Isotype Defects

Chapter 16

Isotype Defects Mirjam van der Burg1, Corry M.R. Weemaes2, and Charlotte Cunningham-Rundles3 1

Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands, 2Department of Pediatric Infectious

Disease and Immunology, Radboud University Nijmegen Medical Centre, The Netherlands, 3Department of Medicine

Allergy & Immunology,

Mount Sinai School of Medicine, New York, NY, USA

Chapter Outline Immunoglobulin Structure and Function IgM IgG IgA and Secretory IgA IgE Isotype Defects Ig Heavy Chain Deletions Definition Genetics Clinical Presentation Igκ and Igλ Light Chain Deficiency Definition Genetics Pathogenesis Clinical Presentation Diagnostics IgG Subclass Deficiency Definition Genetics Pathogenesis Clinical Presentation

389 390 391 392 392 392 393 393 393 393 393 393 393 393 394 394 395 395 395 395 395

IMMUNOGLOBULIN STRUCTURE AND FUNCTION Antibodies are the antigen-specific proteins produced by B lymphocytes and synthesized and secreted by plasma cells, which arise from terminally differentiated B cells.1 Antibodies or Ig molecules are Y-shaped, and consist of two pairs of identical heavy and light chains. The antigenbinding or variable (V) regions vary extensively among antibodies of different specificity, and are generated through assembly of the variable (V), diversity (D), and joining (J) gene segments in a process called V(D)J recombination (Figure 16.1A). The variable part is involved in antigen

Diagnostics Management Prognosis Selective IgA Deficiency Definition Genetics Pathogenesis Clinical Presentation Diagnostics Management Prognosis Selective IgM Deficiency Definition Genetics Pathogenesis Clinical Presentation Diagnostics Management Prognosis References

396 397 397 397 397 397 398 398 401 401 402 402 402 402 402 402 403 403 403 403

binding. The remainder of the antibody molecule is its constant (C) region and exerts the effector functions. A total of 18 different isotypes or classes and subclasses of Igs are present in plasma or expressed on the surface of B lymphocytes. They are composed of five classes of heavy-chain isotypes (μ, δ, γ, α, and ε chains), which include four subclasses of γ chain (γ1, γ2, γ3, and γ4) and two classes of α chain (α1 and α2) that pair with two types of light chains (κ and λ). The gene structure of the constant regions of the Ig heavy chain gene is given in Figure 16.1B. Antibodies are a critical component of host defenses. By themselves, antibodies are often able to neutralize toxins and viruses or prevent colonization by pathogenic organisms. In addition,

K.E. Sullivan and E.R. Stiehm (Eds): Stiehm’s Immune Deficiencies. DOI: http://dx.doi.org/10.1016/B978-0-12-405546-9.00016-9 © 2014 Elsevier Inc. All rights reserved.

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(A)

DH

VH 1

2

3

4

5

6

70

1

2 3

Primary Immune Deficiencies

JH

4

5 27

Cμ

1 2 3 4 5 6 sμ

DH → JH rearrangement

IgH V D J C C

VH → DHJH rearrangement V J C IgL transcription

C

Cµ

VDJ

C

IGH mRNA

translation α β

(B) V DJ

Cμ

Cδ

Cγ3

Sμ V DJ

Sγ3 Cα1

Sγ1

Sγ2

Ψγ

Cα1

Cγ2

Sα1

Cγ2

Ψγ

SμSα1

Ψε

Cγ1

Cγ4 Sγ4

Sγ2

Cε Sε

Cγ4 Sγ4

Cε Sε

Cα2 Sα2

Cα2 Sα2

FIGURE 16.1 (A) Schematic representation of the Ig heavy chain locus with V(D)J recombination resulting in the formation of a V(D)J exon which is spliced at the RNA level to the exons coding the constant region. After translation a heavy chain is formed. Two identical heavy chains and two identical light chains form an Ig molecule. (B) Schematic representation of a rearranged IGH locus with the different constant regions, which are preceded by switch regions (open circles). During class-switch recombination, the constant region can be permanently replaced via recombination of two switch regions. Isotype switching from IgM/IgD to IgA1 is displayed.

TABLE 16.1 Effector Functions of Different Ig Isotypes Functional Activity

IgM

IgG1

IgG2

IgG3

IgG4

IgA

IgE

Neutralization

1

11

11

11

11

11

2

Opsonization

1

111

2

11

1

1

2

Sensitization for killing by NK cells

2

11

2

11

2

2

2

Sensitization of mast cells

2

1

2

1

2

2

111

111

11

1

111

2

1

2

Activation of complement system Table adapted from Murphy (2012).

2

bacteria and fungi opsonized with antibodies can bind to phagocytic cells expressing immunoglobulin receptors to activate their ingestion and subsequent destruction. Antibodies are also able to activate the complement cascade, which enhances opsonization and may directly lyse Grampositive and -negative bacteria (see Table 16.1).2

IgM IgM antibodies are the first antibodies produced during an immune response. For most immune responses, the IgM response wanes as IgG or other isotypes are produced. However, persistent IgM production may be seen for

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polysaccharides (isohemagglutinins) or lipopolysaccharides (anti-endotoxins), and with certain autoantibodies (cold agglutinins and the rheumatoid factors in cryoglobulinemia). IgM exists as a pentamer with disulfide bonding of IgM monomers to each other and to the J chain (Figure 16.2A). IgM is an excellent agglutinin and activator of complement, and its 10 antigen binding sites may provide high avidity even when the affinity of each site is

(A)

low. The majority of IgM (80%) is intravascular, and its half-life is 5 days.

