DISEASES CAUSED BY T LYMPHOCYTES
shown efficacy in such diseases are drugs that inhibit the
recruitment and activities of T cells.
Etiology of T Cell–Mediated Diseases
The major causes of T cell–mediated hypersensitivity
antigens. The autoimmune reactions usually are directed
against cellular antigens with restricted tissue distribution.
Therefore, T cell–mediated autoimmune diseases tend to
be limited to a few organs and usually are not systemic.
Examples of T cell–mediated hypersensitivity reactions
against environmental antigens include contact sensitivity
to chemicals (e.g., various therapeutic drugs and substances
found in plants such as poison ivy). Tissue injury also may
accompany T cell responses to microbes. For example, in
tuberculosis, a T cell–mediated immune response develops
against protein antigens of Mycobacterium tuberculosis, and
Excessive polyclonal T cell activation by certain
microbial toxins produced by some bacteria and viruses
shock. These toxins are called superantigens because
they stimulate large numbers of T cells. Superantigens
bind to invariant parts of T cell receptors on many
CHAPTER 11 Hypersensitivity 231
different clones of T cells, regardless of antigen specificity, thereby activating these cells.
In different T cell–mediated diseases, tissue injury is
caused by inflammation induced by cytokines that
are produced mainly by CD4+ T cells or by killing of
host cells by CD8+ cytotoxic T lymphocytes (CTLs)
(Fig. 11.11). These mechanisms of tissue injury are the
same as the mechanisms used by T cells to eliminate
CD4+ T cells may react against cell or tissue antigens
and secrete cytokines that induce local inflammation
and activate macrophages. Different diseases may be
associated with activation of Th1 and Th17 cells. Th1
responsible for the recruitment of leukocytes, including
neutrophils. The actual tissue injury in these diseases is
caused mainly by the macrophages and neutrophils.
The typical reaction mediated by T cell cytokines
is delayed-type hypersensitivity (DTH), so called
because it occurs 24 to 48 hours after an individual
previously exposed to a protein antigen is challenged
with the antigen (i.e., the reaction is delayed). The delay
occurs because it takes several hours for circulating
effector T lymphocytes to home to the site of antigen
challenge, respond to the antigen at this site, and secrete
monocytes in the tissues (Fig. 11.12), edema and fibrin
deposition caused by increased vascular permeability in
response to cytokines produced by CD4+ T cells, and
tissue damage induced by leukocyte products, mainly
from macrophages that are activated by the T cells.
DTH reactions often are used to determine if people
have been previously exposed to and have responded
applied to the skin, is an indicator of past or active
CD8+ T cells specific for antigens on host cells may
A Cytokine-mediated inflammation
B T cell–mediated killing of host cells
cells is mediated by CD8+ cytotoxic T lymphocytes (CTLs). APC, Antigen-presenting cell.
232 CHAPTER 11 Hypersensitivity
T cells specific for self antigens are present, and both
Clinical Syndromes and Therapy
Many organ-specific autoimmune diseases in humans
animal models in which the diseases are known to be
T cell mediated (Fig. 11.13). These disorders typically
are chronic and progressive, in part because long-lived
resident microbes, are often never cleared. Also, tissue
injury causes release and alteration of self proteins,
which may result in reactions against these newly
encountered proteins. This phenomenon has been
called epitope spreading to indicate that the initial
has been one of the most impressive accomplishments
of immunology. Antagonists of inflammatory cytokines
have proved to be very effective in patients with various
inflammatory and autoimmune diseases. For example,
monoclonal antibodies that block TNF or IL-6 receptor,
used to treat rheumatoid arthritis, and IL-17 blocking
costimulators such as B7. Clinical trials are underway to
test the efficacy of transferring in vitro expanded Tregs
and administering IL-2 to expand endogenous Tregs for
for inducing tolerance in pathogenic T cells.
BETWEEN THE IMMUNE AND NERVOUS
Reflex neural circuits affect innate and adaptive
immune responses and the development of inflammatory diseases. It is well known that the nervous
communications between the nervous and immune
systems, often via secreted molecules. The idea that
neural circuits modulate immunity and the immune
system alters neural functions has fascinated biologists
and clinicians for decades. Some of the earliest findings
on lymphocytes and other immune cells. More recently,
sophisticated genetic and other tools have been used to
dissect bidirectional neural-immune interactions with
are some interesting examples.
Fig. 11.12 Delayed-type hypersensitivity reaction in the
skin. A, Perivascular accumulation (cuffing) of mononuclear
inflammatory cells (lymphocytes and macrophages), with
Courtesy Dr. Louis Picker, Department of Pathology, Oregon
Health Sciences University, Portland, OR.)
CHAPTER 11 Hypersensitivity 233
as TNF, providing a novel mechanism for regulating
inflammation. This has led to clinical trials of vagus
nerve stimulation in patients with rheumatoid arthritis.
• Cholinergic and adrenergic signals in the spleen regulate antibody production.
• Neuropeptides produced in response to microbes
and other local stimuli influence the activation of
type 2 innate lymphoid cells in the airways and hence
type 2 immunity, the basis of allergic diseases.
