Clinical Immunology Exam 1

What are the essential functions of the immune system

• Most important

  • Prevent and eradicate infection

• Other functions

  • Monitor tissues for damaged/changed cells and destroy them

  • Defend against tumors

  • Control tissue regeneration and scarring

  • Induce pathologic inflammation

  • Recognize and respond to tissue grafts and newly introduced proteins

How does innate immunity differ from adaptive imunity

• Innate immunity

  • Present before infection and responds very quickly

  • Acts as the body’s first line of defense by blocking microbial entry

    • Includes epithelial barrier, phagocytes, NK cells, complement system, etc

    • Recognizes structures shared by groups of microbes rather than antigen

  • Doesn’t have high specific memory response

• Adaptive immunity

  • Develops more slowly after exposure but highly specific for antigens/foreign substances

  • Requires cellular activation, proliferation, and differentiation

    • Mediated/assisted by B and T lymphocytes

      • B cells produce antibodies

      • T cells provide cell-mediated immunity

        • Produces cytokines that act in a paracrine manner

  • Produces immunologic memory (so repeated exposure causes a faster and stronger immune response)

According to the clonal selection hypothesis, what are the key characteristics of lymphocyte clones

• These specific lymphocytes develop before encountering their specific antigen

  • Each clone contains lymphocytes with receptors having particular antigen specificity

• When an antigen enters the body, it selects and activates the lymphocyte clone whose receptor recognizes that antigen

  • The selected lymphocytes then undergo clonal expansion

  • Some become effector cells and the rest become memory cells

    • Naive lymphocyte clones are selected on the first encounter with antigens

    • Memory lymphocyte clones are selected on subsequent encounters with antigens

      • More antigen exposure = more effective response

• Explains why the immune system can be specific even though the body may encounter many different antigens

What are 2 major differences between antigens recognized by B cells and T cells

• B cells

  • Can recognize intact or whole antigens

    • Can recognize soluble antigens or molecules directly on the surface of microbes

  • Produce and secrete immunoglobins (Igs)

• T cells

  • Usually recognizes peptide fragments of protein antigens rather than intact

    • Normally displayed on MHC molecules on another cell

  • Helper T cells - produce cytokines

  • Cytotoxic T cells - kill infected cells

  • Regulatory T cells - prevent of limit immune responses

• Overall

  • B cells can directly bind to many antigens while T cells depend on antigen processing and presentation

  • Distinguishable by CD (cluster of differentiation) surface proteins

What is passive immunity and what is an example of it

• Passive immunity occur when a person receives antibodies/lymphocytes/immunoglobins that were produced by another individual

• Participation occurs quickly and is temporary since long term memory is not procuced

• Examples include:

  • Maternal antibodies transferred to a fetus by the placenta

  • Antibodies transferred by breast milk

  • Administration by tetanus immunoglobulin

What are cytokines and what roles do they play in immune responses

• Cytokines are proteins secreted by immune and other cells that allow cells to communicate with one another

• They can activate or regulate other immune cells

• Helper T cells produce cytokines

  • These cytokines can:

    • Activate macrophages

    • Stimulate B cells

    • Recruit and activate other leukocytes to destroy ingested microbes

    • Promote inflammation

  • Cytokines are important in both innate and adaptive responses

  • Different cytokines can either increase immune responses or suppress/control them

Why must the lymphocyte repertoire be both diverse and specific

• Diversity is necessary because humans can encounter many different microbes and antigens

  • The immune system therefore needs lymphocytes capable of recognizing millions of different antigenic structures

• Specificity means that each lymphocyte receptor can distinguish one antigen from another

• Overall it allows the immune system to:

  • Recognize many threats/foreign molecules

  • Direct response toward the correct antigen

  • Avoid using the same nonspecific response against everything

How do antigens from mucocutaneous portals reach lymph nodes

• They usually enter through the skin, GI, respiratory, and genitourinary tracts

• Dendritic cells located in these tissues capture microbial antigens

• Dendritic cells then migrate through lymphatic vessels to the draining lymph nodes

• Free microbes or antigens can also travel through the lymph to the lymph nodes

  • Once there, antigens become concentrated and can be presented to lymphocytes

What are the main functions of helper T cells

• Also known as CD4+ T lymphocytes

• Function

  • Main role is to produce cytokines that coordinate immune responses

    • Can also

      • Activate macrophages to kill ingested microbes more effectively

      • Help activate B cells and promote antibody responses

      • Recruit and activate leukocytes involved in inflammation

      • Help other T cells develop effective responses

• Overall

  • Helper T cells organize and strengthen the activities of other immune cells rather than directly killing infected cells

