‐Cells
factor) o Precursors of T cells leave the bone marrow and mature in the
Thymus
B. CHEMOKINES o T Regulatory Cell
o T Helper Cell – TH1 and TH2
• Cytokines that induce chemotaxis
o T Cytotoxic Cells
• 47 chemokines and 18 chemokine receptors
• B-‐Cells
• Functions:
o Produced by the Bone marrow and also mature there.
o Recruit and activate leukocytes to mount an IR and initiate
o Matures to a plasma cells, that secrete Antibodies
wound healing;

o Homeostatic or housekeeping function (lymphocyte trafficking,

hematopoeisis, sampling in 20 lymphoid tissue, immune

surveillance)

• Have 3-‐4 conserved cysteine residues: C-‐X-‐C (targets neutrophils), C-‐C
(targets monocytes and T cells), C, CX3C

Page 5 of 11
A. T-‐LYMPHOCYTES • Signal 2: COSTIMULATION

o Can be APC + CD40 ligand or B7 interacting with CD28
o Activates the T Cell
T CELL ACTIVATION
• Signal 3: PROFLIFERATION
o Secretion and Proliferation of cytokines
T Cell Activation Summary:

• Recognition by T Cell
• Activated cytokine – i.e IL2 – acts on other cells and on
itself, in an autocrine manner
• Proliferation of a specific protein
• Differentation to different types of T cells

CD Effector Functions

Fig 17. T Cell Activation

• Signal 1: RECOGNITION

• Located in Peripheral Tissues
• Effector CD4+ T Cell: activates macrophages, B cells and other cells

• Memory CD8+ T Cell:

• Effector CD8+ T Cell (CTL): activates macrophages and kills infected

target cells

Question No. 3: T-‐helper cell subsets are identified by:
a. Their respective TCRs
b. Cells they interact with
c. Cytokines they produce
d. Where in the body they are found

T-‐Cell Subpopulation
o APC presents the Antigen through MHC II Class Name Function
o T Cell recognizes the Antigen (Either CD 4 or 8) CD4+CD8 CD4+ Activates both humoral response (Help B
T Helper cell activate & proliferate) and cellular
Cell reponse (delayed type response)
CD4-‐CD8+ CD8 Acts against cells with intracellular
Cytotoxic microbes and against tumor cells
Page 6 of 11
T cell
CD4+CD25+ T
regulatory
Cell

CD4 T Helper Cell Antigen Response
• Affects other cells in the immune response

Figure 11. T-‐cell Development
o Stimulates regulatory cells

o Stimulates cells of the innate immune system
o Initiates phagocytosis
o Stimulates T-‐cells to produce antibodies
Figure 12. Interaction between the antigen presenting cell (APC) and the T cell.
o Kills cytotoxic killing by CD8 T-‐cells
• The first signal is the interaction between T cell receptor and MHC,

which is stabilized by CD4 or CD8. The second signal is the
CD8+ CYTOTOXIC T CELL Antigen Response
interaction between CD80 or CD86 of the APC and CD28 of the T
• Produces cytotoxins that will kill all the infected cell. Both signals need to be present to activate the T cell. There
cells through apoptosis would then be a signalling cascade from the receptor of the T cell
to its nucleus.
• CD4+ and CD8+ cells: markers for T-‐ lymphocytes. They stabilize
attachment of APC and the T cell.

T-‐Helper Cells
o The naïve T-‐helper cells or Th0 matures into different subsets of
T-‐helper cells.
o T-‐helper cell subsets can be identified by the cytokines they
Figure 10. T cytotoxic cell in action. A T cytotoxic cell produce
attacking a microbe/ infected cell. Cell beginning to o If the Th0 cell develops in the presence of IL-‐12, it goes on to be
implode. Finally, killing the infected cell. a Th1 cell that produces mainly interferon gamma which
mediates cell mediated immunity that battles infectious agents
like viruses, mycobacteria, and fungi, and also inhibits Th2
responses.
NOT INCLUDED IN LECTURE: From Section 2016B trans: o If the Th0 or naïve T helper cell develops in the presence of IL-‐
T CELL DEVELOPMENT 4, it matures into a T helper 2 cell producing IL-‐4, -‐5, -‐13 which
o Development starts with a double negative thymocytes (CD3 +, promote humural immunity, regulates immunity against
CD4 -‐, CD8 -‐) going from the subcapsular zone to the cortex. parasites and allergic responses.
o Once in the cortex, it will undergo positive selection (CD3 +, o T regulatory cell: cell that balances action of Th1 and Th2
CD4 +, CD8 +). responses (eg. TGF β and IL 10)
o These double-‐positive cells interact with class I or class II MHC o Th17: pro-‐inflammatory cell that is always present in
molecules on cortical epithelium. During this process, cells autoimmunity eg. cytokine IL 17
with low or moderate affinity for MHC are positively selected.
o Those T cells with excessive or no affinity for MHC + self-‐
peptide undergo clonal deletion (Negative selection) through
induction of apoptosis.
o Once in the medulla, it will undergo negative selection where it

will differentiate to CD4 cell or CD8 cell.
§ CD4 (Helper) cell: CD3 +, CD4 +, CD8 –
§ CD8 (Cytotoxic) cell: CD3 +, CD4 -‐, CD8 +

o All T cells have CD3 on their surface.
• Any disturbance in this process can lead to escape of autoreactive Figure 12. Different maturation pathways of Th0 or naïve T-‐helper cells.
T-‐cells that can trigger autoimmune disease.
• Likewise, differentiating early B cells when they encounter self-‐
antigen, cell-‐associated or soluble, undergo deletion.

