Ch. 2. Innate immunity

Question 1

Innate immunity

Answer 1

Also called natural immunity, or native immunity. Protection against infection that relies on mechanisms that exist before infection, are capable of a rapid response to microbes, and react in essentially the same way to repeated infections.

The innate immune system includes epithelial barriers, phagocytic cells (neutrophils, macrophages), natural killer (NK) cells, the complement system, and cytokines, which are largely made by dendritic cells and mononuclear phagocytes.

Innate immune reactions also eliminate damaged and necrotic host tissues.

Question 2

Inflammation

Answer 2

A complex reaction of vascularized tissue to infection or cell injury that involves extravascular accumulation of plasma proteins and leukocytes.

Acute inflammation is a common result of innate immune responses, and local adaptive immune responses can also promote inflammation.

Although inflammation serves a protective function in controlling infections and promoting tissue repair, it can also cause tissue damage and disease.

Question 3

Pathogen-associated molecular patterns (PAMPs)

Answer 3

Structures produced by microorganisms but not mammalian (host) cells, which are recognized by and stimulate the innate immune system.

Examples include bacterial lipopolysaccharide (LPS) and viral double-stranded RNA.

Question 4

Pattern recognition receptors (PRRs)

Answer 4

Signaling receptors of the innate immune system that recognize PAMPs and DAMPs, and thereby activate innate immune responses.

Examples include Toll-like receptors (TLRs) and NOD-like receptors (NLRs).

Question 5

Damage-associated molecular patterns (DAMPs)

Answer 5

Endogenous molecules that are produced by or released from damaged and dying cells that bind to pattern recognition receptors and stimulate innate immune responses.

Examples include high-mobility group box 1 (HMGB1) protein, extracellular ATP, and uric acid.

Question 6

Infarction

Answer 6

The death of tissue due to loss of its blood supply.

Question 7

About how many types of innate immune receptors are there?

Answer 7

It is estimated that there are about 100 types of innate immune receptors that are capable of recognizing about 1,000 PAMPs and DAMPs.

Question 8

Toll-like receptors (TLRs)

Answer 8

A family of pattern recognition receptors of the innate immune system that are expressed on the surface and in endosomes of many cell types and that recognize microbial structures, such as endotoxin and viral RNA, and transduce signals that lead to the expression of inflammatory and antiviral genes.

Question 9

How many Toll-like receptors (TLRs) are there in vertebrates?

Answer 9

In vertebrates, there are ten different TLRs specific for different components of microbes.

Question 10

TLR-2

Answer 10

Recognizes several glycolipids and peptidoglygans that are made by gram-positive bacteria and some parasites.

Question 11

TLR-3

Answer 11

Recognizes double-stranded RNA.

Question 12

TLR-7 and TLR-8

Answer 12

Recognize single-stranded RNA.

Question 13

TLR-4

Answer 13

Recognizes bacterial LPS (endotoxin), made by gram-negative bacteria.

Question 14

TLR-5

Answer 14

Recognizes a bacterial flagellar protein called flagellin.

Question 15

TLR-9

Answer 15

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

Question 16

What are the most important transcription factors activated by TLRs?

Answer 16

Transcription factors of the nuclear factor KB (NF-KB) family and the interferon regulatory factors (IRFs).

Question 17

Nuclear factor KB (NF-KB) family

Answer 17

A family of transcription factors composed of homodimers or heterodimers of proteins homologous to the c-Rel protein. NF-KB proteins are required for the inducible transcription of many genes important in both innate immunity and adaptive immunity.

Question 18

Interferon regulatory factors (IRFs)

Answer 18

A family of transcription factors that are activated by TLR signals and stimulate production of type I interferons, which are cytokines that inhibit viral replication.

Question 19

NOD-like receptors (NLRs)

Answer 19

A family of cytosolic multidomain proteins that sense cytosolic PAMPs and DAMPs and recruit other proteins to form signaling complexes that promote inflammation.

Question 20

What do NOD1 and NOD2 recognize, and what response do they initiate?

Answer 20

They both recognize peptides derived from bacterial cell wall peptidoglycans, and in response, they generate signals that activate NF-KB transcription factor, which promotes expression of genes encoding inflammatory proteins.

Question 21

Defensins

Answer 21

Cysteine-rich peptides produced by epithelial barrier cells in the skin, gut, lung, and other tissues and in neutrophil granules that act as broad-spectrum antibiotics to kill a wide variety of bacteria and fungi.

The synthesis of defensins is increased in response to stimulation of innate immune system receptors such as Toll-like receptors and inflammatory cytokines such as IL-1 and TNF.

Question 22

Inflammasome

Answer 22

A multiprotein complex in the cytosol of mononuclear phagocytes, dendritic cells, and other cell types that proteolytically generates the active form of IL-1B from the inactive pro-IL-1B precursor.

