Primary Immune Deficiency Diseases

2715CHAPTER 351

Severe forms of dyskeratosis congenita (also known as HoyeraalHreidarsson syndrome) combine a progressive immunodeficiency

that can also include an absence of B and NK lymphocytes, progressive bone marrow failure, microcephaly, in utero growth retardation, and gastrointestinal disease. The disease can be X-linked

or, more rarely, autosomal recessive. It is caused by the mutation of

genes encoding telomere maintenance proteins, including dyskerin

(DKC1).

Finally, immunodeficiency with centromeric and facial anomalies

(ICF) is a complex syndrome of autosomal recessive inheritance that

variably combines a mild T-cell immune deficiency with a more severe

B-cell immune deficiency, coarse face, digestive disease, and mild

mental retardation. A diagnostic feature is the detection by cytogenetic analysis of multiradial aspects in multiple chromosomes (most

frequently 1, 9, and 16) corresponding to an abnormal DNA structure

secondary to defective DNA methylation. It is the consequence of a

deficiency in most cases in the DNA methyltransferase DNMT3B,

ZBTB24, CDCA7, or HELLS.

T-Cell Primary Immunodeficiencies with Hyper-IgE Several

T-cell PIDs are associated with elevated serum IgE levels (as in Omenn

syndrome). A condition sometimes referred to as autosomal recessive

hyper-IgE syndrome is notably characterized by recurrent bacterial

infections in the skin and respiratory tract and severe skin and mucosal

infections by pox viruses and human papillomaviruses, together with

severe allergic manifestations. T and B lymphocyte counts are low.

Mutations in the DOCK8 gene have been found in many of these

patients. This condition is an indication for HSCT.

A very rare, related condition with autosomal recessive inheritance

that causes a similar susceptibility to infection with various microbes

(see above), including mycobacteria, reportedly results from a deficiency in Tyk-2, a JAK family kinase involved in the signaling of many

different cytokine receptors.

Autosomal Dominant Hyper-IgE Syndrome This unique condition, the autosomal dominant hyper-IgE syndrome, is usually diagnosed by the combination of recurrent skin and lung infections that can

be complicated by pneumatoceles. Infections are caused by pyogenic

bacteria and fungi. Several other manifestations characterize hyper-IgE

syndrome, including facial dysmorphy, defective loss of primary teeth,

hyperextensibility, scoliosis, and osteoporosis. Elevated serum IgE levels

are typical of this syndrome. Defective TH17 effector responses have

been shown to account at least in part for the specific patterns of susceptibility to particular microbes. This condition is caused by a heterozygous (dominant) mutation in the gene encoding the transcription factor

STAT3 that is required in a number of signaling pathways following

binding of cytokine to cytokine receptors (such as that of IL-6 and the

IL-6 receptor). It also results in partially defective antibody production

because of defective IL-21 receptor signaling. Hence, immunoglobulin

substitution can be considered as prophylaxis of bacterial infections.

Most recently, a recessive condition that mimics immunologic

aspects of hyper-IgE syndrome has been ascribed to ZNF341 deficiency.

Cartilage Hair Hypoplasia The autosomal recessive cartilage hair

hypoplasia (CHH) disease is characterized by short-limb dwarfism,

metaphyseal dysostosis, and sparse hair, together with a combined Tand B-cell PID of extremely variable intensity (ranging from quasi-SCID

to no clinically significant immune defects). The condition can predispose to erythroblastopenia, autoimmunity, and tumors. It is caused

by mutations in the RMRP gene for a noncoding ribosome-associated

RNA. Schimke immuno-osseous dysplasia is another autosomal recessive condition variably associating combined immunodeficiency, bone

disease, and more importantly severe nephropathy.

CD40 Ligand and CD40 Deficiencies Hyper-IgM syndrome

(HIGM) is a well-known PID that is usually classified as a B-cell

immune deficiency (see Fig. 351-4 and below). It results from defective

Bone marrow Blood Lymphoid organs

HSC CLP proB

CD19

CD34

CD27

IgM

IgG

IgM

CSR

SHM

IgA

IgE

CD27

IgG or

IgA(+)

IgA

deficiency

preB

Immature

B

Memory

B

Memory

B

pre

BCR

surface

IgM

surface

IgM

IgD

B

B

Plasmocyte

Plasmocyte

Agammaglobulinemia

µ heavy chain

λ5

CD79a

CD79b

BLNK

BTK

P85α

E47

Ikaros

CD40L

CD40

IKKγ

AID

UNG

PMS2

ICOS

TACI

BAFFR

CD19

CD20

CD81

CD20

Tweak

PLCγ2

P13KCD

PI3KR1

Hyper IgM

syndrome

CVID

DNA Pol ε

FIGURE 351-4 B-cell differentiation and related primary immunodeficiencies (PIDs). Hematopoietic stem cells (HSCs) differentiate into common lymphoid progenitors

(CLPs), which give rise to pre-B cells. The B-cell differentiation pathway goes through the pre–B-cell stage (expression of the μ heavy chain and surrogate light chain), the

immature B-cell stage (expression of surface IgM), and the mature B-cell stage (expression of surface IgM and IgD). The main phenotypic characteristics of these cells are

indicated. In lymphoid organs, B cells can differentiate into plasma cells and produce IgM or undergo (in germinal centers) Ig class switch recombination (CSR) and somatic

mutation of the variable region of V genes (SHM) that enable selection of high-affinity antibodies. These B cells produce antibodies of various isotypes and generate memory

B cells. PIDs are indicated in the purple boxes. CVID, common variable immunodeficiency.

2716 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

immunoglobulin class switch recombination (CSR) in germinal centers and leads to profound deficiency in production of IgG, IgA, and

IgE (although IgM production is maintained). Approximately half of

HIGM sufferers are also prone to opportunistic infections, for example, interstitial pneumonitis caused by P. jiroveci (in young children),

protracted diarrhea and cholangitis caused by Cryptosporidium, and

infection of the brain with Toxoplasma gondii.

In the majority of cases, this condition has an X-linked inheritance

and is caused by a deficiency in CD40 ligand (L). CD40L induces signaling events in B cells that are necessary for both CSR and adequate

activation of other CD40-expressing cells that are involved in innate

immune responses against the above-mentioned microorganisms.