What are the major characteristics and fucntions of phagocytes

• 2 Major phagocyte types are neutrophils and macrophages

  • Main function is phagocytosis (ingesting and destroying microbes)

• Neutrophils

  • Most abundant

  • Respond rapidly to infection

  • Important against bacterial and fungal infections

  • Short-lived and major cells of acute inflammation

• Macrophages

  • Develop from monocytes that enter tissues

  • Longer-lived

  • Ingest and destroy microbes and dead cells

  • Produce cytokines that promote inflammation

  • Also acts as antigen-presenting cells

How are naive, effector, and memory lymphocytes from the same clone related

• Overall

  • They are different stages/descendants of the same antigen-specific lymphocyte clone

• Naive lymphocytes

  • Matured but have not yet encountered their specific antigen

  • After antigen recognition, they proliferate and differentiate

• Effector lymphocytes

  • Descendants of activated naive cells

  • Carry out functions that eliminate the antigen

  • Ex. Antibody-secreting plasma cells and effector T cells

• Memory lymphocytes

  • Produced from antigen-stimulated lymphocytes

  • Survive for long periods

  • Respond quickly if the same antigen appears again

Describe lymphocyte development and maturation

• Originate from hematopoietic stem cells in the bone marrow

• Primary/generative lymphoid organs are where lymphocytes mature

  • B cells mature in the bone marrow

  • T cell precursors originate in the bone marrow but migrate to the thymus where they mature

  • During maturation, lymphocytes develop their antigen receptors and become capable of responding to antigens

  • Mature naive lymphocytes then enter the circulation and travel to secondary lymphoid organs (where they may encounter their specific antigen)

What are professional antigen-presenting cells and what functions do they perform

• Characteristics and Function

  • Specialized cells that can capture antigens, process them, and present peptide fragments to activate naive T lymphocytes

• Professional APCs include:

  • Dendritic cells

  • Macrophages

  • B cells

• Other functions

  • Produce or display additional molecules needed to activate T cells

    • Dendritic cells are especially important because they are the most effective APCs for activating naive T cells

  • Also connect antigen recognition to the development of an adaptive immune response

Compare primary and secondary lymphoid organs

• Primary/generative lymphoid organs

  • Where lymphocytes develop and mature

  • Bone marrow: B cell maturation

  • Thymus: T cell maturation

• Secondary/peripheral lymphoid organs

  • Where mature naive lymphocytes encounter antigens and adaptive immune responses begin

  • Include: lymph nodes, spleen, and mucosal/cutaneous lymphoid tissues

• Overall

  • Primary = lymphocytes are made and matured

  • Secondary lymphocytes meet antigens and become activated

What similarities exist between lymph nodes and the spleen

• Secondary lymphoid organs

• Concentrate antigens and bring them together with lymphocytes and APCs

• Contain organized:

  • B cell follicles

    • Lymph nodes - follicles in the cortex

    • Spleen - follicles next to the PALS (periarteriolar lymphoid sheaths)

  • T cell zones

    • Lymph nodes - paracortex region

    • Spleen - PALS

  • Dendritic cells

  • macrophages

• Produce activated/effector lymphocytes that can leave the organ

• Can develop germinal centers during B cell responses

• Difference

  • Lymph nodes mainly respond to antigens carried in lymph from tissues

  • Spleen performs a similar function for blood-borne antigens

Compare dendritic cells and follucular dendritic cells

• Dendritic Cells (DCs)

  • Capture microbial protein antigens

  • Process proteins into peptide fragments

  • Present peptides to T cells

  • Important for activating naive T cells

  • Help connect innate and adaptive immunity

  • Help transport Ags to lymph nodes

• Follicular dendritic cells (FDCs)

  • Located in B-cell follicles/germinal centers

  • Display intact antigens to B cells

  • Help activate and select B cells, especially B cells producing high affinity antibodies

  • Help transport Ags to B cells

• Differences

  • Different cell types with different functions

Describe the structure of a lymph node and identify the functions of its major regions

