MOLECULES, CELLS, AND TISSUES OF IMMUNITY

1

# ADHESION MOLECULES

# NATURAL AND ADAPTIVE IMMUNITY

ORGANS AND TISSUES OF THE IMMUNE RESPONSE

ADHESION MOLECULES

Adhesion molecules mediate cell adhesion to their sur­roundings and to neighboring cells. In the immune system, adhesion molecules are critical to most aspects of leukocyte function, including lymphocyte recirculation through lym­phoid organs, leukocyte recruitment into inflammatory sites, antigen-specific recognition and wound healing. There are five principal structural families of adhesion molecules:

• Selectins • Integrins • ImmunoglobuHn superfamily (IgSF) proteins • Cadherins • Mucins

Classification of these major adhesion molecules and their structures and functions are summarized in Table 1.1.

Selectins

Selectins are a group of cell adhesion molecules that are glycoproteins and play an important role in the relationship of circulating cells to the endothelium. The members of this surface molecule family have three separate structural motifs. They have a single N-terminal (extracellular) lectin motif preceding a single epidermal growth factor repeat and various short consensus repeat homology units. They are involved in lymphocyte migration. These carbohy­drate-binding proteins facilitate adhesion of leukocytes to endothelial cells. There is a single chain transmembrane glycoprotein in each of the selectin molecules with a similar modular structure, that includes an extracellular calcium-dependent lectin domain. There are three separate groups of selectins:

• L-selectin (CD62L), expressed on leukocytes • P-selectin (CD62P), expressed on platelets and activated

endothelium

• E-selectin (CD62E), expressed on activated endothelium

Under shear forces their characteristic structural motif is comprised of an N-terminal lectin domain, a domain with homology to epidermal growth factor (EGF) and various complement regulatory protein repeat sequences.

Characteristics, receptors/ligands, cellular affinities, dis­tribution, function, and other related data such as the expression and regulation of selectins are summarized in Table 1.2.

Integrins

Integrins are a family of cell membrane glycoproteins that are heterodimers comprised of oc and (3 chain subunits. They serve as extracellular matrix glycoprotein receptors. They identify the RGD sequence of the (3 subunit, which consists of the arginine-glycine-aspartic acid tripeptide that occa­sionally also includes serine. The RGD sequence serves as a receptor recognition signal. Extracellular matrix glycopro­teins, for which integrins serve as receptors, include fibro-nectin, C3, and lymphocyte function-associated antigen 1 (LFA-1), among other proteins. Differences in the (i chain serve as the basis for division of integrins into three cate­gories. Each category has distinctive a chains. The (3 chain provides specificity. The same 95-kD (3 chain is found in one category of integrins that includes lymphocyte func­tion-associated antigen 1 (LFA-1), pi50, 95, and comple­ment receptor 3 (CR3). The same 130-kD (3 chain is shared among VLA-1, VLA-2, VLA-3, VLA-4, VLA-5, VLA-6, and integrins found in chickens. A 110-kD P chain is shared in common by another category that includes the vitronectin receptor and platelet glycoprotein Ilb/IIIa. There are four repeats of 40 amino acid residues in the P chain extracellular domains. There are 45 amino acid residues in the P chain intracellular domains. The principal function of integrins is to link the cytoskeleton to extracel-

Molecules, Cells and Tissues of Immunity

Table 1.1 Major classes of adhesion molecules

Selectin

Integrin

Immunoglobulin superfamily

Cadherin

Mucin

Structure Function

Single transmembrane polypeptide composed of an extracellular lectin-like domain, an EGF motif, 62 amino acid repeats, a transmembrane region and a cytoplasmic tail

Noncovalent ap~heterodimers with 1 oc chain and 1 P chain which are both transmembrane; 16 a chains and 8 p chains identified, resulting in a minimum of 22 different combinations

Cell surface protein of a variable number of related 70-110 amino acid Ig-like domains, transmembrane segment and cytoplasmic tail

Single-pass transmembrane glycoprotein composed of about 700-750 residues, with extracellular domain containing 5 tandem repeats and calcium binding sites

High molecular weight glycoprotein characterized by extensive and dense array of carbohydrates. The carbohydrates linkages are primarily O-linked with sulfated core groups, termed sialyl-Lewis x (sLe")

Slow intravascular leukocytes before transendothelial migration: initiators of leukocyte adhesion to endothelium; serve as signal transducing receptors

Mediate cell adhesion, mediate interactions with extracellular matrix components and with other cells

Engage in homotypic interaction, neurite outgrowth, and myelination; serve as ligands for Pi and p2 integrins to form firm adhesion of leukocytes

Maintaining tissue integrity, cell sorting in development, epithelial integrity

Serve as counter-receptors for selectins

Table 1.2 Selecdns

Molecule Ligands

L-selectin Sulfated:

(CD62L) GlyCAM-1; CD34; MAdCAM-1

E-selecdn Tetrasaccharides: sialyl-Lewis""; sialyl-Lewis^ (CD62E) cutaneous lymphocyte-associated antigen

P-selectin Tetrasaccharides: sialyl-Lewis"" (CD26P) P-selectin glycoprotein ligand-1