More rarely, the condition is caused by a deficiency in CD40 itself.

The poorer prognosis of CD40L and CD40 deficiencies (relative to

most other HIGM conditions) implies that (1) thorough investigations

have to be performed in all cases of HIGM and (2) potentially curative

HSCT should be discussed on a case-by-case basis for this group of

patients.

Wiskott-Aldrich Syndrome WAS is a complex, recessive,

X-linked disease with an incidence of ~1 in 200,000 live births. It is

caused by mutations in the WASP gene that affect not only T lymphocytes but also the other lymphocyte subsets, dendritic cells, and

platelets. WAS is typically characterized by the following clinical

manifestations: recurrent bacterial infections, eczema, and bleeding

caused by thrombocytopenia. However, these manifestations are highly

variable—mostly as a consequence of the many different WASP mutations that have been observed. Null mutations predispose affected individuals to invasive and bronchopulmonary infections, viral infections,

severe eczema, and autoimmune manifestations. The latter include

autoantibody-mediated blood cytopenia, glomerulonephritis, skin and

visceral vasculitis (including brain vasculitis), erythema nodosum, and

arthritis. Another possible consequence of WAS is lymphoma, which

may be virally induced (e.g., by EBV or Kaposi’s sarcoma–associated

herpesvirus). Thrombocytopenia can be severe and compounded by

the peripheral destruction of platelets associated with autoimmune

disorders. Hypomorphic mutations usually lead to milder outcomes

that are generally limited to thrombocytopenia. It is noteworthy that

even patients with “isolated” X-linked thrombocytopenia can develop

severe autoimmune disease or lymphoma later in life. The immunologic workup is not very informative; there can be a relative CD8+

T-cell deficiency, frequently accompanied by low serum IgM levels

and decreased antigen-specific antibody responses. A typical feature

is reduced-sized platelets on a blood smear. Diagnosis is based on

intracellular immunofluorescence analysis of WAS protein (WASp)

expression in blood cells. WASp regulates the actin cytoskeleton and

thus plays an important role in many lymphocyte functions, including

cell adhesion and migration and the formation of synapses between

antigen-presenting and target cells. Predisposition to autoimmune disorders is in part related to defective regulatory T cells. The treatment

of WAS should match the severity of disease expression. Prophylactic

antibiotics, immunoglobulin G (IgG) supplementation, and careful

topical treatment of eczema are indicated. Although splenectomy

improves platelet count in a majority of cases, this intervention is associated with a significant risk of infection (both before and after HSCT).

Allogeneic HSCT is curative, with good results overall. Gene therapy

trials have been performed. A similar condition has been reported in a

girl with a deficiency in the Wiskott-Aldrich interacting protein (WIP).

A few other complex PIDs are worth mentioning. Sp110 deficiency

causes a T-cell PID with liver venoocclusive disease and hypogammaglobulinemia. Chronic mucocutaneous candidiasis (CMC) is a heterogeneous disease, considering the different inheritance patterns that

have been observed. In some cases, chronic candidiasis is associated

with late-onset bronchopulmonary infections, bronchiectasis, and

brain aneurysms. Moderate forms of CMC are related to autoimmunity and AIRE deficiency (see below). In this setting, predisposition

to Candida infection is associated with the detection of autoantibodies

to TH17 cytokines. Recently, deficiencies in IL-17A, IL-17F, and IL-17

receptor A and C and in the associated protein Act1, and above all,

gain-of-function mutations in STAT1 have been found to be associated

with CMC. In all cases, CMC is related to defective TH17 function.

Innate immunodeficiency in CARD9 also predisposes to chronic invasive fungal infection.

■ B LYMPHOCYTE DEFICIENCIES

(TABLE 351-1, FIG. 351-4)

Deficiencies that predominantly affect B lymphocytes are the most frequent PIDs and account for 60–70% of all cases. B lymphocytes make

antibodies. Pentameric IgMs are found in the vascular compartment

and are also secreted at mucosal surfaces. IgG antibodies diffuse freely

into extravascular spaces, whereas IgA antibodies are produced and

secreted predominantly from mucosa-associated lymphoid tissues.

Although Ig isotypes have distinct effector functions, including Fc

receptor–mediated and (indirectly) C3 receptor–dependent phagocytosis of microorganisms, they share the ability to recognize and

neutralize a given pathogen. Defective antibody production therefore

allows the establishment of invasive, pyogenic bacterial infections as

well as recurrent sinus and pulmonary infections (mostly caused by S.

pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and, less

frequently, gram-negative bacteria). If left untreated, recurrent bronchial infections lead to bronchiectasis and, ultimately, cor pulmonale

and death. Parasitic infections such as caused by Giardia lamblia and

bacterial infections caused by Helicobacter and Campylobacter of the

gut are also observed. A complete lack of antibody production (namely

agammaglobulinemia) can also predispose affected individuals to

severe, chronic, disseminated enteroviral infections causing meningoencephalitis, hepatitis, and a dermatomyositis-like disease.

Even with the most profound of B-cell deficiencies, infections rarely

occur before the age of 6 months; this is because of transient protection

provided by the transplacental passage of immunoglobulins during the

last trimester of pregnancy. Conversely, a genetically nonimmunodeficient child born to a mother with hypogammaglobulinemia is, in the

absence of maternal Ig substitution, usually prone to severe bacterial

infections in utero and for several months after birth.

Diagnosis of B-cell PIDs relies on the determination of serum Ig

levels (Table 351-2). Determination of antibody production following

immunization with tetanus toxoid vaccine or nonconjugated pneumococcal polysaccharide antigens can also help diagnose more subtle

deficiencies. Another useful test is B-cell phenotype determination

in switched μ−δ− CD27+ and nonswitched memory B cells (μ+δ+

CD27+). In agammaglobulinemic patients, examination of bone marrow B-cell precursors (Fig. 351-4) can help obtain a precise diagnosis

and guide the choice of genetic tests.

Agammaglobulinemia Agammaglobulinemia is characterized by

a profound defect in B-cell development (<1% of the normal B-cell

blood count). In most patients, very low residual Ig isotypes can be

detected in the serum. In 85% of cases, agammaglobulinemia is caused

by a mutation in the BTK gene that is located on the X chromosome.