• A lymph node is an encapsulated lymphoid organ located along lymphatic vessels

• Cortex

  • Contains lymphoid follicles

  • Main B cell zone

  • Activated B cells may form germinal centers here

• Paracortex/parafollicular cortex

  • Main T cell zone

  • Contains dendritic cells that present antigens to naive T cells

• Subcapsular and medullary sinuses

  • Contains macrophages and specialized B cells

  • Help capture antigens entering through lymph

• Afferent lymphatic vessels

  • Bring lymph, antigens, and APCs into the node

• Efferent lymphatic vessels

  • Allow lymph and activated lymphocytes to leave

What are high endothelial venule (HEVs) and what role do they play

• HEVs are specialized postcapillary found in lymph nodes

• Allow circulating naive lymphocytes to leave the bloodstream and enter lymph nodes

• Naive T cells bind adhesion molecules and respond to chemokines on HEV endothelial cells

• After entering, T cells move into the paracortex, where they can search dendritic cells for their specific antigen

• HEVs are therefore important since they continuously bring naive lymphocytes into the location where antigens are concentrated

What are the major properties of adaptive immune responses?

• Specificity

  • Each lymphocyte clone recognizes a particular antigen.

  • Allows the immune response to be directed toward the specific antigen that triggered it.

• Diversity

  • The immune system can recognize a very large number of different antigens.

  • This is possible because the body contains many lymphocyte clones with different antigen receptors.

• Clonal expansion

  • When a lymphocyte recognizes its specific antigen, that lymphocyte is activated and proliferates.

  • Produces many cells with the same antigen specificity.

  • Helps generate both effector and memory cells.

• Specialization

  • Different types of microbes stimulate different immune responses.

  • Allows the immune system to use the response that is most effective against a particular type of infection.

• Self-limitation/contraction

  • Immune responses normally decrease after the antigen or infection has been eliminated.

  • Most effector cells die once they are no longer needed.

  • This prepares the immune system to respond to future infections.

• Tolerance

  • Normally prevents the immune system from responding against the body's own self-antigens.

  • Loss of self-tolerance can contribute to autoimmune disease

Compare humoral immunity and cell-mediated immunity

• Humoral immunity

  • Mediated by B lymphocytes and antibodies.

  • B cells recognize antigens and differentiate into plasma cells.

  • Plasma cells secrete antibodies.

  • Antibodies are especially important for eliminating:

    • Extracellular microbes

    • Microbial toxins

  • Antibodies can circulate through the blood and enter tissues to bind microbes or toxins.

• Cell-mediated immunity

  • Mediated by T lymphocytes.

  • Especially important for microbes that survive inside cells, where circulating antibodies cannot easily reach them.

  • CD4+ helper T cells

    • Produce cytokines.

    • Activate macrophages and other leukocytes.

    • Help B cells produce antibodies.

  • CD8+ cytotoxic T cells

    • Kill infected cells containing intracellular microbes.

    • Can also kill certain tumor cells.

• Overall

  • Humoral immunity → mainly B cells + antibodies → extracellular microbes.

  • Cell-mediated immunity → mainly T cells → intracellular microbes/infected cells.

What are regulatory T cells and what is their major function?

• Regulatory T cells (Tregs) are a specialized population of T lymphocytes.

• Their major role is to suppress or limit immune responses.

• They help:

  • Prevent excessive immune responses.

  • Maintain self-tolerance.

  • Prevent immune cells from reacting excessively against the body's own tissues.

• They are different from:

  • Helper T cells → produce cytokines and coordinate immune responses.

  • Cytotoxic T cells → directly kill infected cells.

• Common regulatory T-cell markers include:

  • CD4

  • CD25

  • FoxP3

• Overall: regulatory T cells act as an important control mechanism that prevents immune responses from becoming excessive or attacking self.

Describe the major anatomical regions of the spleen and their immune functions.

• The spleen is a highly vascularized secondary lymphoid organ.

  • Functions similarly to lymph nodes, except it responds primarily to blood-borne antigens.

  • Acts as a major filter for the blood.

  • Contains many phagocytes that ingest microbes circulating in the blood.

• Red pulp

  • Site where old red blood cells and platelets are destroyed.

  • Contributes to iron homeostasis.

• White pulp

  • Contains organized lymphocytes and accessory cells such as:

    • Macrophages

    • Dendritic cells

  • Major location for adaptive immune responses against blood-borne antigens.