IHstrifiiition

Leukocytes (homing receptor)

Endothelial cells

Endothelial cells Platelets

General characteristics:

Expression: Only in vertebrates; in circulatory cells (endothelium and blood cells)

Structure • Single transmembrane polypeptide • N-terminal: Homologous to Ca^"^- dependent lectins • EGF motif • 62 amino acid repeats: Homology to complement

regulatory proteins • Transmembrane region • Cytoplasmic tail

Activation: Induced, then rapidly downregulated

Adhesion • Transient

• Architecture • Binding site: Amino-terminal domain • Connecting arm: Contains EGF-like domain and peptide

repeats • Ca"^~^-dependent • Ligands: Sialated glycans (similar pattern of binding of

sialoadhesins)

Functions • Slow intravascular leukocytes before transendothelial

migration • E-selectin: Mediates initial PMN adhesion to endothehal

cells • Adhesion is rolling, not firm • Firm adhesion via LFA/ICAM-1 and VLA-4/VCAM-1

Immunology Guidebook

lular ligands. They also participate in wound healing, cell migration, kiUing of target cells, and in phagocytosis. Leukocyte adhesion deficiency syndrome occurs when the (3 subunit of LFA-1 and Mac-1 is missing. VLA proteins facilitate binding of cells to collagen (VLA-1, -2, and -3), laminin (VLA-1, -2, and -6), and fibronectin (VLA-3, -4, and -5). The cell to cell contacts formed by integrins are critical for many aspects of the immune response, such as antigen presentation, leukocyte-mediated cytotoxicity and myeloid cell phagocytosis. Integrins comprise an essential part of an adhesion receptor cascade that guides leukocytes from the bloodstream across endothelium and into injured tissue in response to chemotactic signals.

Characteristics, receptors/ligands, cellular affinities, distribution, function, and other related data such as the expression and regulation of integrins are summarized in Table L3.

Immunoglobulin superfamily

The immunoglobulin superfamily is a group of cell surface proteins characterized by the presence of a variable number of related 70-110 amino acid Ig-like domains originally described in the Ig variable and constant regions. Included are CD2, CD3, CD4, CD7, CDS, CD28, T cell receptor (TCR), MHC class I and MHC class II molecules, leuko­cyte function-associated antigen 3 (LFA-3), the IgG recep­tor, and a dozen other proteins. These molecules share in common with each other an immunoglobulin-like domain, with a length of approximately 100 amino acid residues and a central disulfide bond that anchors and stabilizes antipar-allel (3 strands into a folded structure resembling immuno­globulin. Immunoglobulin superfamily members may share homology with constant or variable immunoglobuHn domain regions. Various molecules of the cell surface with polypeptide chains whose folded structures are involved in cell to cell interactions belong in this category. Single gene and multigene members are included.

Characteristics, receptors/ligands, cellular affinities, dis­tribution, function, and other related data such as the expression and regulation of the immunoglobuHn super-family are summarized in Table 1.4.

Cadherlns

Cadherins belong to a family of cell adhesion molecules that enable cells to interact with their environment. Cadherins help cells to communicate with other cells in immune surveillance, extravasation, trafficking, tumor metastasis, wound healing, and tissue localization. Cadherins are cal­cium-dependent. The five different cadherins include N -cadherin, P-cadherin, T-cadherin, V-cadherin, and E-cad-herin. Cytoplasmic domains of cadherins may interact with proteins of the cytoskeleton. They may bind to other recep­

tors based on homophilic specificity, but they still depend on intracellular interactions linked to the cytoskeleton.

Characteristics, receptors/ligands, cellular affinities, dis­tribution, function, and other related data such as the expression and regulation of cadherins are summarized in Table 1.5.

Mucins

Mucins are heavily glycosated serine and threonine-rich proteins that serve as ligands for selectins. They contribute to another major group of adhesion molecules.

Other adhesion molecules

Other adhesion molecules that do not fall into these major classes are summarized in Table 1.6.

Endothellal-leukocyte interactions

Table 1.7 summarizes adhesion molecules involved in endothelial-leukocyte interactions. Their ligands, expres­sion, regulation, and functions are listed.

Inflammation

Adhesion molecules play an important role in inflammation. The leukocyte adhesion cascade is a sequence of adhesion and activation events that is mediated by different adhesion molecules in different steps of capture: rolling, slow rolling, firm adhesion, and transmigration. The leukocyte adhesion cascade in inflammation is demonstrated in Figure 1.1. The adhesion molecules involved in different steps of the cascade are summarized in Table 1.8.

NATURAL AND ADAPTIVE IMMUNITY

Natural immunity

Natural or innate immunity comprises the inborn immune mechanisms that do not depend upon previous exposure to an antigen. It is present from birth and is designed to protect the host from injury or infection without previous contact with the infectious agent. It includes the skin, mucous mem­branes, and other barriers to infection; lysozyme in tears, stomach acid, other antibacterial molecules, and numerous other factors belong to innate immunity. Phagocytes, natural killer cells, complement and cytokines represent key parti­cipants in natural innate immunity. Table 1.9 lists the effec­tor mechanisms of natural immunity, including their components and functions. The cells of natural immunity are summarized as Table 1.10. The functions, structure, and membrane markers of these cells are also compared in the table.

