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YL5: 03.

09 Innate and Adaptive Immunity


09/20/2018 Hematology and Immunology
08:00-09:30
Michelle J. De Vera, M.D.

TABLE OF CONTENTS
II. COMPONENTS OF IMMUNITY
I. INTRODUCTION .................................................................................. 1 A. INNATE VS. ADAPTIVE IMMUNITY
A. HISTORICAL PERSPECTIVE .................................................... 1 Innate Immunity
B. THE IMMUNE RESPONSE ........................................................ 1
II. COMPONENTS OF IMMUNITY .......................................................... 1 • Natural or native immunity
A. INNATE VS. ADAPTIVE IMMUNITY .......................................... 1 • Early line of defense against microbes
III. INNATE/NONSPECIFIC HOST DEFENSES ..................................... 2 • Rapidly responds to infections
A. ANATOMIC BARRIERS ............................................................. 2 • Encoded by genes directly inherited from an individual’s
B. PHYSIOLOGIC BARRIERS ....................................................... 2
C. PHAGOCYTIC/ENDOCYTIC BARRIERS .................................. 2 parents (inborn)
D. INFLAMMATORY BARRIERS ................................................... 3 • Provides defenses for non-specific infection using
IV. REGULATION OF INNATE IMMUNE RESPONSE ........................... 4 phagocytic cells
V. ADAPTIVE/SPECIFIC IMMUNE RESPONSE .................................... 4 • Uses a limited number of secreted proteins and cell-
A. ANTIGENIC SPECIFICITY ......................................................... 4
B. DIVERSITY ................................................................................ 5 associated receptors to detect infection, and to distinguish
C. CLONAL SELECTION ............................................................... 5 between pathogens and host tissues
D. SELF/NON-SELF RECOGNITION ............................................. 6
E. IMMUNOLOGIC MEMORY ........................................................ 6 Adaptive Immunity
F. SELF-LIMITING .......................................................................... 6 • Acquired immunity
VI. COLLABORATION BETWEEN THE INNATE AND ADAPTIVE
IMMUNE SYSTEM .................................................................................. 6 • Later responses to infections
LINKS BETWEEN THE INNATE IMMUNE RESPONSE AND • Defining characteristics: specificity and memory
ADAPTIVE IMMUNITY ................................................................... 6 ® Eliminates infections more efficiently because of
QUICK REVIEW ...................................................................................... 7
A. SUMMARY OF TERMS ............................................................. 7 specificity
® Specific response against infection by potential
pathogens, such as production of antibodies against a
I. INTRODUCTION particular pathogen (highly specific)
® Develops during the lifetime of an individual as an
A. HISTORICAL PERSPECTIVE adaptation to infection with that pathogen
• Bull Thucydides (430 BC)
• Mainly composed of specialized cells:
® Earliest reference to “immunity” during the plague
® T lymphocyte cells
® People who previously got the plague were able to take
® B lymphocyte cells
care of those who were symptomatic and did not get
sick again
• Chinese and Turks (15th century)
® 1st crude attempts to induce immunity
® Variolation: crusts from smallpox pustules were
inhaled or inserted into cuts in the skin

B. THE IMMUNE RESPONSE


• Taken from “The Immune Response” video of Garland
Science. Refer to the references section for the video link.
• An immune response involves events that unfold both
locally (site of infection) and at distant sites (ex. nearby
lymph nodes)
• CD4 T-cell activates macrophages to be more cytotoxic
• Antibodies lyse the bacteria and opsonize bacteria to be Figure 1. Components of Immunity
targeted by phagocyte
• When there is viral infection, CD8 T-cells kill infected cells

Pathogens cross the epidermis when there is injury

Infection is established

Dendritic cell binds pathogens, leaves site of infection, goes


to a lymph node, and then into a draining lymph node

T-cells are activated by dendritic cell antigen

T-cell activates B-cell to release antibodies

Effector T-cell and antibodies go into the circulation and


return to the site of infection
Figure 2. Comparison of Characteristics of Innate and
Figure 1. Mechanism of the Immune Response Adaptive Immunity (Janeway, 2017)

