DISEASES CAUSED BY T LYMPHOCYTES

T cells play a central role in chronic immunologic diseases in which inflammation is a prominent component. Many of the newly developed therapies that have

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

reactions are autoimmunity and exaggerated or persistent responses to microbial or other environmental

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

the response becomes chronic because the infection is difficult to eradicate. The resultant granulomatous inflammation causes injury to normal tissues at the site of infection.

Excessive polyclonal T cell activation by certain

microbial toxins produced by some bacteria and viruses

can lead to production of large amounts of inflammatory cytokines, causing a syndrome similar to septic

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.

Mechanisms of Tissue Injury

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

cell-associated microbes.

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

cells are the source of interferon-? (IFN-?), the principal macrophage-activating cytokine, and Th17 cells are

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

cytokines that induce a detectable reaction. DTH reactions are manifested by infiltrates of T cells and blood

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

to an antigen. For example, a DTH reaction to a mycobacterial antigen, PPD (purified protein derivative),

applied to the skin, is an indicator of past or active

mycobacterial infection.

CD8+ T cells specific for antigens on host cells may

directly kill these cells. CD8+ T cells also produce cytokines, including IFN-? that may induce inflammation

A Cytokine-mediated inflammation

APC

presenting

tissue

antigen

CD4+

T cell

Cytokines

Inflammation

Tissue injury

B T cell–mediated killing of host cells

CD8+

CTLs

Cell death and

tissue injury

Neutrophil

enzymes,

reactive oxygen

species

Normal

cellular

tissue

Fig. 11.11 Mechanisms of T cell–mediated tissue injury (type IV hypersensitivity). T cells may cause tissue

injury and disease by two mechanisms. A, Inflammation may be triggered by cytokines produced mainly by CD4+

T cells in which tissue injury is caused by activated macrophages and inflammatory cells. B, Direct killing of target

cells is mediated by CD8+ cytotoxic T lymphocytes (CTLs). APC, Antigen-presenting cell.

232 CHAPTER 11 Hypersensitivity

in some hypersensitivity diseases. In many T cell–mediated autoimmune diseases, both CD4+ T cells and CD8+

T cells specific for self antigens are present, and both

contribute to tissue injury.

Clinical Syndromes and Therapy

Many organ-specific autoimmune diseases in humans

are believed to be caused by T cells, based on the identification of these cells in lesions and similarities with

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

memory T cells are generated, and the inciting antigens, such as tissue antigens or proteins expressed by

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

immune response against one or a few self antigen epitopes may spread to include responses against many

more self antigens.

The therapy for T cell–mediated hypersensitivity disorders is designed to reduce inflammation and to inhibit

T cell responses. The mainstay of treatment of such diseases has been the potent antiinflammatory steroids, but

these drugs have significant side effects. The development of more targeted therapies based on understanding of the fundamental mechanisms of these diseases

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,

and small molecule inhibitors of the inflammatory cytokine signaling molecule Janus kinase 3 (JAK3), are now

used to treat rheumatoid arthritis, and IL-17 blocking

antibodies are used to treat psoriasis. Other agents developed to inhibit T cell responses include drugs that block

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

the treatment of autoimmune diseases such as type 1 diabetes and lupus. There also is active research on methods

for inducing tolerance in pathogenic T cells.

NEUROIMMUNOLOGY: INTERACTIONS

BETWEEN THE IMMUNE AND NERVOUS

SYSTEMS

Reflex neural circuits affect innate and adaptive

immune responses and the development of inflammatory diseases. It is well known that the nervous

system is the target of autoimmune reactions, as in multiple sclerosis and myasthenia gravis, and inflammation

may contribute to the development of neurodegenerative disorders such as Alzheimer disease. The interesting new developments are the elucidation of molecular

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

suggesting the existence of such interactions were clinical observations that psychological stresses affected the

severity of allergic (Th2-dominant) and contact sensitivity (Th1-dominant) reactions. These associations

were usually interpreted to reflect the actions of neuropeptides, produced during psychological alterations,

on lymphocytes and other immune cells. More recently,

sophisticated genetic and other tools have been used to

dissect bidirectional neural-immune interactions with

greater precision. Among the findings potentially relevant to the development of disease states, the following

are some interesting examples.