Molecules, Cells and Tissues of Immunity

Table 1.3 Integrins

Molecule

oclpl (VLA-1, CD49a/CD29)

Ligands

Laminin; collagen; tenascin, common form

Distrilii;ition

a2pi (VLA-2, CD49b/CD29) Laminin; collagen

a3|3l (VLA-3, CD29c/CD29) Laminin; collagen; fibronectin

a4p l (VLA-4, CD49d/CD29) a4pl;a4|37; fibronectin; VCAM^l;

MAdCAM~I; TSP-1

aSpi (VLA-5, CD49e/CD29) Fibronectin; murine LI

a6pi (VLA^6, CD49f/CD29) Laminin

a7pi

aSpl (CD-/CD29; VLA-8)

a9pl

otvpl

Laminin

Fibronectin; vitronectin; tenascin, common form

Tenascin

Vitronectin; fibronectin; collagen; von Willebrand factor; fibrinogen

aLp2(LFA~la; C D l l a / C D l 8 ) ICAM-1; ICAM-2; ICAM-3

aMP2 (Mac-1, CDl Ib/CD18) ICAM-1; Factor X; iC3b; fibrinogen

aXp2 (P150,95, C D l l c / C D l S ) iC3b; fibrinogen

allbp3(gpllb/ina, CD41/CD61) Fibronectin; vitronectin; von Willebrand

factor; thrombospondin

aVp3(CD51/CD61,Vitronectin-R) Fibronectin; osteoponin; von Willebrand

factor; PE-CAM-1 vitronectin; fibrinogen;

human Ll thrombospondin; collagen

Q^ P4 Laminin

NK, B, and activated T cells; fibroblasts; glial perineurium; Schwann cells; endothelial cells

NK, B, and activated T cells; platelets; endothelial cells; fibroblasts; epithelium astrocytes; Schwann cells; ependymal

Activated T cells; thymocytes; endothelium; fibroblasts; epithelium; astrocytes

NK, B, and T cells; eosinophils; endothelial cells; muscle; fibroblasts; neural-crest derived Function: T cell transendothelial migration

Activated B and T cells; memory T-cells; thymocytes; fibroblasts; epithelium; platelets; endothelial cells; astrocytes a-5 disease: Myopathy in chimeric mouse

Leukocytes; thymocytes; epithelial; T cells (memory and activated); glial; fibroblasts; endothelial cells a-6 disease: Junctional epidermolysis bullosa

Skeletal and cardiac muscle; melanoma a-7 disease: Congenital MD Knockout--^ myopathy

Epithelium; neurons; oligodendroglia

Epithelium (airway); muscle

Oligodendroglia

Leukocytes; thymocytes; macrophages; T cells; microglia

p-2 disease: Leukocyte adhesion deficiency

Myeloid; B cells (activated); NK cells; macrophages; microglia; B leukemic cells

Myeloid; dendritic cells; B cells (activated); macrophages; microglia; B leukemic cells

Platelets

p-3 disease: Glanzmann thrombasthenia, Type B

B cells (activated); T cells (activated and 76); endothelium; monocytes; tumors; glia; Schwann cells; endothehum

Schwann cells; perineum; endothelium; epithelium; fibroblasts Not in immune cells

p-4 disease: Junctional epidermolysis bullosa

Immunology Guidebook

Table 1.3 Integrins

1 Molecule

1 avps (CD51/CD-)

avp6

j avp8

a4p7 (CD49d-)

otIELp? (CD103)

1 ^

{continued)

Ligajids

Vitronectin; fibronectin; fibrinogen

Fibronectin

Fibronectin

Fibronectin; VCAM-1; MAdCAM-1

E-cadherin

General characteristics:

Structure • Heterodimers with 1 oc chain and 1 P chain, 16 oc chains

and 8 P chains, 22 different heterodimers identified • Transmembrane adhesion molecules, both subunits

transmembrane • Non-covalently bound • Usually in low affinity conformation

Activation • Exist in variable activation states

Activated by o Conformational changes: induced by Hgand binding or

intracellular processes o ? Expression at transcriptional level

Adhesion • Binding site: On p subunit

Leukocyte Aitfv^ition

d .Capture Mow HCHL Adhesiciii

Traitsmigratlofi

• Rolling EfiaiHg

,|rffc , \ S Traitsmigratlg

LZI . . J. 1 ^ 1 1 T^I ) SELECTINS

INTEGRINS

0 0 »

0 Chcmo^tractaBts om

mdothdtal cell surface

Otlier €liein@Jittr tMPtjg to

Figure 1.1 Adhesion molecules in leukocyte adhesion cascade of inflammation

DistribBtion

Fibroblasts; monocytes; macrophages; epithelium; oligodendrogHa; tumors

Oligodendroglia; Schwann cells; brain

synapses

NK, B, and T cells Not in neural cells

Intraepithelial T cells (lEL) (intestinal)

