pii: s0140-6736(00)04904-7

IMMUNOLOGY

THE LANCET • Vol 357 • June 2, 2001 1777

Immunity is divided into two parts determined by thespeed and specificity of the reaction. These are named theinnate and the adaptive responses, although in practicethere is much interaction between them. The term innateimmunity is sometimes used to include physical,chemical, and microbiological barriers, but more usuallyencompasses the elements of the immune system(neutrophils, monocytes, macrophages, complement,cytokines, and acute phase proteins) which provideimmediate host defence. The highly conserved nature ofthe response, which is seen in even the simplest animals,confirms its importance in survival.1 Adaptive immunity isthe hallmark of the immune system of higher animals.This response consists of antigen-specific reactionsthrough T lymphoctyes and B lymphocytes. Whereas theinnate response is rapid but sometimes damages normaltissues through lack of specificity, the adaptive response isprecise, but takes several days or weeks to develop. Theadaptive response has memory, so that subsequentexposure leads to a more vigorous and rapid response, butthis is not immediate.2,3

The innate response Neutrophil recruitmentA central feature of the innate reaction is recruitment andactivation of neutrophils at the site of infection to eradicatepathogens.4 The same process occurring inappropriatelyleads to the inflammation of connective tissue diseases,vasculitis, and the systemic inflammatory responsesyndrome. There is intense interest in the mechanismsunderlying the process for the development of new anti-inflammatory therapies.5,6

During the very early stages of infection or tissuedamage, there is release of cytokines from activatedmacrophages. Two of these, granulocyte and granulocyte-macrophage colony stimulating factors, stimulate divisionof myeloid precursors in the bone marrow, releasingmillions of cells into the circulation and causing acharacteristic neutrophil leucocytosis. Neutrophils, likemost cells involved in immune responses, are not static

Lancet 2001; 357: 1777–89

Departments of Immunology (J Parkin PhD) and Medical and DentalEducation (B Cohen BSc), St Bartholomew’s and the Royal LondonHospital School of Medicine and Dentistry, Queen Mary andWestfield College, West Smithfield, London EC1A 7BE, UK

Correspondence to: Dr Jackie Parkin(e-mail: [email protected])

within a particular compartment, but are mobile cells thattravel round the body. They normally flow freely in theblood as the circulating pool, or roll along the vascularendothelium as the marginating pool. To home to a site ofinfection, neutrophils use a multistep process involvingproinflammatory mediators, adhesion molecules,chemoattractants, and chemokines. Although most workwas initially done within the neutrophil system, it is nowclear that all leucocytes, including lymphocytes, use thismechanism of localisation.7 The recruited neutrophilsphagocytose organsisms by making pseudopodia(projections of cytoplasmic membrane) which form amembrane-bound vesicle (phagosome) around theparticle. This fuses with neutrophil cytoplasmic granulesto form the phagolysosome. In this protectedcompartment killing of the organism occurs by acombination of two mechanisms. The oxygen-dependentresponse or respiratory burst, involves the sequentialreduction of oxygen by an NADPH oxidase leading toproduction of toxic oxygen metabolites, such as hydrogenperoxide, hydroxyl radicals, and singlet oxygen. Theoxygen-independent response, uses the highly toxiccationic proteins and enzymes (eg, myeloperoxidase andlyzozyme) contained within the neutrophil cytoplasmicgranules.8 Ingestion and killing of organisms is 100-foldmore effective if the particle is first opsonised with specificantibody or complement (C’). These molecules bind toneutrophil Fc and C’ receptors, increasing adhesionbetween particle and phagocyte and priming the cell foractivation. Some encapsulated organisms, such aspneumococcus and haemophilus are not susceptible toneutrophil phagocytosis unless first coated with antibody.This explains why individuals with antibody deficiency areso susceptible to this type of infection, despite normalneutrophil numbers and function.

Complement The complement system has several important functions ininnate immunity and consists of at least 20 serumglycoproteins, some being regulatory. These are activatedin a cascade sequence, with amplification stages. Thismeans that activation of a single molecule will lead tothousands of molecules being generated. There are threepathways of complement activation that can be driven bythe presence of a foreign substance (figure 1), the classicalby antigen-antibody reactions, the alternative bypolysaccharides from yeasts, and gram negative bacteria.The more recently identified mannan binding lectinpathway9 feeds into the classical sequence by activating it

An overview of the immune system

Jacqueline Parkin, Bryony Cohen

Immunology

We are continually exposed to organisms that are inhaled, swallowed, or inhabit our skin and mucous membranes.Whether these organisms penetrate and cause disease is a result of both the pathogenicity of the organism (thevirulence factors at its disposal) and the integrity of host defence mechanisms. The immune system is an interactivenetwork of lymphoid organs, cells, humoral factors, and cytokines. The essential function of the immune system inhost defence is best illustrated when it goes wrong; underactivity resulting in the severe infections and tumours ofimmunodeficiency, overactivity in allergic and autoimmune disease. In this review we have covered the normalfunction of the immune system in recognising, repelling, and eradicating pathogens and other foreign molecules.

independently of the C1rs complex and is stimulated bymannose containing proteins and carbohydrates onmicrobes, including viruses and yeasts. Many of thecomponents of the classical and alternative pathway arehomologous, suggesting the pathways were initially derivedfrom the same sequence. All three pathways converge withthe activation of the central C3 component. This leads to afinal common pathway, with assembly of C5–C9 forming atransmembrane pore (membrane attack complex) in thecell surface and death by osmotic lysis. The perforins,which are produced by cytotoxic T lymphocytes andnatural killer cells, have a similar structure. Complementactivation is focused on the surface of a cell or organism,which forms a protected site where the inhibitory proteinshave limited access. Normal host cells bear the complementreceptor type 1 and decay accelerating factor, which inhibitC3 convertase and prevent progression of complementactivation. However, microbes lack these molecules and aresusceptible to complement.

In addition to lysis of organisms, complement has otheranti-infective functions. There is the opsonic action ofC3b, the release of soluble C3a and C5a, which areanaphylatoxins and increase vascular permeabilityallowing proteins, such as antibody, to penetrate thetissue, and the chemotactic activity of C5a that induces aninflammatory infiltrate. Complement also has a rolewithin the specific immune response; its activation

and deposition within immunecomplexes helps to target theseto complement-receptor bearingantigen-presenting cells, such asB lymphocytes and folliculardendritic cells.