• Marginal zone (MZ)

  • Located between the red and white pulp.

  • Contains:

    • Macrophages

    • Specialized B cells

  • Helps bridge innate and adaptive immunity.

• Periarteriolar lymphoid sheaths (PALS)

  • Main T-cell zone of the spleen.

• B-cell follicles

  • Located next to the PALS.

  • Germinal centers can develop when B cells are actively proliferating.

  • Activated helper T cells can enter follicles and help B cells produce high-affinity antibodies.

• Effector and memory lymphocytes can leave the spleen through the veins.

What is the mucocutaneous immune system and why is it important?

• The mucocutaneous immune system consists of immune cells and lymphoid tissues associated with:

  • Skin

  • Gastrointestinal tract

  • Respiratory tract

  • Other mucosal surfaces

• These areas are important because they are major locations where microbes can enter the body.

• Contains cells of both innate and adaptive immunity, including:

  • Dendritic cells

  • Macrophages

  • T lymphocytes

  • B lymphocytes

• Some immune cells are scattered beneath epithelial barriers, while others are organized into lymphoid structures.

• Examples of organized mucosal lymphoid tissues include:

  • Tonsils in the pharynx.

  • Peyer's patches in the intestine.

• Mucosal immune tissues must:

  • Protect against invading pathogens.

  • Avoid unnecessary responses against the large number of normally harmless commensal microbes.

• Regulatory T cells and other suppressive signals help prevent inappropriate responses against harmless microbes.

What are the key functions of the innate immune system

• Provides the body’s first and immediate defense against infection

• Blocks microbes from entering through epithelial barriers

• Recognizes microbes and damaged cells

• Eliminates microbes that enter tissues through:

  • Phagocytosis

  • Complement

  • NK-cell killing

  • Antimicrobial substances

• Initiates inflammation

• Removes damaged or dead cells and contribute to tissue repair

• Provides signals needed to activate and guide adaptive immune responses

Where does the innate immune system respond in the body

• Innate immune defenses are found throughout the body, especially at places where microbes are likely to enter

• Locations include:

  • Skin

  • GI tract

  • Respiratory tract

  • Genitourinary tract

  • Connective tissues beneath epithelial barriers

  • Blood

• Epithelial barriers prevent entry, while tissue resident cells recognize microbes that cross those barrier

• Circulating leukocytes and complement can then be recruited to infected tissues

What are the different type of immune cells and their most important function and role in the body

• Neutrophils

  • Rapid phagocytosis

  • Quickly migrate to infections

  • Ingest and kills bacteria and fungi

• Macrophages

  • Phagocytosis + inflammation

  • Ingest microbes and dead cells

  • Produce inflammatory cytokines

  • Can activate other immune cells

• Dendritic cells

  • Antigen presentation

  • Detect microbes and produce cytokines

  • Captures microbial antigens

  • Present antigens to T cells, linking innate and adaptive immunity

• NK cells

  • Killing infected cells

  • Recognize virus-infected and stressed cells

  • Kill these cells through apotosis

  • Produce IFN-y, which actives macrophages

• Mast cells

  • Inflammation

  • Release histamine and other inflammatory mediators

  • Increase blood vessel dilation and permeability

• Innate lymphoid cells (ILCs)

  • Early cytokine production

  • Reside in tissues and produce cytokines that help early immune defense

What pathogen-associated structures are recognized by the innate immune system

• The innate immune system recognizes conserved microbial structures called pathogen-associated molecular patterns (PAMPs)

• Examples include:

  • Lipopolysaccharide (LPS) from gram-negative bacteria.

  • Bacterial lipoproteins and peptidoglycan.

  • Flagellin from bacterial flagella.

  • Viral double-stranded or single-stranded RNA.

  • Microbial DNA with characteristic sequences.

  • Mannose-rich carbohydrates on microbial surfaces.

• Pattern-recognition receptors such as TLRs and NLRs detect these structures.

Where are pathogen-associated molecular patterns least likely to be found

• PAMPs are least likely to be found on normal healthy host cells.

• This is important because PAMPs represent molecular structures that are characteristic of microbes.

• The innate immune system can therefore recognize many microbes while normally avoiding attacks against healthy cells.

What is the inflammasome and how does it function

• The inflammasome is a cytoplasmic multiprotein complex involved in detecting infection or cellular damage.

• A major example is the NLRP3 inflammasome.