Uterus; heart; skeletal muscle; smooth muscle containing tissue

Modified by metal binding to a subunit o oc submit may mediate specificity of ligand binding Binding also influenced by divalent cations Often occurs after selectin binding Extracellular hgands: Binding is low affinity o Often single specific IgCAM o Subset of extracellular matrix molecules: Fibronectin;

laminins Intracellular ligands: Talin; a-actinin Intracellular ligands then linked to o Structural proteins; vinculin; actin microfilaments o Signaling pathways

» Partly via ppl25^^^, a focal adhesion-associated kinase

Effects of extracellular ligand binding o Receptor clustering o Autophosphorylation of tyrosine residues o Loss of integrin interaction may induce apoptosis

Adaptive immunity Adaptive or acquired immuni ty is the protect ion mechanism

from an infectious disease agent as a consequence of clinical

or subclinical infection with that agent or by deliberate

immuniza t ion against that agent with products from it.

Th i s type of immuni ty is mediated by B and T cells follow­

ing exposure to a specific antigen. It is characterized by

specificity, immunological memory , and self/nonself recog­

nition. T h e response involves clonal selection of l ympho­

cytes that respond to a specific antigen. T cells and B cells

are the two major components of adaptive immuni ty .

Compar i son of these two cell types is presented in T a b l e

1.11.

Adaptive immun i ty has features in contrast to innate

immuni ty . T a b l e 1.12 compares the characteristics, cellular

receptors, functions, markers, and other features of these

two limbs of the i m m u n e response.

Molecules, Cells and Tissues of Immunity

Table 1.4 Immunoglobul

1 Molecule

1 Adhesion molecule on glia (AMOG)

LI CAM

j Myelin-associated 1 glycoprotein (MAG)

1 Myelin-oligodendrocyte 1 glycoprotein (MOG)

1 NCAM-1 (CD56)

1 NrCAM

1 OBCAM

1 Po protein

1 PMP-22 protein

j Also neurofascin and 1 NgCAM

1 Molecule

j ALCAM(CD166)

1 Basigin (CD147)

1 BL-CAM(CD22)

1 CD44

1 ICAM-1 (CD54)

1 ICAM-2 (CD102)

1 ICAM-3 (CD50)

1 Lymphocyte function 1 antigen-2 (LFA-2) (CD2)

1 LFA-3 (CD58)

1 Major histocompatibility 1 complex (MHC) 1 molecules

n (Ig) superfamily

NEURAI^SFECIFIC

Ligands

Axonin

MAG

NCAM-1 via polysialic acid; modulated by sialyltransferase X; polysialyltransferase

Ig superfamily

Opioids (^); acidic lipids

Po

PMP-22

Tenascin-R, axonin-1, Fll

IgCAMS . 1

Distributioii . j

Glial neural migration j

Neural j

Myelin j

1 Myelin; oligodendrocytes I

Neural cells j

Neural j

Brain j

Myelin j

Myelin j

Neural i

SYSTEMIC IgCAMS j

Ligands

CD6; CD166; NgCAM; 35 kD protein

Sialylated glycoproteins LCA (CD45)

Hyaluronin; ankyrin; fibronectin; MIPiP osteopontin

aLp2; LFA-1

aLp2 (LFA-1)

aLp2

LFA-3

LFA-2

Distribiidoii 1

Neural; leukocytes j

Leukocytes; RBCs; platelets; endothelial cells j

B cells 1

Lymphocytes; epithelial; WM perivascular astrocytes; j glial tumors (malignant); metastases {CD44v splice | variant) |

Leukocytes; endothelial cells; dendritic cells; fibroblasts; 1 epithelium; synovial cells j Disease: Lys29Met mutation e I Susceptibility to cerebral malaria 1

Endothelial cells; lymphocytes; monocytes 1

Leukocytes I

Lymphocytes; thymocytes 1

Leukocytes; stroma endothelial cells; astrocytoma 1

Immunology Guidebook

Table 1.4 Immunoglobulin (Ig) superfamily {continued)

1 Molecule Ligand^

1 MAdCAM-1 a4p7; L-selectin

PECAM(CD31) CD31;avp3

1 T cell receptor (C-region)

VCAM-1 a4pi;a4p7

NEURAL^SFECIFIC IgCAMS

Distribution 1

Mucosal endothelial cells 1

Leukocytes; synovial cells; endothelial cells j

Satellite cells; monocytes; synovial cells; activated j endothelial cells j

General characteristics: Expression: Evolutionarily ancient; widely expressed Structure

• 1 or more repeats of Ig fold of 60-100 amino acids: form sites of adhesion

• Ig domain: No somatic hypermutations o Sandwiches of 2 P sheets held together by hydrophobic

interactions • Constitutive or long-term upregulated • Anchor: Transmembrane segment and cytoplasmic tail

Interactions • Homophilic: Neural specific Ig cell adhesion molecules

(IgCAMs)