The formation of the inflammasome complex, one variety of which includes NLRP3 (a NOD-like pattern recognition receptor), the ASC (apoptosis associated speck like protein containing a CARD domain) adaptor and procaspase-1, is stimulated by a variety of microbial products, cell damage-associated molecules, and crystals.

Question 23

NLR-family proteins (sensors)

Answer 23

There are many different types of inflammasomes, most of which use one of ten different NLR-family proteins as sensors.

These sensors directly recognize microbial products in the cytosol or sense changes in the amount of endogenous molecules or ions in the cytosol that indirectly indicate the presence of infection or cell damage.

Question 24

AIM-family proteins (DNA sensors)

Answer 24

Some inflammasomes use sensors that are not in the NLR family.

Question 25

NLRP3 inflammasome

Answer 25

The NLRP3 inflammasome reacts to injury affecting various cellular components and is one of the best characterized inflammasomes.

It uses NLRP3 as its sensor and is expressed in innate immune cells including macrophages and neutrophils, as well as keratinocytes in the skin and other cells.

A wide variety of stimuli induce formation of the NLRP3 inflammasome, including crystalline substances such as uric acid (a by-product of DNA breakdown, indicating nuclear damage) and cholesterol crystals, extracellular adenosine triphosphate (ATP) (an indicator of mitochondrial damage) binding to cell surface purinoceptors, reduced intracellular potassium (K+) concentration (which indicates plasma membrane damage), and reactive oxygen species.

Question 26

Pyroptosis

Answer 26

A form of programmed cell death of macrophages and dendritic cells (DCs) induced by inflammasome activation of caspase-1, characterized by swelling, loss of plasma membrane integrity, and release of inflammatory mediators, such as IL-1A.

Pyroptosis results in the death of certain microbes that gain access to the cytosol, enhances inflammatory clearance of bacteria, but also contributes to septic shock.

Question 27

Autoinflammatory syndromes

Answer 27

Refers to a disorder characterized by recurrent episodes of systemic inflammation in the apparent absence of pathogens, autoantibodies, or self-reactive lymphocytes.

These disorders are caused by dysfunction of the innate immune system.

Examples of such disorders include Behçet’s disease, Familial Mediterranean Fever, and Cryopyrin-Associated Periodic Syndrome.

Question 28

Gout

Answer 28

A disease in which defective metabolism of uric acid causes arthritis (especially in the smaller bones of the feet), deposition of chalkstones, and episodes of acute pain.

Question 29

RIG-like receptors (RLRs)

Answer 29

Cytosolic proteins that sense viral RNA and induce the production of the antiviral type I IFNs.

Question 30

Mitochondrial antiviral signaling (MAVS) protein

Answer 30

A protein that is essential for antiviral innate immunity. MAVS is located in the outer membrane of the mitochondria, peroxisomes, and endoplasmic reticulum (ER). Upon viral infection, a group of cytosolic proteins will detect the presence of the virus and bind to MAVS, thereby activating them. The activation of MAVS leads the virally infected cell to secrete cytokines. This induces an immune response which kills the host’s virally infected cells, resulting in clearance of the virus.

Question 31

Cytosolic DNA sensors (CDSs)

Answer 31

Molecules that detect microbial double-stranded DNA in the cytosol and activate signaling pathways that initiate antimicrobial responses, including type 1 interferon production and autophagy.

Question 32

Autophagy

Answer 32

The normal process by which a cell degrades its own components by lysosomal catabolism. Autophagy plays a role in innate immune defense against infections, and polymorphisms of genes that regulate autophagy are linked to risk for some autoimmune diseases.

Question 33

Stimulator of IFN genes (STING)

Answer 33

An adaptor protein located in the endoplasmic reticulum membrane, which is utilized by several cytoplasmic DNA sensor molecules to transduce signals that activate the IRF3 transcription factor, leading to type 1 IFN gene expression.

Question 34

Lectins

Answer 34

Carbohydrate-binding proteins that are highly specific for sugar groups that are part of other molecules.

Question 35

Dectins

Answer 35

Pattern recognition receptors expressed on dendritic cells that recognize fungal cell wall carbohydrates and induce signaling events that promote inflammation and activate the dendritic cells.

Question 36

Mannose receptor

Answer 36

A carbohydrate-binding protein (lectin) expressed by macrophages that binds mannose and fucose residues on microbial cell walls and mediates phagocytosis of the organisms.

Question 37

Formyl peptide receptor 1

Answer 37

A cell surface receptor expressed mainly on phagocytes that recognizes polypeptides with an N-terminal formylmethionine (fMet?), which is a specific feature of bacterial proteins.

Question 38

Cathelicidins

Answer 38

Polypeptides produced by neutrophils and various barrier epithelia that serve various functions in innate immunity, including direct toxicity to microorganisms, activation of leukocytes, and neutralization of lipopolysacharide.