• It can respond to microbial products and signs of cell injury such as:

  • Extracellular ATP

  • Crystals

  • Potassium loss from cells

  • Reactive oxygen species

• Once assembled, it activates caspase-1.

• Caspase-1 converts inactive pro-IL-1β into active IL-1β.

• IL-1β then promotes acute inflammation.

• Inflammasomes also promote production of active IL-18.

How does complement link innate and adaptive immunity

• Complement can function in both innate and adaptive immunity.

• In innate immunity:

  • Microbes can directly activate the alternative or lectin pathway.

• In adaptive immunity:

  • Antibodies attached to microbes can activate the classical pathway.

• Complement also strengthens B-cell responses.

• For example, C3d deposited on microbes binds CR2 on B cells, which enhances B-cell activation and antibody production.

• Therefore, complement activation during an innate response can help stimulate a stronger adaptive response

Compare the three complement pathways

• Alternative pathway

  • Activated directly on microbial surfaces.

  • Does not require antibodies.

  • Triggered when C3b, produced from spontaneous C3 hydrolysis, covalently binds to proteins/polysaccharides on a microbe → C3b opsonizes the microbe.

    • Microbe-bound C3b binds Factor B → Factor D cleaves Factor B, producing the Bb fragment.

    • C3b + Bb → C3bBb (C3 convertase).

      • Properdin stabilizes C3bBb.

      • C3 convertase cleaves more C3 → more C3b, greatly amplifying C3b coating of the microbe.

    • Some C3bBb binds another C3b → C3bBb3b (C5 convertase).

    • C5 convertase cleaves C5 → begins the late steps of complement activation.

  • Flow: C3b → Factor B → Factor D → Bb → C3bBb (C3 convertase) → + C3b → C3bBb3b (C5 convertase) → C5

• Lectin pathway

  • Does not require antibodies.

  • Triggered when mannose-binding lectin (MBL) binds mannose-containing carbohydrates on microbes.

    • Serine proteases associated with MBL become activated → activate C4 and C2.

    • From here, the pathway is essentially the same as the classical pathway.

    • C4b + C2a → C4b2a (C3 convertase).

    • C3 convertase cleaves C3 → C3b, which opsonizes the microbe.

    • C3b joins C4b2a → C4b2a3b (C5 convertase).

    • C5 convertase cleaves C5 → begins the late steps

  • Flow: MBL binds mannose → activates C4 + C2 → C4b2a (C3 convertase) → C3b → C4b2a3b (C5 convertase) → C5

• Classical pathway

  • Usually part of adaptive humoral immunity.

  • Triggered when certain classes of immunoglobins bind to microbial Ags

    • C1 binds the Fc regions of antigen-bound antibodies.

      • C1 contains C1q (binding component) + C1r and C1s (proteases).

      • Binding activates the Ig-C1 complex.

    • Activated C1 cleaves C4 and C2.

      • C4b attaches to the microbial surface and binds C2.

      • Cleavage of C2 produces C4b2a (C3 convertase).

    • C4b2a cleaves C3 → C3b, which opsonizes the microbe.

    • Some C3b joins C4b2a → C4b2a3b (C5 convertase).

    • C5 convertase cleaves C5 → begins the late steps.

  • Flow: Antibody + Ag → C1 → C4 + C2 → C4b2a (C3 convertase) → C3b → C4b2a3b (C5 convertase) → C5

• All three last step:

  • C5 binds C5 convertase → C5 is cleaved into C5a + C5b.

  • C5b begins assembly of the MAC.

  • C6 → C7 → C8 → C9 sequentially bind to the C5b complex.

  • C9 polymerizes → membrane attack complex (MAC).

  • MAC creates a pore in the microbial membrane → water and ions enter → cell lysis/death

What is the membrane attack complex and what does it do

• The membrane attack complex (MAC) is the final cytolytic complex produced during complement activation.

• It consists of C5b, C6, C7, C8, and multiple C9 molecules.

• C9 polymerizes and forms a pore in the microbial membrane.

• Water and ions enter through the pore.

• This damages the membrane and can cause lysis and death of the microbe.

• MAC formation is particularly important against certain bacteria such as Neisseria.

What are the functions of complement receptors CR1 and CR2

• CR1 (CD35)

  • Binds complement-coated particles.

  • Helps promote clearance/phagocytosis of complement-coated microbes and immune complexes.