• Heterophilic: Systemic IgCAMs Adhesion

• Sites: Ig fold(s) domains (distal); fibronectin type III (Fn3) domains

• Inhibited by sialylation • Ca "'"''-independent

Functions • Neurite outgrowth • Myelination • Firm adhesion of leukocytes

« Via LFA/ICAM-1 and VLA-4/VCAM-1

Toll-like receptors (TLBs)

The innate immune system recognizes a wide spectrum of pathogens without a need for prior exposure. The main cells responsible for innate immunity, neutrophils, monocytes, and macrophages, phagocytose pathogens and trigger the cytokine and chemokine network resulting in inflammation and specific immune responses. Receptors of innate immu­nity have broad specificity. They recognize many related molecular structures called pathogen-associated molecular patterns (PAMPs). To recognize different types of PAMPs, macrophages have a set of transmembrane receptors called toll-like receptors (TLRs). The TLR family was first dis­covered in Drosophila and has significant homology in its cytoplasmic domain to IL-1 receptor Type I. In macro­phages the pathogen is exposed to the TLRs when it is inside the phagosome. The TLR(s) to which it binds deter­mine what the response will be. In this way, the TLRs identify the nature of the pathogen and turn on an appro­priate effector response. These signaling cascades lead to the expression of various cytokine genes. For example, TLR2 and TLR4 activate the N F - K B pathway, which regulates cytokine expression, through the adaptor molecule MyD88. Activation of the N F - K B pathway leads to initia­tion of the adaptive immune response by production of inflammatory cytokines such as IL-1, IL-2, IL-8, TNF-a , IL-12, chemokines and induction of costimulatory mole­cules. In addition to induction of cytokines, MyD88 binds

FADD and triggers apoptosis through the Caspase cascade. Activation of the apoptosis pathway via TLRs contributes to the defense mechanisms used by innate immunity. To date, ten toll-like receptors have been reported in the human and the mouse. Table LI3 shows the chromosomal location, distribution, and function of these TLRs. Figures L2 and L3 illustrate the role of the TLR family in immunity against the pathogens.

ORGANS AND TISSUES OF THE IMMUNE RESPONSE

The immune system is found throughout the body and is made up of many different cells, organs, and tissues. The organs and tissues of the system can be classified into two main groups: (1) primary lymphoid organs, in which lym­phocytes are generated and undergo development and maturation; and (2) secondary lymphoid organs and tissues, where mature lymphocytes interact with antigen. The ves­sels of the blood and lymphatic systems connect lymphoid organs and tissues and unite them into a fimctional whole. Leukocytes, or white blood cells, are found within the blood, lymph, and lymphoid tissues and organs. The vertebrate immune system contains many types of leukocytes, but only the lymphocytes have the attributes of receptor diver­sity, antigen specificity, and self/nonself recognition that are the hallmarks of adaptive immunity.

Molecules, Cells and Tissues of Immunity

Table 1.5 Cadherins

1 Moleci:iles

1 Cadhetin E (1)

1 Cadherin N (2)

1 Cadherin BR (12)

1 Cadherin P (3)

1 Cadherin R (4)

1 Cadherin M (15)

1 Cadherin VE(5) (CD144)

1 Cadherin T and H (13)

1 Cadherin OB (11)

1 Cadherin 7

1 Cadherin 8

1 Cadherin KSP (16)

1 Cadherin LI (17)

1 Cadherin 18

1 Cadherin, fibroblasts 1

1 Cadherin, fibroblasts 2

1 Cadherin, fibroblasts 3

1 Cadherin23

1 Desmocollin 1

1 Desmocollin 2

1 Desmoglein 1

1 Desmoglein 2

1 Desmoglein 3

j Protocadherin 1, 2, 3, '

(19)

(20)

(21)

7 ,8,9

Ligands

H

0

M

O

P

H

I

L

I

C

Distributioii j

Epithelial 1

Neural j

Brain j

Placental j

Retinal |

Muscle 1

Epithelial j

Heart j

Osteoblast 1

Brain; kidney |

Brain |

Kidney 1

GI tract; pancreas |

CNS; small cell lung cancer 1

Fibroblasts p

Fibroblasts p

Fibroblasts J

Ear 1

Skin 1

Epithelium; mucosa; myocardium; lymph nodes |

Epidermis, tongue i

All 1

Epidermis; tongue; antibody target in pemphigus 1

General characteristics: Expression: Evolutionarily ancient; widely expressed Structure

• Extracellular domain: 5 tandem repeats; each comprising sandwich of p sheets

• Ofi:en present as dimers • Anchor: Transmembranse segment; cytoplasmic carboxy-

terminal domain

Adhesion • Homophilic: Via most distal cadherin repeats • Requires: Ca^; specific intracytoplasmic binding • Intracellular

o Cytoplasmic domain binds catenins o Catenins then bind to actin cytoskeleton

• Types

Immunology Guidebook

o Interactive with actin cytoskeleton: Cadherins N, P, R, B, E

o Desmosome-associated: Desmogleins and desmocollins « Interact with intermediate filaments ^ Location: In tight junctions

o Protocadherins '^ Homology to cadherins: Extracellular, but not

intracellular, domains Functions and diseases

• Cadherin E (1): Reduction correlates with tumor malignancy o Gynecologic malignancies