The BTK gene product is a kinase that participates in (pre) B-cell

receptor signaling. When the kinase is defective, there is a block (albeit

a leaky one) at the pre-B to B-cell stage (Fig. 351-4). Detection of BTK

by intracellular immunofluorescence of monocytes, and lack thereof

in patients with X-linked agammaglobulinemia (XLA), is a useful

diagnostic test. Not all of the mutations in BTK result in agammaglobulinemia, since some patients have a milder form of hypogammaglobulinemia and low but detectable B-cell counts. These cases should

not be confused with common variable immunodeficiency (CVID,

see below). About 10% of agammaglobulinemia cases are caused by

alterations in genes encoding elements of the pre-B-cell receptor, i.e.,

the μ heavy chain, the λ5 surrogate light chain, Igα or Igβ, the scaffold

protein BLNK, the p85 α subunit of phosphatidylinositol 3 phosphate

kinase (P13K), the E47, and the Ikaros transcription factors. In 5% of

cases, the defect is unknown. It is noteworthy that agammaglobulinemia can be observed in patients with ICF syndrome, despite the presence of normal peripheral B-cell counts. Lastly, agammaglobulinemia

can be a manifestation of a myelodysplastic syndrome (associated or

not with neutropenia). Treatment of agammaglobulinemic patients

is based on immunoglobulin replacement (see below). Profound

Primary Immune Deficiency Diseases

2717CHAPTER 351

hypogammaglobulinemia is also observed in adults, in association

with thymoma.

Hyper-IgM (HIGM) Syndromes HIGM is a rare B-cell PID

characterized by defective Ig CSR. It results in very low serum levels

of IgG and IgA and elevated or normal serum IgM levels. The clinical severity is similar to that seen in agammaglobulinemia, although

chronic lung disease and sinusitis are less frequent and enteroviral

infections are uncommon. As discussed above, a diagnosis of HIGM

involves screening for an X-linked CD40L deficiency and an autosomal recessive CD40 deficiency, which affect both B and T cells. In 50%

of cases affecting only B cells, these isolated HIGM syndromes result

from mutations in the gene encoding activation-induced deaminase,

the protein that induces CSR in B-cell germinal centers. These patients

usually have enlarged lymphoid organs. In the other 50% of cases, the

etiology is unknown (except for rare UNG and PMS2 deficiencies).

Furthermore, IgM-mediated autoimmunity and lymphomas can occur

in HIGM syndrome. It is noteworthy that HIGM can result from fetal

rubella syndrome or can be a predominant immunologic feature of

other PIDs, such as the immunodeficiency associated with ectodermic

anhydrotic hypoplasia X-linked NEMO deficiency and the combined

T- and B-cell PIDs caused by DNA repair defects such as AT and Cernunnos deficiency.

Common Variable Immunodeficiency CVID is an ill-defined

condition characterized by low serum levels of one or more Ig isotypes. Its prevalence is estimated to be 1 in 20,000. The condition is

recognized predominantly in adults, although clinical manifestations

can occur earlier in life. Hypogammaglobulinemia is associated with

at least partially defective antibody production in response to vaccine antigens. B lymphocyte counts are often normal but can be low.

Besides infections, CVID patients may develop lymphoproliferation

(splenomegaly), granulomatous lesions, colitis, antibody-mediated

autoimmune disease, and lymphomas that define disease prognosis. A

family history is found in 10% of cases. A clear-cut dominant inheritance pattern is found in some families, whereas recessive inheritance

is observed more rarely. In most cases, no molecular cause can be

identified. A small number of patients in Germany were found to carry

mutations in the ICOS gene encoding a T-cell membrane protein that

contributes to B-cell activation and survival. In 10% of patients with

CVID, monoallelic or biallelic mutations of the gene encoding TACI

(a member of the tumor necrosis factor [TNF] receptor family that

is expressed on B cells) have been found. In fact, heterozygous TACI

mutations correspond to a genetic susceptibility factor, since similar

heterozygous mutations are found in 1% of controls. NFkB1 transcription factor mutations have been found in a small fraction of patients

with CVID. The B-cell activating factor (BAFF) receptor was found to

be defective in a kindred with CVID, although not all individuals carrying the mutation have CVID. A group of patients with hypogammaglobulinemia and lymphoproliferation was shown to exhibit dominant

gain-of-function mutations in the PIK3CD gene encoding the p110δ

form of P13 kinase or in the PI3KR1 gene encoding the regulatory

p85α subunit of PI3 kinase. Rare cases of hypogammaglobulinemia

were found to be associated with CD19, CD20, CD21, and CD81 deficiencies. These patients have B cells that can be identified by typing for

other B-cell markers.

A diagnosis of CVID should be made after excluding the presence

of hypomorphic mutations associated with agammaglobulinemia or

more subtle T-cell defects; this is particularly the case in children. It is

possible that many cases of CVID result from a constellation of factors,

rather than a single genetic defect. Hypogammaglobulinemia can be

associated with neutropenia and lymphopenia in the WHIM syndrome

caused by a dominant gain-of-function mutation of CXCR4, resulting

in cell retention in the bone marrow.

Selective Ig Isotype Deficiencies IgA deficiency and CVID

represent polar ends of a clinical spectrum due to the same underlying gene defect(s) in a large subset of these patients. IgA deficiency is

the most common PID; it can be found in 1 in every 600 individuals.

It is asymptomatic in most cases; however, individuals may present

with increased numbers of acute and chronic respiratory infections

that may lead to bronchiectasis. In addition, over their lifetime, these

patients experience an increased susceptibility to drug allergies, atopic

disorders, and autoimmune diseases. Symptomatic IgA deficiency is

probably related to CVID, since it can be found in relatives of patients

with CVID. Furthermore, IgA deficiency may progress to CVID. It is

thus important to assess serum Ig levels in IgA-deficient patients (especially when infections occur frequently) in order to detect changes

that should prompt the initiation of immunoglobulin replacement.

Selective IgG2 (+G4) deficiency (which in some cases may be associated with IgA deficiency) can also result in recurrent sinopulmonary

infections and should thus be specifically sought in this clinical setting.