A B

Fig. 11.12 Delayed-type hypersensitivity reaction in the

skin. A, Perivascular accumulation (cuffing) of mononuclear

inflammatory cells (lymphocytes and macrophages), with

associated dermal edema and fibrin deposition. B, Immunoperoxidase staining reveals a predominantly perivascular cellular infiltrate that marks positively with anti-CD4 antibodies. (B,

Courtesy Dr. Louis Picker, Department of Pathology, Oregon

Health Sciences University, Portland, OR.)

CHAPTER 11 Hypersensitivity 233

• Activation of the efferent vagus nerve inhibits the production of pro-inflammatory innate cytokines such

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

Disease Specificity of

pathogenic T cells

Clinicopathologic

manifestations

Type 1 diabetes

Rheumatoid

arthritis

Multiple sclerosis

Crohn disease

Pancreatic islet

antigens

Unknown antigens

in joint

Myelin proteins

Unknown, ? role of

intestinal microbes

Impaired glucose

metabolism, vascular

disease

Inflammation of

synovium and erosion

of cartilage and bone

in joints

Demyelination in the

central nervous

system, sensory and

motor dysfunction

Inflammation of the

bowel wall; abdominal

pain, diarrhea,

hemorrhage

Psoriasis Unknown Chronic skin

inflammation

Chronic infections

(e.g., tuberculosis)

Contact sensitivity

(e.g., poison ivy,

drug reaction)

Microbial proteins

Modified skin proteins

Chronic

(e.g., granulomatous)

inflammation

DTH reaction in skin,

rash

Fig. 11.13 T cell–mediated diseases. Diseases in which T cells play a dominant role in causing tissue

injury; antibodies and immune complexes may also contribute. Note that multiple sclerosis, rheumatoid

arthritis, and type 1 diabetes are autoimmune disorders. Crohn disease, an inflammatory bowel disease, is

likely caused by reactions against microbes in the intestine and may have a component of autoimmunity.

The other diseases are caused by reactions against foreign (microbial or environmental) antigens. In most of

these diseases, the role of T cells is inferred from the detection and isolation of T cells reactive with various

antigens from the blood or lesions, and from the similarity with experimental models in which the involvement of T cells has been established by a variety of approaches. The specificity of pathogenic T cells has

been defined in animal models and in some of the human diseases. Viral hepatitis and toxic shock syndrome

are disorders in which T cells play an important pathogenic role, but these are not considered examples of

hypersensitivity. CTL, Cytotoxic T lymphocyte; DTH, delayed-type hypersensitivity; HBV, hepatitis B virus;

HCV, hepatitis C virus.

234 CHAPTER 11 Hypersensitivity

abnormalities in this circuit contribute to intestinal

inflammation.

• In addition to these examples of neural signals affecting immune responses, the converse is also true, that

immune reactions alter neurological and psychological functions. For instance, neuronal development is

regulated by complement breakdown products and

cytokines, and cytokines produced by immune cells

may influence cognitive functions such as memory

and social behavior.

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

diseases.

SUMMARY

• Immune responses that cause tissue injury are called

hypersensitivity reactions, and the diseases caused by

these reactions are called hypersensitivity diseases.

• Hypersensitivity reactions may arise from uncontrolled or abnormal responses to foreign antigens or

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

encounter with the allergen.

• 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

their effects on end organs.

• 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

molecules and receptors.

• In immune complex diseases (type III hypersensitivity), antibodies may bind to circulating antigens to

form immune complexes, which deposit in vessels,

leading to inflammation in the vessel wall (vasculitis), which secondarily causes tissue injury due to

impaired blood flow.

• T cell–mediated diseases (type IV hypersensitivity)

result from inflammation caused by cytokines produced by CD4+ Th1 and Th17 cells, or killing of host

cells by CD8+ CTLs.

REVIEW QUESTIONS

1. What are the major types of hypersensitivity reactions?

2. What types of antigens may induce immune

responses that cause hypersensitivity reactions?