« Point mutations in tumor cells

» Somatic loss of heterozygosity common o Gastric malignancies o Susceptibility to Listeria monocytogenes infection Cadherin N: Role in establishment of left-right asymmetry Cadherin P (3): Congenital hypotrichosis with juvenile muscular dystrophy Cadherin23: Deafness Catenin pi (cadherin-associated protein): Mutations in malignancies o Colon, hepatoblastoma, pilomatricoma, ovarian

(endometrioid) Desmoglein 3: Antibody target in pemphigus

LPSA.BP

dsRJSIA

CpG DNA

Bacterial & Yeast Glycoproteins

i N F - K B

Figure L2 Role of toll-like receptors in immunity against pathogens

10 Molecules, Cells and Tissues of Immunity

Table 1.6 Other adhesion molecules

1 Molecules

1 Agrin (neural)

1 CD34

1 GlyCAM-1

1 OHgodendrocyte-1 (OMGP)

-myelin glycoprotein

Ligands

MuSK; NCAM; laminin; heparin-binding proteins; heparan sulfate proteoglycan

MAdCAM-1; L-selectin

L-selectin

Dlsmbutidn j

Nerve |

Immature lymph/ 1 myeloid j

Lymph nodes j

Myelin; j oligodendrocytes j

Table 1.7 Endothelial-leukocyte adhesion molecules

j Molecy!e(s)

1 aLp2 1 LFA-1 1 C D l l a / C D 1 8

1 aMp2 j Mac-1 1 C D U c / C D l S

1 axp2 1 P 150,95 1 C D l l c / C D l S

a4pl CD49d/CD29

1 a4p7

1 Mole€iile(s)

1 E-selectin CD62E

1 L-selectin j CD62L

Ligaiid{s)

ICAM-1, rCAM-2, ICAM-3

ICAM-l, C3bi unidentified endothelial ligand

C3bi, others?

VCAM-1

MAdCAM-1

L%aiid(s)

Sialyl-Lewis"" glycoproteins, glycoHpids (?) on P M N

GlyCAM-1, CD34 on lymph node HEV; evidence for extralymphatic ligand(s)

INTEGRINS

Dtstrtbiidoii

Lymphocytes > neutrophils; monocytes

Macrophages > monocytes; neutrophils

Macrophages; monocytes

Lymphocytes; monocytes; eosinophils

Lymphocytes

E^nlatioii

Conformational^ activated by chemoattractants

Upregulated by degranulation; activated bf T N F , chemoattractants

Upregulated by degranulation

Constitutively active (?) affinity regulation; higher expression on memory T cells

Constitutive

SELECTINS

Distribution

Activated endothelium

Resting neutrophils; most lymphocytes

E e g a k t i o 0

Upregulated by T N F , IL^l Max. expression at 4-6 hr

Constitutive, shed from surface by chemoattractant

Ftiitctioii j

Lymphocyte, granulocyte adhesion to j

resting endothelium |

Granulocyte, monocyte adhesion to | resting and activated endothelium j transmigration; C3bi binding; leukocyte j activation; phagocytosis j

Complement fixation; phagocytosis? j

Lymphocyte, monocyte adhesion to j endothelium and fibronectin j

Mucosal lymphocyte homing j

FiJ0ctioii 1

Adhesion and rolling of neutrophils; | adhesion of T cells; monocytes; slow | (3 |im/s) leukocyte rolling in vivo ]

Lymphocyte homing to lymph nodes; j sustained leukocyte rolling in vivo; 1 critical for P M N recruitment; mediates j leukocyte capture j

Immunology Guidebook 11

Table 1.7 Endothelial-leukocyte adhesion molecules [continued)

1 P-selectin 1 CD62P

1 Moleeule(s)

1 ICAM-1 1 CD54

ICAM-2 1 CD102

1 ICAM-3 1 CD50

1 VCAM-1

1 PEC AM-1 1 CD-31

1 MAdCAM-1

1 Moleciile(s)

1 PSGL-1 1 CD162

GlyCAM-1

1 CD34

1 ESL-1

1 Unidentified

PSGL-1 on myeloid cells

Ogaiid(s)

LFA-1, Mac-1

LFA-1

LFA-1

VLA-4 (a4pi integrin), a4p7 integrin

PECAM-1 (homotypic) other ligand(s)?

OC4P7 integrin, L-selectin (glycosylation-dependent)

Ligaiid(s)

P-selectin

L-selectin

L-selectin

E-selectin

L-selectin

Activated platelets; thrombin-, histamine-, cytokine-activated endothelium

Surface expressed by degranulation, transcriptional regulation by TNF, IL-i

IMMUNOGLOBUUNS

Distribution

Endothelium; smooth muscle fibroblasts; T cells

Endothelial cells

Resting T cells

Cytokine-stimulated endothelium

High on endothelium, moderate on monocytes, PMN, platelets

Mucosal venules; Peyer's patch HEV; mesenteric lymph node

Regnktioii

Constitutive, increased expression by IL-1, IFN-y

Constitutive

Constitutive

IL~1, IL-4, TNF upregulate expression, max. at 4-24 hr

Constitutive, redistribution to cell borders in confluent EC

Constitutive, different glycosylation in PP and MLN

SELECTIN LIGANDS

Distribudou

All leukocytes

Lymph node HEV; serum

Lymph node HEV; other endothelia

Murine myeloid cells

Activated endothelial cells

Regnlatioii

Constitutive; dimer

Constitutive; secreted; expression depends on lymph flow

Constitutive; expression depends on lymph flow

Constitutive

Induced by TNF in vitro, by tissue trauma in vivo

Platelet-leukocyte adhesion; leukocyte 1 rolling in vivo; critical for PMN 1 recruitment |