EosinophilsThe main physiological role ofeosinophils is in protection of thehost from parasitic (particularlynematode) infections. Suchinfections induce antigen-specificIgE production, the antibodiescoating the organism. Eosinophilsbind to the antibody using theirlow affinity receptors (Fc�RII).Eosinophils are not phagocytic,but have large granules containingmajor basic protein, eosinophiliccationic protein, eosinophil per-oxidase, and eosinophil-derivedneurotoxin, which are highlycytotoxic when released onto thesurface of organisms. In more-developed countries the eosino-phil is more often viewed as apathological participant in aller-gic reactions.

Mast cells and basophilsAlthough basophils and mastcells are relatively few in numbercompared with the other whitecells, they are involved in some ofthe most severe immunologicalreactions, such as angioedemaand anaphylaxis. There are atleast two populations of mastcells, based on the enzymes theycontain and their tissue location.T mast cells (mucosal mast cells)

contain only trypsin, whereas connective tissue mast cellscontain both trypsin and chymotrypsin. Basophils aremorphologically similar cells found in the blood. Mastcells and basophils bear high-affinity receptors for IgEFc�RI (CD23) which rapidly absorb any local IgE.Crosslinking of these receptors by the binding of antigento IgE leads to degranulation and release of preformedmediators, such as the vasoactive amines, histamine andserotonin. Membrane derived mediators such asleucotrienes B4, C4, D4 and E4, prostaglandins andplatelet activating factor are also produced leading toincreased vascular permeability, bronchoconstriction, andinduction of an inflammatory response.

Natural killer cellsNatural killer cells have the morphology of lymphocytes butdo not bear a specific antigen receptor. They recogniseabnormal cells in two ways. First, they bearimmunoglobulin receptors (FcR) and bind antibody-coated targets leading to antibody-dependent cellularcytotoxicity. Second, they have receptors on their surfacefor MHC class I. If on interaction with a cell, this receptoris not bound, the natural killer cell is programmed to lysethe target. This is achieved by secretion of perforins ontothe surface of the cell to which the natural killer cell hasadhered. Perforins make holes in the cell membrane andgranzymes are injected through the pores. The granzymes

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1778 THE LANCET • Vol 357 • June 2, 2001

Cell lysis

Classical pathway

Started by:antibody bindingto antigen

C3 cleavage byC3 convertases

–ve controlC3 convertase inhibitorsCR1, C4 binding protein,DAF, MCP, factor H, factor I+ve controlC3 convertase stabilisationby properdin

–ve controlProlectin (CD59)

–ve controlC1 esteraseinhibitor

AnaphylatoxinsSmooth muscle contractionVascular permeabilityMast cell degranulation

Neutrophil, monocytechemotactic agent

C5 cleavage byC5 convertases

Membrane attackcomplexassembly

C5b

C5a

C3b

C4/C2 cleavage

C3a

Started by:mannan binding lectinbinding to mannoseresidues

Started by:C3b binding toactivating surface

Mannan bindinglectin pathway

Alternative pathway

Alternative pathwayPositive feedback loop

OpsonisationStimulates phagocytosisand antigen-presenting celland B cell endocytosis

Figure 1: Complement pathwaysThe three pathways of complement activation. Regulatory proteins are shown in orange. Components ofactivation pathways are shown in green.

cause induction of apoptosis in the target. Normal hostcells are MHC class I positive, the binding of this moleculeto its receptor on the natural killer cell inhibits the deathpathway. Tumour cells and viruses (especially those of theherpesvirus family) often cause downregulation of class I.Although this may offer some advantage to the pathogenimpairing recognition by cytotoxic T cells, it does leavethem open to natural killer cell attack.

Discrimination of pathogens by the innatesystemAlthough not antigen-specific, the innate system is able todiscriminate foreign molecules from self. Phagocytes bearpattern-recognition receptors, with lectin-like activity.These recognise structures termed pathogen-associatedmolecular patterns present on microbes, but not hostcells.9 Examples are lipopolysaccharide, lipotechoic acid,and mannans on gram negative, gram positive, and yeastcell walls, respectively. The pattern-recognition receptormolecules fall into three groups depending on function;those inducing endocytosis and thus enhancing antigen-presentation; those initiating nuclear factor ��transduction and cell activation (toll-like receptors)10 andthose, for example mannan binding lectin, which aresecreted acting as opsonins. The increasing knowledge ofthese recognition pathways, highlights the close relationbetween the innate and specific reponse—a pattern-recognition receptor recognises broad patterns onmicrobes and then presents the processed product toantigen-specific T cells.

The interactions allowing the innate response toeradicate infectious agents, such as phagocytosis,opsonisation, and complement-mediated lysis, requireexposure to the surface of the microbe. The response is

therefore largely confined to eradicating extracellularorganisms, mostly bacteria. This system is not able todetect intracellular organisms, notably viruses,mycobacteria, some fungi, protozoa, or other facultativeintracellular pathogens. In addition, the response is fairlynon-specific and often poorly targeted, leading toindiscriminate tissue damage.

Cellular communicationIn order for cells to work effectively they need to berecruited to sites of inflammation and appropriatelyactivated. This is achieved by the interaction of cellularreceptors which signal internally to the nucleus, andexternal factors, such as cytokines, which are able to bindthe receptors, and with other adhesion molecules.

Adhesion moleculesAdhesion molecules are surface-bound molecules involvedin cell-to-cell interactions.11 Their main function is infacilitating processes where close contact of cells isrequired—eg, in directing cell migration, phagocytosis,and cellular cytotoxicity. Adhesion molecules associatewith cytoplasmic proteins and cytoskeletal components tocause cytoskeletal reorganisation, allowing cells toundergo directed movement. Signal transduction afterligation of the adhesion molecule, also leads to cellactivation, alteration in receptor expression, cytokineproduction, and effects on cell survival. Cells can expressadhesion molecules constitutively, or upregulate them onexposure to cytokines, chemokines, or other proinflam-matory molecules, such as complement activationproducts and microbial metabolites. Some adhesionmolecules are expressed mainly on leucocytes, others onendothelial cells enabling interaction between the two.

IMMUNOLOGY


Adhesion molecule Tissue distribution Ligand

Immunoglobulin superfamilyICAM-1 Endothelial cells, monocytes, T and B cells, dentritic cells, LFA-1

keratinocytes, chondrocytes, epithelial cellsICAM-2 Endothelial cells, monocytes, dendritic cells, subpopulations of lymphocytes LFA-1ICAM-3 Lymphocytes LFA-1, Mac-1VCAM-1 Endothelial cells, kidney epithelium, macrophages, dendritic cells, myoblasts, VLA-4

bone marrow fibroblastsPECAM-1 Platelets, T cells, endothelial cells, monocytes, granulocytes ?MAdCAM-1 Endothelial venules in mucosal lymph nodes �4�7 integrin and L-selectin

Selectin familyE-selectin/ELAM-1 Endothelial cells ?L-selectin Lymphocytes, neutrophils, monocytes CD34P-selectin Megakaryocytes, platelets and endothelial cells ?