3. What is the sequence of events in a typical immediate hypersensitivity reaction? What is the late-phase

reaction, and how is it caused?

4. What are some examples of immediate hypersensitivity disorders, what is their pathogenesis, and how

are they treated?

5. How do antibodies cause tissue injury and disease?

6. What are some examples of diseases caused by antibodies specific for cell surface or tissue matrix antigens?

7. How do immune complexes cause disease, and how

are the clinical manifestations different from most

diseases caused by antibodies specific for cell surface

or tissue matrix proteins?

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

available at Student Consult.

235

Diseases Caused by

Defective Immunity

12

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

eradicate it. These consequences of defective immunity are predictable because, as emphasized throughout this book, the normal function of the immune

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)

immunodeficiencies.

In this chapter we describe the causes and pathogenesis of congenital and acquired immunodeficiencies. Among the acquired diseases, we emphasize

acquired immunodeficiency syndrome (AIDS),

which results from infection by human immunodeficiency virus (HIV) and is one of the most devastating

health problems worldwide. We address the following

questions:

• What are the mechanisms by which immunity is

compromised in the most common congenital

immunodeficiency diseases?

• How does HIV cause the clinical and pathologic

abnormalities of AIDS?

• 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

medicine.

Congenital and Acquired

Immunodeficiencies

CHAPTER OUTLINE

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

Diseases, 243

Therapy of Congenital Immunodeficiencies, 243

Acquired (Secondary) Immunodeficiencies, 243

Acquired Immunodeficiency Syndrome, 243

Human Immunodeficiency Virus, 244

Pathogenesis of AIDS, 246

Clinical Features of HIV Infection and AIDS, 248

Therapy and Vaccination Strategies, 250

Summary, 250

236 CHAPTER 12 Congenital and Acquired Immunodeficiencies

CONGENITAL (PRIMARY)

IMMUNODEFICIENCIES

Congenital immunodeficiencies are caused by genetic

defects that lead to impaired maturation or function of

different components of the immune system. It is estimated that as many as 1 in 500 individuals in the United

States and Europe suffer from congenital immune deficiencies of varying severity. These immunodeficiencies

share several features, the most common being increased

susceptibility to infections (Fig. 12.1). Congenital immunodeficiency diseases may, however, differ considerably

in clinical and pathologic manifestations. Some of these

disorders result in greatly increased incidence of infections that may manifest early after birth and may be fatal

unless the immunologic defects are corrected. Other

congenital immunodeficiencies lead to mild infections

and may first be detected in adult life.

Mutations in over 300 different genes have been identified as causes of primary immunodeficiencies. Predictably, most of these genes are expressed in immune cells.

Some interesting features of these mutations are worth

noting. First, immune deficiency is more frequently

caused by mutations in X-linked genes than in autosomal genes. Because boys have only one X chromosome,

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

function of the encoded protein, may lead to a very different disease. As an example, complete loss of function

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

of the brain (encephalitis), while mutations in interleukin-12 (IL-12) and genes related to Th1 cell development

or function result in atypical mycobacterial infections.

Type of

immunodeficiency

Histopathology and

laboratory abnormalities

Common infectious

consequences

B cell deficiencies

T cell deficiencies

Innate immune

deficiencies

Often absent or reduced

follicles and germinal centers

in lymphoid organs

Reduced serum Ig levels

May be reduced T cell zones

in lymphoid organs

Reduced DTH reactions to

common antigens

Defective T cell proliferative

responses to mitogens in vitro

Variable, depending on which

component of innate immunity

is defective

Pyogenic bacterial infections,

enteric bacterial and viral

infections

Viral and other intracellular

microbial infections (e.g.,

Pneumocystis jiroveci, other fungi,

nontuberculous mycobacteria)

Some cancers (e.g.,

EBV-associated lymphomas,

skin cancers)

Variable; pyogenic

bacterial and viral infections

Fig. 12.1 Features of immunodeficiency diseases. The figure summarizes the important diagnostic features and clinical manifestations of immunodeficiencies affecting different components of the immune system. Within each group, different diseases, and even different patients with the same disease, may show

considerable variation. Reduced numbers of circulating B or T cells are often detected in some of these

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

form the membrane attack complex contribute to Neisseria infections. These restricted clinical phenotypes

suggest considerable redundancy in host defense mechanisms, so defects in one pathway can be compensated

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.