These conditions are ill-defined and often transient during childhood.

A pathophysiologic explanation has not been found.

Selective Antibody Deficiency to Polysaccharide Antigens

Some patients with normal serum Ig levels are prone to S. pneumoniae

and H. influenzae infections of the respiratory tract. Defective production of antibodies against polysaccharide antigens (such as those in the

S. pneumoniae cell wall) can be observed and is probably causative.

This condition may correspond to a defect in marginal zone B cells, a

B-cell subpopulation involved in T-independent antibody responses.

Immunoglobulin Replacement IgG antibodies have a half-life

of 21–28 days. Thus, injection of plasma-derived polyclonal IgG containing a myriad of high-affinity antibodies can provide protection

against disease-causing microorganisms in patients with defective IgG

antibody production. This form of therapy should not be based on

laboratory data alone (i.e., IgG and/or antibody deficiency) but should

be guided by the occurrence or not of infections; otherwise, patients

might be subjected to unjustified IgG infusions. Immunoglobulin

replacement can be performed by IV or subcutaneous routes. In the

former case, injections have to be repeated every 3–4 weeks, with a

residual target level above 800 mg/mL in patients who had very low

IgG levels prior to therapy. Subcutaneous injections are typically performed once a week, although the frequency can be adjusted on a caseby-case basis. A trough level above 800 mg/mL is desirable. Whatever

the mode of administration, the main goal is to reduce the frequency

of the respiratory tract infections and prevent chronic lung and sinus

disease. The two routes appear to be equally safe and efficacious, and so

the choice should be left to the preference of the patient.

In patients with chronic lung disease, chest physical therapy with

good pulmonary toilet and the use of antibiotics, notably azithromycin,

are also needed. Immunoglobulin replacement is well tolerated by most

patients, although the selection of the best-tolerated Ig preparation

may be necessary in certain cases. Since IgG preparations contain a

small proportion of IgAs, caution should be taken in patients with

residual antibody production capacity and a complete IgA deficiency,

as these subjects may develop anti-IgA antibodies that can trigger

anaphylactic shock. These patients should be treated with IgA-free IgG

preparations. Immunoglobulin replacement is a lifelong therapy; its

rationale and procedures have to be fully understood and mastered by

the patient and his or her family in order to guarantee the strict observance required for efficacy.

PRIMARY IMMUNODEFICIENCIES

AFFECTING REGULATORY PATHWAYS

(TABLE 351-1)

An increasing number of PIDs have been found to cause homeostatic

dysregulation of the immune system, either alone or in association with

increased vulnerability to infections. Defects of this type affecting the

innate immune system and autoinflammatory syndromes will not be

covered in this chapter. However, three specific entities (hemophagocytic lymphohistiocytosis [HLH], lymphoproliferation, and autoimmunity) will be described below.

■ HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS

HLH is characterized by an unremitting activation of CD8+ T lymphocytes and macrophages that leads to organ damage (notably in the

2718 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

liver, bone marrow, and central nervous system). This syndrome results

from a broad set of inherited diseases, most of which impair T and NK

lymphocyte cytotoxicity. The manifestations of HLH are often induced

by a viral infection. EBV is the most frequent trigger. In severe forms

of HLH, disease onset may start during the first year of life or even (in

rare cases) at birth.

Diagnosis relies on the identification of the characteristic symptoms

of HLH (fever, hepatosplenomegaly, edema, neurologic diseases, blood

cytopenia, increased liver enzymes, hypofibrinogenemia, high triglyceride [hyper ferritinemia] levels, elevated markers of T-cell activation,

and hemophagocytic features in the bone marrow or cerebrospinal

fluid). Functional assays of postactivation cytotoxic granule exocytosis (CD107 fluorescence at the cell membrane) can suggest genetically determined HLH. The conditions can be classified into three

subsets:

1. Familial HLH with autosomal recessive inheritance, including perforin deficiency (30% of cases) that can be recognized by assessing

intracellular perforin expression; Munc13-4 deficiency (30% of

cases); syntaxin 11 deficiency (10% of cases); Munc18-2 deficiency

(20% of cases); and a few residual cases that lack a known molecular

defect.

2. HLH with partial albinism. Three conditions combine HLH and

abnormal pigmentation, where hair examination can help in the

diagnosis: Chédiak-Higashi syndrome, Griscelli syndrome, and

Hermansky-Pudlak syndrome type II. Chédiak-Higashi syndrome is

also characterized by the presence of giant lysosomes within leukocytes (Chap. 64), in addition to a primary neurologic disorder with

slow progression of symptoms over time.

3. XLP is characterized in most patients by the induction of HLH

following EBV infection, while other patients develop progressive

hypogammaglobulinemia similar to what is observed in CVID and/

or certain lymphomas. XLP is caused by a mutation in the SH2DIA

gene that encodes the adaptor protein SAP (associated with a

SLAM family receptor). Several immunologic abnormalities have

been described, including low 2B4-mediated NK cell cytotoxicity,

impaired differentiation of NKT cells, defective antigen-induced

T-cell death, and defective T-cell helper activity for B cells. A related

disorder (XLP2) has recently been described. It is also X-linked and

induces HLH (frequently after EBV infection), although the clinical

manifestation may be less pronounced. The condition is associated

with a deficiency of the antiapoptotic molecule XIAP. The pathophysiology of XLP2 remains unclear; however, it may be related

to control of inflammation in macrophages as there is a functional

link between XIAP and NLRC4, an inflammasome component, in

which gain of function can also induce HLH. XLP2 is also frequently

associated with colitis.

HLH is a life-threatening complication. The treatment of this condition requires aggressive immunosuppression with either the cytotoxic

agent etoposide or anti–T-cell antibodies; specific therapy targeting

IFN-γ, which is critical in causing HLH, is an additional option to consider. Once remission has been achieved, HSCT should be performed,

since it provides the only curative form of therapy. Of note, acquired

forms of HLH are more commonly observed in adults as a complication of infection, malignancies or autoimmune diseases or sometimes

on its own.

