Innate Immunity versus Adaptive Immunity
 Shared characteristic of mechanisms of innate immunity is that they recognize and respond to microbes but
don’t react against non-microbial substances
o May also be triggered by host cells that are damaged by microbes
 Adaptive immunity must be stimulated by and adapts to encounters with microbes before it can be effective
o May be directed against microbial as well as non-microbial antigens
 Innate immune system instructs adaptive immune system to respond to different microbes in ways that are
effective for combating microbes
o Adaptive immune response often uses mechanisms of innate immunity to eradicate infections
 Constant bidirectional cross-talk occurs between innate immunity and adaptive immunity
Recognition of Microbes by Innate Immune System
 Components of innate immunity recognize structures shared by various classes of microbes and are not present
on host cells; each component may recognize many bacteria, viruses, or fungi
o Phagocytes express receptors for bacterial lipopolysaccharide (LPS or endotoxin), which is present in cell
wall of many bacterial species but is not produced by mammalian cells
o Other receptors of phagocytes recognize terminal mannose residues, which are typical of bacterial but
not mammalian glycoproteins
o Phagocytes recognize and respond to double-stranded RNA, which is found in many viruses
 May recognize unmethylated CpG oligonucleotides, which are common in microbial DNA but not
abundant in mammalian DNA
o Microbial molecules that are targets of innate immunity sometimes called pathogen-associated
molecular patterns
o Receptors of innate immunity that recognize shared structures are pattern recognition receptors
 Some components of innate immunity capable of binding to host cells but are prevented from being activated
by the cells
o If plasma proteins of complement system deposited on host cells, activation of the complement proteins
blocked by regulatory molecules present on host cells but aren’t present on microbes
 Components of innate immunity evolved to recognize structures of microbes often essential for survival and
infectivity of microbes; makes it highly effective defense mechanism because a microbe can’t evade innate
immunity simply by mutating or not expressing targets of innate immune recognition
o Microbes that don’t express functional forms of structures lose their ability to infect and colonize host
o Microbes frequently evade adaptive immunity by mutating antigens recognized by lymphocytes because
these antigens usually not required for life of microbes
 Innate immune system can also recognize molecules released from stressed or necrotic cells
o Subsequent response serves to eliminate these cells
o Molecules released are damage-associated molecular patterns
 Receptors of innate immune system encoded in germline and not produced by somatic recombination of genes
 Antigen receptors of lymphocytes, namely antibodies and T cell receptors, produced by random recombination
of receptor genes during maturation of these cells
o Gene recombination can generate many more structurally different receptors than can be produced
from inherited germline genes, but these different receptors can’t have predetermined specificity for
microbes; specificity of adaptive immunity much more diverse than that of innate immunity, and
adaptive immune system capable of recognizing many more chemically distinct structures
o Receptors of adaptive immune system clonally distributed (each clone of lymphocytes (B cells and T
cells) has different receptor specific for particular antigen
o In innate immune system, receptors non-clonally distributed; identical receptors expressed on all cells of
particular type, such as macrophages
 Innate immune system doesn’t react against host; partly because of inherent specificity of innate immunity for
microbial structures and partly to fact that mammalian cells express regulatory molecules that prevent innate
immune reactions
o Adaptive immunity – lymphocytes that recognize self either die or are inactivated on encounter with
self-antigens; reacts more quickly and more efficiently second time around
 2 principal types of reactions of innate immune system are inflammation and antiviral defense
o Inflammation consists of recruitment and activation of leukocytes
o Defense against intracellular viruses mediated mainly by NK cells and cytokines (interferons)
 Receptors that innate immune system uses to react to microbes expressed on phagocytes, dendritic cells,
lymphocytes, epithelial cells, and endothelial cells; receptors expressed in different cellular compartments
where microbes may be located (cell surface, ER (rapidly recruited to endosomes), cytoplasm)
o TLRs – specific for different components of microbes; some on cell surface and some in endosomes;
signals generated by engagement of TLRs activate transcription factors that stimulate expression of
genes encoding cytokines, enzymes, and other proteins involved in antimicrobial functions of activated
phagocytes and dendritic cells
 2 of most important transcription factors activated by TLR signals are NF-κB (promotes
expression of various cytokines and endothelial adhesion molecules) and IRF-3 (stimulates