  • Also helps regulate complement activation by promoting breakdown of C3b and C4b and interfering with C3 convertases.

• CR2 (CD21)

  • Is expressed on B cells.

  • Recognizes C3d attached to microbial antigens.

  • Works with the B-cell receptor to strengthen B-cell activation.

  • Therefore helps connect complement activation with antibody production.

What is the acute-phase response and what are its major features

• The acute-phase response is a systemic reaction to infection and inflammation.

• Cytokines such as IL-1, IL-6, and TNF help produce systemic effects.

• Important features include:

  • Fever

  • Increased production of leukocytes

  • Increased liver production of acute-phase proteins

• Acute-phase proteins help strengthen host defense and inflammatory responses.

• These systemic changes allow the body to respond to an infection beyond just the local infected tissue.

What are the major features and symptoms of inflammation

• Inflammation is a protective response that brings leukocytes and plasma proteins to sites of infection or tissue injury.

• Major features include:

  • Redness

  • Warmth

  • Swelling

  • Pain

• Blood vessels dilate, increasing blood flow and causing redness and warmth.

• Vascular permeability increases, allowing fluid and proteins to enter tissues, causing swelling.

• Leukocytes, especially neutrophils and monocytes, are recruited to destroy microbes.

• Although protective, excessive inflammation can also damage normal tissue.

Explain the process of phagocytosis

• Phagocytosis begins when receptors on neutrophils or macrophages recognize and bind a microbe.

• Recognition is especially strong if the microbe has been opsonized with antibodies or complement.

• The phagocyte membrane extends around the microbe.

• The microbe becomes enclosed inside a vesicle called a phagosome.

• The phagosome fuses with lysosomes to form a phagolysosome.

• The microbe is then destroyed by:

  • Reactive oxygen species (ROS)

  • Nitric oxide

  • Lysosomal enzymes/proteases

• Because these substances are mainly generated inside the phagolysosome, they can destroy microbes while limiting damage to the phagocyte itself.

Compare the actions of neutrophils and macrophages and explain how pus forms

• Neutrophils

  • Arrive rapidly during acute infection.

  • Are especially effective against bacteria and fungi.

  • Perform phagocytosis and produce ROS.

  • Can release granule enzymes and form neutrophil extracellular traps (NETs).

  • Are short-lived and often die after fighting microbes.

• Macrophages

  • Usually arrive or become activated later.

  • Are longer-lived.

  • Phagocytose microbes and dead tissue.

  • Produce inflammatory cytokines.

  • Can participate in tissue repair and antigen presentation.

• Pus

  • Forms from the accumulation of dead neutrophils, microbes, and damaged cellular/tissue debris at an infected site.

How is an antiviral state established during viral infection

• Virus-infected cells and certain dendritic cells recognize viral nucleic acids using innate immune receptors.

• This causes production of type I interferons, especially:

  • IFN-α

  • IFN-β

• Type I interferons bind receptors on infected and nearby cells.

• They stimulate these cells to produce proteins that interfere with viral replication, creating an antiviral state.

• Type I interferons also:

  • Increase MHC class I expression.

  • Activate NK cells.

• NK cells then kill infected cells, helping eliminate reservoirs of viral infection

What mechanisms do microbes use to evade innate immunity

• Pathogens have evolved several ways to avoid or resist innate immune defenses.

• Some bacteria resist phagocytosis, such as through protective capsules.

• Some microbes resist the reactive oxygen species produced by phagocytes.

• Listeria can escape from the phagosome into the cytoplasm, avoiding killing mechanisms concentrated inside phagolysosomes.

• Mycobacteria can prevent phagosome-lysosome fusion.

• Some microbes have cell walls that resist complement-mediated killing.

• Some bacteria interfere with complement activation or C3b deposition.

• Viruses may:

  • Prevent production of type I interferons.

  • Block signaling through interferon receptors.

  • Modify viral nucleic acids so innate receptors have difficulty recognizing them.

• These mechanisms allow microbes to survive long enough to establish an infection despite the body's immediate defenses.

What are the major families of pattern-recognition receptors (PRRs), and where are they located?

• Pattern-recognition receptors (PRRs)

  • Receptors of the innate immune system that recognize microbial structures and products.

  • Recognize common molecular patterns rather than one highly specific antigen.