Page 7 of 11

B. B-‐LYMPHOCTES o Neutralization
§ Phagocyte clearance through reticuloendothelial system
§ Neutralize toxins or enzymes
o Opsonization
§ Attach to receptors of phagocytes
§ Facilitate removal of antigen by phagocytic cells
§ Participate in cell-‐mediated immunity by promoting

antibody-‐dependent cellular cytotoxicity functions of

certain T-‐lymphocytes.
o Complement fixation
§ Have receptors for complement on the constant region
which cause target cells to lyse
§ Deposition of complement components on the surface of
invaders
Figure 13. B-‐cell antigen receptor
§ Will initiate the classical pathway
• Recognized by receptors (antibody) on its surface
• Have antigen binding sites • Classes of Antibodies
• Functions of the Mature B Cells: Table 1. Classes of Antibodies

o Endocytose the Antigen
o Present the Antigen to the T helper cell à T helper cells G Adaptive Immunity AMPLIFIES innate immunity
stimulate the B cells to produce antibodies • They work together to mount an immune response

ANTIBODY

Figure 14. Structure of a typical antibody

• Has a constant Fc region which attaches to its receptors on Lymphoid Tissues
neutrophils and other phagocytes) • Central: Bone Marrow and Thymus
• Also has a variable antigen binding site • Peripheral: Lymphoid Tissue

• Bone marrow:
Functions of Immunoglobulins
o Principal site of maturation of immune cells

o Where stem cells become committed precursors
• Thymus:
o Principal site of T-‐lymphocyte maturation
• Lymph nodes:
o Peripheral lymphoid tissue
o Contains T and B lymphocytes
o Site of presentation of lymph-‐borne antigen (via APC) to T
lymphocytes; area of recognition and lymphocyte activation

Page 8 of 11
Immune Response to Extracellular Bacteria

Figure 15. Lymphoid tissues. Central: Thymus and Bone marrow,
Peripheral: Spleen and lymph nodes.
Figure 17. Once the skin barrier has been breached, bacteria enter. The
• Spleen innate immune system is initiated
o Largest peripheral lymphoid organ
o Site where blood-‐borne antigens are recognized A. ENTRY
o Parts:
• Rapidly dividing bacteria in non-‐intact skin locally activate
4 Red pulp – collection of red blood cells and accessory
complement in the extracellular tissue.
cells (macs and DCs)
• Proinflammatory complement fragments (innate immunity) like
4 White pulp – large collection of lymphocytes that
C3a and C5a (anaphylotoxins) recruit neutrophils and activate local
surround the branching afferent blood vessels; marginal
mast cells which increase blood flow and release a further cascade
zone– where polysaccharide antigens are stored and B
of proinflammatory mediators.
cells recognize them and become activated by them
o Mast cells also produce mediators to keep the vascular walls
• Mucosal Immune System
permeable, so that the inflammatory cells will be able to pass
4 Non-‐encapsulated
through them and reach the bacteria.
o Consists of tonsils, Peyer’s patches, lymphoid aggregates of
• Recruited neutrophils phagocytose complement-‐coated bacteria
appendix and airways (tonsils)
and kill them.
o Recognize and respond to antigens that enter the body via

these tracts
o B cells in these tissues produce IgA B. PROCESSING
• Local Langerhans cells (dendritic macrophages in the skin) also
engulfs the pathogen and it processes extracellular protein
antigens derived from the bacteria and present them mainly in
association with HLA class II.

C. MIGRATION
• Dendritic cells migrate to the T zones of lymph nodes via the
lymphatics where they present antigen to T cells.
• T cells migrate from the blood through high endothelial venules
(HEV) in lymph node. These T cells “look” for antigen expressed by
dendritic cells in paracortical T cell areas.

Figure 16. Mucosal Immune System: Oral, Nasal, Rectal, Vaginal
Figure 18. Dendritic cells presenting the viral antigen goes to the lymph

node and T cells “look” for the antigen expressed by dendritic cells in

paracortical T cell areas.