The following discussion summarizes the pathogenesis of select immunodeficiencies, several of which were

mentioned in earlier chapters to illustrate the physiologic importance of various components of the immune

system. Congenital deficiencies in molecules involved in

self-tolerance are manifested as autoimmune diseases,

as discussed in Chapter 9.

Defects in Innate Immunity

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

well as Aspergillus and Candida species of fungi. Catalase-producing bacteria can degrade hydrogen peroxide, which is an alternative source of free radicals

that CGD leukocytes could use to kill bacteria. The

Disease Functional deficiencies Mechanisms of defect

Chronic

granulomatous

disease

Leukocyte

adhesion

deficiency type 1

Leukocyte

adhesion

deficiency type 2

Chediak-Higashi

syndrome

Defective production of reactive

oxygen species by phagocytes;

recurrent intracellular bacterial

and fungal infections

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

and fungal infections

Defective vesicle fusion and

lysosomal function in neutrophils,

macrophages, dendritic cells, NK

cells, cytotoxic T cells, and many

other cell types; recurrent infections

by pyogenic bacteria

Mutations in genes of phagocyte

oxidase complex; phox-91

(cytochrome b558 a subunit)

is mutated in X-linked form

Mutations in gene encoding

the ß chain (CD18) of

ß2 integrins

Mutations in gene encoding

GDP-fucose transporter-1,

required for transport of fucose

into the Golgi and its incorporation

into sialyl-Lewis X

Mutations in gene encoding LYST,

a protein involved in fusion of

vesicles (including lysosomes)

Toll-like receptor

signaling defects

Recurrent infections caused by

defects in TLR signaling

Mutations in TLR3 and MyD88

compromise NF-?B activation

and type I interferon production in

response to microbes

Fig. 12.2 Congenital immunodeficiencies caused by defects in innate immunity. The figure lists immunodeficiency diseases caused by defects in various components of the innate immune system. NF-?B, NF-nuclear factor ?B; NK, natural killer, TLR, toll-like receptors.

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

try to control the infections. These collections resemble granulomas, giving rise to the name of this disease.

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

other cells. As a result of these mutations, blood leukocytes do not bind firmly to vascular endothelium

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

infection.

Rare patients have been described with mutations

affecting TLRs or signaling pathways downstream of TLRs,

including molecules required for activation of the nuclear

factor ?B (NF-?B) transcription factor. As mentioned earlier, several of these mutations make patients susceptible

to only a limited set of infections. For example, mutations

affecting MyD88, an adaptor protein required for signaling by most TLRs, are associated with severe bacterial

(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

HSC

CLP

Jc�JAK3,

ADA, PNP

ZAP70,

TAP1,2

Pro-B

Pro-T Pre-T

CD4+CD8+

T cells

CD4+

T cells

CD8+

T cells

Pre-B

Immature B

Mature

B cell

MHC

class II

expression RAG1, RAG2,

ARTEMIS

RAG1, RAG2,

ARTEMIS

VDJ

recombination

VDJ

recombination

Pre-BCR

checkpoint

BTK

Pre-TCR

checkpoint

CD3

Fig. 12.3 Congenital immunodeficiencies caused by genetic defects in lymphocyte maturation. Lymphocyte maturation pathways are described in Chapter 4. Janus kinase 3 (JAK3) is a kinase involved in signaling by many cytokine receptors; ARTEMIS is a protein involved in antigen receptor gene recombination;

Bruton tyrosine kinase (BTK) is a kinase that delivers signals from the pre–B cell receptor (BCR) and BCR;

ZAP70 is a kinase involved in TCR signaling; and TAP proteins transport peptides for presentation by class I

MHC molecules. ADA, Adenosine deaminase; CLP, common lymphoid progenitor; HSC, hematopoietic stem

cell; PNP, purine nucleoside phosphorylase; RAG, recombination-activating gene; TCR, T cell receptor.