production of type I interferons (cytokines that block viral replication))
 TLR-2 attacks several bacterial lipoglycans
 TLR-3, TLR-7, and TLR-8 attack double-stranded RNA
 TLR-4 attacks LPS (bacterial endotoxin)
 TLR-5 attacks flagellin (in bacterial flagella)
 TLR-9 attacks unmethylated CG-rich (CpG) oligonucleotides (more abundant in bacteria than
mammalian cells)
o Cell surface receptor recognizes peptides that being with N-formyl methionine (peculiar to bacterial
proteins)
o Receptor for terminal mannose residues involved in phagocytosis of bacteria
o Several cytoplasm receptors recognize viral nucleic acids or bacterial peptides
o Other cytoplasmic receptors recognize microbes as well as components of dead cells, including uric acid
and DNA; some associate with inflammasome (multi-protein complex; transmits signals that activate
enzyme that cleaves precursor of cytokine IL-1 to generate biologically active form)
 IL-1 is powerful inducer of inflammatory reaction to microbes and damaged tissues
 Gain-of-function mutations affecting components of inflammasome are cause of rare
autoinflammatory syndromes; clinical manifestations are result of excessive IL-1 production; IL-1
antagonists are highly effective therapies
Components of Innate Immunity
 Common portals of entry of microbes (skin, GI tract, and respiratory tract) protected by continuous epithelia
that provide physical and chemical barriers against infection
o Epithelial cells also produce peptide antibiotics that kill bacteria
o Epithelia contain type of lymphocyte (intraepithelial lymphocytes) that belong to T cell lineage but
express antigen receptors of limited diversity
 Some of T cells express receptors composed of 2 chains (γ and δ chains) that are similar to (but
not identical to) the highly diverse αβ T cell receptors expressed on a majority of T lymphocytes
 Intraepithelial lymphocytes (including γδ T cells) often recognize microbial lipids and other
structures that are shared by microbes of the same type
 Serve as sentinels against infectious agents that attempt to breach epithelia
 Neutrophils (PMNs) – production from bone marrow increases rapidly in response to infection; production
stimulated by cytokines (CSFs) secreted by many cell types in response to infections and act on bone marrow
stem cells to stimulate proliferation and maturation of neutrophil precursors
o First cell type to respond to most infections, particularly bacterial and fungal infections
o Ingest microbes in circulation and rapidly enter extravascular tissues at sites of infection where they
ingest microbes and die after a few hours
 Monocytes and macrophages – mononuclear phagocyte system; resident macrophages found in CT and every
organ in body, where they serve to phagocytose invaders
 Neutrophils and monocytes migrate to extravascular sites of infection by binding to endothelial adhesion
molecules and in response to chemoattractants produced on encounter with microbes
o If microbe breaches epithelium and enters subepithelial tissue, resident macrophages recognize the
microbe and respond by producing cytokines, two of which (TNF and IL-1) act on endothelium of small
vessels at site of infection
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Cytokines stimulate endothelial cells to rapidly express E-selectin and P-selectin; circulating neutrophils
and monocytes express surface carbs that bind weakly to selectins
o Neutrophils become tethered to endothelium, flowing blood disrupts this binding, bonds reform
downstream, and so on, resulting in “rolling” of leukocytes on endothelial surface
o Leukocytes express integrins (adhesion molecules) that integrate extrinsic signals in cytoskeletal
alterations; present in low-affinity state on unactivated leukocytes
o As leukocytes roll on endothelium, tissue macrophages that encountered the microbe and endothelial
cells responding to macrophage-derived TNF and IL-1 produce cytokines (chemokines) that bind to
glycoproteins on luminal surface of endothelial cells and are thus displayed at high concentration to
leukocytes that are rolling on endothelium
o Chemokines stimulate rapid increase in affinity of leukocyte integrins for their ligands on endothelium
o TNF and IL-1 act concurrently on endothelium to stimulate expression of ligands for integrins; firm
binding of integrins to their ligands arrests rolling leukocytes on endothelium
o Cytoskeleton of leukocytes reorganized, and cells spread out on endothelial surface; chemokines also
stimulate motility of leukocytes; as a result, leukocytes begin to migrate between endothelial cells,
through vessel wall, and along chemokine concentration gradient to site of infection
o Sequence of selectin-mediated rolling, integrin-mediated firm adhesion, and chemokine-mediated
motility leads to migration of blood leukocytes to extravascular site of infection within minutes
o Inflammation – accumulation of leukocytes at sites of infection, with concomitant vascular dilation and
increased leakage of fluid and proteins in tissue
o Inherited deficiencies in integrins and selectin lead to defective leukocyte recruitment to sites of
infection and increased susceptibility to infections (leukocyte adhesion deficiencies)