Question 39

Intraepithelial T lymphocytes

Answer 39

T lymphocytes present in the epidermis of the skin and in mucosal epithelia that typically express a limited diversity of antigen receptors.

Some of the lymphocytes, called invariant NKT cells, may recognize microbial products, such as glycolipids, associated with nonpolymorphic class I MHC-like molecules.

Others, calls gamma-delta T cells, recognize various nonpeptide antigens, not presented by MHC molecules.

Intraepithelial T lymphocytes may be effector cells of innate immunity.

Question 40

What are the two types of circulating phagocytes?

Answer 40

Neutrophils and monocytes.

Question 41

Neutrophil

Answer 41

Also called polymorphonuclear leukocyte (PMN).

A phagocytic cell charactered by a segmented lobular nucleus and cytoplasmic granules filled with degradative enzymes.

PMNs are the most abundant type of circulating white blood cells and are the major cell type in acute inflammatory responses to bacterial infections.

Question 42

Colony-stimulating factors (CSFs)

Answer 42

Cytokines that promote the expansion and differentiation of bone marrow progenitor cells.

CSFs are essential for the maturation of red blood cells, granulocytes, monocytes, and lymphocytes.

Examples of CSFs include granulocyte-monocyte colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), and IL-3.

Question 43

Monocyte

Answer 43

A type of bone marrow-derived circulating blood cell that is the precursor of tissue macrophages. Monocytes are actively recruited into inflammatory sites, where they differentiate into macrophages.

Question 44

Macrophage

Answer 44

A hematopoietically derived phagocytic cell that plays important roles in innate and adaptive immune responses.

Macrophages are activated by microbial products such as endotoxin and by T cell cytokines such as IFN-gamma. Activated macrophages phagocytose and kill microorganisms, secrete pro-inflammatory cytokines, and present antigens to helper T cells.

Macrophages included cells derived from recently recruited blood monocytes at sites of inflammation and long-lived tissue-based cells derived from fetal hematopoietic organs.

Tissue macrophages are given different names and may serve special functions; these include the microglia of the central nervous system, Kupffer cells in the liver, alveolar macrophages in the lung, and osteoclasts in bone.

Question 45

Mononuclear phagocytes

Answer 45

Cells with a common bone marrow lineage whose primary function is phagocytosis. These cells function as effector cells in innate and adaptive immunity.

Mononuclear phagocytes circulate in the blood in an incompletely differentiated form call monocytes, and after they settle in tissues, they mature in macrophages.

Question 46

Classical macrophage activatation

Answer 46

Macrophage activation by interferon-gamma, Th1 cells, and TLR ligands, leading to a pro-inflammatory and microbicidal phenotype.

“Classically activated” macrophages are also called M1 macrophages.

Question 47

Alternative macrophage activation

Answer 47

Macrophage activation by IL-4 and IL-13 leading to an anti-inflammatory and tissue-reparative phenotype, in contrast to classical macrophage activation by interferon-gamma and TLR ligands.

“Alternatively activated” macrophages are also called M2 macrophages.

Question 48

Dendritic cells

Answer 48

Bone marrow-derived cells found in epithelial and lymphoid tissues that are morphologically characterized by thin, membranous processes.

Many subsets of dendritic cells exist with diverse functions. Classical (conventional) dendritic cells function as innate sentinel cells and APCs for naive T lymphocytes, and they are important for initiation of adaptive immune responses to protein antigen.

Immature (resting) classical dendritic cells are important for induction of tolerance to self antigens.

Plasmacytoid dendritic cells (pDCs) produce type 1 interferons in response to exposure to viruses.

Question 49

Mast cell

Answer 49

The major effector cell of immediate hypersensitivity (allergic) reactions. Mast cells are derived from the marrow, reside in most tissues adjacent to blood vessels, express a high-affinity Fc receptor for IgE, and contain numerous mediator-filled granules.

Antigen-induced cross-linking of IgE bound to the mast cell Fc-epsilon receptors causes release of their granule contents as well as new synthesis and secretion of other mediators, leading to an immediate hypersensitivity reaction.

Question 50

Prostaglandins

Answer 50

A class of lipid inflammatory mediators that are derived from arachidonic acid in many cells types through the cyclooyxegenase pathway and that have vasodilator, bronchoconstrictor, and chemotactic activities.

Prostaglandins made by mast cells are important mediators of allergic reactions.

Question 51

Leukotrienes

Answer 51

A class of arachidonic acid-derived lipid inflammatory mediators produced by the lipoxygenase pathway in many cell types.

Mast cells make abundant leukotriene C4 (LTC4) and its degradation products LTD4 and LTE4, which bind to specific receptors on smooth muscle cells and cause prolonged bronchoconstriction.

Leukotrienes contribute to the pathology of asthma.

Collectively, LTC4, LTD4, and LTE4 constitute what was once called slow-reacting substance of anaphylaxis.