• The gut microbiome induces signals from enteric
nerves that induce macrophages to develop an antiinflammatory and tissue-protective phenotype and
regulates the balance between pro-inflammatory
Th17 cells and protective Treg cells. Thus, the microbiome uses neural circuits to maintain immune
homeostasis in the gut, raising the possibility that
Psoriasis Unknown Chronic skin
234 CHAPTER 11 Hypersensitivity
abnormalities in this circuit contribute to intestinal
regulated by complement breakdown products and
cytokines, and cytokines produced by immune cells
may influence cognitive functions such as memory
Many other neural-immune interactions have
been described, and their impact on autoimmune
and allergic diseases is being explored. The hope is
that elucidation of these pathways will lead to the
development of new classes of therapies for these
• Immune responses that cause tissue injury are called
hypersensitivity reactions, and the diseases caused by
these reactions are called hypersensitivity diseases.
autoimmune responses against self antigens.
• Hypersensitivity reactions are classified according to
the mechanism of tissue injury.
• Immediate hypersensitivity (type I, commonly called
allergy) is caused by the activation of Th2 cells and
IL-4-producing Tfh cells and production of IgE
antibody against environmental antigens or drugs
(allergens), sensitization of mast cells by the IgE,
and degranulation of these mast cells on subsequent
• Clinicopathologic manifestations of immediate
hypersensitivity result from the actions of mediators
secreted by the mast cells: amines increase vascular
permeability of and dilate blood vessels, arachidonic
acid metabolites cause bronchial smooth muscle
contraction, and cytokines induce inflammation,
the hallmark of the late-phase reaction. Treatment
of allergies is designed to inhibit the production of
mediators, antagonize their actions, and counteract
• Antibodies against cell and tissue antigens may cause
tissue injury and disease (type II hypersensitivity).
IgM and IgG antibodies activate complement, which
promotes phagocytosis of cells to which they bind,
induces inflammation, and causes cell lysis. IgG also
promotes Fc receptor–mediated phagocytosis of cells
and leukocyte recruitment. Antibodies may interfere
with the functions of cells by binding to essential
form immune complexes, which deposit in vessels,
• T cell–mediated diseases (type IV hypersensitivity)
result from inflammation caused by cytokines produced by CD4+ Th1 and Th17 cells, or killing of host
1. What are the major types of hypersensitivity reactions?
2. What types of antigens may induce immune
responses that cause hypersensitivity reactions?
reaction, and how is it caused?
5. How do antibodies cause tissue injury and disease?
7. How do immune complexes cause disease, and how
are the clinical manifestations different from most
diseases caused by antibodies specific for cell surface
8. What are some examples of diseases caused by
T cells, what is their pathogenesis, and what are their
principal clinical and pathologic manifestations?
Answers to and discussion of the Review Questions are
Defects in the development and functions of the
immune system result in increased susceptibility to
infections and some cancers. The infections may be
newly acquired or the reactivation of latent infections such as cytomegalovirus, Epstein-Barr virus,
and tuberculosis, in which the normal immune
response keeps the infection in check but does not
system is to defend individuals against infections
and cancers. Disorders caused by defective immunity are called immunodeficiency diseases. Some
of these diseases may result from genetic abnormalities in components of the immune system;
these are called congenital (or primary) immunodeficiencies. Other defects in immunity may
result from infections, nutritional abnormalities,
or medical treatments that cause loss or inadequate
function of various components of the immune
system; these are called acquired (or secondary)
acquired immunodeficiency syndrome (AIDS),
health problems worldwide. We address the following
• What are the mechanisms by which immunity is
compromised in the most common congenital
• How does HIV cause the clinical and pathologic
• What approaches are being used to treat immunodeficiency diseases?
Information about the clinical features of these
disorders can be found in textbooks of pediatrics and
Congenital (Primary) Immunodeficiencies, 236
Defects in Innate Immunity, 237
Defects in Lymphocyte Maturation, 238
Severe Combined Immunodeficiency (SCID), 239
Selective B Cell Deficiency, 240
Defects in Lymphocyte Activation and Function, 240
Defects in B Cell Responses, 240
Defective Activation of T Lymphocytes, 242
Lymphocyte Abnormalities Associated With Other
Therapy of Congenital Immunodeficiencies, 243
Acquired (Secondary) Immunodeficiencies, 243
Acquired Immunodeficiency Syndrome, 243
Human Immunodeficiency Virus, 244
Clinical Features of HIV Infection and AIDS, 248
Therapy and Vaccination Strategies, 250
236 CHAPTER 12 Congenital and Acquired Immunodeficiencies
Congenital immunodeficiencies are caused by genetic
defects that lead to impaired maturation or function of
share several features, the most common being increased
in clinical and pathologic manifestations. Some of these
unless the immunologic defects are corrected. Other
congenital immunodeficiencies lead to mild infections
and may first be detected in adult life.
Some interesting features of these mutations are worth
noting. First, immune deficiency is more frequently
mutations in only one gene will cause the disease in
boys (and girls with the mutation will be carriers but
not affected because they have two X chromosomes).