Integrin familyVLA subfamily

VLA-1 to VLA-4 Endothelial cells, resting T cells, monocytes, platelets, and epithelial cells Various molecules including laminin,fibronectin, collagen, and VCAM1

VLA-5 (fibronectin receptor) Endothelial cells, monocytes, and platelets LamininVLA-6 (laminin receptor) Endothelial cells, monocytes, and platelets Laminin�1�7 Endothelial cells, ? Laminin�1�8 Endothelial cells, ? ?�1�v Platelets and megakaryocytes Fibronectin�2 Widely distributed Collagen, laminim, vitronectin

Leucam subfamilyLFA-1 Leucocytes ICAMs-1 to 3Mac-1 Endothelial cells, ? ICAM-1, fibrinogen, C3bi

Cytoadhesin subfamilyVitronectin receptor Platelets and megakaryocytes Vitronectin, fibrinogen, laminim, fibronectin,

von Willebrand factor, thrombospondinB4�6 Endothelial cells, thymocytes, and platelets LamininB5�v Platelets and megakaryocytes, ? Vitronectin, fibronectinB6�v Platelets and megakaryocytes, ? Fibronectin�7�4/LPAM-1 Endothelial cells, thymocytes, monocytes Fibronectin, Vcam-1�8�v Platelets and megakaryocytes, ? ?

ICAM=intercellular adhesion molecule, VCAM=vascular cell adhesion molecule, MAdCAM-1=mucosal addressin, E-selectin or ELAM=endothelial leukocyte adhesion molecule,LPAM=lymphocyte Peyer’s patch adhesion molecule, PECAM=platelet/endothelial cell adhesion molecule, VLA=very late antigen. Reprinted from Kumar & Clark. Clinical Medicine,4th edn, by permission of the publisher WB Saunders.

Table 1: Adhesion molecules

There are families of adhesion molecules based onstructure and function (table 1). The main ones are theintercellular adhesion molecules, integrins, selectins, andcadherins (calcium-dependent adherins). In addition to themolecules on leucocytes, and vascular endothelium, thereare also tissue-specific adhesion molecules called addresins.These are mainly involved in targeting lymphocytes toparticular groups of lymphoid tissues such as in the gut,lung, skin, peripheral lymph nodes and possibly to brain,lung, and synovium.

ChemokinesChemokines are particular members of the cytokine familythat have a key role in leucocyte migration (table 2). Theyhave substantial chemotactic function (inducing thedirectional movement of cells). Chemokines are named bythe position of two cysteine (C) residues compared with theother amino acids (X). The two main subgroups are CXC(�-chemokines) and CC (�-chemokines). Chemokines areproduced by most cells on stimulation withproinflammatory cytokines or bacterial products andchemokine receptors are found on all leucocytes. Theeffects of chemokines are more prolonged than otherchemoattractants such as complement activation products,as they bind to glycosamino-glycans on cell surfaces and theextracellular matrix. Chemokines that cause recruitment ofleucocytes are termed inflammatory. Additionally, there arelymphoid chemokines which regulate leucocyte positioningwithin the spleen and other lymphoid tissues.12

Neutrophil migration in response to infection orinflammationA good example of how adhesion molecules and cytokinesenable dynamic interactions between cells is given byneutrophil migration/recruitment. Chemokines and otherchemoattractants use two mechanisms to recruitneutrophils. First, they induce local upregulation ofadhesion molecule expression on vascular endothelium andneutrophils, making the cells stick to the vessel wall. Second,they activate neutrophil migration between the endotheialcells and into the tissue along the chemotactic gradient.

Release of tumour necrosis factor �, interleukin 1, andendotoxin from activated macrophages, mast cells, andorganisms at the site of infection, causes localupregulation of E-selectin on endothelial cells.Neutrophils also bear their own type of selectin (L-selectin) and bind to the activated endothelium. Selectinscause the formation of tight bonds between the cells,however, these dissociate rapidly, releasing the neutrophil

to move downstream to attach to another selectin-bearingendothelial cell. This causes the intermittent tetheringmotion known as rolling.8 This slows the cell and allowsthe less strong, but stable bond to be formed between theintegrin leucocyte function antigen on neutrophils andintercellular adhesion molecule type 1 on the vascularendothelial cell. At the same time there is the productionof powerful neutrophil chemoattractants (effective atnanomolar concentrations) such as N-formyl-methionyl-leucylphenylalanine from bacterial cell walls, which causesthe release of another chemotactic product, leucotrieneB4, from tissue mast cells; the chemokine interleukin 8 issecreted from stimulated macrophages andchemoattractant C5a from complement activation.Neutrophils move along the chemotactic gradientproduced, and leave the circulation by diapedesis throughspaces between endothelial cells. The same molecules alsoenhance intercellular adhesion molecule type 1 expressionleading to further cell recruitment. Low concentrations ofchemoattractants induce neutrophil migration. At highconcentrations receptors for chemoattractants aredownregulated and the cells remain at the inflammatorysite. Activated neutrophils therefore accumulate. In largenumbers this leads to pus formation, the characteristicgreen/yellow colour being due to the peroxidase enzymeswithin the cells. The importance of adhesion molecules inneutrophil migration is illustrated by individuals with acongenital deficiency of the common � chain of the �2integrins (LFA-1, Mac-1, and p150,95). The patientshave severe infections due to paucity of neutrophils in thetissues. Paradoxically, there is a neutrophil leucocytosis inthe blood due to the paralysed cells being unable to leavethis compartment.13

The only endothelial cells that constitutively expressadhesion molecules are the high endothelial venules oflymph nodes. These bind lymphocytes (but notneutrophils) and direct the trafficking of these cells fromthe blood into lymphoid tissue. Endothelial cells withinother blood vessels express adhesion molecules only whenactivated by the presence of local tissue damage ormicrobes. Even then the adhesion molecules are onlyexpressed on postcapillary venules, preventing the tissueanoxia that could result if large numbers of leucocytesaccumulate in arteriolar or capillary vessels.