IgG IgG has four subclasses: IgG1, IgG2, IgG3, and IgG4 (Figure 16.2C). IgG is distributed equally between the intravascular and extravascular compartments. The mean half-life for IgG is the longest of any plasma protein,

(B) VH

Vκ/Vλ Cκ/Cλ

SS

SS

CH1

CH2 CH3

SS

SS

SS

SS

SS

S SSS

SSS S

SS

SS SS

SS

SS

SS

SS

J chain

SS

SS

SS

SS

SS

SS

SS

SS

SS

CH4

SS SS

SS

secretory component

SS

J chain

SS

SS

SS

SS

SS

SS

IgA dimer

IgM pentamer

SS

SS SS

IgG1

SS

SS SS SS SS

SS SS SS SS SS SS SS SS SS SS SS SS SS SS SS

SS

SS

SS

SS

SS

SS

(C)

SS SS

IgG4

IgG2

IgG3

FIGURE 16.2 (A) Structure of an IgM pentamer with disulfide bonding of IgM monomers to each other and to the J chain. (B) Structure of dimeric IgA, associated with the J chain and covalently attached to the secretory component. (C) Structures of four IgG subclasses that differ in length due to the number of disulfide bondings between the Ig heavy chains.

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approximately 23 days. Moreover, the half-life or fractional catabolic rate of IgG is not fixed but varies inversely with the concentration of IgG. Thus, the half-life of IgG in patients with agammaglobulinemia may be greater than 35 days, but it may be as short as 10 days in patients with hypergammaglobulinemia. IgG1, IgG2, and IgG4 all have a 23-day half-life, but the half-life of IgG3 is only 9 days. The long half-life of IgG and its unique relationship to serum levels are due to the FcRn, or Fc receptor of the neonate,3 5 which was originally described on neonatal intestinal epithelium in animals, where it mediates uptake of colostral IgG from the gut. However, FcRn is also located widely on vascular endothelium, permitting continued re-entry of tissue IgG back into the bloodstream and thus extending its effective half-life. Differences in the regulation of IgG subclass expression are evident by the strikingly different levels in serum and characteristic differences in ontogeny. In infants, IgG1 and IgG3 levels increase quickly with age; IgG2 and IgG4 display a slower increase and reach adult levels at puberty (Figure 16.3). The order of appearance of the IgG subclasses in children follows precisely the downstream order of the IgG heavy chain constant region gene segments on chromosome 14 (Cγ3, Cγ1, Cγ2, Cγ4) (Figure 16.1B). The half-life of IgG3 is 9 days less than half that of the other subclasses. IgG3 and IgG4 are more susceptible to proteolytic digestion than the other subclasses. IgG subclass restriction has been reported for antibodies against many bacterial and viral antigens. Antibody titers to pneumococcal polysaccharides correlate best with serum IgG2 concentrations.6 In adults antibody activity to polysaccharides is found predominantly in the IgG2 fraction,7,8 whereas tetanus antibody is found predominantly in the IgG1 subclass9 and the high titers of

1000

Serum concentration (mg/dl)

IgG1 IgG2 100

IgG3 IgG4

10

1 0

2

4

6

8

10 Years

12

14

Adult

FIGURE 16.3 Kinetics of IgG subclass expression level in serum.

Primary Immune Deficiencies

antibody in patients with chronic schistosomiasis10 and filariasis11 are limited to the IgG4 subclass.

IgA and Secretory IgA IgA is synthesized primarily by plasma cells located in the lamina propria just below the basement membrane of the epithelium, at surfaces of exocrine glands and all mucous membranes. Some of the IgA, mostly in a monomeric form, enters the blood and circulates as serum IgA, with a half-life of about 9 days. In other plasma cells, two monomeric IgA molecules bind through their carboxy end to the J chain (Figure 16.2B). Dimeric IgA, associated with the J chain, is secreted by the plasma cell and binds to the polymeric immunoglobulin receptor (poly-Ig receptor) on the basolateral surface of mucosal epithelial cells. Binding of the IgA results in its internalization and transport in a transcytotic vesicle to the apical (luminal) surface of the epithelial cell. At the apical surface, the extracellular, ligand-binding portion of the poly-Ig receptor is enzymatically cleaved and becomes the secretory component (SC) that remains covalently attached to secretory IgA (Figure 16.2B). Secretory IgA is then released from the cell into the mucosal site. The 80-kDa SC renders secretory IgA resistant to proteolytic cleavage at these mucosal locations.

IgE IgE mediates type 1 hypersensitivity allergic reactions. Plasma levels of IgE are normally very low (100,000-fold lower than for IgG), but can be markedly increased in certain allergic conditions, such as bronchopulmonary aspergillosis, or with parasitic diseases, such as schistosomiasis. IgE plasma cells are present in mucosal areas, especially in the respiratory tract, where the secreted IgE mediates allergic reactions, and the gastrointestinal tract, where it may mediate expulsion of parasitic worm infestations. The halflife of IgE in plasma is only 2 3 days, but is prolonged to 2 3 weeks after IgE binds to the Fc receptor FcεRI on the surface of mast cells, basophils, or dendritic cells.