Question 52

Innate lymphoid cells (ILCs)

Answer 52

Cells that arise from the common lymphoid progenitor in the bone marrow, which have a lymphocyte morphology and perform effector functions similar to T cells, but do not express TCRs.

Three groups of innate lymphoid cells, called ILC1, ILC2, and ILC3 produce cytokines and express different transcription factors analogous to the Th1, Th2, and Th17 subsets of CD4+ effector T lymphocytes, respectively.

Natural killer cells are related to ILC1s.

Question 53

Natural killer (NK) cells

Answer 53

A subset of lymphoid cells, related to group 1 innate lymphoid cells (ILC1s), that function in innate immune responses to kill microbe-infected cells by directed lytic mechanisms and by secreting IFN-gamma.

NK cells do not express clonally distributed antigen receptors like Ig receptors or TCRs, and their activation is regulated by a combination of cell surface stimulatory and inhibitory receptors, the latter recognizing self MHC molecules.

Question 54

Antibody-dependent cell-mediated cytotoxicity (ADCC)

Answer 54

A process by which NK cells are targeted to IgG-coated cells, resulting in lysis of the antibody-coated cells.

A specific receptor for the constant region of IgG, call Fc-gamma-RIII (CD16), is expressed on the NK cell membrane and mediates binding to the IgG.

Question 55

Immunoreceptor tyrosine-based motifs (ITAMs)

Answer 55

A conserved protein motif composed of two copies of the sequence tryosine-x-x-leucine (where x is an unspecified amino acid) found in the cytoplasmic tails of various membrane proteins in the immune system that are involved in signal transduction.

ITAMs are present in the zeta and CD3 proteins of the TCR complex, in Ig(alpha) and Ig(beta) proteins in the BCR complex, in receptors for costimulators, and in several Ig Fc receptors.

When these receptors bind their ligands, the tyrosine residues of the ITAMs become phosphorylated and form docking sites for other molecules involved in propagating cell-activating signal transduction pathways.

Question 56

Killer cell immunoglobulin-like receptors (KIRs)

Answer 56

Ig superfamily receptors expressed by NK cells that recognize different alleles of HLA-A, HLA-B, and HLA-C molecules.

Some KIRs have signaling components with ITIMs in their cytoplasmic tails, and these deliver inhibitory signals to inactivate the NK cells.

Some members of the KIR family have short cytoplasmic tails without ITIMs but associate with other ITAM-containing polypeptides and function as activating receptors.

Question 57

Immunoreceptor tyrosine-based inhibitory motifs (ITIMs)

Answer 57

A six-amino-acid (isoleucine-x-tyrosine-x-x-leucine) motif found in the cytoplasmic tails of various inhibitory receptors in the immune system, including FC(gamma)RIIB on B cells, killer cell Ig-like receptors (KIRs) on NK cells, and some coinhibitory receptors of T cells.

When these receptors bind their ligands, the ITIMs become phosphorylated on their tyrosine residues and form a docking site for protein tyrosine phosphatases, which in turn function to inhibit other signal transduction pathways.

Question 58

(gamma)(delta) T cell receptor (TCR)

Answer 58

A form of TCR that is distinct from the more common (alpha)(beta) TCR and is expressed on a subset of T cells found mostly in epithelial tissues.

Although the (gamma)(delta) TCR is structurally similar to the (alpha)(beta) TCR, the forms of antigen recognized by (gamma)(delta) TCRs are poorly understood; they do not recognize peptide complexes bound to polymorphic MHC molecules.

Question 59

Natural killer T (NKT) cells

Answer 59

A numerically small subset of lymphocytes that express T cell receptors and some surface molecules characteristic of NK cells.

Some NKT cells, called invariant NKT (iNKT), express (alpha)(beta) T cell antigen receptors with very little diversity and recognize lipid antigens presented by CD1 molecules.

The physiologic functions of NKT cells are not well defined.

Question 60

Mucosal associated invariant T (MAIT) cells

Answer 60

A subset of T cells that express an invariant (alpha)(beta) TCR specific for fungal and bacterial riboflavin metabolites presented by a non-polymorphic class I MHC-related molecule.

Most MAIT cells are CD8+, are activated either by microbial riboflavin derivatives or by cytokines, and may have inflammatory and cytotoxic functions.

MAIT cells account for 20% to 40% of T cells in the human liver.

Question 61

B-1 lymphocytes

Answer 61

A subset of B lymphocytes that develop earlier during ontogeny than do conventional (follicular) B cells, express a limited repertoire of V genes with little junctional diversity, and secrete IgM antibodies that bind T-independent antigens.

Many B-1 cells express the CD5 molecule.

Question 62

Natural antibodies

Answer 62

IgM antibodies, largely produced by B-1 cells, specific for bacteria that are common in the environment and gastrointestinal tract.

Normal individuals contain natural antibodies without any evidence of infection or overt antigen exposure, and these antibodies serve as a preformed defense mechanism against microbes that succeed in penetrating epithelial barriers.