CytokinesCytokines are small molecular weight messengers secretedby one cell to alter the behaviour of itself or another cell(table 3). Cytokines send intracellular signals by bindingto specific cell-surface receptors. Although most aresoluble, some may be membrane-bound, making thedifferentiation between cytokine and receptor difficult.Cytokines are produced by virtually all cells and have awide variety of functions. The biological effect depends onthe cytokine and the cell involved, but typically thesemolecules will affect cell activation, division, apoptosis, ormovement. They act as autocrine, paracrine, or endocrinemessengers. Cytokines produced by leucocytes and havingeffects mainly on other white cells are termed interleukins.Cytokines that have chemoattractant activity are calledchemokines. Those that cause differentiation andproliferation of stem cells are called colony-stimulatingfactors. Those that interfere with viral replication arecalled interferons.

InterferonsInterferons are a major class of cytokine that have aparticular role in immunity. They are divided into type 1(� and � interferons) and type 2 (� or immune interferon).

IMMUNOLOGY


Chemokine Class* Sites of production Biological activity

Macrophage -CC- Macrophages, Attracts monocytes chemoattractant fibroblasts, and memory T cells to protein-1 keratinocytes inflammatory sites

Macrophage -CC- Macrophages Attracts monocytesinflammatory and T cellsprotein-1�

MIP-1� macrophage -CC- Monocytes, Attracts monocytesimflammatory macrophages, and CD8+ T cellsprotein-1� endothelial cells,

T and B cells

RANTES -CC- Platelets and T cells Attracts monocytes, T cells, and eosinophils

Interleukin 8 -CXC- Macrophages Attracts neutrophils,naive T cells

*Refers to a double cysteine amino acid structure (-CC-) within the cytokine; in somecases this is interspersed with another amino aid (-CXC-). RANTES=regulated onactivation, normal T-cell expressed and secreted. Reprinted from Kumar & Clark.Clinical Medicine, 4th edn, by permission of the publisher WB Saunders.

Table 2: Chemokines and associated function

Type 1 interferons have potent antiviral activity and areproduced mainly by fibroblasts and monocytes as a reactionto infection. Both � and � interferon bind to the samecellular receptor and protect uninfected cells by inducingthe intracellular production of molecules that inhibit orinterfere with viral RNA and DNA production. Theyincrease the expression of MHC class I molecules leadingto enhanced recognition of virally infected cells by specificcytotoxic T lymphocytes. Type 1 interferons also haveantiproliferative function. � interferon is used in thetreatment of chronic hepatitis B and C infections incombination with antiviral drugs14,15 as well as in someforms of leukaemia.16 � interferon reduces the relapse ratein subgroups of patients with multiple sclerosis.17

Interferon � has different functions, acting directly on theimmune system to activate macrophage and neutrophilintracellular killing, stimulate natural killler cell function,and enhance antigen presentation by increasing MHC classII expression on antigen presenting cells. Interferon � is

only produced by cells of the immune system and uses aseparate receptor to that of the type 1 interferons. It is usedin the treatment of a specific congenital neutrophil defect(chronic granulomatous disease)18 and in patients withdefects in the production of interferon � or its receptor, andin the adjunct therapy of some macrophage-basedinfections (leishmaniasis, atypical mycobacterial disease).19

Specific immunityThe characteristic of adaptive immunity is the use ofantigen-specific receptors on T and B cells to drivetargeted effector responses in two stages. First, the antigenis presented to and recognised by the antigen specific T orB cell leading to cell priming, activation, anddifferentiation (figure 2), which usually occurs within thespecialised environment of lymphoid tissue. Second, theeffector response takes place, either due to the activatedT cells leaving the lymphoid tissue and homing to thedisease site, or due to the release of antibody from

IMMUNOLOGY


Cytokine Source Mode of action

Interleukin 1 Macrophages Immune activation; induces an inflammatory responseInterleukin 2 Mainly T cells Activates T (and natural killer) cells and supports their growth. Formerly called T cell

growth factorInterleukin 3 T cells Mainly promotes growth of haemopoietic cellsInterleukin 4 T helper cells Lymphocyte growth factor; involved in IgE responsesInterleukin 5 T helper cells Promotes growth of B cells and eosinophilsInterleukin 6 Fibroblasts Promotes B cell growth and antibody production, induces acute phase responseInterleukin 7 Stromal cells Lymphocyte growth factor; important in the development of immature cellsInterleukin 8 Mainly macrophages Chemoattractant Interleukin 10 CD4 cells, activated monocytes Inhibits the production of interferon �, interleukin 1, interleukin 6, tumour necrosis

factor �, and stops antigen presentationInterleukin 12 Monocyte/macrophages Augments T helper 1 responses and induces interferon �Interleukin 13 Activated T cells Stimulates B cellsGranulocyte colony stimulating factor Mainly monocytes Promotes growth of myeloid cellsMonocyte colony stimulating factor Mainly monocytes Promotes growth of macrophagesGranulocyte-macrophage colony stimulating factor Mainly T cells Promotes growth of monomyelocytic cellsInterferon � Leucocytes Immune activation and modulationInterferon � Fibroblasts Immune activation and modulationInterferon � T cells and natural killer cells Immune activation and modulation Tumour necrosis factor � Macrophages Stimulated generalised immune activation as well as tumour necrosis. Also known as

cachectinTumour necrosis factor � T cells Stimulates immune activation and generalised vascular effects. Also known as

lymphotoxinTransforming growth factor � Platelets Immunoinhibitory but stimulates connective tissue growth and collagen formation

Reprinted from Kumar & Clark. Clinical Medicine, 4th edn, by permission of the publisher WB Saunders.

Table 3: Cytokines

B cells

Development

Bone marrow

PERIPHERYB cell encountersantigen

T-cell dependent response

T-cell independent response

Processes and expresses antigenin MHC class IImolecules

(1)

(2)TI antigen

Plasma cell

Plasma cell

Secretesantibody

B cell

Th 2helper cell

Pre-B cell

generearrangement

Naive matureB cellantigen specific

Secretesantibody

T cells

Development PERIPHERYArmed effector cellsT-cell priming

Antigen presented with MHC

T-cell proliferationand differentiation

CD4 Th 1 inflammatory cells activate macrophages

CD4 Th 2 cellshelp antibody responses

CD8 cytotoxic cell

(1)

(2)

(3)

Bonemarrow Thymocytes

undergo positiveand negativeselection

Naive CD4 or CD8 T-cellantigen specific

Figure 2: The role of T and B lymphocytes in specific immunity

activated B cells (plasma cells) into blood and tissuefluids, and thence to the infective focus.