ISOTYPE DEFECTS Several disorders are described to result from isotype defects. These include: (1) Ig heavy chain deletions; (2) Igκ and Igλ chain deficiency; (3) isolated IgG subclass deficiency; (4) IgA with IgG subclass deficiency; (5) selective IgA deficiency; and (6) selective IgM deficiency (summarized in Table 16.2).12,13 Except for selective IgM deficiency, these disorders have been included in the IUIS classification for primary immunodeficiencies.14 They are all characterized by aberrant serum Ig expression, but they do not always result in clinical symptoms. The frequency

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TABLE 16.2 Characteristics of the Six Disorders Caused by Isotype Defects Isotype Disorder Serum Ig

Associated Features

Genetic Defect

Frequency

1. Ig heavy chain deletion

One or more IgG and/or IgA May be asymptomatic subclasses as well as IgE may be absent

Chromosomal deletion at 14q32

Relatively common

2. Igκ deficiency

All immunoglobulins have lambda or kappa light chains

Asymptomatic

Mutations or deletions in IGK

Extremely rare

3. IgG subclass deficiency

Reduction in one or more IgG subclasses

Usually asymptomatic; a minority may have poor antibody response to specific antigens and recurrent viral/bacterial infections

Unknown

Relatively common

4. IgA with IgG subclass deficiency

Reduced IgA with decrease in one or more IgG subclasses

In majority, recurrent bacterial infections

Unknown

Relatively common

5. Selective IgA deficiency

IgA decreased/absent

Usually asymptomatic; may have recurrent infections, allergies, or autoimmune diseases

Unknown

Most common

6. Selective IgM deficiency

Reduced IgM

Infections, atopy, autoimmunity or malignant conditions, but may also be symptomatic

Unknown

Rare

Table based on Notarangelo et al. (2013)13; Al-Herz et al. (2011).12

of isotype defects varies from extremely rare (Igκ and Igλ chain deficiency) to the most common primary immunodeficiency (selective IgA deficiency). Deletions in the Ig heavy chain genes and mutations in the Igκ and Igλ chain genes are the only proven genetic defects described so far.

Ig Heavy Chain Deletions

Clinical Presentation Ig heavy chain deletions are generally asymptomatic and do not require treatment. For specific deletions involving one or more classes or isotypes (IgG and/or IgA) giving rise to partial IgA deficiency and/or IgG subclass deficiency, see accompanying sections.

Definition

Igκ and Igλ Light Chain Deficiency

Patients with Ig heavy chain deletions lack one or more IgG, IgA, and/or IgE classes due to a biallelic genetic deletion. Ig heavy chain deletions can be asymptomatic but can also present as isotype deficiency, depending on the deleted part of the Ig locus.

Definition

Genetics Ig heavy chain deletion is an autosomal recessive disorder caused by chromosomal deletions of a cluster of genes, the constant regions of the IgG and/or IgA and IgE genes (OMIM #147100). In this disorder deletion of IgM is not involved, because deletions of the IGHM gene, which are mediated via transposable elements,14 give rise to agammaglobulinemia; without IgM expression the precursor B cell differentiation is blocked at the pre-B-II cell stage and no mature B cells can be formed.15 Deletion of the IgG locus was first described by Lefranc et al. in 198216 and further extended by Bottaro et al..17 Homologous recombination is involved in the deletion process, and several deletion haplotypes have been described (Figure 16.4).17 19

Deficiency of immunoglobulin kappa or lambda light chains (Igκ and Igλ) is an autosomal recessive disorder in which all immunoglobulin molecules express only a Igκ or Igλ light chain. In the case of heterozygous defects in the IGK or IGL genes, the ratio between Igκ and Igλ expression deviates from the normal ratio (1.5 2.1).20 Igκ and Igλ deficiencies are asymptomatic, but can be seen in combination with other conditions.

Genetics Igκ deficiency is caused by mono- or biallelic mutations in the IGK gene (OMIM #147200, chromosome 2p11).

Pathogenesis During precursor B cell development in bone marrow, V(D)J recombination is initiated at the IGH locus.21 If this results in expression of a functional Igμ chain, V(D)J

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V DJ

Cμ

Cδ

Cγ3C

Cγ1

Ψε

Cα1

Ψγ

Primary Immune Deficiencies

Cγ2

Cγ4

Cε

Cα2

5'

3' Sμ

Sγ3

Sγ1

Sα1

Sγ2

Sγ4

Sε

Sα2

5'γ3 – 5'γ1 5'γ3 – 5'γ4 3'γ3

–

3'γ1

3'γ3 – 3'Ψγ/ 5'γ1 – 5'γ2 3'γ3 – 3'γ2/ 5'γ1 – 5'γ4 3'γ3

–

3'γ4 3'γ1 – 3'Ψγ 3'γ1 – 3'γ2

γ1Ψε – γ4ε / 3'γ1 – 3'γ4 Ψεα1 – εα2 3'α1 – 3'α2 3'Ψγ – 3'γ2 / 5'γ2 – 5'γ4 3'Ψγ

–

3'γ4 3'γ2 – 3'γ4

FIGURE 16.4 Deletions due to homologous recombination in the IGH locus; colored boxes represent haplotypes that have been described whereas white boxes indicate deletions that would be the result of homologous recombination, but have not yet been found. Figure adapted from Olsson et al.19

recombination continues at the IGK locus in an attempt to generate an Igκ light chain that matches the Igμ chain forming the B cell receptor. If no functional Igκ light chain is formed, V(D)J recombination takes place at the IGL locus in order to generate a functional Igλ chain.22 Expression of Igκ occurs more frequently than Igλ, resulting in an Igκ/λ distribution between 1.5 2.1.23