Some of these antibodies cross-react with ABO blood group antigens and are responsible for transfusion reactions.

Question 63

Marginal zone B lymphocytes

Answer 63

A subset of B lymphocytes, found exclusively in the marginal zone of the spleen, that respond rapidly to blood-borne microbial antigens by producing IgM antibodies with limited diversity.

Question 64

Alternative pathway of complement activation

Answer 64

An antibody-independent pathway of activation of the complement system that occurs when the C3b fragment of the C3 protein binds to microbial cell surfaces.

The alternative pathway is a component of the innate immune system and mediates inflammatory responses to infection as well as direct lysis of microbes.

The alternative pathway, as well as the classical and lectin pathways, terminate with formation of the membrane attack complex (MAC).

Question 65

Classical pathway of complement activation

Answer 65

The complement pathway that is an effector arm of humoral immunity (i.e., antibody-dependent), generating inflammatory mediators, opsonins for phagocytosis of antigens, and lytic complexes that destroy cells.

The classical pathway is initiated by binding of antigen-antibody complexes to the C1 molecule, leading to proteolytic cleavage of C4 and C2 proteins to generate the classical pathway C3 convertase.

The classical pathway, as well as the alternative and lectin pathways, terminate with formation of the membrane attack complex (MAC).

Question 66

Lectin pathway of complement activation

Answer 66

A pathway of complement activation triggered by the binding of microbial polysaccharides to circulating lectins such as MBL.

MBL is structurally similar to C1q and activates the C1r-C1s enzyme complex (like C1q) or activates another serine esterase, called mannose-binding protein-associated serine esterase.

The remaining steps of the lectin pathway, beginning with cleavage of C4, are the same as the classical pathway.

Question 67

Opsonization

Answer 67

The process of attaching opsonins, such as IgG or complement segments, to microbial surfaces to target the microbes for phagocytosis.

Question 68

Phagocytosis

Answer 68

The process by which certain cells of the innate immune system, including macrophages and neutrophils, engulf large particles (> 0.5 micrometers in diameter) such as intact microbes.

The cells surround the particle with extensions of its plasma membrane by an energy- and cytoskeleton-dependent process; this process results in the formation of an intracellular vesicle called a phagosome, which contains the ingested particle.

Question 69

Mannose-binding lectin (MBL)

Answer 69

A plasma protein that binds to mannose residues on bacterial cell walls and acts as an opsonin by promoting phagocytosis of the bacteria by macrophages.

Macrophages express a surface receptor for C1q that can also bind MBL and mediate uptake of the opsonized organisms.

Question 70

What are the three main functions of the complement system on host defense?

Answer 70

(1) Opsonization and phagocytosis
(2) Inflammation
(3) Cell lysis

Question 71

Membrane attack complex (MAC)

Answer 71

A lytic complex of the terminal components of the complement cascade, including complement proteins C5, C6, C7, C8, and multiple copies of C9, which forms in the membranes of target cells.

The MAC causes lethal ionic and osmotic changes in cells.

Question 72

Collectins

Answer 72

A family of proteins, including mannonse-binding lectin (MBL), that is characterized by a collagen-like domain and a lectin (i.e., carbohydrate-binding) domain.

Collections play a role in the innate immune system by acting as microbial pattern recognition receptors, and they may activate the complement system by binding to C1q.

Question 73

C-reactive protein (CRP)

Answer 73

A member of the pentraxin family of plasma proteins involved in innate immune responses to bacterial infections.

CRP is an acute-phase reactant, and it binds to the capsule of pneumococcal bacteria.

CRP also binds to C1q and may thereby activate complement or act as an opsonin by interacting with phagocyte C1q receptors.

Increased serum CRP is a marker of inflammation.

Question 74

Acute-phase response

Answer 74

The increase in plasma concentrations of several proteins, called acute-phase reactants, that occurs as part of the early innate immune response to infections.

Question 75

Paracrine factor

Answer 75

A molecule that acts on cells in proximity to the cell that produces the factor.

Most cytokines act in a paracrine fashion.

Question 76

Autocrine factor

Answer 76

A molecule that acts on the same cell that produces the factor.

For example, IL-2 is an autocrine T cell growth factor that stimulates mitotic activity of the T cell that produces it.

Question 77

Endocrine factor

Answer 77

A molecule that acts on cells far from the cell that produces the factor.

Question 78

Fibrinogen

Answer 78

Fibrinogen (factor I) is a glycoprotein complex, made in the liver,[1] that circulates in the blood of all vertebrates.[2] During tissue and vascular injury, it is converted enzymatically by thrombin to fibrin and then to a fibrin-based blood clot. Fibrin clots function primarily to occlude blood vessels to stop bleeding. Fibrin also binds and reduces the activity of thrombin. This activity, sometimes referred to as antithrombin I, limits clotting.[1] Fibrin also mediates blood platelet and endothelial cell spreading, tissue fibroblast proliferation, capillary tube formation, and angiogenesis and thereby promotes revascularization and wound healing.[3]

Question 79

Septic shock

Answer 79

A severe complication of bacterial infections that spread to the blood stream (sepsis), and is characterized by vascular collapse, disseminated intravascular coagulation, and metabolic disturbances.