Formation of antigen-specific receptors on T and B cellsB and T lymphocytes develop from progenitor cells withinthe bone marrow. B cells remain within the marrow forthe duration of their development, but T cells migrate tothe thymus at an early stage as thymocytes. Theproduction of antigen-specific receptors in both cell typesis the result of an unusual process of randomrearrangement and splicing together of multiple DNAsegments that code for the antigen-binding areas of thereceptors (complementarity-determining regions). Generearrangement occurs early in the development of thecells, before exposure to antigen, which leads to theproduction of a repertoire of over 108 T-cell receptors and1010 antibody specificities,19 adequate to cover the range ofpathogens likely to be encountered in life.

The process for B-cell receptor rearrangement will bedescribed, but the mechanism is similar for the T-cellreceptor. There are four segments of gene involved inreceptor formation called the variable (V), diversity (D),joining (J), and constant (C) regions. These are foundon different chromosomes within the developing cell.The segments are cut out by nucleases and splicedtogether using ligases (a product of the recombinationactivation genes, RAG-1 and RAG-2). This forms thefinal gene sequence from which protein will betranscribed to form the receptor molecule. There areseveral ways in which clonal diversity occurs. First, thereis a multiplicity of all these regions within the DNA(V=25–100 genes, D~25 genes, and J~50 genes), butonly one of each is needed. There is combinationalfreedom in that any one of the genes can join with anyone other to form the final VDJ region. Second, thesplicing is inaccurate and frameshift in basepairs leads tothe production of a different aminoacid (junctionaldiversity). Third, the enzyme deoxyribonucleo-tidyltransferase can insert nucleotides to further alter thesequence. A greater repertoire of B-cell receptors isproduced as further immunoglobulin gene rearrange-ment occurs during B-cell division after antigenstimulation (somatic hypermutation).

In T lymphocytes the receptor has two forms. The mostcommon consists of a heterodimer of an � and � chain,each with a constant and variable domain. The other form(<10% T cells) has � and � chains (the function of thistype of T-cell receptor bearing cell remains uncertain).The T-cell receptor forms a complex with the CD3molecule, with its associated signalling molecules(figure 5). In B cells the gene product is a membrane-bound form of IgM, initially expressed alone and later withIgD. Early in B-cell development this molecule acts as theantigen receptor, being able to induce signal transductionin a similar way to the T-cell receptor. The membranebound molecule can also internalise antigen, inducingprocessing, and re-expression for antigen presentation to Tcells. After B-cell activation the secreted form of antibodyis produced by plasma cells. Despite the similarities ingene rearrangement processes, the T and B cell receptorsrecognise antigen differently. The T-cell receptor bindslinear peptides usually of eight to nine aminoacids. Thisgenerally means antigen that has been broken down byintracellular processing. Antibody recognises theconformational structure (shape) of epitopes, and suchantigens do not require processing.

The creation of new clones of T and B cells continuesthrough life, although slows after the mid 20s, meaningthat such individuals are slower to reconstitute their

immune system after bone marrow transplant or onintroduction of effective antiretroviral therapy in HIV-related immunodeficiency.20

Organisation of the immune systemThe cells that emerge from the thymus and bone marrowhaving undergone gene rearrangement are naive—ie, theyhave not yet encountered their specific antigen within animmune response. These cells populate the secondarylymphoid tissues of the lymph nodes, spleen, tonsils, andmucosa associated lymphoid tissue. Because there areonly a few naive T and B cells capable of reactingspecifically with a foreign particle, in order for them toencounter their specific antigen, there has to be a systemto bring them together. The lymphoid tissues provide themicroenvironment for this process. In addition to T andB lymphocytes, they contain efficient antigen-presentingcells and are able to produce the cytokines necessary tomaintain T and B lymphocytes. Lymphoid tissues expressadhesion molecules in an ordered array, allowing cells tomove through the tissue and increase the chance oflymphocytes being brought into contact with antigen. Thelymphoid organs communicate with the tissues usinglymphatics and blood vessels.

T lymphocytesDevelopment in thymusOnce receptor rearrangement has occurred, T and B cellsare able to respond to their antigen and induce animmune response. However, cell activation is tightlyregulated to ensure that only damaging antigens elicit areaction. Regulation particularly involves the initiation ofT lymphocyte activation. This requires that antigen ispresented to the T cell within the peptide binding grooveof a self MHC molecule. This is because the T-cellreceptor does not just recognise the antigenic epitope, butrecognises the complex of the peptide in association withthe self-MHC molecule. The delicate process of positiveselection of T cells that can react with self-MHC andpeptide adequately to induce immune responses, but are not excessively MHC-reactive to the extent whichwould cause self-tissue destruction, occurs in the thymus(figure 3).

The meeting of naive T cell and antigenNaive T cells bear receptors (peripheral node addressins)that bind to adhesion molecules on the high endothelialvenules of lymph nodes, enter the nodes, and pass throughbinding transiently to the multiple antigen-presenting cells.Although about 95% of T lymphocytes are sequesteredwithin the lymphoid tissue, they are not static but movecontinuously from one lymphoid tissue to another, via theblood or lymph, travelling around the whole body in 1–2days. The traffic of lymphocytes is considerable, the outputof cells in the efferent lymph being 3·0�107 cells/g oflymphoid tissue.21 Therefore, within a short while a T cellshould meet its antigen. When the T cell meets anantigen-presenting cell bearing its antigen, activationoccurs over the next 2–3 days.

The antigen is brought to the lymphoid tissue directly inthe lymphatics, or within dendritic (or other antigen-presenting cells) cells that have endocytosed the antigenlocally. Dendritic cells actively take up debris in theirhousekeeping role. However, if there is inflammationwithin a tissue, the dendritic cells are activated to leave thesite, migrating to the downstream lymph node. Antigens inthe blood are taken to the spleen, in the tissues to thelymph nodes, and from the mucosae to the mucosaassociated lymphoid tissue. Dendritic cells express

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receptors for lymphoid chemokines and migrate into thelymphoid tissue which expresses these constitutively.Dendritic cells are particularly important in activatingprimary naive T cells. The antigens may be furtherprocessed by antigen-presenting cells (macrophages,interdigitating dendritic cells, and B cells) ready to attractantigen-specific T cells and induce an immune response.

Antigen presentation and the MHC moleculesThere are two ways in which antigen loading onto MHCcan occur. The antigen may have been producedendogenously within the cell (such as viral or tumourproteins) and is complexed with MHC class 1 throughintracellular processing pathways (figure 4a). Alternatively,specialised professional antigen-presenting cells might have

taken up exogenous antigen by endocytosis. Antigen-presenting cells include dendritic cells (the interdigitatingdendritic cells of lymph nodes, veiled cells in the blood, andLangerhan’s cells in the skin), B cells, and macrophages.Exogenous antigen is processed via a different pathway toendogenous, and re-expressed with MHC class IImolecules (figure 4b). MHC class II has restrictedexpression, in normal circumstances being expressed onlyon these specialised cells.