Clinical Presentation Deficiencies of Igκ or Igλ have been reported in a few individuals with immune deficiency. Zegers et al. described a patient with complete absence of Igκ expression, cystic fibrosis, and selective IgA deficiency.24 A sister had a similar Igκ deficiency. Sequence analysis of the patient’s constant region of the IGK gene revealed two different missense mutations, one in each allele, resulting in substitution of a single amino acid in the Igκ light chain molecule.25 A patient with a heterozygous deletion of chromosome 2 region p11.2p13, including the IGK locus, had

dysmorphism of the face, genital region, and limbs, psychomotor retardation, and vitiligo.26 He had a significantly reduced Igκ:Igλ ratio of 0.7, but did not have immunological aberrations or clinical signs of immune deficiency. Earlier reports describe patients with disturbed Igκ:Igλ ratios, but these were not genetically confirmed. Bernier et al. described a child with recurrent respiratory infections and diarrhea who had an Igκ:Igλ ratio of 0.66.27 She also had an IgA deficiency but normal IgG and some antibody function. Barandun and co-workers reported two boys with hypogammaglobulinemia, frequent infections, and pernicious anemia. One had an Igκ:Igλ ratio of 0.01 (Igκ deficiency) and the other a ratio of 6.0 (Igλ deficiency), but no genetic studies were reported.28

Diagnostics Diagnosis is made by assessing serum levels of Igκ and Igλ chains or by immunoelectrophoretic analysis of the patient’s serum with antisera to Igκ and Igλ.

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Alternatively, flow cytometric immunophenotyping of Igκ and Igλ expression on peripheral blood B cells can be used for assessing the Igκ:Igλ ratio. Molecular diagnosis can be made by genetic analysis of the IGK locus.

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Except for the IGHC gene deletions as found in a few patients, the molecular mechanisms of IgG subclass deficiencies in the majority of patients are not exactly known, but are presumed to be due to an aberrant regulation of expression of IGHC genes. As a result, many of the IgG subclass deficiencies are not restricted to a single subclass, but often affect multiple isotypes within a given region of the IGHC locus i.e., IgG2/IgG4 or IgG1/IgG3.30 Aberrant regulation may involve negatively altered regulation of germline transcription through the S and C regions upon activation by particular cytokines.30,31 Alternatively, deregulation of cytokine expression itself can be implicated in IgG subclass deficiency via their ability to regulate germline transcription. For example, defective IFN-γ production has been reported in IgG2 subclass deficiency, although its exact role in the pathogenesis remains to be defined.32

with an IgG1 subclass deficiency generally have some degree of hypogammaglobulinemia (because IgG1 makes up 70% of the total IgG), but some IgG1 is present. IgG subclass deficiency is usually identified among individuals with recurrent upper respiratory infections or lung problems such as asthma, bronchitis, or bronchiectasis. IgG subclass deficiency may also occur as part of another primary immunodeficiency syndrome (e.g., selective IgA deficiency [sIgAD], impaired polysaccharide responsiveness, ataxia-telangiectasia, Wiskott-Aldrich syndrome)34 or as part of a secondary antibody deficiency (e.g., HIV infection, cirrhosis). As patients with CVID have low serum IgG by definition, variable decreases in IgG subclasses are always found. Subclass defects have also been noted in a number of autoimmune disorders (e.g., immune thrombocytopenic purpura [ITP], lupus erythematosus) and as part of several miscellaneous syndromes. Subclass deficiency should be suspected in patients who have recurrent respiratory infections, similarly to patients with impaired polysaccharide responsiveness (see Chapter 17) or sIgAD (see below). The usual respiratory infections are chronic otitis, sinusitis, or bronchitis, but occasionally may be more serious, such as mastoiditis, pneumonia, or bronchiectasis. The offending bacteria are often those with a polysaccharide capsule, such as pneumococci, H. influenzae, meningococci, and group B streptococci. Some patients present with refractory asthma triggered by respiratory infections. Some patients are identified after laboratory testing discloses decreased antibody function, including poor polysaccharide antibody responses (see Chapter 17). Some subclass-deficient patients are identified in patients with low normal IgG levels or selective IgA deficiency. Many patients with an IgG subclass deficiency are not ill or have only mild respiratory symptoms. If their antibody function is intact, the subclass deficiency is less likely to be the cause of these symptoms. Most of these patients have low but not absent IgG1, IgG2, or IgG3 levels. IgG4 also may be absent in a significant percentage (i.e., 10 20%) of subjects, depending on the sensitivity of the assay. A clinically significant subclass deficiency necessitates an accompanying antibody deficiency with poor or absent response to vaccine antigens. Most of these latter patients have refractory respiratory infections. IgG subclass deficiencies are often multiple (affecting more subclasses) and may be associated with selective IgA deficiency. Although clinical features alone do not allow identification of which particular subclass is deficient, each subclass deficiency has some characteristic clinical features.

Clinical Presentation

IgG1 Deficiency

Most IgG subclass-deficient subjects are asymptomatic, particularly those with an IgG4 deficiency.33 Patients

IgG1 deficiency is usually associated with hypogammaglobulinemia because IgG1 makes up 70% of the total

IgG Subclass Deficiency Definition Selective IgG subclass deficiency is defined as a deficiency of one or more IgG subclasses but normal total IgG concentrations.29 The usual criterion of an IgG subclass deficiency is a level less than 2 SDs below the mean for age. Up to 20% of the population has a subnormal IgG subclass level for one or more subclasses. Most IgG subclass-deficient subjects are asymptomatic, particularly those with an IgG4 deficiency. Thus, IgG subclass deficiency does not define a disease; instead, it denotes a clinical laboratory finding. A clinically significant IgG subclass deficiency occurs when the IgG subclass deficiency is associated with recurrent infection and a significant defect in antibody responsiveness.

