1.

Overview of the human immune response

David D. Chaplin, MD, PhD Birmingham, Ala
This activity is available for CME credit. See page 5A for important information. The human immune system mobilizes a broad repertoire of innate and adaptive responses to protect against the universe of pathogens it encounters. Central to these protective responses are its mechanisms to distinguish self from nonself. This overview describes the major mechanisms used by the immune system to respond to invading microbes and identies settings in which disturbed immune function exacerbates tissue injury. (J Allergy Clin Immunol 2006;117:S430-5.) Key words: Adaptive immunity, atopy, dendritic cell, inammation, innate immunity, Toll-like receptors

Abbreviations used APC: Antigen-presenting cell ITAM: Immunoreceptor tyrosine-based activation motif NF-kB: Nuclear factor kB NK: Natural killer TCR: T-cell receptor TLR: Toll-like receptor

The primary function of the immune system is to protect the host from infectious microbes in its environment. Environmental pathogens threaten the host with a large spectrum of pathologic mechanisms. The immune response therefore uses a complex array of protective mechanisms to control and usually eliminate these organisms. All of these mechanisms rely on detecting structural features of the pathogens that mark them as distinct from host cells. Such host-pathogen discrimination is essential to permit the host to eliminate the pathogen without excessive damage to its own tissues. Host mechanisms for recognition of microbial structures are of 2 general classes: (1) hard-wired responses that are encoded by genes in the hosts germline and that recognize molecular patterns that are shared by many microbes but are not present in the mammalian host (constituting innate immune responses) and (2) responses that are encoded by gene elements that somatically rearrange to assemble antigen-binding molecules with exquisite specicity for individual unique microbial and environmental structures (constituting the adaptive immune response). Because the recognition molecules used by the innate system are expressed broadly on a large number of cells, this system is poised to act rapidly after an invading pathogen is encountered. Thus it provides the initial host response. Because the adaptive immune system initially produces only small numbers of cells with specicity for any individual pathogen, cells that encounter and recognize a pathogen must proliferate to attain sufcient numbers to mount an effective response. Thus the adaptive response generally expresses itself temporally after the innate response in host defense. A key

feature of the adaptive response is that it produces longlived cells that persist in an apparently dormant state but that can re-express effector functions rapidly when they encounter their cognate antigen for a second time. This allows the adaptive response to express immune memory, resulting in a more effective host response against specic pathogens when they are encountered a second time, even decades after the initial sensitizing encounter.

DISCRIMINATION OF SELF FROM NONSELF

Because the immune system uses many different effector mechanisms to destroy the broad range of microbial cells and particles that it encounters, it is critical for the immune response to avoid unleashing these destructive mechanisms against its own tissues. This avoidance of destruction of self-tissues is referred to as self-tolerance. Mechanisms to avoid reaction against self-antigens are expressed in many parts of both the innate and the adaptive immune response. Failure of self-tolerance underlies the broad class of autoimmune diseases.

GENERAL FEATURES OF INNATE AND ADAPTIVE IMMUNITY

The innate immune system includes all defense mechanisms that are encoded in the germline genes of the host. These include the epithelial barriers and the mucociliary blanket that sweeps away inhaled or ingested particles. They also include soluble proteins and bioactive small molecules that are either constitutively present in biologic uids (eg, the complement proteins1 and defensins2) or that are released from cells as they are activated (including cytokines that regulate the function of other cells, chemokines that attract inammatory leukocytes, lipid mediators of inammation, and bioactive amines and enzymes). Lastly, the innate immune system includes cell-surface receptors that bind molecular patterns expressed on the surfaces of invading microbes.3 Unlike the innate immune system, the adaptive immune system manifests exquisite specicity for its target

From the University of Alabama at Birmingham. Disclosure of potential conict of interest: D. Chaplin has consultant agreements with Pzer. Reprint requests: David D. Chaplin, MD, PhD, University of Alabama at Birmingham, 845 19th St South, BBRB 276/11, Birmingham, AL 35294-2170. E-mail: dchaplin@uab.edu. 0091-6749/$32.00 2006 American Academy of Allergy, Asthma and Immunology doi:10.1016/j.jaci.2005.09.034