This syndrome is most often due to the effects of bacterial cell wall components, such as LPS or peptidoglycan, that bind to TLRs on various cell types and induce expression of inflammatory cytokines, including TNF and IL-12.

Question 80

Innate immune reactions

Answer 80

• Extracellular bacteria and fungi are defended against mainly by the acute inflammatory response, in which neutrophils and monocytes are recruited to the site of infection, aided by the complement system.
• Intracellular bacteria, which can survive inside phagocytes, are eliminated by phagocytes that are activated by Toll-like receptors and other innate sensors as well as by cytokines.
• Protection against viruses is provided by type I interferons and natural killer cells.

Question 81

Selectin

Answer 81

Any one of three separate but closely related carbohydrate-binding proteins that mediate adhesion of leukocytes to endothelial cells.

Each of the selectin molecules is a single-chain transmembrane glycoprotein with a similar modular structure, including an extracellular calcium-dependent lectin domain.

The selectins include L-selectin (CD62L), expressed on leukocytes; P-selectin (CD62P), expressed on platelets and activated endothelium; and E-selectin (CD62E), expressed on activated endothelium.

Question 82

Integrins

Answer 82

Heterodimeric cell surface proteins whose major functions are to mediate the adhesion of cells to other cells or to extracellular matrix.

Integrins are important for T cell interactions with APCs and for migration of leukocytes from blood into tissues.

The ligand-binding activity of leukocyte integrins depends on signals induced by chemokines binding to chemokine receptors.

Two integrins important in the immune system are VLA-4 (very late antigen 4) and LFA-1 (leukocyte function-associated antigen 1).

Question 83

Chemokines

Answer 83

A large family of structurally homologous low-molecular-weight cytokines that:

• Stimulate leukocyte chemotaxis.
• Regulate the migration of leukocytes from the blood to tissues by activating leukocyte integrins.
• Maintain the spatial organization of different subsets of lymphocytes and antigen-presenting cells within lymphoid organs.

Question 84

What is the sequence of events in migration of blood leukocytes to sites of infection?

Answer 84

1. Selectin-mediated rolling of leukocytes.
2. Integrin-mediated firm adhesion.
3. Chemokine-mediated leukocyte migration/motility (extravasation).

Question 85

Extravasation

Answer 85

Extravasation is the leakage of a fluid out of its container into the surrounding area, especially blood or blood cells from vessels. In the case of inflammation, it refers to the movement of white blood cells from the capillaries to the tissues surrounding them (leukocyte extravasation, also known as diapedesis).

Question 86

ICAM-1

Answer 86

ICAM-1 (Intercellular Adhesion Molecule 1) also known as CD54 (Cluster of Differentiation 54) is a protein that in humans is encoded by the ICAM1 gene.[5][6] This gene encodes a cell surface glycoprotein which is typically expressed on endothelial cells and cells of the immune system. It binds to integrins of type CD11a / CD18, or CD11b / CD18 and is also exploited by rhinovirus as a receptor for entry into respiratory epithelium.[7]

Question 87

VCAM-1

Answer 87

Vascular cell adhesion protein 1, also known as vascular cell adhesion molecule 1 (VCAM-1) or cluster of differentiation 106 (CD106), is a protein that in humans is encoded by the VCAM1 gene.[5] VCAM-1 functions as a cell adhesion molecule.

Question 88

Leukocyte adhesion deficiencies (LADs)

Answer 88

One of a rare group of congenital (primary) immunodeficiency diseases with infectious complications that is caused by defective expression of leukocyte adhesion molecules required for tissue recruitment of phagocytes and lymphocytes.

LAD-1 is due to mutations in the gene encoding the CD18 protein, which is part of (beta)2 integrins.

LAD-2 is caused by mutations in a gene that encodes a fucose transport involved in the synthesis of leukocyte ligands for endothelial selectins.

Question 89

Reactive oxygen species (ROS)

Answer 89

Highly reactive metabolites of oxygen, including superoxide anion, hydroxyl radical, and hydrogen peroxide, that are produced by activated phagocytes, particularly neutrophils.

Reactive oxygen species are used by the phagocytes to form oxyhalides that damage ingested bacteria.

They may also be released from cells and promote inflammatory responses or cause tissue damage.

Question 90

Inducible nitric oxide synthase (iNOS)

Answer 90

An enzyme, produced mainly in macrophages, that catalyzes the conversion of arginine to nitric oxide (NO), a microbicidal substance.