Genetics IgG subclass deficiency has been shown in a few cases to be due to homozygous deletions of the corresponding constant region of the IGH locus (IGHC genes; see section above), created by non-equal homologous recombination or looping out excision.16 18

Pathogenesis

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IgG, and if low, the total IgG level is low. Therefore, most of the patients with IgG1 deficiency will be classified as common variable immunodeficiency (CVID) if IgA or IgM, or both, is also reduced (see Chapter 14). Selective IgG1 deficiency with normal total IgG would be uncommon. IgG1 deficiency is considerably more frequent in adults than children and is often associated with other subclass deficiencies.35 Many of the pediatric IgG1deficient patients are younger than 5 years of age and are emerging from transient hypogammaglobulinemia of infancy. Older patients with IgG1 deficiency may be developing CVID. IgG2 Deficiency After IgG4 deficiency, IgG2 deficiency is the most common subclass deficiency in children, and males are more commonly affected than females.35 In children, it is the subclass deficiency most often associated with recurrent infections. Most symptomatic patients have recurrent or chronic respiratory infections, often with H. influenzae or pneumococci. Others may have allergy and asthma, and a rare child has severe infections, including meningitis.36,37 O’Keefe and Finnegan38 reported IgG2 deficiency in many patients with obstructive lung disease, particularly in those with long duration of disease and receiving steroid therapy. Because IgG2 contains most of the antibodies to polysaccharide antigens, a deficiency of IgG2 is often associated with impaired polysaccharide responsiveness.39 41 Some of these children have permanent, but more commonly transient, defects in their ability to respond to polysaccharide antigens.42 44 However, among adults, Avanzini and colleagues45 could not correlate antibody responses to H. influenzae conjugate vaccines, IgG subclass deficiencies, and respiratory problems.45 IgG2 deficiency may be a marker for recurrent respiratory responses, rather than the cause of the problem.43 IgG3 Deficiency IgG3 deficiency is less common than IgG4 or IgG2 deficiency in children; however, the frequencies vary considerably between different studies46 for example, some studies reported IgG3 as the most common IgG subclass deficiency,47,48 perhaps because it is considerably more common in adults.35 IgG3 antibodies may be important in the response to respiratory viral infections as well as responses to Moraxella catarrhalis and Streptococcus pyogenes.8,49,50 Most symptomatic IgG3-deficient patients have an associated deficiency of another subclass. These patients have recurrent respiratory infection,51 including refractory sinusitis52 54 or asthma.52,55,56 IgG3 deficiency has also been described in a patient with recurrent lymphocytic meningitis,57 and in patients with an elevated

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IgE and recurrent infections (often with an IgA or IgG4 deficiency)58 and recurrent parotitis.59 IgG4 Deficiency IgG4 deficiency is the most common subclass immunodeficiency. Using insensitive assays such as radial diffusion of immunoprecipitation in which levels less than 5 7 mg/dl are recorded as absent, up to 15% of normal children and 10% of adults may have an IgG4 deficiency.33 Most are asymptomatic. In infants younger than 5 years, the incidence of IgG4 is even higher. Using more sensitive assays, such as ELISA or radioimmunoassay, IgG4 is detectable in nearly all sera, and a deficiency can be defined as a level less than 1 mg/dl.60 Although most IgG4-deficient patients are asymptomatic, several groups have identified IgG4deficient patients who have recurrent respiratory (particularly pulmonary) infection and bronchiectasis.60 62 Hill and co-workers found an IgG4 deficiency in 5% of patients with bronchiectasis, while other subclass deficiencies were found in 1% of patients.63 IgG4 deficiency may be a marker for susceptibility to respiratory infection, possibly associated with an enrichment of IgG4 in the secretions.62,64 Most of these patients have normal antibody responses to vaccine antigens. IgG4 deficiency is often associated with IgG2 deficiency, IgA deficiency, or combined IgG2 IgA deficiency, and many of these children have recurrent infections and poor antibody responses to polysaccharide antigens.62,65 The contribution of the IgG4 deficiency to their infection susceptibility is not known. IgG4 deficiency has been noted in Wiskott-Aldrich syndrome, IgM deficiency34 ataxia-telangiectasia,56 and mucocutaneous candidiasis.66 Other disorders with IgG4 deficiency include Down syndrome,67 immune thrombocytopenia, lupus erythematosus, and growth hormone deficiency (with IgG2 deficiency).34,68

Diagnostics IgG subclass determinations are not recommended in the initial evaluation of individuals with recurrent infection, because functional antibody studies are the paramount test; in the presence of normal antibody function, a subclass deficiency is not clinically significant. Some authorities question the value of subclass determination at any time.33,69 We recommend IgG subclass determinations for patients with selective IgA deficiency, for patients with detectable immunoglobulins but selective antibody deficiencies, and for patients in which an early stage of CVID is suspected. IgG subclass tests will also pick up clonal proliferations, and excesses of one subclass over all the others is suggestive of this. IgG subclass levels must be compared with age-matched controls because levels increase with age, particularly in the first 2 years. For children aged 4 to 10 years, an IgG1 level less than