Autosomal recessive diseases are seen in populations in
which cosanguinous marriages are common, and these
are being detected more frequently now because of the
widespread use of whole genome sequencing. Second,
while a complete loss-of-function mutation in a gene
might lead to one disease state, a hypomorphic mutation
in the same gene, which only partially compromises the
mutations in RAG1 or RAG2, discussed below, lead to
a disorder called severe combined immunodeficiency
(SCID), whereas a hypomorphic mutation in one of these
genes can lead to a very different disease (called Omenn
syndrome) in which autoimmunity predominates. The
third interesting feature is that mutations in certain sets
of genes contribute to susceptibility to specific subsets
of pathogens. For example, mutations affecting Toll-like
receptor 3 (TLR3) and proteins in the TLR3 signaling
pathway contribute to herpes simplex virus infection
or function result in atypical mycobacterial infections.
follicles and germinal centers
Defective T cell proliferative
responses to mitogens in vitro
Pyogenic bacterial infections,
Pneumocystis jiroveci, other fungi,
bacterial and viral infections
diseases. DTH, Delayed-type hypersensitivity; EBV, Epstein-Barr virus; Ig, immunoglobulin.
CHAPTER 12 Congenital and Acquired Immunodeficiencies 237
Mutations in complement genes encoding proteins that
by other pathways, and patients are not susceptible to a
wide variety of infections. Clearly the immune system
has evolved numerous pathways that are often specialized for combating subsets of pathogens.
system. Congenital deficiencies in molecules involved in
self-tolerance are manifested as autoimmune diseases,
Abnormalities in two components of innate immunity,
phagocytes and the complement system, are important
causes of immunodeficiency (Fig. 12.2).
• Chronic granulomatous disease (CGD) is caused by
mutations in genes encoding subunits of the enzyme
phagocyte NADPH oxidase, which catalyzes the production of microbicidal reactive oxygen species in
lysosomes (see Chapter 2). Affected neutrophils and
macrophages are unable to kill the microbes they
phagocytose. The most common infections in CGD
patients are bacteria that make the enzyme catalase, as
that CGD leukocytes could use to kill bacteria. The
Disease Functional deficiencies Mechanisms of defect
Defective production of reactive
recurrent intracellular bacterial
Defective leukocyte adhesion to
endothelial cells and migration into
tissues linked to decreased or absent
expression of ß2 integrins; recurrent
bacterial and fungal infections
Defective leukocyte rolling on
endothelium and migration into
tissues because of decreased or
absent expression of leukocyte
ligands for endothelial E- and
P-selectins; recurrent bacterial
lysosomal function in neutrophils,
macrophages, dendritic cells, NK
cells, cytotoxic T cells, and many
other cell types; recurrent infections
Mutations in genes of phagocyte
required for transport of fucose
into the Golgi and its incorporation
Mutations in gene encoding LYST,
a protein involved in fusion of
vesicles (including lysosomes)
Recurrent infections caused by
and type I interferon production in
238 CHAPTER 12 Congenital and Acquired Immunodeficiencies
immune system tries to compensate for this defective
microbial killing by calling in more macrophages and
by activating T cells, which stimulate recruitment and
activation of phagocytes. Therefore, collections of
macrophages accumulate around foci of infections to
The most common form of CGD is X-linked, caused
by mutations in a subunit of the NADPH oxidase that
is encoded by a gene on the X chromosome.
• Leukocyte adhesion deficiency is caused by mutations in genes encoding integrins, enzymes required
for the expression of ligands for selectins, or signaling
molecules activated by chemokine receptors that are
required to activate integrins. Integrins and selectin
ligands are involved in the adhesion of leukocytes to
and are not recruited normally to sites of infection.
• Deficiencies of almost every complement protein,
and many complement regulatory proteins, have
been described (see Chapter 8). C3 deficiency results
in severe infections and may be fatal. Deficiencies of
C2 and C4, two components of the classical pathway
of complement activation, may result in increased
bacterial or viral infection or increased incidence of
systemic lupus erythematosus, presumably because
of defective clearance of immune complexes. Deficiencies of complement regulatory proteins lead to
various syndromes associated with excessive complement activation.
• The Chédiak-Higashi syndrome is an immunodeficiency disease in which the lysosomal granules of
leukocytes do not function normally. The immune
defect affects phagocytes and natural killer (NK) cells
and manifests as increased susceptibility to bacterial
Rare patients have been described with mutations
affecting TLRs or signaling pathways downstream of TLRs,
including molecules required for activation of the nuclear
to only a limited set of infections. For example, mutations
(most often pneumococcal) pneumonias, and mutations
affecting TLR3 are associated with recurrent herpesvirus
encephalitis but apparently not other viral infections.
Defects in Lymphocyte Maturation
Many congenital immunodeficiencies are the result
of genetic abnormalities that cause blocks in the
MHC molecules. ADA, Adenosine deaminase; CLP, common lymphoid progenitor; HSC, hematopoietic stem
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