• Five major families discussed in the textbook include:

  • Toll-like receptors (TLRs)

    • Found on the cell surface and within endosomes.

  • C-type lectin receptors (CLRs)

    • Located mainly on cell surfaces.

    • Recognize microbial carbohydrates/polysaccharides.

  • NOD-like receptors (NLRs)

    • Located in the cytoplasm.

    • Recognize microbial products and products associated with damaged cells.

  • RIG-like receptors (RLRs)

    • Located in the cytoplasm.

    • Important for recognizing viral nucleic acids, particularly viral RNA.

  • Cytosolic DNA sensors (CDSs)

    • Located in the cytoplasm.

    • Detect microbial DNA.

• Why location matters

  • Cell-surface receptors can detect extracellular microbial structures.

  • Endosomal receptors can detect microbes/nucleic acids after microbes are ingested.

  • Cytosolic receptors can detect microbes or microbial products that enter the cell's cytoplasm.

What do the major Toll-like receptors (TLRs) recognize?

• TLRs are pattern-recognition receptors that recognize different microbial products.

• TLR2

  • Often functions with TLR1 or TLR6.

  • Recognizes bacterial:

    • Lipopeptides

    • Peptidoglycans

  • Especially associated with products from gram-positive bacteria.

• TLR4

  • Recognizes lipopolysaccharide (LPS/endotoxin).

  • LPS is an important component of gram-negative bacteria.

• TLR5

  • Recognizes flagellin.

  • Flagellin is the major protein found in bacterial flagella.

• TLR3

  • Recognizes double-stranded RNA (dsRNA).

• TLR7 and TLR8

  • Recognize single-stranded RNA (ssRNA).

• TLR9

  • Recognizes unmethylated CpG DNA, which is abundant in microbial genomes.

• Location

  • TLRs recognizing microbial proteins, lipids, and polysaccharides are generally located on the cell surface.

  • TLRs recognizing microbial nucleic acids are located within endosomes

What happens after Toll-like receptors recognize microbial products?

• When a TLR recognizes its microbial target, it initiates intracellular signaling pathways.

• These signals activate transcription factors that cause the cell to produce proteins needed for immune defense.

• Two important groups of transcription factors are:

  • NF-κB

    • Stimulates production of inflammatory cytokines.

    • Promotes expression of endothelial adhesion molecules.

    • Therefore plays an important role in inflammation.

  • Interferon regulatory factors (IRFs)

    • Stimulate production of type I interferons.

    • Type I interferons are especially important for antiviral immunity.

• TLR signaling can therefore lead to:

  • Inflammation.

  • Increased antimicrobial activity.

  • Production of cytokines.

  • Antiviral responses.

• Overall: TLR recognizes microbial product → intracellular signaling → transcription factors activated → inflammatory or antiviral immune response.

How do epithelial barriers contribute to innate immunity?

• Epithelial surfaces are one of the body's first lines of defense because many microbes enter through:

  • Skin

  • Gastrointestinal tract

  • Respiratory tract

  • Genitourinary tract

• Physical barriers

  • Epithelial cells are tightly connected and prevent microbes from passing between cells.

  • Keratin on the skin helps form a protective barrier.

  • Mucus at mucosal surfaces traps microbes and helps prevent them from reaching underlying tissues.

• Chemical barriers

  • Epithelial cells produce antimicrobial peptides, including:

    • Defensins

    • Cathelicidins

  • These molecules can kill bacteria and some viruses by disrupting their outer membranes.

• Intraepithelial lymphocytes

  • Lymphocytes are also present within epithelial tissues.

  • Some can recognize and respond to infectious agents attempting to cross epithelial barriers.

• Overall

  • Epithelia do more than physically cover the body.

  • They provide physical + chemical + cellular defenses that help stop microbes before they establish an infection

How does septic shock develop and what are its major effects?

• Septic shock can develop when a severe infection causes an excessive systemic innate immune response.

• Large amounts of inflammatory cytokines, especially TNF and other mediators, are released.

• Instead of inflammation staying localized, it becomes widespread.

• Major effects can include:

  • Widespread blood-vessel dilation

  • Increased vascular permeability

  • Falling blood pressure

  • Activation of coagulation

  • Reduced cardiac output

  • Metabolic abnormalities

  • Reduced blood flow to organs

  • Multiple-organ dysfunction

• In severe cases, septic shock can be fatal.