Function 1

Cytotoxic T-cell conjugates, leukocyte- 1 endothelial adhesion, transmigration? 1

Leukocyte adhesion to resting 1 endothelium |j

Homotypic lymphocyte aggregation |

Adhesion of monocytes, eosinophils, 1 lymphocytes to activated endothelium; 1 expressed in atherosclerotic plaques j

Critically involved in neutrophil | transmigration; endothelial monolayer j integrity; neutrophil adhesion (?) 1

Lymphocyte homing to mucosal sites; | lymphocyte rolling (contains mucin j domain) |

FBitction 1

Adhesion of myeloid cells to ! P-, L-selectin j

Homing of lymphocytes to lymph node 1 HEV (?); modulation of 1 L-selectin-dependent adhesion? 1

Homing of lymphocyte to lymph node j HEV 1

Function unknown, homologous to | FGF-receptor j

Mediates neutrophil adhesion; j L-selectin-dependent rolling j

12

Central lymphoid organs

Central lymphoid organs are requisite for the development of the lymphoid and, therefore, the immune system. These mclude the thymus, bone marrow, and bursa of Fabricus. Central lymphoid organs are also termed primary lym-

Molecules, Cells and Tissues of Immunity

phoid organs. They are sites where lymphocytes are gen­erated. Both T and B cells originate in the bone marrow but only B cells mature there. Human T cells mature in the thymus.

Protein F \ T I W 4 i

104

••J m-m m % \ M M M ^

J* TRAI^

t MB<K1

''^^

Prolnflammatoi7 Cytokines

Figure 1.3 Pathways of toll-Hke receptors

^Table 1.8 Adhesion molecules involved in leukocyte emigration from vessels during inflammation

Rolling • Sialyl-Lewis'' • L-selectin • P-selectin • E-selectin

Stopping • p2 integrins • VLA-4(a4Pi) • ICAM-1 • VCAM-1 • a4P7 integrins • Made AM-1

^ggrcgmon and shape change • CDl lb /CDl8 (Mac~ l ) • C D l l a / C D l 8 ( L F A - l ) • P-selectin

Migration through vessel wall • p2 integrins • ICAM-1 • VCAM-1 • PECAM-1

Immunology Guidebook 13

Table 1.9 Effector mechanisms of natural immunity

1 ^^ 1 Skin

1 Ey^

1 Nasopharynx

1 Lung

1 GI tract

1 Blood and lymphoid organs

1 Other serous fluids

Component

Squamous cells, sweat

Tears

Mucus, saliva

Tracheal cilia

Columnar cells

K cells, LAK cells, NK cells

Lactoferrin, transferrin; interferons, TNF-a; fibronectin, complement; lysozyme

Functioii • 1

Desquamation; antimicrobial secretions, e.g. fatty acids; 1 flushing 1

Flushing; lysozyme 1

Flushing; lysozyme j

Mucociliary elevator; surfactants j

Stomach acidity, bile salts, fatty acids, peristalsis j

Direct and antibody-dependent cytolysis j

Iron deprivation; phagocyte activation; opsonization; 1 enhanced phagocytosis; peptidoglycan hydrolysis j

Table 1.10 (

j Neutrophils

1 Macrophages

1 Natural killer (NK)

j cells

1 K cells

I ells of natural immunity

Function

Phagocytosis, intracellular killing, inflammation and tissue damage

Phagocytosis, intracellular and extracellular killing, tissue repair, antigen presentation for specific immune response

Kill infected cells and malignant cells; LAK cells kill transformed cells and malignant cells

Recognize antibody-coated targets

Structure characteristics

Characteristic nucleus and cytoplasm

Characteristic nucleus

Also known as large granular lymphocytes (LGL); activated by IL-2 and IFN to become LAK cells

Morphologically undefined

mmummm

Membrane marker j

CD67 1

CD14 1

CD56, CD16 j

Could be NK cells (IgG), I macrophages (IgG), j eosinophils (IgE) or other cells j (IgG) J

Table 1.11 Cells of

1 Origin

1 Site of maturation

1 Antigen receptor

1 Target of binding

1 Branch of immune j response

1 MHC and antigen j presentation

adapt tive immunity

B cells

Bone marrow

Bone marrow

B cell receptor (BCR)