Antigen recognition by T cellsThis recognition of antigen by the T-cell receptor isdifferent for CD4+ and CD8+ cells. CD4 lymphocytesonly recognise antigen presented with MHC class II andCD8 cells with MHC class I. Since CD4+ and CD8+

IMMUNOLOGY


SUBCAPSULARREGION

CORTEX

CORTICO-MEDULLARYJUNCTION

MEDULLA

SELF-TOLERANT SINGLE POSITIVE T-CELLS

PERIPHERY

NEGATIVE SELECTION

POSITIVE SELECTION POSITIVESELECTIONMediated bycorticalepithelial cells

NEGATIVESELECTIONLargelymediated bydendritic cells andmacrophages ofbone marroworigin

Cortical epithelialcell of thymicstroma 'nurse cell'

CD4CD8T cell receptor

Doublenegativethymocytes(CD4-CD8-)

Doublepositivethymocytes(CD4+CD8+)

Corticalepithelial cell

MHCclass Imolecule

MHCclass IImolecule

Self peptide/antigen

CD4lost

CD8retained

CD4retained

CD8lost

Macrophage

Apoptosis ofself-reactivecells

Dendritic cell

CD8 T cellReacts to specificantigen presentedby MHC class I

CD4 T cellReacts to specificantigen presentedby MHC class II

Subcapsular epithelium Capsule Trabecula

Figure 3: T cell development in the thymusThymocytes enter the thymus in the subcapsular region. Cells bearing a T-cell receptor that recognises self MHC are positively selected in thecortex and pass into the corticomedullary junction. Here, T cells that react with self-antigens are deleted by apoptosis in a process known asnegative selection. The cells that exit are self-tolerant but able to recognise foreign antigen when presented with self MHC.

cells have very different functions, the MHC moleculethat is used to present an antigen will determine the typeof effector response generated. Endogenous antigenscomplexed with MHC class I molecules activate CD8+cytotoxic T cells. Because all nucleated cells expressMHC class I, this means that any such cell that is infectedwith a virus or other intracellular pathogen, or isproducing abnormal tumour antigens can present theseantigens with class I and be removed by cytotoxic attack.Whereas these CD8 responses are highly targeted to thecell that they recognise, CD4 activation leads toproduction of cytokines which in turn activate a widerange of cells around them. The reaction therefore needsto be kept in check, which is achieved by only a smallnumber of class II antigen-presenting cells being able todrive the response.

The need for intracellular processing and expression withMHC ensures that only antigens derived from foreignmolecules that have either invaded the interior of a hostcell, or have induced an inflammatory response to activateendocytosis by antigen-presenting cells, are recognised asforeign. Innocuous antigens are largely ignored. Anothersafety net to avoid inappropriate antigen-presentation oreffector cell attack is in place because binding of the T-cellreceptor to the antigen-MHC complex alone, is notadequate to induce activation of the cell: coreceptorstimulation is also required.

T-cell receptor signallingT-cell receptors on the surface of cells are associated withthe CD3 complex of molecules that transmit signals intothe cell when antigen is bound to the T-cell receptor.Aggregation of the receptor causes phosphorylation oftyrosines within the cytoplasmic tail of the CD3 complexand the transduction of signals downstream to the nucleusleading to activation of gene sequences leading to T-cellproliferation (figure 5). Recruitment of the receptor andassociated molecules into lipid rafts enhances theinteraction.22 Coreceptors are molecules on the surface ofthe T cell that send signals to the cell to cause activation ifthe T-cell receptor is also engaged. Without thesecosignals the cell will either become anergic (unreactive)or die by programmed cell death. The main coreceptorsfor T-cell activation (apoptosis) are CD80 (B7-1), CD86(B7-2), and CD40, that bind CD28, CTLA-4, and CD40ligand on the T cell, respectively. Activated dendritic cellsare the most potent stimulators of naive T cells, bearinglarge amounts of B7 and CD40. Inflammatory mediatorsinduce the upregulation of costimulatory molecules,therefore a T cell is much more likely to be activated if itmeets its specific antigen via an antigen-presenting cell,which has been exposed to an inflammatory environment.

Division and clonal expansion of each T cell produces upto 1000 progeny. Most are armed effector cells, whichupregulate receptors enabling them to leave the lymphoidtissue and be guided to the site of inflammation. Organ-specific adhesion molecules attract both the effector andlong-lived effector memory cells to the disease site.23 There

IMMUNOLOGY


MHC CLASS I MOLECULES

Antigen peptide fragments are transported into the endoplasmic reticulum and picked up by MHC class I molecules

Viral or tumour peptides produced within the cell are released into the cell cytoplasm

TAP transporter binds to MHC class I

Proteasome digestscytoplasmic proteins

Calnexin holds MHC class I molecule in a semi-folded state in the endoplasmic reticulum where it is assembled

When �2-microglobulin binds to the MHC class I � chain the complex disassociates from calnexin and binds to a TAP transporter protein to await a suitable peptide

After binding the peptide the MHC molecule fully folds, detaches from the TAP transporter and leaves the endoplasmic reticulum

Antigens derived from viruses and tumour cells

Antigen peptides are presented on cell surface by MHC class I molecules

Antigen recognition by CD8 T cells which take appropriateaction (usually kill host cell)

CELL SURFACE

CELL CYTOSOL

ENDOPLASMIC RETICULUM

Viral, tumour or bacterial protein

TAP-2TAP-1

MHC class I moleculeand bound peptide

Delivery to surfacevia golgi complex

Figure 4A: The pathway of endogenous antigen delivery to class IMHC molecules

the T cells will recognise target cells expressing the specificforeign antigen with MHC and initiate either a cytotoxicattack, or stimulate an inflammatory response. Some of theactivated T cells remain in the lymph nodes as centralmemory cells. Naive and memory T cells are partlydifferentiated by the presence of CD45RA (naive) andCD45RO (memory) surface molecules. Memory cells maylive for 10 years or more. They react more quickly onsubsequent exposure because the log phase for their celldivision is short (12 h compared with 24 h) and they have alonger lifespan due to decreased apoptosis.

Effector T cellsTwo major types of effector T cells have been identified,T helper (Th) and T cytotoxic (Tc), bearing either CD4or CD8 molecules on their surface, respectively. CD4+Th cells are the orchestrating cells of the immuneresponse, recognising foreign antigen, and activating otherparts of the cell-mediated immune response to eradicatethe pathogen. They also play a major part in activation ofB cells. CD8+ cytotoxic cells are involved in antiviral and

possibly antitumour activity. Both types have a major rolein the control of intracellular pathogens.