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III. INNATE/NONSPECIFIC HOST DEFENSES Pattern Recognition Receptors (PRRs)
A. ANATOMIC BARRIERS • Expressed by:
Skin ® Phagocytes
• Mechanical barriers retard the entry of microbes into ® Dendritic cells
circulation ® Epithelial cells that form the barrier interface between
® First line of defense the body and the external environment
® Retards the entry of microbes • Binding of PRR to PAMPs and DAMPs activate a signal
• Keratin: Outer epidermal layer for waterproofing transduction leading to inflammation and antimicrobial
• Dermis: connective tissue, blood vessels, hair follicles, functions
sebaceous glands, sweat glands ® Production of:
® Sebum (composed of lactic acid and FA): gives the skin § Cytokines and chemokines
its acidic pH (~3-5) § Adhesion molecules on endothelial cells
§ Retards growth of microbes o Cells need to adhere so they can go to where
§ Commensal bacteria in sebaceous glands block they are supposed to go
and use sebum for the benefit = gives rise to acne § Co-stimulatory molecules
o Needed to activate B cells and T cells
Mucous Membranes • Expression of type I interferon genes and secretion of
• Lines conjunctivae, alimentary, respiratory, urogenital tracts type I IFN (Ɣ) gamma will lead to an antiviral state
• Saliva, tears mucous secretions wash away potential • PPRs are encoded by inherited (germline) gene
invaders ® You only get what’s inherited; it doesn’t change. It’s not
• Mucous traps foreign microorganisms very diverse. That’s why there are only a specific
• Cilia propel microorganisms out of body (e.g. in amount of PAMPs and DAMPs that can be recognized.
gastrointestinal tract, and respiratory tract)
• Normal flora: outcompete other microbes for attachment Table 1. List of PAMPs
Pathogen-Associated Molecular Microbe Type
sites and nutrients Patterns (PAMPs)
® Non-pathogenic bacteria Nucleic Acids ssRNA Virus
dsDNA Virus
B. PHYSIOLOGIC BARRIERS CpG Bacteria, Virus
Temperature
Proteins Pilin Bacteria
• Normal temperature inhibits growth of pathogens
Flagellin Bacteria
• Fever response inhibits growth of some pathogens
Cell Wall LPS Gram positive bacteria
Low pH Lipids Lipoteichoic acid Gram positive bacteria
Carbohydrates Mannan Fungi, Bacteria
• Acidity of stomach kills most ingested microorganisms
Glucans Fungi
Chemical mediators
• Lysozyme (tears, mucous): cleaves bacterial cell wall Table 2. List of DAMPs
• Interferon (IFN): induces antiviral state in uninfected cells Damage-Associated Microbe
Molecular Patterns (DAMPs) Type
• Complement lyse organisms, facilitates phagocytosis
Stress-induced proteins HSPs
C. PHAGOCYTIC/ENDOCYTIC BARRIERS Crystals Pilin
Nuclear Proteins HMGB1

• According to doc, you don’t need to memorize the table.


You just have to know that there are PRRs and PAMPs and
DAMPs and that’s how they recognize each other.

Mechanism
• The pattern recognition receptor will recognize the PAMP
and it will tell them to phagocytose the microbe.
• Cytokines will be made to
® be co-stimulatory molecules for T cells
® activate T cells and B cells to make antibodies.
• These antibodies can go back, reconnect itself to the innate
immune system.
• There are many cross interactions between the innate and
adaptive immunity. Otherwise, it won’t work effectively.

Figure 3. Macrophages are activated by pathogens through


different receptors

• Various cells endocytose and break down foreign


macromolecules
• Specialized cells phagocytose, kill, and digest whole
microorganisms