Question 91

Nitric oxide (NO)

Answer 91

A molecule with a broad range of activities that in macrophages functions as a potent microbicidal agent to kill ingested organisms.

Question 92

Phagosome

Answer 92

A membrane-bound intracellular vesicle that contains microbes or particulate material ingested from the extracellular environment.

Phagosomes are formed during the process of phagocytosis. They fuse with other vesicles, such as lysosomes, leading to enzymatic degradation of the ingested material.

Question 93

Lysosome

Answer 93

A membrane-bound, acidic organelle abundant in phagocytic cells that contains proteolytic enzymes that degrade proteins derived both from the extracellular environment and from within the cell.

Lysosomes are involved in the class II MHC pathway of antigen processing.

Question 94

Phagolysosome

Answer 94

A phagolysosome, or endolysosome, is a cytoplasmic body formed by the fusion of a phagosome with a lysosome in a process that occurs during phagocytosis. Formation of phagolysosomes is essential for the intracellular destruction of microorganisms and pathogens. It takes place when the phagosome’s and lysosome’s membranes ‘collide’, at which point the lysosomal contents—including hydrolytic enzymes—are discharged into the phagosome in an explosive manner and digest the particles that the phagosome had ingested. Some products of the digestion are useful materials and are moved into the cytoplasm; others are exported by exocytosis.

Question 95

Phagocyte oxidase

Answer 95

An enzyme that rapidly assembles in the phagolysosomal membrane (mainly in neutrophils) and converts oxygen into superoxide anion and free radicals, a process called the oxidative burst (or respiratory burst).

Question 96

Oxidative burst (respiratory burst)

Answer 96

Respiratory burst (or oxidative burst) is the rapid release of the reactive oxygen species (ROS), superoxide anion ( and hydrogen peroxide (H2O2), from different cell types.

This is usually utilised for mammalian immunological defence, but also plays a role in cell signalling. Respiratory burst is also implicated in the ovum of animals following fertilization. It may also occur in plant cells.

Question 97

Lysosomal proteases

Answer 97

Enzymes in the phagolysosome that break down microbial proteins.

Question 98

Neutrophil extracellular traps (NETs)

Answer 98

Neutrophil extracellular traps (NETs) are networks of extracellular fibers, primarily composed of DNA from neutrophils, which bind pathogens.[2] Neutrophils are the immune system’s first line of defense against infection and have conventionally been thought to kill invading pathogens through two strategies: engulfment of microbes and secretion of anti-microbials. In 2004, a novel third function was identified: formation of NETs. NETs allow neutrophils to kill extracellular pathogens while minimizing damage to the host cells.[3] Upon in vitro activation with the pharmacological agent phorbol myristate acetate (PMA), Interleukin 8 (IL-8) or lipopolysaccharide (LPS), neutrophils release granule proteins and chromatin to form an extracellular fibril matrix known as NET through an active process.[2]

Question 99

Chronic granulomatous disease (CGD)

Answer 99

A rare inherited immunodeficiency disease caused by mutations in genes encoding components of the phagocyte oxidase enzyme complex that is needed for microbial killing by polymorphonuclear leukocytes (neutrophils) and macrophages.

The disease is characterized by recurrent intracellular bacterial and fungal infections, often accompanied by chronic cell-mediated immune responses and the formation of granulomas.

Question 100

Granuloma

Answer 100

A nodule of inflammatory tissue composed of clusters of activated macrophages, usually with associated fibrosis.

Granulomatous inflammation is a form of chronic, delayed-type hypersensitivity, often in response to persistent microbes, such as Mycobacterium tuberculosis and some fungi, or in response to particulate antigens that are not readily phagocytosed.

Question 101

Fibroblasts

Answer 101

A fibroblast is a type of biological cell that synthesizes the extracellular matrix and collagen,[1] produces the structural framework (stroma) for animal tissues, and plays a critical role in wound healing.[2] Fibroblasts are the most common cells of connective tissue in animals.

Question 102

What do type I interferons do?

Answer 102

They inhibit viral replication and induce an antiviral state, in which cells become resistant to infection.

Question 103

Suppressors of cytokine signaling (SOCs)

Answer 103

SOCS (suppressor of cytokine signaling proteins) refers to a family of genes involved in inhibiting the JAK-STAT signaling pathway.

Question 104

What are some of the mechanisms that microbes have evolved to evade innate immunity?

Answer 104

1. Resistance to phagocytosis.
2. Resistance to reactive oxygen intermediates in phagocytes.
3. Resistance to complement activation (alternative pathway)
4. Resistance to antimicrobial peptide antibiotics

Question 105

Danger signals

Answer 105

“Danger signals” are normal intracellular molecules that are not found in the extracellular space under physiological conditions. The danger model has evolved over the years.[7] “Danger signals” include DNA, RNA, heat shock proteins (Hsps), hyaluronic acid, serum amyloid A protein, ATP, uric acid and also cytokines like interferon-α, interleukin-1β, CD40L and so on.[4] [6][8]

Question 106

What are the two signals necessary for the activation of antigen-specific lymphocytes?