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antigens by virtue of the antigen-specic receptors expressed on the surfaces of T and B lymphocytes. The antigen-specic receptors of the adaptive response are assembled by means of somatic rearrangement of germline gene elements to form intact T-cell receptor (TCR) and immunoglobulin genes.4 The assembly of antigen receptors from a collection of a few hundred germlineencoded gene elements permits the formation of millions of different antigen receptors, each with potentially unique specicity for a different antigen.5 The innate and adaptive immune systems are often described as contrasting separate arms of the host response; however, they usually act together, with the innate response representing the rst line of host defense and the adaptive response becoming prominent after several days as antigen-specic T and B cells have undergone clonal expansion. Furthermore, the antigen-specic cells amplify their responses by recruiting innate effector mechanisms to bring about the complete control of invading microbes. Thus although the innate and adaptive immune responses are fundamentally different in their mechanisms of action, synergy between them is essential for an intact and fully effective immune response.

ANTIGEN RECOGNITION BY T LYMPHOCYTES MHC molecule-antigen complexes A major function of T lymphocytes is to identify and destroy cells that have been infected by pathogens that multiply intracellularly. For intracellular pathogens, the host cell provides a favorable microenvironment for the organism to replicate protected from many of the host defense mechanisms that target extracellular microbes. In fact, if the immune system had only one recognition system that was equally able to recognize extracellular microbes and infected cells, a microbe that generated large numbers of extracellular organisms might overwhelm the recognition capacity of the immune system, allowing the infected cells to avoid immune recognition. The very mechanism by which the T cell recognizes its target antigen focuses the T-cell response on infected cells or on cells that have taken up microbial antigens by means of phagocytosis or pinocytosis and not on the free antigen in solution. T cells recognize a molecular complex of a microbial antigen plus a self-structure. The self-structures are the antigenic peptide-binding MHC molecules (also designated HLA antigens), 2 classes of cell-surface glycoproteins that bind fragments of proteins that either have been synthesized within the cell (class I MHC molecules) or that have been ingested by the cell and proteolytically processed (class II MHC molecules). Class I MHC molecules There are 3 major HLA class I molecules designated HLA-A, HLA-B, and HLA-C. The class I molecules are cell-surface heterodimers consisting of a polymorphic transmembrane 44-kd a-chain associated noncovalently with the 12-kd nonpolymorphic b2-microglobulin protein.4

The a-chains, encoded by genes located within the MHC on chromosome 6, determine whether the class I protein is an HLA-A, HLA-B, or HLA-C molecule. The b2-microglobulin gene is encoded on chromosome 15. The structures of the class I molecules and their mechanisms of acquiring, binding, and presenting endogenously synthesized peptide antigens to T cells have been recently reviewed in detail.4 Briey, the membrane distal portions of the a-chain fold into 2 a-helices that are supported on a sheet of b-strands. This forms a physical groove that binds 9- to 11-amino-acid-long peptides derived from protein antigens by means of proteolytic degradation. The display of antigenic peptides on the surface of cells bound within the groove of the HLA molecules is described as antigen presentation. Generally, the peptides bound in the grooves of the HLA class I molecules are derived from proteins synthesized within the cell that bears the class I molecules. They are, consequently, described as endogenous antigens. Critical for their biologic function, HLA molecules manifest high structural polymorphism. As of July 2005, the World Health Organization Nomenclature Committee recognized 396 alleles at the HLA-A locus, 699 alleles at the HLA-B locus, and 198 alleles at the HLA-C locus, with the main structural variability in amino acids located in the oor and sides of the peptide-binding groove. Given that most individuals in the human population are heterozygous for HLA and that each class I protein can bind many different antigenic peptides, each individual can bind a very diverse collection of peptides. On a population level, the diversity of peptide-binding motifs is huge. Mutations in microbial antigens might permit the microbe to avoid binding (and, consequently, recognition) by a few HLA class I alleles, but no mutations will permit the microbe to avoid recognition broadly throughout the population.

Class II MHC molecules The class II HLA molecules, like the class I molecules, consist of 2 polypeptide chains, but both are MHCencoded transmembrane proteins, designated a and b. There are 3 major class II proteins designated HLA-DR, HLA-DQ, and HLA-DP. Like the class I HLA proteins, the membrane distal portions of the class II dimers fold together to form 2 a-helices that are supported over a b-sheet structure, forming a peptide-binding groove for presentation of fragments of protein antigens as a complex with the HLA protein. Unlike peptides presented by class I molecules, the peptides that are presented by class II HLA molecules are generally derived from exogenous proteins that were taken up by the antigen-presenting cell (APC) by means of phagocytosis and degraded into peptides within a lysosomal or endosomal compartment before transport to the specialized class II loading compartment. Thus although class I proteins present peptide fragments of proteins that are synthesized within the APC (primarily components of intracellular pathogens), class II proteins present fragments of proteins taken up by means of phagocytosis or endocytosis from the extracellular compartment.