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Mechanism of the Inflammatory Response
1. Vasodilation of the local blood vessels
2. Increased permeability of the capillaries
3. Clotting of the fluid in the interstitial spaces due to fibrinogen
and other proteins leaking from the capillaries
4. Migration of large numbers of granulocytes and monocytes
into the tissue
5. Swelling of the tissue cells
® Tissue products that cause these reactions:
§ Histamine
§ Bradykinin
§ Serotonin
§ Prostaglandins
§ Reaction products of the complement system and
the blood clotting systems
§ Lymphokines
• “Walling-Off” Effect of Inflammation
® Fibrinogen clots block or wall-off antibodies and keep
Figure 4: Interaction between innate and adaptive them inside the wound
immunity (De Vera Slides, 2018) ® Tissue spaces and lymphatics are blocked by
fibrinogen clots; delays the spread of bacteria or toxic
D. INFLAMMATORY BARRIERS products
The Inflammatory Response
• Inflammation: accumulation of leukocytes, plasma protein, Neutrophil Migration to Sites of Infection
and fluid derived from the blood at extravascular tissue site • Rolling: E-selectin binds with s-Lex
of injection or injury ® Rolls on the membrane due to weak bonds made
• Roman MD Celsus: 4 cardinal signs of inflammation between s-Lex and E-selectin
® Rubor: redness ® Signals more adhesion molecules to be made through
® Tumor: swelling tight binding
® Calor: heat • Tight Binding: ICAM-1 recognizes LFA-1
® Dolor: pain ® Creates a tighter bond to CXCL8R (IL-8 Receptor)
• Galen: 5th sign • Diapedesis: movement from the blood vessels to the site
® Functio laesa (loss of function) of infection
• Neutrophils: most abundant leukocyte recruited to the site • Migration to the tissue
• Monocytes à macrophages in tissue: increasingly ® Secretion of chemokines signaling the immune
prominent over time and may become dominant during response where to go
infection ® Different chemokines give instructions for migration for
• Plasma Proteins different cells
® Acute phase reactants à produced by liver • Monocytes à macrophages (in tissue)
® Complement: effector molecules of innate system • Plasma proteins:
® Antibodies ® Acute phase reactants by the liver
• Blood vessel changes facilitate entry of cells and plasma ® Complement: effector molecules of IS
proteins: ® Abs
® Increased blood flow • Blood vessel changes facilitate entry of cells and plasma
® Increased adhesiveness of circulating leukocytes to proteins
endothelium ® Increase in:
® Increased permeability of capillaries and venules § Blood flow
§ Adhesiveness of circulating leukocytes to
endothelium
§ Permeability of capillaries and venules

Figure 6. Neutrophils leave the blood and migrate to sites of


infection in a multi-step process
Figure 5: Steps of the Inflammatory Response

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Complement
• 3 pathways
® Classical Pathway: Antigen to Antibody Complexes
® MB-Lectin Pathway (mannose binding): Mannose
on pathogen surface
® Alternative Pathway: pathogen surfaces
• Leads to the formation of the C3 convertase and ultimately
results in a cascade of enzymatic signals

Figure 9. Cytokine Network: Convergence of Bone Marrow


and Thymus

IV. REGULATION OF INNATE IMMUNE RESPONSE


• Inhibitory mechanisms limit potential damage to tissues
® To maintain homeostasis
• Begin at the same time or shortly after initiation of
inflammation
® Regulation is stimulated by the same thing that
stimulates the inflammation
• Stimulated by PAMPs and DAMPs
® IL-10
§ Produced by and inhibits activation of
Figure 7. The different complement pathways and their effects
macrophages and dendritic cells
§ Inhibits production of inflammatory cytokines
Cytokines
o IL-1, TNF, IL-12
• Every cytokine has a particular role
§ Alternatively activated macrophages (M2) make
• Important are: TNF-a, IL-6, IL-10, IL-12, IL-4
more than M1
• Can be used for targeted cancer treatment § Also produced by regulatory T cells and some
non-lymphoid cells
• IL-1 receptor antagonist (IL-1RA): antagonizes receptors in
mononuclear phagocytes
• Negative signaling pathways
• Autophagy genes
® Cause apoptosis

V. ADAPTIVE/SPECIFIC IMMUNE RESPONSE


• Capable of recognizing and selectively eliminating specific
foreign microorganisms and molecules
• Characteristic Attributes:
® Antigenic Specificity
® Diversity
® Clonal Selection
® Self/Non-Self Recognition
® Immunologic Memory
® Self-Limiting

A. ANTIGENIC SPECIFICITY
Figure 8. The different kinds of cytokines and their local and • To distinguish subtle differences among antigens
systemic effects • Recognition of Antigen by B and T Lymphocytes
® Recognition of antigenic determinants or “epitopes”
§ Proteins, glycoproteins, and immunogens may
have multiple epitopes
§ Epitopes are recognized by antigen receptors of B
cells, T cells, and antibodies
o Epitopes: the part of an antigen molecule to
which an antibody attaches itself

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Figure 10. Epitope

® Humoral branch (B cell) recognize epitopes:


§ Surface of bacteria or viral particles
§ Soluble proteins, glycoproteins, polysaccharide
released from invading pathogens
® Cell-mediated branch (T cell) recognize epitopes +
MHC on self-cells:
§ T cells protect us by recognizing ‘altered’ cells’
§ Altered self-cells: virus infected cells or
cancerous cells
§ MHC molecules are encoded in a cluster of genes
called major histocompatibility complex (MHC)
§ Antigens recognized by T cells can be derived Figure 12. Diversity pathway
from proteins of intracellular pathogens, such as
virus, or from extracellular pathogens
® B-cell maturation in BM: ordered sequence of gene
§ No secreted form of T cells 15
arrangement = 10 combination different antibodies
® Genome rearrangement essential feature of
lymphocyte differentiation
§ No other vertebrate cell type has been shown to
undergo this process
® Separate genes encode immunoglobin V & C regions
® Genes are rearranged in the course of B cell
differentiation
® Each individual B cell expresses a unique antibody
® Mature B cell is anti-genetically committed
® T-cell maturation: random rearrangement of gene
segments to encode TCR
18
® Generates 10 unique antigenic specificities
® Diminished through selection process in thymus to
Figure 11. T-cell recognition eliminate T-cell with self-reactivity receptors

B. DIVERSITY C. CLONAL SELECTION


• Allows recognition of billions of uniquely different structures • Immunocompetent individual has large number of Ag-
on foreign antigens reactive clones of T and B cells
• Generation of Lymphocyte Specificity and Diversity • Specificity of each T and B lymphocyte determined before
® Specific T-cell, B-cell receptors are generated during its contact with antigen by random gene rearrangement
development and differentiation to endow lymphocyte • Provides framework for understanding
with structurally unique receptor to recognize a ® Specificity
microbial pathogen. ® Self-non-self recognition characteristic of adaptive
® Specific unique receptors are not encoded in the immunity
germline.
§ Diversity of repertoire of receptors is generated
randomly
® Ability to respond to apparently limitless array of
foreign antigens
® B-cell antigenic specificity determined by antibody
expressed on the cell
® T-cell specificity determined by T-cell receptor (TCR)

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Figure 14. Kinetics of the Antibody Response

F. SELF-LIMITING
• Presence of regulatory mechanisms
® T-regs, complement inhibition, idiotypic antibodies, etc.
• Elimination of antigen signals the regulatory mechanism
such that antigens won’t replenish themselves anymore
when the disease is gone
• In an autoimmune disease: antigen = self
Figure 13. Lymphocyte Clonal Selection
® Body has no means of regulation and this results in
loss of homeostasis = disease
• A single progenitor can give rise to several lymphocytes for
• Duration of lymphocyte activity is brief
specificity
• A removal of self-reactive immature lymphocytes occurs by
clonal deletion à results in mature naïve lymphocytes
VI. COLLABORATION BETWEEN THE INNATE
• These lymphocytes can recognize foreign antigens and a AND ADAPTIVE IMMUNE SYSTEM
proliferation of lymphocytes occurs in order to eliminate the • Phagocytic cells crucial to nonspecific immune response
antigen involved in activating specific immune response
• Soluble factors produced by specific immune response can
Postulates of the Clonal Selection Hypothesis augment activity of phagocytic cells
• Each lymphocyte bears a single type of receptor with a • Carefully regulated interplay between innate and adaptive
unique specificity immune systems work to eliminate foreign pathogens
• Interaction between a foreign molecule and a lymphocyte
receptor capable of binding that molecule with high affinity LINKS BETWEEN THE INNATE IMMUNE
leads to lymphocyte activation RESPONSE AND ADAPTIVE IMMUNITY
• Differentiated effector cells derived from an activated • Macrophages, dendritic cells and B cells express pattern
lymphocyte will bear receptor of identical specificity to those recognition receptors and serve as antigen-presenting cells
of the parental cell from which that lymphocyte was derived for the adaptive immune response
• Lymphocytes bearing receptors specific for ubiquitous self • Cytokines produced by activated T-cells (for example,
molecules are deleted at an early stage in lymphoid cell interferon-Ɣ) stimulate the expression of important co-
development and are therefore absent from the repertoire signaling molecules (B7-1/B7-2) on the surface of antigen-
of mature lymphocytes presenting cells
• T cells produce cytokines that activate important effector
D. SELF/NON-SELF RECOGNITION pathways of innate immunity, for example, macrophages
• Responds only to foreign antigens and NK cells
• Presence of MHC marks the cell as a “friend” • Cells of the innate immune system (for example,
• Presence of antigens marks cell as a “foe” macrophages) produce cytokines such as IL-12 that direct
T cells to become Th1 T cells that produce interferon Ɣ, and
• Ex. Antigens on the surface of red blood cells activates are important effector pathways for intracellular microbial
antibody activity for people with different blood group organisms
• Antibodies (opsonins) enhance the phagocytic pathway of
the innate immune system
E. IMMUNOLOGIC MEMORY • Complement type 2 receptor functions as a co-receptor for
• Consequence of clonal selection humoral immune responses and links the complement
• A 2nd encounter with the same antigen induces heightened pathway via C3d with antibody production
state of immune activity
• Confers a lifelong immunity after initial encounter
• Primary response is smaller compared to secondary
response
® This is the effect induced by Memory T-Cells