■ AUTOIMMUNE LYMPHOPROLIFERATIVE

SYNDROME

Autoimmune lymphoproliferative syndrome (ALPS) is characterized

by nonmalignant T and B lymphoproliferation causing splenomegaly

and enlarged lymph nodes; 70% of patients also display autoimmune

manifestations such as autoimmune cytopenias, Guillain-Barré syndrome, uveitis, and hepatitis (Chaps. 66 and 349). A hallmark of

ALPS is the presence of CD4–CD8– TCRαβ+ T cells (2–50%) in the

blood of affected individuals. Hypergammaglobulinemia involving

IgG and IgA is also frequently observed. The syndrome is caused by

a defect in Fas-mediated apoptosis of lymphocytes, which can thus

accumulate and mediate autoimmunity. Furthermore, ALPS can lead

to malignancies.

Most patients carry a heterozygous mutation in the gene encoding

Fas that is characterized by dominant inheritance and variable penetrance, depending on the nature of the mutation. A rare and severe

form of the disease with early onset can be observed in patients carrying a biallelic mutation of Fas, which profoundly impairs the protein’s

expression and/or function. Fas-ligand, caspase 10, caspase 8, and

somatic neuroblastoma RAS viral oncogene homologue (NRAS) and

KRAS mutations have also been reported in a few cases of ALPS. Many

cases of ALPS have not been precisely delineated at the molecular level.

A B cell–predominant ALPS has recently been found associated with

a protein kinase Cδ gene mutation. Treatment of ALPS is essentially

based on the use of proapoptotic drugs, which need to be carefully

administered in order to avoid toxicity.

■ COLITIS, AUTOIMMUNITY, AND PRIMARY

IMMUNODEFICIENCIES

Several PIDs (most of which are T cell–related) can cause severe gut

inflammation. The prototypic example is immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX), characterized by

a widespread inflammatory enteropathy, food intolerance, skin rashes,

autoimmune cytopenias, and diabetes. The syndrome is caused by

loss-of-function mutations in the gene encoding the transcription factor FOXP3, which is required for the acquisition of effector function

by regulatory T cells. In most cases of IPEX, CD4+CD25+ regulatory

T cells are absent from the blood. This condition has a poor prognosis

and requires aggressive immunosuppression. The only possible curative approach is allogeneic HSCT. IPEX-like syndromes that lack a

FOXP3 mutation have also been described. In some cases, CD25 (IL-2

receptor α subunit) and CD122 (IL-2 receptor β subunit) deficiencies

have been found. Defective IL-2 receptor expression also impairs

regulatory cell expansion/function. This functional T-cell deficiency

means that IL-2 receptor–deficient patients are also at increased risk

of opportunistic infections. It is noteworthy that abnormalities in

regulatory T cells have been described in other PID settings, such as

in Omenn syndrome, STAT5b deficiency, STIM1 (Ca flux) deficiency,

and WAS; these abnormalities may account (at least in part) for the

occurrence of inflammation and autoimmunity. The autoimmune

features observed in a small fraction of patients with DiGeorge’s syndrome may have the same cause. Severe, early-onset inflammatory gut

disease has been described in patients with a deficiency in the IL-10

receptor or IL-10.

Dominant mutations in genes encoding the regulatory molecule

CTLA-4, recessive mutations in the gene encoding LRBA (a molecule

involved in recycling of CTLA-4), as well as dominant gain-of-function

mutation of STAT3 cause a multifaceted lymphoproliferative and

autoimmune syndrome, frequently involving inflammatory bowel

disease that can be associated with hypogammaglobulinemia. Molecular diagnosis is required before adapted targeted therapies are

undertaken.

A distinct autoimmune entity is observed in autoimmune polyendocrinopathy candidiasis ectodermal dysplasia (APECED) syndrome,

which is characterized by autosomal recessive inheritance. It consists

of multiple autoimmune manifestations that can affect solid organs

in general and endocrine glands in particular. Mild, chronic Candida

infection is often associated with this syndrome. The condition is due

to mutations in the autoimmune regulator (AIRE) gene and results in

impaired thymic expression of self-antigens by medullary epithelial

cells and impaired negative selection of self-reactive T cells that leads

to autoimmune manifestations.

A combination of hypogammaglobulinemia, autoantibody

production, cold-induced urticaria or skin granulomas, or autoinflammation has been reported and has been termed PLCγ2-

associated antibody deficiency and immune dysregulation (PLAID or

APLAID).

Urticaria, Angioedema, and Allergic Rhinitis

2719CHAPTER 352

CONCLUSION

The variety and complexity of the clinical manifestations of the many

different PIDs strongly indicate that it is important to raise awareness

of these diseases. Indeed, early diagnosis is essential for establishing an

appropriate therapeutic regimen. Hence, patients with suspected PIDs

must always be referred to experienced clinical centers that are able

to perform appropriate molecular and genetic tests. A precise molecular diagnosis is not only necessary for initiating the most suitable

treatment, but is also important for genetic counseling and prenatal

diagnosis.

One pitfall that may hamper diagnosis is the high variability that

is associated with many PIDs. Variable disease expression can result

from the differing consequences of various mutations associated with

a given condition, as exemplified by WAS and, to a lesser extent, XLA.

There can also be effects of modifier genes (as also suspected in XLA)

and environmental factors such as EBV infection that can be the main

trigger of disease in XLP conditions. Furthermore, it has recently been

established that somatic mutations in an affected gene can attenuate

the phenotype of a number of T-cell PIDs. This has been described for

ADA deficiency, X-linked SCID, RAG deficiencies, NF-κB essential

modulator (NEMO) deficiency, and, most frequently, WAS. In contrast, somatic mutations can create disease states analogous to PID, as

reported for ALPS. Lastly, cytokine-neutralizing autoantibodies can

mimic a PID, as shown for IFN-γ.

Many aspects of the pathophysiology of PIDs are still unknown, and

the disease-causing gene mutations have not been identified in all cases

(as illustrated by CVID and IgA deficiency). However, our medical

understanding of PIDs has now reached the stage where scientifically

based approaches to the diagnosis and treatment of these diseases can

be implemented. A genetic diagnosis has become a milestone step in

the care of PID patients.

■ FURTHER READING

Abolhassani H et al: Current genetic landscape in common variable

immune deficiency. Blood 135:656, 2020.