Neutrophils and macrophages use TLRs and other pattern recognition receptors to recognize microbes in blood
and extravascular tissues and initiate responses that function to destroy the microbes
o Some receptors involved mainly in activating phagocytes (include TLRs, receptors for formyl methionine
peptides, and receptors for cytokines, mainly IFN-γ and chemokines)
o Other receptors involved in phagocytosis of microbes as well as activation of phagocytes
 Receptors for products of complement activation and for antibodies avidly bind microbes that
are coated with complement proteins or antibodies and function in ingestion of microbes and
activation of phagocytes
Phagocytosis begins with membrane receptors binding to microbe, followed by extension of phagocyte PM
around microbe; membrane closes around and pinches off, and microbe internalized in membrane-bound
vesicle (phagosome)
o Phagosomes fuse with lysosomes (phagolysosomes)
o At same time microbe is being bound by phagocyte’s receptors and ingested, receptors deliver signals
that activate several enzymes in phagolysosomes
 Phagocyte oxidase converts molecular oxygen into superoxide anion and free radicals
 Inducible nitric oxide synthase catalyzes conversion of arginine to NO
 Lysosomal proteases break down microbial proteins
o In some instances, same enzymes and ROS may be liberated into extracellular space and may injure host
tissues – why inflammation may cause tissue injury as well
o Inherited deficiency of phagocyte oxidase enzyme is cause of immunodeficiency disease (chronic
granulomatous disease) where phagocytes unable to eradicate intracellular microbes, and host tries to
contain infection by calling in more macrophages and lymphocytes, resulting in collections of cells
around microbes (granulomas)
o Macrophages produce cytokines that recruit and activate leukocytes; secrete growth factors and
enzymes that function to repair injured tissue and replace it with CT; stimulate T lymphocytes and
enhance adaptive immunity; respond to products of T cells and function as effector cells of cellmediated immunity
Dendritic cells – respond to microbes by producing cytokines that recruit leukocytes and initiate adaptive
immune responses; constitute bridge between innate and adaptive immunity
NK cells – class of lymphocytes that recognize infected and stressed cells and respond by killing these cells and
secreting macrophage-activating cytokine (IFN-γ)
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Make up approximately 10% of lymphocytes in blood and peripheral lymphoid organs
Contain abundant cytoplasmic granules and express characteristic surface markers, but don’t express
Ig’s and T cell receptors
o Activation triggers discharge of proteins contained in cytoplasmic granules toward infected cells
(molecules that enter infected cells and activate enzymes that induce apoptotic death)
o Activated NK cells also synthesize and secrete IFN-γ, which activates macrophages to become more
effective at killing phagocytosed microbes
Macrophages ingest microbes and produce IL-12, which activates NK cells
Activation of NK cells determined by balance between engagement of activating and inhibitory receptors
o Activating receptors recognize cell surface molecules commonly expressed on stressed cells, including
those infected with viruses and intracellular bacteria
 Other types of stress that lead to expression of ligands for activating receptors are DNA damage
and malignant transformation; NK cells function to eliminate irreparably injured and tumor cells
 NKG2D recognizes molecules that resemble class I MHC proteins and is expressed in response to
many types of cellular stress
 Activating receptor specific for IgG bound to cells; recognition results in killing cells (antibodydependent cytotoxicity (ADCC)); NK cells are principal mediators of ADCC
 Activation receptors on NK cells have signaling subunits that contain ITAMs in cytoplasmic tails
 ITAMs also present in subunits of lymphocyte antigen receptors; become
phosphorylated on tyrosine residues when receptors bind their ligands
 Phosphorylated ITAMs bind and promote activation of cytoplasmic protein tyrosine
kinases, and these enzymes phosphorylate, and thereby activate, other substrates in
several different downstream signal transduction pathways, eventually leading to
cytotoxic granule exocytosis and production of IFN-γ
o Inhibitory receptors of NK cells specific for self class I MHC molecules expressed on all healthy nucleated
cells and function to block signaling by activating receptors
 2 major families of NK cell inhibitory receptors: killer cell immunoglobulin-like receptors (KIRs –
share structural homology with Ig molecules) and receptors consisting of protein (CD94) and
lectin subunit (NKG2)
 Both families contain structural motifs in cytoplasmic domains (ITIMs) which become
phosphorylated on tyrosine residues when receptors bind class I MHC molecules
 Phosphorylated ITIMs bind and promote activation of cytoplasmic protein tyrosine
phosphatases, which remove phosphate groups from tyrosine residues of various signaling
molecules, thereby blocking activation of NK cells through activating receptors
 When inhibitory receptors of NK cells encounter self MHC molecules, NK cells shut off