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c) Early line of defense against microbes
d) All of the above
e) None of the above
4. Which cytokine directs T cells to become Th1 T Cells?
The Complement System and
a) IL3
Adverse Pregnancy Outcomes
b) IL6
c) IL12
CASE: Complement regulation is apparent at the placental d) IL8
interface from early pregnancy with some degree of e) IL10
complement activation occurring normally throughout 5. All of the following are innate/nonspecific host defenses
gestation. However, a number of pregnancy complications except:
including early pregnancy loss, fetal growth restriction, a) Anatomic Barriers
hypertensive disorders of pregnancy and preterm birth are b) Inflammatory Barriers
associated with excessive or misdirected complement c) Cytokines
activation, and are more frequent in women with inherited or d) Antigenic Specificity
acquired complement system disorders or complement gene 6. The adaptive and innate immunity work separately, without
mutations. Targeted complement therapeutics are already in overlapping interactions.
use to control adverse pregnancy outcomes in select a) True
situations. b) False
7. The self-limiting characteristic of the immune response
De Vera, 2018 refers to:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4447554 a) Regulation
b) Proliferation
c) Maturation
d) Recognition
QUICK REVIEW e) All of the above
A. SUMMARY OF TERMS
• Innate Immunity: natural, inborn and nonspecific. Early Answers
line of defense that responds rapidly to infection. 1A. Through the clonal selection of lymphocytes allows
® Anatomic Barriers: Skin and Mucous Membranes individuals to have large numbers of Ag-reactive clones of T and
® Physiologic Barriers: Temperature, Low pH, B cells whose specificity is determined prior to contact with an
Chemical Mediators antigen by random gene arrangement.
® Pattern Recognition Receptors: recognize PAMPs 2A. The adaptive immunity creates memory cells after its first
and DAMPs encounter with the infection so that if a second infection occurs,
® Inflammatory Barriers: these memory cells are capable of recognizing it.
§ Complement Pathways: 3 Pathways 3D. All of the choices describe innate immunity.
o Classical Pathway: Activated by Ag:Ab 4C. IL12 directs the T cells to become Th1 that produce
o Lectin Pathway: mannose on pathogen interferon-γ and are important effector pathways for intracellular
surfaces microbial organisms
o Alternative: Pathogen surfaces 5D. Antigenic Specificity is an adaptive/specific immune
§ Cytokines response.
• Adaptive Immunity: acquired immunity that has specificity 6B. There is an overlap between the two types of immunity.
and memory. Responds slower to infections. Composed of 7A. The self-limiting characteristic of the adaptive immune
T and B lymphocyte cells response refers to the regulatory mechanisms used to eliminate
® Antigenic Specificity: can distinguish subtle antigen signals when the disease has passed.
differences among antigens
§ B Cells: recognize epitopes REFERENCES
§ T Cells: recognize epitopes associated with MHC REQUIRED
® Diversity: Allows recognition of billions of uniquely (1) De Vera, Michelle. 20 September 2018. Innate and
different structures on foreign antigens Adaptive Immunity [lecture slides].
® Clonal Selection: Postulates of the clonal Selection (2) Garland Science. 2009. The Immune Response [Video].
® Self/Non-Self Recognition: responds only to foreign Retrieved from
antigens https://www.youtube.com/watch?v=G7rQuFZxVQQ
® Immunologic Memory: second encounter with same (3) Murphy, Kenneth, and Casey Weaver. Janeway's
antigen induces heightened state of immune activity Immunobiology. New York, Garland Science, 2017.
® Self-Limiting: Regulatory Mechanisms (4) The Complement System and Adverse Pregnancy
Outcomes
B. REVIEW QUESTIONS (required)
1. Immunocompetent individuals have Ag-reactive clones of T
and B cells in great numbers.
a) True
b) False
2. The adaptive immunity is capable of creating memory cells
that develop as an adaptation to a previously encountered
infection.
a) True
b) False
3. Which of the following statements describes innate
immunity?
a) Natural or native immunity
b) Encoded by genes directly inherited

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