Casanova JL et al: Guidelines for genetic studies in single patients:

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immunodeficiencies and beyond. J Exp Med 217:e20190607, 2020.

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Section 2 Disorders of Immune-Mediated Injury

352 Urticaria, Angioedema,

and Allergic Rhinitis

Katherine L. Tuttle, Joshua A. Boyce

■ INTRODUCTION

The term atopy implies a tendency to manifest asthma, rhinitis, urticaria, food allergy, and atopic dermatitis alone or in combination, in

association with the presence of allergen-specific IgE. However, individuals without an atopic background may also develop hypersensitivity reactions, particularly urticaria and anaphylaxis, associated with the

presence of IgE. Since mast cells are key effector cells in allergic rhinitis

and asthma, and the dominant effector in urticaria, anaphylaxis, and

systemic mastocytosis, mast cell developmental biology, activation

pathway, product profile, and target tissues will be considered in the

introduction to these clinical disorders. Dysregulation of mast cell

development seen in mastocytosis will be covered in a separate chapter.

The binding of IgE to human mast cells and basophils, a process

termed sensitization, prepares these cells for subsequent antigenspecific activation. The high-affinity Fc receptor for IgE, designated

FcεRI, is composed of one α, one β, and two disulfide-linked γ chains,

which together cross the plasma membrane seven times. The α chain is

responsible for IgE binding, and the β and γ chains provide for signal

transduction that follows the aggregation of the sensitized tetrameric

receptors by polymeric antigen. The binding of IgE stabilizesthe α chain

at the plasma membrane, thus increasing the density of FcεRI receptors

at the cell surface while sensitizing the cell for effector responses. This

accounts for the correlation between serum IgE levels and the numbers

of FcεRI receptors detected on circulating basophils. Signal transduction is initiated through the action of a Src family–related tyrosine

kinase termed Lyn that is constitutively associated with the β chain. Lyn

transphosphorylates the canonical immunoreceptor tyrosine-based

activation motifs (ITAMs) of the β and γ chains of the receptor, resulting in recruitment of more active Lyn to the β chain and of Syk tyrosine

kinase. The phosphorylated tyrosines in the ITAMs function as binding

sites for the tandem src homology two (SH2) domains within Syk. Syk

activates not only phospholipase Cγ, which associates with the linker of

activated T cells at the plasma membrane, but also phosphatidylinositol

3-kinase to provide phosphatidylinositol-3,4,5-trisphosphate, which

allows membrane targeting of the Tec family kinase Btk and its activation by Lyn. In addition, the Src family tyrosine kinase Fyn becomes

activated after aggregation of IgE receptors and phosphorylates the

adapter protein Gab2 that enhances activation of phosphatidylinositol

3-kinase. Indeed, this additional input is essential for mast cell activation, but it can be partially inhibited by Lyn, indicating that the extent

of mast cell activation is in part regulated by the interplay between these

Src family kinases. Activated phospholipase Cγ cleaves phospholipid

membrane substrates to provide inositol-1,4,5-trisphosphate (IP3

) and

1,2-diacylglycerols (1,2-DAGs) to mobilize intracellular calcium and

activate protein kinase C, respectively. The subsequent opening of

calcium-regulated activated channels provides the sustained elevations

of intracellular calcium required to recruit the mitogen-activated

protein kinases ERK, JNK, and p38 (serine/threonine kinases), which

provide cascades to augment arachidonic acid release and to mediate

nuclear translocation of transcription factors for various cytokines.

The calcium ion–dependent activation of phospholipases cleaves membrane phospholipids to generate lysophospholipids, which, like 1,2-

DAG, may facilitate the fusion of the secretory granule perigranular

membrane with the cell membrane, a step that releases the membranefree granules containing the preformed mast cell mediators.

The secretory granule of the human mast cell has a crystalline

structure. IgE-dependent cell activation results in solubilization and

2720 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

swelling of the granule contents within the first minute of receptor

perturbation; this reaction is followed by the ordering of intermediate

filaments about the swollen granule, movement of the granule toward

the cell surface, and fusion of the perigranular membrane with that of

other granules and with the plasmalemma to form extracellular channels for mediator release while maintaining cell viability.

In addition to exocytosis, aggregation of FcεRI initiates two additional pathways for generation of bioactive products, namely, lipid

mediators, chemokines, and cytokines. Cytokines elaborated by mast

cells include tumor necrosis factor α (TNF-α), interleukin (IL) 1, IL-6,

IL-4, IL-5, IL-13, and granulocyte-macrophage colony-stimulating

factor (GM-CSF).

Lipid mediator generation (Fig. 352-1)involvestranslocation of calcium

ion–dependent cytosolic phospholipaseA2 to the outer nuclear membrane,

with subsequent release of arachidonic acid for metabolic processing by

the distinct prostanoid and leukotriene pathways. The constitutive prostaglandin endoperoxide synthase-1 (PGHS-1/cyclooxygenase-1) and the

de novo inducible PGHS-2 (cyclooxygenase-2) convert released arachidonic acid to the sequential intermediates, prostaglandins G2 and H2

.

The glutathione-dependent hematopoietic prostaglandin D2 (PGD2

)

synthase then converts PGH2 to PGD2

, the predominant mast cell

prostanoid. The PGD2 receptor DP1 is expressed by platelets, natural

killer cells, dendritic cells, and epithelial cells, whereas DP2 is expressed

by TH2 lymphocytes, innate lymphoid type 2 cells, eosinophils, and

basophils. Mast cells also generate thromboxane A2 (TXA2

), a short

lived but powerful mediator that induces bronchoconstriction and

platelet activation through the T prostanoid (TP) receptor.