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Isotype Defects

250 mg/dl, an IgG2 level less than 50 mg/dl, an IgG3 level less than 15 mg/dl, and an IgG4 level less than 1 mg/dl are considered abnormal. For subjects older than age 10, an IgG1 level less than 300 mg/dl, an IgG2 level less than 75 mg/dl, an IgG3 level less than 25 mg/dl, and an IgG4 level less than 1 mg/dl are abnormal. If radial diffusion is used to measure IgG4, levels between 1 mg/dl and 8 mg/dl are usually reported as non-detectable, thus increasing the frequency of the diagnosis of IgG4 deficiency. However, to substantiate a clinically significant subclass deficiency, the response to protein and/or polysaccharide antigens must be deficient, as outlined in Chapter 17 and in the section on impaired polysaccharide responsiveness in this chapter. The definition of a poor response to pneumococcal antigens is that used in the impaired polysaccharide-responsive patients (i.e., failure to respond to a majority of the pneumococcal antigens following a pneumococcal polysaccharide vaccine, or failure to exhibit a two-fold rise in titer to serotypes for which there are non-protective levels). Most patients with an IgG4 deficiency are excluded by this criterion. Because one or more IgG subclasses are depressed in transient hypogammaglobulinemia of infancy (THI), a subclass deficiency can rarely be diagnosed before age 4.70 Instead, these patients most likely have THI.

Management Asymptomatic individuals with one or more subclass deficiencies and normal antibody responses require no treatment. Because only a tiny percentage of these patients (particularly those with IgG1, IgG2, or IgG3 deficiencies) may show evolution into CVID, individuals with respiratory infections and an IgG subclass deficiency but with normal antibody function are not candidates for Ig replacement therapy; indeed, this is probably the most common reason for the misuse of Ig treatment.71 Alternative treatments, such as antibiotics, inhaled steroids, bronchodilators, and surgical procedures for obstructive lesions, may be needed. Individuals with severe recurrent respiratory infections and a subclass deficiency (sometimes with an associated IgA deficiency), as well as a documented antibody deficiency, may benefit from Ig therapy. This is particularly true for individuals who have deficient antibody responses to both protein and polysaccharide antigens. A failure of prolonged antibiotics, severe symptoms, and persistent radiographic abnormalities also favors the use of IG replacement. Under such circumstances, Ig therapy can be given as for other patients with primary antibody deficiency. This has reportedly been effective in reducing infection in several patients with subclass deficiencies.72 When the Ig replacement therapy is to be discontinued after several months of therapy, it should be stopped in the warmer months to avoid community respiratory viral

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infections (which will be blamed on cessation of the therapy). The child younger than age 5 years with frequent, non-life endangering respiratory infections and a subclass deficiency or impaired polysaccharide responsiveness is a special problem. Lawton points out that most infectionprone children attending preschool who are given Ig replacement will almost certainly have a decreased number of respiratory infections,70 and if a mild immunodeficiency has been diagnosed as the cause this will emphatically affirm the diagnosis, and the parents will be reluctant to stop Ig treatment. Indeed, if stopped, the frequency of infection increases temporarily, and lessens the physician’s credibility.

Prognosis Children younger than ages 6 to 8 years usually outgrow their IgG subclass deficiency, but adults rarely do. Recovery is more common if the subclass is low but not absent. A rare patient may progress to CVID.

Selective IgA Deficiency Definition Selective IgA deficiency (sIgAD; OMIM #137100) defines a disorder with serum IgA levels ,0.07 g/l or less, with normal IgM and IgG levels in individuals $ 4 years of age (definition as established by the Pan-American Group for Immunodeficiencies and the European Society for Immunodeficiencies).13 Most individuals are clinically asymptomatic; however, sIgAD can be associated with recurrent infections, allergies, and autoimmunity.

Genetics Although the genetic cause for sIgAD is unknown, there is evidence for a genetic predisposition based on familial clustering and association with known genetic loci. The pattern of sIgAD inheritance is unclear; however, a family history (first degree relatives) for sIgAD or common variable immunodeficiency (CVID) is a significant risk factor.73 75 In 2005, two groups reported that genetic variants in the TNFRSF13B gene, which encodes TACI (transmembrane activator and CAML interactor), were associated with sIgAD and CVID.76,77 While TACI mediates isotype switching in B cells (for details see Chapter 14), another study did not find that these variants as associated with IgA deficiency. In addition, TACI variants can also be found in healthy individuals,78,79 suggesting that these variants are disease-modifying rather than disease-causing.80 Associations between sIgAD and certain major histocompatibility complex (MHC) class I, II, and III haplotypes have been proposed for many years.81 In sIgAD and type 1 diabetes mellitus (T1D), HLA-B8 frequency was found to

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be increased in some studies. HLA-B8 frequency was also higher in IgA deficiency and autoimmune disorders. However, these findings may be secondary to the presence of diabetes mellitus or autoimmune disorders rather than sIgAD itself.82 A recent study questioning the frequently implied higher risk for sIgAD deficiency with the HLA8 DR3 haplotype has shown that sIgAD is not associated with a distinct haplotype; rather, the risk is conferred by the common extended MHC haplotype HLA A1, B8, DR3, and DQ2 (the 8.1 haplotype) acting in a multiplicative manner.83 In some populations up to 45% of IgAD patients carry at least one copy of the ancestral 8.1 haplotype, as compared with 16% in the general population, and homozygosity for this haplotype increases the risk even further.83 The HLA-DR7, DQ2, and DR1, DQ5 haplotypes have also been shown to be risk factors for sIgAD, whereas the DR15, DQ6 haplotype has been reported to confer an almost complete protection against the disorder.84,85 Association of non-HLA genes with sIgAD has recently been demonstrated for IFIH1 and CLEC16A in a genome-wide association study.86 A non-synonymous variant in the IFIH1 gene, encoding the interferon-induced helicase C domain-containing protein 1, was associated not only with sIgAD but also with T1D and SLE.87 IFIH1 functions together with RIG-1 as sensor for viral infections.85,88 Similarly, variants in the C-type lectin domain family 16 gene (CLEC16A), which functions on B cells, NK cells, and dendritic cells, were found to be associated not only with sIgAD,86 but also with other autoimmune diseases like type 1 diabetes and multiple sclerosis.89 These findings support the hypothesis that autoimmune mechanisms may contribute to the pathogenesis of sIgAD.