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Like the class I proteins, structural polymorphism of the class II proteins is central to their function. Altogether, there are almost 500 alleles of the HLA-DR molecules. The HLA-DQ subregion encodes 1 polymorphic a chain (28 alleles) and 1 polymorphic b chain (66 alleles). The HLA-DP subregion encodes 1 polymorphic a chain (23 alleles) and 1 polymorphic b chain (119 alleles). As for the class I molecules, the total repertoire of peptide-binding class II HLA molecules is huge.

T LYMPHOCYTES
The major class of T cells is dened by its surface expression of the ab TCR. This receptor recognizes peptide antigens presented in a complex with class I or class II MHC proteins. ab T cells differentiate into several different subsets, including CD81 T cells, which act to kill cells infected with intracellular microbes, and CD41 T cells, which regulate the cellular and humoral immune responses.

array of TCRs, activating only a very small fraction of the total pool of T cells. Superantigens, in contrast, are microbial products that bind to large subsets of TCR proteins and MHC molecules, so that a single superantigen can activate up to 20% or more of the total T cells in the body. Superantigens do this by binding without proteolytic processing to the MHC molecule outside of the antigen-binding groove and to TCR proteins outside of their antigen-MHC binding site. For example, the toxic shock syndrome toxin 1 produced by Staphylococcus aureus can bind to and activate all T cells with TCRs using the Vb2 and Vb5.1 chains. The activation of large numbers of T cells induced by superantigens results in the massive release of cytokines, producing clinical conditions such as toxic shock syndrome.4

T-cell development Individual T cells bear TCRs with a single specicity. A repertoire of T cells that can protect against the vast universe of microbial pathogens must therefore include a very large number of cells encoding a huge array of discrete TCRs. The mechanisms leading to the somatic rearrangement of TCR gene elements to form functional ab TCRs and the mechanisms governing selection in the thymus of MHC-restricted but not autoreactive T cells have been recently described.4 T-cell activation through the TCR Interaction between the TCR and peptide-MHC provides only a partial signal for cell activation and can, under some conditions, lead to T-cell anergy. Full activation requires the additional interaction between the costimulatory molecule CD28 on the T cell and CD80 or CD86 (also designated B7.1 and B7.2, respectively) on the APC. The cytoplasmic portions of each of the CD3 chains contain sequences designated immunoreceptor tyrosinebased activation motifs (ITAMs). When tyrosines in these ITAMs are phosphorylated by the receptor-associated kinases Lck and Fyn, the ITAMs interact with the linker proteins ZAP-70 (z-chainassociated phosphoprotein of 70 kd), LAT (linker for activation of T cells), and SLP-76 (SH2 domain-containing leukocyte protein of 76 kd), leading to activation of phospholipase C, the G proteins Ras and Rac, protein kinase C, and the mitogen-activated protein kinases. Activation of these pathways leads to expression of genes that induce cell proliferation and differentiation. The pathways that downregulate the activation pathways are less well understood but include the protein phosphatase CD45.4 T-cell activation by superantigens Conventional antigenic peptides bind to a subset of MHC molecules and to a very small fraction of the huge