o Many viruses have mechanisms that block expression of class I molecules in infected cells, which allows
them to evade killing by virus-specific CD8+ cytotoxic T lymphocytes (CTLs); when this happens, NK cell
inhibitory receptors not engaged, and if virus induces expression of activating ligands at same time, NK
cells become activated and eliminate virus-infected cells
 Ability of NK cells to protect against infections enhanced by cytokines secreted by macrophages
and dendritic cells that have encountered microbes
 NK-activating cytokines include IL-15, IFNs, and IL-12
 IL-15 important for development and maturation of NK cells
 IFNs and IL-12 enhance killing functions of NK cells
Host uses CTLs to recognize MHC-displayed viral antigens, viruses shut off MHC expression, and NK cells have
evolved to responds to absence of MHC molecules; many tumors also attempt to evade CTL-mediated killing by
reducing expression of class I MHC molecules
Several types of lymphocytes that have some features of T and B lymphocytes function in early defense and can
be considered as part of innate immune system; unifying characteristic is they express somatically rearranged
antigen receptors (like B and T cells) but have limited diversity
o γδ T cells present in epithelia
o NK-T cells, some of which express surface molecules typically found on NK cells, present in epithelia and
lymphoid organs; recognize microbial lipids bound to class I MHC-related molecule (CD1)
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B-1 cells – B lymphocytes found mostly in peritoneal cavity and mucosal tissues, where they produce
antibodies in response to microbes and microbial toxins that pass through walls of intestine
 Most of circulating IgM found in blood of normal individuals (natural antibodies) are products of
B-1 cells, and many of the antibodies specific for carbs present in cell walls of many bacteria
o Marginal zone B cells – present at edges of lymphoid follicles in spleen and other organs; involved in
rapid antibody responses to blood-borne polysaccharide-rich microbes
Complement system – collection of circulating and membrane-associated proteins important in defense against
microbes; many complement proteins proteolytic enzymes, and complement activation involves sequential
activation of these enzymes (enzymatic cascade)
o Complement cascade activated by 3 pathways
 Alternative pathway – triggered when some complement proteins activated on microbial
surfaces and can’t be controlled because complement regulatory proteins not present on
microbes (but are on host cells) – innate immunity
 Classical pathway – triggered after antibodies bind to microbes or other antigens; component of
humoral arm of adaptive immunity
 Lectin pathway – activated when plasma protein (mannose-binding lectin) binds to terminal
mannose residues on surface glycoproteins of microbes; lectin activates proteisn of classical
pathway, but because it is initiated by a microbial product in absence of antibody, it is still
innate immunity
o Activated complement proteins function as proteolytic enzymes to cleave other complement proteins in
enzymatic cascade that can be rapidly amplified
o Central component of complement is plasma protein C3, which is cleaved by enzymes generated in early
steps; major proteolytic fragment (C3b) becomes covalently attached to microbes and is able to activate
downstream complement proteins on microbial surface
 C3b coats microbes and promotes binding of these microbes to phagocytes, by virtue of
receptors for C3b expressed on phagocytes; microbes that are opsonized with complement
proteins rapidly ingested and destroyed by phagocytes
o Some proteolytic fragments (C5a and C3a) chemoattractants for phagocytes; promote leukocyte
recruitment (inflammation) at site of complement activation
o Complement activation culminates in formation of polymeric protein complex that inserts into microbial
cell membrane, disturbing permeability barrier and causing either osmotic lysis or apopototic death of
microbe
In response to microbes, dendritic cells, macrophages, and other cells secrete cytokines that mediate many of
cellular reactions of innate immunity
o Cytokines – soluble proteins that mediate immune and inflammatory reactions and are responsible for
communications between leukocytes and between leukocytes and other cells
o Most of molecularly defined cytokines are interleukins (produced by leukocytes and act on leukocytes)
o In innate immunity, principal sources of cytokines are dendritic cells and macrophages activated by
recognition of microbes
o Binding of bacterial components such as LPS or of viral molecules such as double-stranded RNA to TLRs
of dendritic cells and macrophages is powerful stimulus for cytokine secretion by cells
o Also produced in cell-mediated immunity; major sources of cytokines are helper T lymphocytes
o Secreted in small amounts in response to external stimulus and bind to high-affinity receptors on target
cells; most cytokines act on cells that produce them (autocrine) or on adjacent cells (paracrine)
 Enough dendritic cells and macrophages may be activated that large amounts of cytokines
produced, and they may be active distant from their site of secretion (endocrine)