Pathogenesis The exact pathological mechanism of sIgAD is unknown, but it is believed to be a heterogeneous disorder that arises through several mechanisms. Patients with sIgAD have reduced IgA-positive switched memory B cells similarly to CVID, but the reduction is less pronounced.90,91 Although reduced, IgA-positive B cells are present, but apparently they fail in differentiation into IgA-secreting plasma cells in vitro upon stimulation with IL-10 and CD40L.92 T cell abnormalities have often been sought in sIgAD, because a T cell regulatory abnormality is an attractive hypothesis.93 A reversible T cell influence might explain why IgA deficiency can resolve spontaneously after exposure to certain drugs. Despite these reasons for suspecting a T cell defect in IgA deficiency, few IgA-deficient patients seem to have identifiable defects using current analytical methods. IgA deficiency is associated with certain MHC haplotypes (see Genetics, above). This suggests that the inheritance of a certain gene in the MHC area of chromosome 6

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confers susceptibility to IgA deficiency. A gene of this sort may potentially activate IgA B cell maturation. Molecular analyses have demonstrated some errors of switch (S)μ to Sα recombinations in peripheral B cells from IgA-deficient subjects. Two types of defects low expression of both secreted and membrane forms of productive constant (C), a messenger RNA (mRNA) in IgAswitched B cells and impaired IgA switching were characterized in IgA-deficient subjects homozygous for the MHC haplotype (HLA-B8, HLA-SC01, HLA-DR3). This could reflect a blockade in post-IgA switch differentiation of B cells.94

Clinical Presentation sIgAD was first described in children with ataxia-telangiectasia,95 but soon sIgAD was identified in other patients and even in healthy subjects. Most individuals with IgA deficiency (85 90%) are clinically asymptomatic82; however, recurrent respiratory and gastrointestinal tract infections and allergy have often been reported both in children and adults.96 99 sIgAD is the most common primary immunodeficiency in whites, with an estimated frequency of 1:600.100 Its prevalence ranges from 1:155 to 1:18550 in community populations from different countries.101,102 Some studies have investigated the prevalence of sIgAD in predominantly male blood donors or in Rhnegative women. Although there are no apparent gender differences in the occurrence of sIgAD in healthy persons,103 male IgA-deficient individuals appear more prevalent in hospitalized groups.104 sIgAD may occasionally be familial, and several studies have noted a higher frequency of mother-to-child inheritance of sIgAD than of father-to-child inheritance.73,105 Investigation of families in which IgA deficiency and common variable immunodeficiency were present in more than one individual showed that 30 affected children had affected fathers whereas 118 children had unaffected fathers. In contrast, 75 affected children were born to affected mothers, and 95 affected children were born to unaffected mothers.106 One explanation is the potential transplacental passage of anti-IgA antibodies, which could result in sIgAD in the infant. Petty and colleagues studied 27 offspring of IgA-deficient mothers; 12 had IgA levels more than 1 standard deviation (SD) below normal, and 7 had levels more than 2 SDs below normal. Of the 7 with the lowest IgA levels, 5 had mothers with anti-IgA antibodies during gestation.107 IgA Deficiency in Healthy Subjects Because secretory IgA is important in protecting mucous surfaces, it is of course a mystery why most IgA-deficient subjects remain healthy. This lack of disease in sIgAD has been attributed to a compensatory increase in IgM in the

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secretions.108 In IgA-deficient individuals there may be an increase in secretory IgM (lgM attached to secretory component) in the saliva and other intestinal fluids, and in IgM-bearing plasma cells in the gastrointestinal mucosa. Similarly, the colostrum of IgA-deficient subjects has been shown to contain abundant amounts of IgM.109 The saliva of IgA-deficient individuals contains biologically active IgM antibody, such as secretory IgM to Streptococcus mutans.110 Although secretory IgM is functionally active, it may not confer mucosal protection equivalent to that of secretory IgA. Norhagen and associates questioned the view that IgM can compensate for sIgAD in the secretions, but could not relate salivary IgM levels to health or frequency of illness in 63 IgA-deficient subjects.111 Conversely, Mellander and colleagues found that infections are more common in IgA-deficient individuals with low or absent secretory IgM.112 Nilssen and co-workers have shown that oral cholera-vaccinated, IgA-deficient individuals preferentially activate intestinal IgG-producing cells rather than IgM.113 The response to this vaccination (which in normal subjects produces a predominantly IgA response) was not significantly different from that in healthy, asymptomatic IgA-deficient individuals. Another reason some IgA-deficient individuals might remain healthy is that secretory IgA is produced in normal amounts in up to 3% of IgA-deficient individuals having normal levels of secretory IgA114 and possessing normal numbers of IgA-bearing plasma cells in the intestine. In any case, sIgAD in healthy adults appears to be a stable defect over many years of follow-up. sIgAD in Specific Disorders Despite the fact that most IgA-deficient subjects are not ill, sIgAD has been associated with an large number of specific disorders.81,115 118 Jorgensen et al. studied 32 adults with sIgAD and compared them with 63 age- and gender-matched controls.99 The sIgAD individuals reported significantly more often with various upper and lower respiratory infections and increased prevalence of allergic diseases and autoimmunity, with a total of 84.4% being affected by any of these diseases, compared with a total of 47.6% of the controls (P , 0.01). sIgAD and Sinopulmonary Infections Recurrent sinopulmonary infections are the most common illnesses associated with sIgAD. These infections are mostly due to encapsulated bacteria, such as Haemophilus influenzae and Streptococcus pnemoniae.82 Children with sIgAD experience recurrent otitis media, sinusitis, and/or pneumonia. Recurrent upper respiratory tract infections are more frequent than lower respiratory tract infections (77.1% versus 22.9%).97 Adults with sIgAD also suffer from recurrent sinusitis and pulmonary infections, but