T-cell subpopulations In the thymus ab T cells differentiate into subpopulations expressing CD4 (helper cells) or CD8 (cytotoxic T cells). In addition to their roles as phenotypic markers of the helper and cytotoxic T-cell subsets, CD4 and CD8 serve as coreceptors in the T cellAPC interaction. CD4 on the surface of helper T cells stabilizes the interaction between that T cell and the APC by interacting with the membrane-proximal b2 domain of the antigen-presenting class II HLA molecule. The CD8 molecule, in turn, stabilizes the interaction between the cytotoxic T cell and its target by binding to the membrane-proximal a3 domain of peptide-loaded class I molecules on the target cell.4 Cells expressing both CD4 and CD25 and secreting TGF-b and IL-10 represent another functional subset designated T regulatory cells and provide important downregulating signals. Approximately 5% to 10% of T cells in the peripheral blood, lymph nodes, and spleen are CD42CD82. Some of these cells use ab TCRs and others use gd TCRs. Doublenegative cells do not recognize antigen in the context of MHC class I or class II. Some recognize glycolipid antigens presented by the class Irelated protein CD1. When naive CD41 or CD81 T cells are activated by APCs, they differentiate into functionally distinct effector subsets depending on the cytokines and costimulatory signals they receive during the activation process. For example, naive CD41 T cells that are activated by APCs secreting IL-12 differentiate to effector cells producing high levels of IFN-g and IL-2 (designated TH1 cells), whereas naive CD41 T cells activated by IL-4stimulated dendritic cells that express CD86 differentiate to effector cells producing IL-4, IL-5, IL-9, and IL-13 (designated TH2 cells).6 Generally, TH1 cells support cell-mediated immune responses, and TH2 cells support humoral, antihelminthic, and allergic responses. In most immune responses TH cells show a combination of TH1 and TH2 features; however, after prolonged immunization, the response can become dominantly TH1-like or TH2-like. CD81 T cells can also manifest type 1 and type 2 cytokine responses.7 Recent studies have identied new members of the IL-12 cytokine family. IL-12 is a heterodimer, consisting

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of p35 and p40 subunits. A close IL-12 homolog designated IL-23 consists of a p40/p19 heterodimer. IL-23 appears to play an important or even dominant role in several models of autoimmune disease,8 perhaps because it drives the development of a unique subset of CD41 T cells that produce IL-17, a cytokine known to elicit destructive inammation in several experimental arthritis models.9 Another member of the IL-12 family, IL-27, is a heterodimer of one p28 subunit (a structural homolog of IL-12 p35) and of one EBI3 subunit (a structural homolog of IL-12 p40 rst identied as a molecule induced by EBV).8 IL-27 can have both proinammatory (exacerbating tissue specic autoimmune phenomena) and antiinammatory (enhancing TH2-type responses) effects.10 Understanding the factors that govern whether a TH response adopts a predominantly TH1-type or TH2-type response is crucial to the allergistclinical immunologist. Recent progress using immunization with different types of adjuvants (eg, CpG DNA) demonstrates the feasibility of reprogramming allergic TH2-type responses in atopic patients to nonallergic TH1-type responses.11 Additional insights based on an understanding of the roles of the IL-17, IL-23, and IL-27 cytokines might uncover additional therapeutic opportunities to interrupt atopic responses.9

tissues, organs with separate B-cell zones (follicles), and zones enriched for T cells. The follicles also contain clusters of follicular dendritic cells that bind antigenantibody complexes and provide sites for B-cell maturation, somatic mutation, and selection of high-afnity B cells. The T-cell zones contain dendritic cells that are potent APCs for T-cell activation. Specialized high endothelial venules express adhesion molecules that facilitate egress of naive T and B cells from the circulation into the lymphoid organ. Dendritic cells that have taken up antigen in peripheral tissues enter into lymph nodes through afferent lymphatics, and efferent lymphatics export effector and memory cells back into the circulation.

EFFECTORS OF INNATE IMMUNITY

Initially, the innate and adaptive immune responses were thought to act independently, with innate immunity providing the rst line of defense against invading microbes and adaptive immunity acting later to sterilize the infection. It is now apparent that the adaptive response has co-opted many of the innate effector mechanisms to enhance its effectiveness. Thus these 2 arms of the immune response should be viewed as complementary and cooperating.

B LYMPHOCYTES
B cells, representing approximately 15% of peripheral blood leukocytes, are dened by their production of the immunoglobulin antigen-binding proteins. A fundamental difference between antigen recognition by immunoglobulin and by the TCRs is that immunoglobulin can recognize complex 3-dimensional structures (described as conformational determinants), whereas the TCR recognizes only short linear peptide epitopes when bound in the groove of class I or class II MHC molecules. Although the dominant function of B cells is to produce antigen-specic Ig, they can also present antigen through their class II proteins to T cells. This latter process is critical for the cellular interactions underlying T-cell help for immunoglobulin production. The molecular mechanisms for assembly of immunoglobulin heavy and light chains share many features with those supporting the formation of TCR chains, and these, as well as mechanisms underlying isotype switching, somatic mutation, signaling through the B-cell antigen receptor, and T cell dependent and independent activation, have been recently reviewed.4