For leukotriene biosynthesis, the released arachidonic acid is

metabolized by 5-lipoxygenase (5-LO) in the presence of an integral

nuclear membrane protein, 5-LO activating protein (FLAP). The

calcium ion–dependent translocation of 5-LO to the nuclear membrane converts the arachidonic acid to the sequential intermediates,

5-hydroperoxyeicosatetraenoic acid (5-HPETE) and leukotriene (LT)

A4

. LTA4 is conjugated with reduced glutathione by LTC4 synthase, an

integral nuclear membrane protein homologous to FLAP. Intracellular LTC4 is released by a carrier-specific export step for extracellular

OH

O OH

PGD2

PGH2

PGG2

PGD2 synthase

Cyclooxygenase

Cell-membrane Phospholipases

phospholipids

OH

COOH

LTC4 Glu

LTC 4

synthase

COOH O

OH OH

OH

COOH

COOH

OH

Cys

LTD4

LTE4

Transport

Transport

Binding protein

(FLAP)

5-Lipoxygenase

OOH

COOH

LTA 4

LTB4

LTB4 receptors

LTA 4

hydrolase

COOH

Arachidonic acid

COOH

LTC , 4 LTD4 and LTE4

receptors

5-HPETE

Cys-Gly

Cys-Gly

COOH

FIGURE 352-1 Pathways for biosynthesis and release of membrane-derived lipid

mediators from mast cells. In the 5-lipoxygenase pathway, leukotriene A4

 (LTA4

) is

the intermediate from which the terminal-pathway enzymes generate the distinct

final products, leukotriene C4

 (LTC4

) and leukotriene B4

 (LTB4

), which leave the cell

by separate saturable transport systems. Gamma glutamyl transpeptidase and a

dipeptidase then cleave glutamic acid and glycine from LTC4

 to form LTD4

 and LTE4

,

respectively. The major mast cell product of the cyclooxygenase system is PGD2

.

metabolism to the additional cysteinyl leukotrienes, LTD4 and LTE4

,

by the sequential removal of glutamic acid and glycine. Alternatively,

cytosolic LTA4 hydrolase converts some LTA4 to the dihydroxy leukotriene LTB4

, which also undergoes specific export. Two receptors

for LTB4

, BLT1 and BLT2

, mediate chemotaxis of human neutrophils.

Two receptors for the cysteinyl leukotrienes, CysLT1 and CysLT2

, are

present on smooth muscle of the airways and the microvasculature

and on hematopoietic cells such as macrophages, eosinophils, and mast

cells. Whereas the CysLT1 receptor has a preference for LTD4 and is

blocked by the receptor antagonists in clinical use, the CysLT2 receptor

is equally responsive to LTD4 and LTC4

, is unaffected by these antagonists, and is a negative regulator of the function of the CysLT1 receptor.

LTD4

, acting at CysLT1 receptors, is the most potent known bronchoconstrictor, whereas LTE4 induces a vascular leak and mediates the

recruitment of eosinophils to the bronchial mucosa. Recently, GPR99,

initially identified as a receptor for α-ketoglutarate, was identified as

an LTE4 receptor. The lysophospholipid formed during the release of

arachidonic acid from 1-O-alkyl-2-acyl-sn-glyceryl-3-phosphorylcholine can be acetylated in the second position to form platelet-activating

factor (PAF). Serum levels of PAF correlated positively with the severity

of anaphylaxis to peanut in a recent study, whereas the levels of PAF

acetyl hydrolase (a PAF-degrading enzyme) were inversely related to

the same outcome.

Human mast cells express receptors for anaphylatoxin, C5a and C3a,

toll-like receptors, receptors for epithelial alarmins thymic stromal

lymphopoietin (TSLP) and IL-33, and a newly recognized Mas-related

G protein–coupled receptor (MRGPX2), all which activate mast cells

in an IgE-dependent manner. MRGPX2 is a target of many smallmolecule drugs with a central tetrahydroisoquinoline motif, such

as ciprofloxacin and rocuronium, which may explain the observed

episodes of anaphylaxis to these medications without evidence of IgEmediated hypersensitivity.

Unlike most other cells of bone marrow origin, mast cells circulate as committed progenitors lacking their characteristic secretory

granules. These committed progenitors express c-kit, the receptor for

stem cell factor (SCF). Unlike most other lineages, they retain and

increase c-kit expression with maturation. The SCF interaction with

c-kit is an absolute requirement for the development of both constitutive connective tissue and skin mast cells and for the accumulation

of mast cells at mucosal surfaces during TH2-type immune responses.

Several T cell–derived cytokines (IL-3, IL-4, IL-5, and IL-9) can potentiate SCF-dependent mast cell proliferation and/or survival in vitro

in mice and humans. Indeed, mast cells are absent from the intestinal

mucosa in clinical T-cell deficiencies but are present in the submucosa.

Historical mast cell classification has been based on the immunodetection of secretory granule neutral proteases. Mast cells in the lung

parenchyma and intestinal mucosa selectively express tryptase, and

those in the intestinal and airway submucosa, perivascular spaces,

skin, lymph nodes, and breast parenchyma express tryptase, chymase,

and carboxypeptidase A (CPA). Selective environmental cues, such

as TH2 inflammation, can lead to different protease expression; in the

mucosal epithelium of severe asthmatics and apical epithelium of nasal

polyps, mast cells can express tryptase and CPA without chymase. The

secretory granules of mast cells selectively positive for tryptase exhibit

closed scrolls with a periodicity suggestive of a crystalline structure by

electron microscopy, whereas the secretory granules of mast cells with

multiple proteases are scroll-poor, with an amorphous or lattice-like

appearance. In addition to immunodetection of proteases, expression

profiling through single-cell RNA sequencing methods has further

elucidated different mast cell populations.

Mast cells are distributed at cutaneous and mucosal surfaces and

in submucosal tissues about venules and could influence the entry

of foreign substances by their rapid response capability (Fig. 352-2).