Answer 106

1. Antigen.

2. Innate immune responses to microbes and to host cells damaged by microbes (danger signals).

Question 107

Adjuvant

Answer 107

A substance, distinct from antigen, that enhances T and B cell activation mainly by promoting innate immune responses, which enhance the accumulation and activation of antigen-presenting cells (APCs) at the site of antigen exposure.

Adjuvants stimulate expression of T cell-activating costimulators and cytokines by APCs and may also prolong the expression of peptide-MHC complexes on the surface of APCs.

Question 108

Costimulator

Answer 108

A molecule expressed on the surface of APCs in response to innate immune stimuli, which provides a stimulus (the “second signal”), in addition to antigen (the “first signal”), required for the activation of naive T cells.

The best defined costimulators are the B7 molecules (CD80 and CD86) on APCs that bind to the CD28 receptor on T cells.

Question 109

How must intracellular and phagocytosed microbes be eliminated?

Answer 109

They must be eliminated by cell-mediated immunity, the adaptive response mediated by T lymphocytes. Microbes that are encountered and ingested by dendritic cells or macrophages induce the second signals–that is, costimulators and cytokines–that stimulate T cell responses.

Question 110

How must blood-borne microbes be eliminated?

Answer 110

They must be eliminated by antibodies, which are produced by B lymphocytes during humoral immune responses. Blood-borne microbes activate the plasma complement system, which in turn stimulates B cell activation and antibody production.

Question 111

Plasmacytoid dendritic cell (pDC)

Answer 111

Plasmacytoid dendritic cells (pDCs) are a rare type of immune cell that are known to secrete large quantities of type 1 interferon (IFNs) in response to a viral infection. They circulate in the blood and are found in peripheral lymphoid organs. They develop from bone marrow hematopoietic stem cells and constitute < 0.4% of peripheral blood mononuclear cells (PBMC).[1] Other than conducting antiviral mechanisms, pDCs are considered to be key in linking the innate and adaptive immune systems. However, pDCs are also responsible for participating in and exacerbating certain autoimmune diseases like lupus.[2] pDCs that undergo malignant transformation cause a rare hematologic disorder, blastic plasmacytoid dendritic cell neoplasm.[3]

Question 112

Acute-phase proteins

Answer 112

Proteins, mostly synthesized in the liver in response to inflammatory cytokines such as IL-1, IL-6, and TNF, whose plasma concentrations increase shortly after infection as part of the acute phase response.

Examples include C-reactive protein (CRP), complement proteins, fibrinogen, and serum amyloid A protein.

The acute-phase reactants play various roles in the innate immune response to microbes.

Also called acute phase reactants.

Question 113

VLA-4

Answer 113

The integrin VLA-4 is expressed on the cell surfaces of stem cells, progenitor cells, T and B cells, monocytes, natural killer cells, eosinophils, and neutrophils. It functions to promote an inflammatory response by the immune system by assisting in the movement of leukocytes to tissue that requires inflammation.[2] It is a key player in cell adhesion.[3]

Question 114

LFA-1

Answer 114

Lymphocyte function-associated antigen 1 (LFA-1) is an integrin found on lymphocytes and other leukocytes.[1] LFA-1 plays a key role in emigration, which is the process by which leukocytes leave the bloodstream to enter the tissues. LFA-1 also mediates firm arrest of leukocytes.[2] Additionally, LFA-1 is involved in the process of cytotoxic T cell mediated killing as well as antibody mediated killing by granulocytes and monocytes.[3] As of 2007, LFA-1 has 6 known ligands: ICAM-1, ICAM-2, ICAM-3, ICAM-4, ICAM-5, and JAM-A.[2] LFA-1/ICAM-1 interactions have recently been shown to stimulate signaling pathways that influence T cell differentiation.[4] LFA-1 belongs to the integrin superfamily of adhesion molecules.[1]

Question 115

What are the five major families of cellular receptors in innate immunity?

Answer 115

1. TLRs (Toll-like receptors)
2. CLRs (C-type lectin receptors)
3. NLRs (NOD-like receptors)
4. RLRs (RIG-like receptors)
5. CDSs (cytosolic DNA sensors)

Question 116

Peripheral blood mononuclear cell (PBMC)

Answer 116

A peripheral blood mononuclear cell (PBMC) is any peripheral blood cell having a round nucleus.[1] These cells consist of lymphocytes (T cells, B cells, NK cells) and monocytes, whereas erythrocytes and platelets have no nuclei, and granulocytes (neutrophils, basophils, and eosinophils) have multi-lobed nuclei. In humans, lymphocytes make up the majority of the PBMC population, followed by monocytes, and only a small percentage of dendritic cells.