LYMPHOID TISSUES
Protective immunity, particularly helper T celldependent production of high-afnity antibody and immune memory, requires cell-cell interactions. The naive subject must bring rare antigen-specic B cells together with rare antigen-specic T cells and with APCs presenting the specic antigen. This occurs in the secondary lymphoid

Toll-like receptors Toll was rst identied in Drosophila species, where Toll controlled polarity of the developing embryo and later was recognized to participate in antifungal immunity in ies.3 The human Toll-like receptors (TLRs) are transmembrane receptors with extracellular domains that contain leucine-rich repeating units and cytoplasmic domains with homology to the cytoplasmic domain of the IL-1 receptor (designated the Toll/IL-1 receptor [TIR] domain, Fig 1). Ten human TLRs have now been dened. The primary function of the TLR is to signal that microbes have breached the bodys barrier defenses. They appear to do this largely by recognizing common structural features of microbes known as pathogen-associated molecular patterns. These molecular patterns include LPS from gram-negative bacteria, peptidoglycan, lipoteichoic acid, lipoarabinomannan, and unmethylated DNA with a CpG motif characteristic of microbial DNA. TLRs are particularly found on macrophages and dendritic cells but also are expressed on neutrophils, eosinophils, epithelial cells, and keratinocytes. Most TLRs are cell-surface transmembrane proteins, but TLR9 and TLR3 are expressed intracellularly. Activation of most Toll receptors induces cellular responses associated with acute and chronic inammation.3 When TLR ligands interact with their specic TLRs, intracellular adaptor proteins transduce signals that lead to enhanced expression of genes encoding cytokines and other inammatory mediators (Fig 1). For example, binding of bacterial agellin to TLR5 or bacterial nonmethylated DNA containing CpG sequences to TLR9 induces recruitment of the intracellular protein MyD88 to the Toll/IL-1 receptor domain of the TLR. This then signals to the

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inherited complement deciency states have been recently reviewed.1,4

FIG 1. Myeloid differentiation factor 88 (MyD88)dependent and MyD88-independent TLR signaling. The TLR1/2 complex (recognizing bacterial peptidoglycan) and the TLR4/myeloid differentiation protein 2 (MD2) complex (recognizing endotoxin) use the linkers Toll-IL-1R domain-containing adaptor protein (TIRAP) and MyD88 to signal through IL-1Rassociated kinases (IRAKs) and TNF-Rassociated factor 6 (TRAF6), ultimately activating NF-kB. TLR3 (recognizing dsRNA) and the TLR4/MD2 complex (recognizing LPS) signal through the TIR domain-containing adaptor inducing IFN-b (TRIF), the TRIF-related adaptor molecule (TRAM)/TRIF complex, and TRAF family memberassociated NF-kB activatorbinding kinase 1 (TBK1) to activate the IFN regulatory factor 3 (IRF3) for production of IFN-b.

IL-1Rassociated kinase (IRAK)-4, IRAK-1, and the TNF receptorassociated factor 6 (TRAF6), leading to activation of the broadly proinammatory transcription factor nuclear factor kB (NF-kB).12 Binding of bacterial LPS to TLR4 in association with the MD-2 coreceptor elicits signaling through both the MyD88 pathway (using the adapter TIRAP) to activate NF-kB and proinammatory responses and also through an MyD88-independent pathway, including the adaptors TRIF (TIR domaincontaining adaptor inducing IFN-b), TRAM (TRIF-related adaptor molecule), and TBK1 (TRAF family memberassociated NF-kB activator-binding kinase 1), leading to activation of expression of IFN-b and induction of anti-inammatory responses (Fig 1). Thus activation of most TLRs (especially TLR9) elicits mediators that program TH cells toward a nonatopic TH1 response, but activation of other TLRs, including TLR2, can lead to responses that enhance TH2 cytokine production.13 With this caveat in mind, it is nevertheless encouraging that animal studies are showing that signaling through TLR9, activated by interaction with CpG DNA, can divert established TH2-driven atopic responses to nonatopic TH1dominated responses.11