T helper CD4+ cellsTh cells are subdivided functionally by the pattern ofcytokines they produce.24 On stimulation, precursor Th 0lymphocytes become either Th 1 or Th 2 cells. Thedifference between these cells is only in the cytokinessecreted; they are morphologically indistinguishable.However, the response they generate is very different. Th 1cells produce interleukin 2, which induces T cellproliferation (including that of CD4+ cells in an autocrineresponse). Interleukin 2 stimulates CD8+ T cell divisionand cytotoxicity, by decreasing activation thresholds. Theother major cytokine produced by Th 1 cells, interferon �activates macrophages to kill intracellular pathogens suchas mycobacteria, fungi, and protozoa and induces naturalkiller cells to cytotoxicity. Its importance has been shown inpatients lacking the interferon � receptor who suffer severemycobacterial infections.25 The Th 1 cytokines thereforeinduce mainly a cell-mediated inflammatory response—eg,the granulomatous lesions of tuberculosis. There is apositive feedback loop as interferon � stimulates other Th 0cells to become Th 1 and inhibits Th 2 differentiation.

IMMUNOLOGY


Figure 4B: The pathway of exogenous antigen delivery to class IIMHC molecules

MHC CLASS II MOLECULES

Vesicles fuse in cell cytoplasm so that MHC class II molecules can bind antigen peptides

Antigen peptides are presented on cell surface by MHC class II molecules

Calnexin holds MHC class II molecule and invariant chain components while they are being assembled together

Newly synthesised, partly folded MHC class II molecule

Peptide fragments from antigen enter specialised endosomal compartment holding MHC class II molecule

Invariant chain is cleaved by proteases leaving a small fragment, CLIP, bound to the class II molecule

The invariant chain transports the MHC class II molecule from the endoplasmic reticulum to a specialised endosomal compartment via the golgi complex where the molecule can interact with antigen peptide fragments

Completed MHC class II:Ii complex releases from calnexin (there are actually three MHC class II molecules in each complex)

Antigen is taken up into the cell and enclosed in a vesicle, an endosome, by endocytosis

Antigen recognition by CD4 T cells which take appropriate action

Internalised protein antigens are degraded in acidic endosomes

MHC class II molecules in endoplasmic reticulum are exported in vesicles

Antigens are derived from pathogens, extracellular pathogens and proteins internalised by phagocytosis, and proteins bound to surface immunoglobulin on B cells, internalised by endocytosisCELL SURFACE

CELL CYTOSOL

EndosomeEndosomes becomeincreasingly acidic

Protein antigen

ENDOPLASMICRETICULUM

CLIP

Invariant chainprevents MHC moleculebinding peptides

MHC class II molecule andbound peptide on cell surface

CLIP fragmentis replacedby antigenpeptide

Interleukin 12 secreted by the interferon-�-stimulatedmacrophages, further increases interferon � production byT cells. A Th 1 response is essential to the host to controlthe replication of intracellular pathogens, but possiblycontributes to the pathogenesis of autoimmune diseasesuch as rheumatoid arthritis and multiple sclerosis.Conversely, Th 2 cells produce interleukin 4, interleukin 5,interleukin 6, and interleukin 10, that favour antibodyproduction. Interleukin 4 induces class-switching in B cellsto IgE production and interleukin 5 promotes the growthof eosinophils. Interleukin 4 provides positive feedback toinduce further Th 2 responses and suppress Th 1differentiation. Thus the Th 2 response is associated withallergic disease.

T cytotoxic (CD8+) cellsThese are directly cytotoxic to cells bearing their specificantigen. After binding to the target cell, Tc insertperforins into the cell membrane, in the same way asnatural killer cells. Cytoplasmic granules containinggranzymes pass through the pores from the T cell into thetarget cytoplasm. These activate caspase enzymes thatinduce DNA fragmentation and cell apoptosis. Tc alsobind target cell surface Fas (death inducing) molecules bytheir Fas ligand (FasL), which also activates apoptosis. Inthe same way as Th differentiate to Th 1 and Th 2, Tc 0cells have been shown to differentiate to Tc 1 and Tc 2based on cytokine secretion is documented. Thesesubtypes have a limited cytokine repertoire and their roleis not yet clear. It is also postulated that some CD8+ Tcells have a suppressor function in downregulatinglymphocyte responses.

The activation of macrophages via CD4+ cell cytokinesto kill facultative intracellular pathogens, and the role ofCD8+ T cells in killing of virally infected cells, providethe control of intracellular infections that cannot beachieved by the innate system.

B lymphoctyesB cells produce antibody. This serves to neutralise toxins,prevents organisms adhering to mucosal surfaces, activatescomplement, opsonises bacteria for phagocytosis, andsensitises tumour and infected cells for antibody-dependent cytotoxic attack by killer cells. Thus antibodyacts to enhance elements of the innate system. Althoughultimately antibody is the secreted product of activatedB cells with the functions listed, early in B-celldevelopment it is a membrane bound molecule that acts asthe B-cell receptor. In this role it internalises antigen andprocesses it to act as an antigen-presenting cell for T-cellresponses (figure 6).

Different classes of antibody predominate at differentcompartments of the body (IgM being intravascular, IgGthe main antibody of the blood and tissues, IgA insecretions). Mucosa associated lymphoid tissue consists oflymphoid tissue at several mucosal sites (bronchus, gut,urogenital tract). However, these are all linkedfunctionally as subpopulations of B cells home to thesetissues specifically. A response generated at one site will induce immune responses to the same antigen at other sites. This effect can be used therapeuticallybecause vaccination at one mucosal site can potentiallyinduce generalised mucosal immunity.26 For example, an oral vaccine could induce vaginal and rectal immunity

IMMUNOLOGY


Co-stimulatory molecules

Antigen-presenting cell

CD4+ lymphocyte

NUCLEUS

CD4

� � � �

� �

GrbSns

Raf

P13kinase

ICAM-1CD54

CD2

LFA-3

MHC-2

Ag

p59fyn

p56lck

ZAP 70

PIP2 PKCDAG

B7-1

CD28

PLC�1

Ras

Mek

MAPK

CD3

TCR

LFA-1CD11a/18

Figure 5: Activation of T cellsLck=lymphocyte cytoplasmic kinase, ZAP=zeta-associated protein, DAG=diacyl glycerol, Ras=rous adenosarcoma, Sos=son of sevenless, Raf=ras associatedfactor, Mek=mitogenic extracellular kinase, MAPK=mitogenic assoicated proliferation kinase, PKC=protein kinase C, PLC=phospholipase C, EPK=extracellularreceptor associated kinase. Crosslinking of the T-cell receptor causes aggregation with the CD3 complex containing �, �, g chains together with the threedimers and activation of phosphorylation and differentiation. If the costimulatory molecules are not activated at the same time a different sequence of signalsis activated leading to cell death and apoptosis.

which could be particularly relevant in infections such as HIV.

