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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 identifies settings
in which disturbed immune function exacerbates tissue injury.
(J Allergy Clin Immunol 2006;117:S430-5.)

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

Key words: Adaptive immunity, atopy, dendritic cell, inflammation,


innate immunity, Toll-like receptors

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 specificity 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
specificity for any individual pathogen, cells that encounter and recognize a pathogen must proliferate to attain
sufficient numbers to mount an effective response. Thus
the adaptive response generally expresses itself temporally after the innate response in host defense. A key

From the University of Alabama at Birmingham.


Disclosure of potential conflict of interest: D. Chaplin has consultant agreements with Pfizer.
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

S430

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 specific
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
fluids (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 inflammatory leukocytes, lipid mediators
of inflammation, 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 specificity for its target

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VOLUME 117, NUMBER 2

antigens by virtue of the antigen-specific receptors


expressed on the surfaces of T and B lymphocytes. The
antigen-specific 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
specificity 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 first line of host defense and the
adaptive response becoming prominent after several days
as antigen-specific T and B cells have undergone clonal
expansion. Furthermore, the antigen-specific 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

Chaplin S431

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 Briefly, 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
floor 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.

S432 Chaplin

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 defined 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.

T-cell development
Individual T cells bear TCRs with a single specificity.
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

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FEBRUARY 2006

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 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 identified 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 inflammation 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 first identified as a molecule induced
by EBV).8 IL-27 can have both proinflammatory (exacerbating tissue specific autoimmune phenomena) and antiinflammatory (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

B LYMPHOCYTES
B cells, representing approximately 15% of peripheral
blood leukocytes, are defined 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-specific 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-affinity antibody and immune
memory, requires cell-cell interactions. The naive subject
must bring rare antigen-specific B cells together with rare
antigen-specific T cells and with APCs presenting the
specific antigen. This occurs in the secondary lymphoid

Chaplin S433

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-affinity 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 first 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.

Toll-like receptors
Toll was first identified in Drosophila species, where
Toll controlled polarity of the developing embryo and
later was recognized to participate in antifungal immunity
in flies.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 defined. 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 inflammation.3
When TLR ligands interact with their specific TLRs, intracellular adaptor proteins transduce signals that lead to enhanced expression of genes encoding cytokines and other
inflammatory mediators (Fig 1). For example, binding of
bacterial flagellin 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

S434 Chaplin

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FEBRUARY 2006

inherited complement deficiency 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 proinflammatory 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 proinflammatory 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-inflammatory 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

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

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 influence of IL-2 and IL-15. When activated, they
adopt the morphology of large granular lymphocytes. NK
cells have no antigen-specific 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 inflammation, however, is often
an important part of an effective response. With inflammation comes the danger of significant tissue damage and
fibrosis during the resolution of the inflammatory state.
Usually this damage is physiologic and tolerated; however, if inflammation 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
superficially, autoimmune and atopic diseases appear to

Bonilla and Geha S435

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VOLUME 117, NUMBER 2

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
identification 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

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8. Hunter CA. New IL-12-family members: IL-23 and IL-27, cytokines
with divergent functions. Nat Rev Immunol 2005;5:521-31.
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IL-27 receptor (WSX-1) is an inhibitor of innate and adaptive elements of
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11. Hayashi T, Gong X, Rossetto C, Shen C, Takabayashi K, Redecke V,
et al. Induction and inhibition of the Th2 phenotype spread: implications
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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.
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2. Update on primary immunodeficiency 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 immunodeficiency 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 immunodeficiency have been described. Little
by little, the genetic heterogeneity of the common variable
immunodeficiency and IgA deficiency 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 defined immunodeficiencies, such as hyper-IgE
syndrome and idiopathic CD4 lymphocytopenia, are also
discussed. Finally, significant adverse effects in some patients
have tempered initial enthusiasm for gene therapy. (J Allergy
Clin Immunol 2006;117:S435-41.)

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

Key words: Genetic diseases, human, immunodeficiency, immunology, infection

This updated chapter on primary immunodeficiency


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 deficiency 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 immunodeficiency
(lymphocyte defects resulting in antibody deficiencies,
cellular immune deficiencies, and combined deficiencies,
as well as phagocyte and complement defects). Table II
contains a listing and classification of selected molecular
defects associated with primary immunodeficiency.
Table III indicates the alterations in the major subpopulations of peripheral blood lymphocytes in several forms
of severe combined immunodeficiency (SCID). A more