Phagocytic and natural killer cells The major phagocytic cells are neutrophils, macrophages, and monocytes. These cells engulf pathogenic microbes and use intracellular vacuoles to focus toxic molecules, such as nitric oxide, superoxide, and degradative enzymes, on their destruction. Phagocytic cells use a variety of Fc receptors and complement receptors to enhance uptake of particles that have been marked by the adaptive and innate immune systems for destruction. Natural killer (NK) cells represent a distinct lineage of lymphoid cells that develops in the bone marrow under the inuence of IL-2 and IL-15. When activated, they adopt the morphology of large granular lymphocytes. NK cells have no antigen-specic receptors. Rather, they have both inhibitory and activating receptors that recognize self-MHC molecules and other cell-surface ligands.14 They have prominent antitumor effects and are potent killers of virally infected cells. NK T cells are a distinct lineage of CD31 T cells that display NK surface antigens.15 They are listed among innate effector cells because they express a limited repertoire of TCR chains (mostly Va24 and Vb11) and respond quickly to glycolipid antigens presented by the HLA class I homolog CD1. They have potent cytotoxic activities but can also produce IL-4 and IL-13, suggesting that they might play important roles in the pathogenesis of asthma and allergic disease.16 IMMUNOPATHOLOGY AND ATOPY
Properly regulated immune responses protect the host from pathogens and other environmental challenges. Often it is impossible to eradicate an invading pathogen without destroying infected cells. By using cellular apoptosis to remove infected cells, damage to nearby normal cells is minimized. Local inammation, however, is often an important part of an effective response. With inammation comes the danger of signicant tissue damage and brosis during the resolution of the inammatory state. Usually this damage is physiologic and tolerated; however, if inammation is intense or chronic, it can lead to severe organ dysfunction and scarring. All too commonly, patients present with conditions of tissue damage that appear to occur without an underlying stimulus. When this occurs in the form of autoimmune or atopic diseases, there appears to be a fundamental misdirection of the immune response, with tissue damage when no real danger was present. The cellular and humoral immune responses against components of self-tissues that occur in most autoimmune disorders generally manifest features of a TH1-type response. Atopic diseases, in contrast, appear to represent an overly aggressive TH2-type response, leading to hypersensitivity to a broad spectrum of normally encountered environmental antigens. At least supercially, autoimmune and atopic diseases appear to

Complement Complement is a critical effector pathway in both adaptive and innate immunity, particularly in association with Ig. The complement system is composed of more than 25 plasma and cell-surface proteins in 3 activation pathways and in downmodulating regulatory pathways. The features of the downmodulating regulatory pathways, the 3 activation pathways, and the acquired and

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represent opposite ends of a spectrum of a diathesis in the regulation of helper T-cell phenotype differentiation. Such a simple interpretation, however, is not supported by epidemiologic studies showing that the presence of atopy provides little protection against development of the TH1-predominant illness rheumatoid arthritis. In fact, some studies have suggested that patients with a TH1 illness are more likely to have a TH2 illness, suggesting that they have a common underlying cause.17 The identication of novel cytokines and regulatory cell subsets, including those producing IL-23 and IL-17, offers hope for deeper understanding of the mechanisms underlying autoimmune and atopic diseases and the development of new and effective therapies.8,9

REFERENCES 1. Morgan BP, Marchbank KJ, Longhi MP, Harris CL, Gallimore AM. Complement: central to innate immunity and bridging to adaptive responses. Immunol Lett 2005;97:171-9. 2. Selsted ME, Ouellette AJ. Mammalian defensins in the antimicrobial immune response. Nat Immunol 2005;6:551-7. 3. Beutler B, Hoebe K, Du X, Ulevitch RJ. How we detect microbes and respond to them: the Toll-like receptors and their transducers. J Leukoc Biol 2003;74:479-85. 4. Chaplin DD. 1. Overview of the immune response. J Allergy Clin Immunol 2003;111(suppl):S442-59.