Soluble antigens

Antibody-mediated immune response

Class II MHC molecules

T cells 1

Bone marrow 1

Thymus 1

T cell receptor (TCR) 1

Biomolecular complex displayed at the surface of APC I

Cell-mediated and antibody-mediated immune response 1

1 Class I MHC molecules (CDS"^ T cells) and class II MHC molecules 1 (CD4+ T cells) 1

14 Molecules, Cells and Tissues of Immunity

Table 1.12 Characteristics of innate and adaptive immunity

Innate immunity

Components Physical barriers (skin, gut villi, lung cilia, etc); protein and non-protein secretions; phagocytes, KK cells, eosinophils, K cells

Antigen dependent

Antigen specific

No: system in place prior to exposure to antigen

No: lacks discrimination among antigens

Time lag No: immediate response

Immunologic No memory

Pathogen

Pathogen recognition

Receptor specificity

Essentially polysaccharides and polynucleotides

Pathogen recognized by receptors encoded in the germline

Broad specificity, i.e. recognize many related molecular structures called pathogen-associated molecular patterns

Receptors Pattern recognition receptors

Enhancement Can be enhanced after exposure to antigen through effects of cytokines

Existence Occurs in all metazoans

Adaptive immianity

ImmunoglobuHns (antibodies), T cells, B cells

Yes: induced by antigens

Yes; shows fine discrimination

Yes: delayed (3-5 days) response

Yes

Most derived from polypeptides (proteins)

Pathogens recognized by receptors generated randomly

Very narrow specificity, i.e. recognize a particular epitope

B cell receptors and T cell receptors

Enhanced by antigens

Occurs in vertebrates only

Table 1.13 Toll-like receptors

Name

TLRl (TIL, Rsc786)

TLR2 (TIL4)

TLR3

Distribtition Chromosome (mENA/protein)

Human: 4 Leukocytes; upregulated on Mouse: 5 macrophages

Human: 4 Monocytes, granulocytes; Mouse: 3 or 8 upregulated on macrophages

Function/comments

Associates with and regulates TLR2 response

Interacts with microbial lipoproteins and peptidoglycans: CDH-dependent and-independent response to LPS; NF-KB pathway

Human: 4 Dendritic cells; upregulated on Interacts with dsRNA, activates N F - K B pathway; induces Mouse: 3 or 8 endothelium and epithelium production of type I interferons, MyD88-dependent and

-independent response to poly (I:C)

TLR4 (h Toll, Ly87, Rasl2-8, RAN/ Ml)

TLR5 (TIL3)

Human: 9 Mouse: 4

Human: 1 Mouse: 1

Monocytes Interacts with microbial lipoproteins; CDl4-dependent response to LPS; N F - K B pathway

Leukocytes, prostate, ovary, liver, lung

Interacts with microbial lipoproteins; N F - K B , response to Salmonella

Immunology Guidebook 15

Table 1.13

Name

TLR6

TLR7

TLR8

TLR9

TLRIO

RP105 (CD180, Ly78)

MD-1 (Ly64, Irrp, 14/AlO)

MD-2 (Ly96)

Toll-like receptors {continued)

Chromosome

Human: 4 Mouse: 5

Human: X Mouse: X?

Human: X Mouse: X?

Human; 3 Mouse: 6

p

Human: 5 Mouse: 13

Human: 6

Distdbiitioii (mRNA/protein)

Leukocytes, ovary, lung

Spleen, placenta, lung; upregulated on macrophages

Leukocytes, lung

Leukocytes

Lymphoid tissues

Mature B cells

Mature B cells

Macrophages

Fiiiictioji/commeiits

Interacts with microbial lipoproteins; protein sequence most similar to hTLRl; associates with and regulates TLR2 response

Low similarity to other TLR family members

Receptor for CpG bacterial DNA, weakly similar to TLR3; may mediate protein-protein interaction

Most closely related to TLRl and TLR6

B cell activation; LPS recognition

Associates and regulates surface expression of RP105

Associates and regulates surface expression of TLR4; signals LPS presence

Peripheral lymphoid organs

Peripheral lymphoid organs are not required for onto- the lymph nodes, spleen, tonsils, and mucosal-associated geny of the immune response. They are sites where lymphoid tissues in which immune responses are adaptive immune responses are initiated and where lym- induced. phocytes are maintained. Peripheral lymphoid organs are Table L14 depicts the constituents of the primary and also termed secondary lymphoid organs. They include secondary lymphoid organs.

Table 1.14 Organs and tissues of the immune response :fe:%S8?««"«?^.^»i^«*»<iS«««

Pfimaty lymphoid organs Secondary lymphoid organs

Component Bone marrow, fetal liver, thymus

Proliferation and Antigen-independent differentiation

Product

Event

Immunocompetent cells (B cells and T cells)

Development and maturation of B and T cells

Spleen, lymph nodes, and mucosa-associated lymphoid tissue (MALT) including tonsils, adenoids, respiratory, genitourinary, and gastrointestinal tracts

Antigen-dependent

Effector cells (antibody-secreting plasma cells for humoral immune response and T helper and T cytotoxic cells for cell-mediated immune response)

Induction of immune response: encounter of antigens and antigen-presenting cells (AFC) with mature B and T cells, generation of effector cells, and memory cells