o TNF, IL-1, and chemokines are principal cytokines involved in recruiting blood neutrophils and
monocytes to sites of infection
o At high concentrations, TNF promotes thrombus formation on endothelium and reduces blood pressure
by combination of reduced myocardial contractility and vascular dilatation and leakiness
o Severe, disseminated gram-negative bacterial infections sometimes lead to septic shock; characterized
by low blood pressure (defining feature of shock), disseminated intravascular coagulation, and
metabolic disturbances
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Early clinical and pathologic manifestations of septic shock caused by very high levelsof TNF
produced in response to bacteria
o Dendritic cells and macrophages also produce IL-12 in response to LPS and other microbial molecules
o Because IFN-γ produced by T cells as well as NK cells, it is considered a cytokine of both innate immunity
and adaptive immunity
o In viral infections, dendritic cells, macrophages, and other infected cells produce cytokines (type I
interferons) that inhibit viral replication and prevent spread of infection to uninfected cells
o Type I IFN (IFN-α) used to clinically treat chronic viral hepatitis
 Circulating proteins also involved in defense against infections
o Plasma mannose-binding lectin (MBL) – protein that recognizes microbial carbs and can coat microbes
for phagocytosis or activate complement cascade by lectin pathway
 MBL belongs to collectin family of proteins (share homology to collagen and contain carbbinding (lectin) domain)
o Surfactant proteins in lung belong to collectin family and protect airways from infection
o C-reactive protein (CRP) binds to phosphorylcholine on microbes and coats microbes for phagocytosis by
macrophages, which express receptor for CRP
o Circulating levels of many plasma proteins increase rapidly after infection (acute phase response)
 Extracellular bacteria and fungi combated by phagocytes and complement system and by acute phase proteins
 Defense against intracellular bacteria and viruses mediated by phagocytes, dendritic cells, and NK cells, with
cytokines providing communications between leukocytes
Evasion of Innate Immunity by Microbes
 Some intracellular bacteria resist destruction inside phagocytes – Listeria monocytogenes produces protein that
enables it to escape from phagocytic vesicles and enter cytoplasm of infected cells, where it is no longer
susceptible to ROS and NO
 Cell walls of mycobacteria contain lipid that inhibits fusion of vesicles containing ingested bacteria with
lysosomes
 Other microbes have cell walls that are resistant to actions of complement proteins
 Same mechanisms enable microbes to resist effector mechanisms of cell-mediated and humoral immunity
Role of Innate Immunity in Stimulating Adaptive Immune Responses
 In addition to defense functions, innate immune response to microbes serves important warning function by
alerting adaptive immunity that effective immune response needed (second signals, together with antigens)
 Full activation of antigen-specific lymphocytes requires 2 signals: antigen itself (signal 1) and microbes, innate
immune responses to microbes, and host cells damaged by microbes (signal 2)
 Requirement for microbe-dependent second signals ensures that lymphocytes respond to infectious agents and
not harmless, non-infectious substances
 Adaptive immune responses may be induced by antigens without microbes (vaccination); in such instances,
antigens have to be administered with substances (adjuvants) that elicit same innate immune reactions as
microbes do
o Many potent adjuvants are products of microbes
 Microbes (or IFN-γ produced by NK cells in response to microbes) stimulate dendritic cells and macrophages to
produce 2 types of second signals that can activate T lymphocytes
o Dendritic cells and macrophages express surface molecules (costimulators) that bind to receptors on
naïve T cells and function together with antigen recognition to activate T cells
o Dendritic cells and macrophages secrete IL-12, which stimulates differentiation of naïve T cells into
effector cells of cell-mediated adaptive immunity
 Blood-borne microbes activate complement system by alternative pathway
o One of proteins produced during complement activation (C3d) becomes covalently attached to microbe
o B lymphocytes recognize microbial antigens by their antigen receptors, and at same time they recognize
C3d bound to microbe by receptor for C3d; combination of antigen recognition and C3d recognition
initiates process of B cell differentiation into antibody-secreting cells; complement produce serves as
second signal for humoral immune response
 Second signals not only stimulate adaptive immunity but also guide nature of adaptive immune response
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Blood-borne microbes need to be combated by antibodies produced by B lymphocytes during humoral
immune responses; blood-borne microbes activate plasma complement system, which in turn
stimulates B cell activation and antibody production
Different types of microbes induce different innate immune responses, which then stimulate types of
adaptive immunity best able to combat the different infectious pathogens