5. Alam R, Gorska M. 3. Lymphocytes. J Allergy Clin Immunol 2003; 111(suppl):S476-85. 6. de Jong EC, Smits HH, Kapsenberg ML. Dendritic cell-mediated T cell polarization. Springer Semin Immunopathol 2005;26:289-307. 7. Woodland DL, Dutton RW. Heterogeneity of CD4(1) and CD8(1) T cells. Curr Opin Immunol 2003;15:336-42. 8. Hunter CA. New IL-12-family members: IL-23 and IL-27, cytokines with divergent functions. Nat Rev Immunol 2005;5:521-31. 9. Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, et al. IL-23 drives a pathogenic T cell population that induces autoimmune inammation. J Exp Med 2005;201:233-40. 10. Artis D, Villarino A, Silverman M, He W, Thornton EM, Mu S, et al. The IL-27 receptor (WSX-1) is an inhibitor of innate and adaptive elements of type 2 immunity. J Immunol 2004;173:5626-34. 11. Hayashi T, Gong X, Rossetto C, Shen C, Takabayashi K, Redecke V, et al. Induction and inhibition of the Th2 phenotype spread: implications for childhood asthma. J Immunol 2005;174:5864-73. 12. Takeda K, Akira S. Microbial recognition by Toll-like receptors. J Dermatol Sci 2004;34:73-82. 13. Redecke V, Hacker H, Datta SK, Fermin A, Pitha PM, Broide DH, et al. Cutting edge: activation of Toll-like receptor 2 induces a Th2 immune response and promotes experimental asthma. J Immunol 2004;172:2739-43. 14. Yokoyama WM. Natural killer cell immune responses. Immunol Res 2005;32:317-26. 15. Bos JD, de Rie MA, Teunissen MB, Piskin G. Psoriasis: dysregulation of innate immunity. Br J Dermatol 2005;152:1098-107. 16. Akbari O, Stock P, Meyer E, Kronenberg M, Sidobre S, Nakayama T, et al. Essential role of NKT cells producing IL-4 and IL-13 in the development of allergen-induced airway hyperreactivity. Nat Med 2003;9:582-8. 17. Rottem M, Gershwin ME, Shoenfeld Y. Allergic disease and autoimmune effectors pathways. Dev Immunol 2002;9:161-7.

2. Update on primary immunodeciency diseases

Francisco A. Bonilla, MD, PhD, and Raif S. Geha, MD Boston, Mass
This activity is available for CME credit. See page 5A for important information. The pace of discovery in primary immunodeciency continues to accelerate. In particular, lymphocyte defects have been the source of the most impressive expansion in recent years. Novel forms of agammaglobulinemia, class-switch defects, and T-B1 severe combined immunodeciency have been described. Little by little, the genetic heterogeneity of the common variable immunodeciency and IgA deciency phenotypes continues to be unraveled as new molecular defects have been reported in these patients as well. The phenotypic spectrum of DiGeorge syndrome has been further developed, along with promising advances in therapy. Defects of nuclear factor kB regulation and Toll-like receptor signaling have been described, along with defects of chemokine receptors and cytoplasmic proteases. Clinically dened immunodeciencies, such as hyper-IgE syndrome and idiopathic CD4 lymphocytopenia, are also discussed. Finally, signicant adverse effects in some patients have tempered initial enthusiasm for gene therapy. (J Allergy Clin Immunol 2006;117:S435-41.) Key words: Genetic diseases, human, immunodeciency, immunology, infection

From the Division of Immunology, Childrens Hospital, Boston, and the Department of Pediatrics, Harvard Medical School, Boston. Reprint requests: Francisco A. Bonilla, MD, PhD, Childrens Hospital, Boston, Fegan Building, 6th Floor, 300 Longwood Ave, Boston, MA 02115. E-mail: francisco.bonilla@childrens.harvard.edu. 0091-6749/$32.00 2006 American Academy of Allergy, Asthma and Immunology doi:10.1016/j.jaci.2005.09.051

This updated chapter on primary immunodeciency serves as a companion to the chapter published in the most recent edition of the full Primer on Allergic and Immunologic Diseases.1 This update contains important new material, as well as useful information that was not included in the original chapter because of space constraints. Potential new literature sources for this update were collected through a PubMed search using the MeSH major topic immunologic deciency syndromes with the Boolean operator NOT linked to HIV and AIDS. Changes have been made to all of the tables, and they are included here in their entirety. Table I describes the major classes of infectious susceptibilities associated with each of the principal categories of immunodeciency (lymphocyte defects resulting in antibody deciencies, cellular immune deciencies, and combined deciencies, as well as phagocyte and complement defects). Table II contains a listing and classication of selected molecular defects associated with primary immunodeciency. Table III indicates the alterations in the major subpopulations of peripheral blood lymphocytes in several forms of severe combined immunodeciency (SCID). A more