B cell activation Most B cells remain in the lymphoid tissue, therecirculating pool being small. B cells usually recognise freeantigen brought to lymphoid tissues by the routesdescribed previously. However, during subsequentinfections by the same pathogen B cells can be activated byfollicular dendritic cells which bear Fc and complementreceptors, bind immune complexes containing antigen, andtrap this to activate the B-cell response (follicular dendriticcells are a different family to dendritic cells and do notendocytose and present antigen).

T-cell dependent responsesAntigen recognised by the surface IgM of the B cell, isinternalised, processed, and re-expressed on the MHCclass II molecule of the B cell. This can then present theantigen to a primed specific T cell (which recognises adifferent part of the same antigen). The T cell in turn

produces cytokines (B-cell growth factors) leading to B-cell division and maturation to antibody secreting cells.Further T-cell interactions, in particular the binding ofCD40 on B cells with the CD40 ligand on T cells inducesisotype switching from the initial IgM response. However,as the VDJ gene is not further altered the same antigen-binding site is used throughout. Thus, a mature but naiveB cell, that has rearranged its VDJ gene, will initially makean IgM response on primary antigen stimulation becausethis is the first constant chain to be translocated. IgG andother isotype responses develop later and requireadditional T cell help. The process of B-cell activationoccurs mainly within the germinal centres of lymph nodes.At this site somatic hypermutation occurs, leading to agreater diversity of antibody. Those cells whose surfaceantibody binds the antigen most avidly proliferate mostefficiently and therefore the antibody response matureswith increased affinity. Once the switch from IgM toanother isotype has occurred, some of the activated cellsbecome long-lived memory cells. These react rapidly torechallenge and the characteristic IgG production of the

IMMUNOLOGY


Figure 6: The pathway of B lymphocyte development from stem cell to plasma cellReproduced with permission by Keith Nye.

secondary response occurs. The activated B cells leave thelymphoid tissue as plasma cells. The spleen has aparticular role in antibacterial polysaccharide (capsule)responses, especially in the production of the IgG2 subclassof antibody, which is important in protection frompneumococcus, haemophilus, and meningococcus.Marginal zone B cells in the spleen are important in thisprocess. The low number of these cells in infancy or theirremoval as a result of splenectomy, correlates with poorantibody responses to this type of organism.

T-cell independent responsesB cells can also respond to some antigens in a T-cellindependent reaction.27 The antigens that can induce thishave numerous repeating epitopes (mainly polysaccharides)that bind multiple B-cell receptors and activate the B celldirectly to secrete IgM antibody. However, as there is nogerminal centre formation, no affinity maturation takesplace, and there is no class switching or generation ofmemory. Therefore T-cell independent responses are IgMlimited, of poor specificity, and shortlived.

Regulation of autoimmune responsesThis process of random antigen receptor productioninevitably leads to development of autoreactive receptorsthat bind self antigens.28 However, there are systems inplace to induce tolerance (a state in which the immunesystem fails to respond to an antigen) and reduce the risk ofautoimmune disease. First, the binding of specific antigento the T or B cell receptor in immature lymphocytes(within the thymus or the bone marrow), leads toprogrammed cell death (apoptosis) and clonal deletion.29

This is due to the lack of costimulatory molecule activation,either because these are not expressed or because of lowproduction of cytokines. Over 90% thymocytes die byapoptosis (either due to failing to be positively selected, ordue to self-reactivity, and negative selection) highlightingthe degree of regulation that occurs during thymicprocessing.30 However, there will be some autoantigens thatare not expressed in the primary lymphoid tissues, but willbe met in the periphery. Exposure in this circumstanceinduces the autoreactive cell to anergy (unresponsiveness).This is again the result of the lack of costimulatorymolecules being activated as there is no tissue damage. Tcell tolerance would be expected to reduce the chances of aB cell reacting to autoantigens, in addition to the clonaldeletion of self-reactive B cells in the marrow. However,there are additional mechanisms postulated to preventautoimmunity in B cells. Those cells that inadvertentlyproduce self-reactive antibody might be able to undergoreceptor editing to change antibody specificity. Anti-idiotypic antibodies that bind to the idiotype marker(antigen-binding site) on B cells, may also suppressautoantibody production. Immature B1 cells, whichexpress the CD5 molecule, produce low affinity naturalantibodies which often recognise autoantigens. These cellscould play a part in autoimmune disease. More matureB cells lack this molecule (B2 cells).

Interactions within and outside of the immunesystemThe immune system is a major target for development oftreatment strategies, in particular to improve themanagement of infections, tumours, and autoimmunedisease resistant to conventional therapies. Approachesinclude immuomodulation with cytokines or theirantagonists,31 therapeutic vaccination with designeradjuvants to drive specified types of immune response,32

and regulation of cell function and survival by

manipulation of coreceptor signalling molecules.33 Theimmune system is easily accessible through stem cells inthe bone marrow. The possibilities of manipulationthrough gene therapy has been raised with the successfulintegration of the adenosine deaminase gene into the cellsof children with severe combined immunodeficiency.34

However, immune reactions are complex, changes in onecomponent could affect several others; this is illustrated inthe cytokine network theory, where alteration of theconcentration of one cytokine will lead to a cascade ofeffects on others. High concentrations of cytokines willcommonly cause shedding of the receptors for thecytokines from cell surfaces reducing further responses.Such soluble receptors could absorb cytokine from tissuefluids, either reducing its function, increasing its clearance,or possibly extending its half-life by preventing breakdown.An understanding of these interactions are crucial to theuse of cytokines or their inhibitors in clinical practice.35 It isbecoming clear that the immune system does not work inisolation, but has close communications with other tissues.The interaction of immune cells and lymphokines with theneurological and endocrine systems is now documented.36

Lymphoid cells bear steroid and insulin-like growth factorreceptors on their surface and can respond to changes inconcentrations of hormones. Conversely, lymphokinessuch as interleukin 1 can affect the central hypothalamic-pituitary axis. A better knowledge of these interactions mayhave far-reaching effects on our understanding of theeffects of social, psychological, and environmental factorson the development and evolution of illness.

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