Upon stimulus-specific activation and secretory granule exocytosis,

histamine and acid hydrolases are solubilized, whereas the neutral

proteases, which are cationic, remain largely bound to the anionic proteoglycans, heparin and chondroitin sulfate E, with which they function as a complex. Histamine and the various lipid mediators (PGD2

,

Urticaria, Angioedema, and Allergic Rhinitis

2721CHAPTER 352

Lipid mediators

Secretory granule

preformed mediators

Cytokines

• LTB4 • LTC4 • PAF

• PGD2

• Histamine

• Proteoglycans

• Tryptase and chymase

• Carboxypeptidase A

• IL-3

• IL-4

• IL-5

• IL-6

• GM-CSF

• IL-1

• IL-13

• IFN-γ

• TNF-α

• Chemokines

Leukocyte responses

Fibroblast responses

Substrate responses

Microvascular responses

• Adherence

• Chemotaxis

• IgE production

• Mast cell proliferation

• Eosinophil activation

• Proliferation

• Vacuolation

• Globopentaosylceramide production

• Collagen production

• Activation of matrix

 metalloproteases

• Activation of coagulation cascade

• Augmented venular permeability

• Leukocyte adherence

• Constriction

• Dilatation

Activated mast cell

FIGURE 352-2 Bioactive mediators of three categories generated by IgE-dependent activation of murine mast cells can elicit common but sequential target cell effects

leading to acute and sustained inflammatory responses. GM-CSF, granulocyte-macrophage colony-stimulating factor; IL, interleukin; IFN, interferon; LT, leukotriene; PAF,

platelet-activating factor; PGD2

, prostaglandin D2

; TNF, tumor necrosis factor.

LTC4

/D4

/E4

, PAF) alter venular permeability, thereby allowing influx of

plasma proteins such as complement and immunoglobulins, whereas

LTB4 mediates leukocyte–endothelial cell adhesion and subsequent

directed migration (chemotaxis). The accumulation of leukocytes and

plasma opsonins facilitates defense of the microenvironment. The

inflammatory response can also be detrimental, as in asthma, where

the smooth-muscle constrictor activity of the cysteinyl leukotrienes is

evident and much more potent than that of histamine.

The cellular component of the mast cell–mediated inflammatory

response is augmented and sustained by cytokines and chemokines.

IgE-dependent activation of human skin mast cells in situ elicits TNF-α

production and release, which in turn induces endothelial cell responses

favoring leukocyte adhesion. Similarly, activation of purified human lung

mast cells or cord blood–derived cultured mast cells in vitro results in

substantial production of proinflammatory (TNF-α) and immunomodulatory cytokines (IL-4, IL-5, IL-13) and chemokines. Bronchial biopsy

specimens from patients with asthma reveal that mast cells are immunohistochemically positive for IL-4 and IL-5, but that the predominant

localization of IL-4, IL-5, and GM-CSF isto T cells, defined as TH2 by this

profile. IL-4 modulates the T-cell phenotype to the TH2 subtype, determines the isotype switch to IgE (as does IL-13), and upregulates FcεRImediated expression of cytokines by mast cells based on in vitro studies.

An immediate and late cellular phase of allergic inflammation can be

induced in the skin, nose, or lung of some allergic humans with local

allergen challenge. The immediate phase in the nose involves pruritus

and watery discharge; in the lung, it involves bronchospasm and mucus

secretion; and in the skin, it involves a wheal-and-flare response with

pruritus. Diminished nasal patency, reduced pulmonary function, or

erythema with swelling at the skin site in a late-phase response at 6–8 h

is associated with biopsy findings of infiltrating and activated TH2 cells,

eosinophils, basophils, and some neutrophils. The progression from

early mast cell activation to late cellular infiltration has been used as

an experimental surrogate of rhinitis or asthma. However, in asthma,

there is an intrinsic hyperreactivity of the airways independent of the

associated inflammation. Moreover, early- and late-phase responses (at

least in the lung) are far more sensitive to blockade of IgE-dependent

mast cell activation (or actions of histamine and cysteinyl leukotrienes)

than are spontaneous or virally induced asthma exacerbations.

Consideration of the mechanism of immediate-type hypersensitivity

diseases in the human has focused largely on the IgE-dependent recognition of otherwise innocuous substances. A region of chromosome

5 (5q23-31) contains genes implicated in the control of IgE levels

including IL-4 and IL-13, as well as IL-3 and IL-9, which are involved

in mucosal mast cell hyperplasia, and IL-5 and GM-CSF, which are

central to eosinophil development and their enhanced tissue viability.

Genes with linkage to the specific IgE response to particular allergens

include those encoding the major histocompatibility complex (MHC)

and certain chains of the T-cell receptor (TCR-αδ). The complexity of

atopy and the associated diseases includes susceptibility, severity, and

therapeutic responses, each of which is among the separate variables

modulated by both innate and adaptive immune stimuli.

The induction of allergic disease requires sensitization of a predisposed individual to a specific allergen. The greatest propensity for

the development of atopic allergy occurs in childhood and early adolescence. The allergen is processed by antigen-presenting cells of the

monocytic lineage (particularly dendritic cells) located throughout the

body at epithelial surfaces that contact the outside environment, such

as the nose, lungs, eyes, skin, and intestine. These antigen-presenting

cells present the epitope-bearing peptides via their MHC to T helper

cells and their subsets. The T-cell response depends both on cognate

recognition and on the cytokine microenvironment provided by the

antigen-presenting dendritic cells, with IL-4 directing a TH2 subset,

interferon (IFN) γ a TH1 profile, and IL-6 with transforming growth

factor β (TGF-β) a TH17 subset. Allergens can induce an epithelial alarmin response, with expression of IL-25, TSLP, and IL-33, which stimulate group 2 innate lymphoid cells, which can generate large quantities

of IL-5 and IL-13. Allergens also contain pattern recognition ligands

that facilitate the immune response by direct initiation of cytokine generation from innate cell types such as basophils, mast cells, eosinophils,

and others. The TH2 response is associated with activation of specific

B cells that can also present allergens or that transform into plasma

cells for antibody production. Synthesis and release into the plasma of

allergen-specific IgE results in sensitization of FcεR1-bearing cells such

as mast cells and basophils, which become activated on exposure to the

specific allergen. In certain diseases, including those associated with

atopy, the monocyte and eosinophil populations can express a trimeric

FcεR1, which lacks the β chain, and yet respond to its aggregation.

URTICARIA AND ANGIOEDEMA

■ DEFINITION

Urticaria and angioedema represent the same pathophysiologic process

occurring at different levels of the skin. Urticaria involves dilation

of vascular structures in the superficial dermis, while angioedema

originates from the deeper dermis and subcutaneous tissues. Not

surprisingly, they often appear together, with roughly 40% of patients

reporting both, and affect >20% of the population at some time

during their life span. Urticaria can occur on any area of the body