Page 9 of 11

D. ANTIGEN PRESENTATION 4 Immune Response to Intracellular Agents
• The dendritic cell, with the processed antigen bound on its MHC2,
finds its corresponding antigen-‐specific naïve T-‐helper cell. They
interact together to form the T-‐cell receptor complex and activate
the T-‐cell.
• Proliferation and differentiation of the naïve T-‐helper cells would
then occur. The differentiated T-‐helper cells would then produce
their own cytokines, which would in turn exert their effect on the
other cells.
• Effects of the produced cytokines include:
o Recruitment of more neutrophils to produce inflammation
o Activation of macrophages for phagocytosis and bacterial
killing
o Activates and helps the B-‐cell produce antibodies against the
bacteria

Figure 21. Virus invading the respiratory epithelium

• Neutralizing antibody plays a crucial role in eliminating intact
viruses by preventing the infection of other cells.
• NK cells kill virus-‐infected cells
• Infected cells are able to produce Type I Interferon that protect
nearby cells from being infected further.
• Virus essentially has the same mechanism (i.e. entry, processing,
migration stated above), which elicits antibody responses to other
protein antigens. The difference is that there is a second
important mechanism, which is the generation of CD8 cytotoxic T

Figure 19. Inside the T cell zone cells.
• To combat infection, all nucleated cells have machinery for
generating peptide fragments for cytosolic (self and viral) proteins
(the proteasome).
• Peptide fragments derived from cytosolic proteins are transported
(by tap proteins) into the endoplasmic reticulum where they are
loaded onto nascent Class I Molecules and transported to the cell
surface where they can be seen by CD8 cytotoxic T cells.
• CD4 and CD8 T cells recognize antigen on the dendritic cells
leading to T cell help form, CD4 cells (IL-‐2), for the development
and expansion of cytotoxic CD8 T cells.

Figure 20. Antigen-‐specific T cells become primed by a combination of
antigen, co-‐stimulatory molecules and cytokines (IL-‐12), expressed by
activated dendritic cells.

• Th1 cells
o Inflammatory cells which secrete IFNγ, IL-‐2 and other
cytokines which recruit inflammatory cells to inflamed tissue
o Their pathway of migration is distinct from Th2 cells in that
they migrated via the blood and recognize receptors on
inflamed endothelium, hence gaining access to infected
tissue.
o Activate macrophages via IFNγ and release of
proinflammatory cytokines to ensure the blood supply is Figure 22. Activation of Cytotoxic (CD8) T-‐cell by the T-‐helper cells
maintained
• Th2 cells • Antigen-‐specific T cells become primed by a combination of
o Promote antibody formation and secrete IL-‐4, -‐5, and -‐10 antigen, co-‐stimulatory molecules and cytokines (IL-‐12), expressed
o Help B cells to undergo clonal expansion and affinity by activated dendritic cells.
maturation within germinal centers • Once primed, cytotoxic CD8 T cells migrate out into tissue and can
o As a consequence of this, high affinity antibody is generated kill virally infected targets. CD8 T cells play a crucial role in
which is effective at neutralizing bacterial toxins regulating viral infections.
o Class switching to IgG antibodies promote the much more
efficient opsonisation and removal of bacteria by phagocytes

Page 10 of 11
Restoration of Homeostasis
• After the immune system has done its function (killed off the
invading antigens), it has to restore homeostasis, which is done
by:
o Upregulation of inhibitory receptors, with the use of TGF-‐B,
IL-‐10 from T-‐regulatory cells
o Activation-‐induced cell death (Apoptosis)
4 After the inflammatory process, the cells (T or B
lymphocytes) begin to express the Fas marker on its
surface. A cytotoxic cell, either a killer T-‐cell or NK cell,
comes along and attaches to the target cell thru its Fas
ligand, and caspases are then activated, eventually
leading to apoptosis. Apoptosis does not induce any
inflammatory response.

Figure 24. Immune response on the first and second exposures to the
antigen. On re-‐encounter of the pathogen, serum antibody titers would
increase at a higher concentration and faster rate

MINI QUIZ
1) Antibodies is to extracellular microorganisms as ____ is to
intracellular:
a. NK Cells
b. Complement
c. Cytotoxic T cell
d. Helper T cell

Figure 23. Killer T-‐cells or NK cells induce apoptosis on the target cells
(unneeded T or B lymphocytes) by binding to the Fas marker and 2. C3 deficiency will lead to recurrent infections from encapsulated
activating caspases. bacteria due to the deficiency of:
A.Nuclear Superoxide
B. Chemotaxis
C. Opsonization
D. Osmotic lysis of target organisms

3. The link between innate and adaptive immunity is provided by the:
a. Dendritic cells
b. Natural Killer Cells
c. Eosinophil
d. Macrophages

Figure 24. Apoptosis

4 In addition to generating effector B and T cells, memory B and T
lymphocytes are produced which make rapid and more efficient
responses upon re-‐exposure to the infection.
4 Memory T cells are created with specificity toward the
antigenic epitopes of the previously encountered pathogen.
They are ready to respond when they come across the
specific antigen again.

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(PED) 3.04a Immunology - Dr. Foronda

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(PED) 3.04a Immunology - Dr. Foronda

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3.

Figure 1. Complement System

! Q: How have T cells been designed to fight intracellular

! Q: Why does the adaptive immune system need both T

T Cell Activation Summary:

o Stimulates regulatory cells

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