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otits media is less common. There are several reports of chronic serious lung disease in sIgAD, including sarcoidosis, recurrent pneumonia, chronic obstructive lung disease and chronic bronchitis, and pulmonary hemosiderosis.115,119,120 Some patients may develop end organ damage such as bronchiectasis secondary to recurring or chronic infections.121,122 sIgAD and Allergy sIgAD has long been associated with the development of allergy.97,104,123,124 The most common allergic disorders in IgA-deficient individuals are allergic conjunctivitis, rhinitis, urticaria, atopic eczema, and bronchial asthma.115,125,126 Many clinicians notice that IgA-deficient subjects with asthma have a worse disease severity compared to controls99; perhaps their susceptibility to secondary respiratory infections aggravates the associated inflammation. Food allergy may be more common in IgA-deficient patients.124 However, it should be noted that serum IgE levels are often reduced in individuals with sIgAD,85 and in another study in adults atopy was not found to be more frequent in sIgAD as compared to controls.127 sIgAD and Gastrointestinal Tract Disorders Patients with sIgAD have an increased frequency of gastrointestinal diseases. The best known association is infection with Giardia lamblia.128,129 Presumably the lack of secretory IgA permits the attachment to and proliferation of these protozoa on the intestinal epithelium.130,131 If giardiasis occurs in sIgAD, malabsorption resulting from flattened villi, often accompanied by nodular lymphoid hyperplasia, may develop. Diagnosis warrants multiple stool analyses and an examination of the duodenal fluid. Relapses after treatment with metronidazole or quinacrine hydrochloride are fairly common. The most common non-infectious gastrointestinal complication in patients with sIgAD is celiac disease.132,133 Conversely, sIgAD is present in 2% of celiac patients and is equally prevalent among adults and children.134 Such patients will lack the characteristic IgA anti-endomysial antibody used in diagnosis of celiac disease,135 but IgG serologies may be persistently elevated despite histology recovery.134 IgG anti-tTG and IgG EMA autoantibody tests are highly efficient in detecting celiac disease in IgAdeficient patients.136 139 Intestinal biopsy specimens of patients with co-existing sIgAD and celiac disease are similar to those of patients with celiac disease alone, and their responses to a gluten-free diet are also similar.140 Inflammatory bowel disease, including ulcerative colitis and Crohn’s disease, also occur with increased frequency in sIgAD,141 although the pathophysiologic relationship is unclear.142 144

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Nodular lymphoid hyperplasia and malabsorption are associated with sIgAD too,145,146 but malabsorption can be present without nodular lymphoid hyperplasia.147 Severe diarrhea in association with sIgAD and lymphoid hyperplasia or malabsorption may be difficult to treat. Associations between sIgAD and other autoimmune intestinal diseases have included chronic hepatitis,148 biliary cirrhosis,149 and pernicious anemia.150 Ulcerative colitis and regional enteritis are also associated with sIgAD. IgA Deficiency and Autoimmune Diseases Autoantibodies, such as antibodies against sulfatide, Jo-1, cardiolipin, phosphatidylserine, and collagen, can be detected in up to 90% of IgA-deficient patients even if clinical disease is not found.151 Also, in children an increased frequency of autoantibodies is found without correlation with clinical manifestation.152 Patients with sIgAD can also develop overt autoimmune diseases,133 of which systemic lupus erythematosus (SLE)153 155 and juvenile or adult-onset rheumatoid arthritis156 158 are the most commonly reported. Autoimmune diseases are highly prevalent in individuals with IgAD and more common in their first-degree relatives than expected, thus suggesting a possible common genetic component.159 An association of Graves’ disease and type 1 diabetes has also been described.85,133,160 Genetic factors are important for the development of both IgAD and various autoimmune disorders, including Graves disease, SLE, type 1 diabetes, celiac disease, myasthenia gravis, and rheumatoid arthritis, and a strong association with the major histocompatibility complex (MHC) region has been reported. In addition, non-MHC genes, such as interferon-induced helicase 1 (IFIH1) and c-type lectin domain family 16, member A (CLEC16A), are also associated with the development of IgAD and some of the autoimmune diseases.133 sIgAD and Malignancy Carcinoma (particularly adenocarcinoma of the stomach) and lymphoma (usually of B cell origin) are also associated with IgA deficiency.161 Often the lymphomas are extranodal and involve the jejunum. Whether nodular lymphoid hyperplasia leads to lymphoma is not known. In one cancer hospital, 12 of 4210 patients had selective IgA deficiency an incidence of 1 in 342 (0.3%). However, there are no data demonstrating a substantially increased risk of malignancies in sIgAD.

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level was lower than 5 mg/dl; in most such cases, however, the IgA level is between 5 and 30 mg/dl (i.e., partial IgA deficiency).164 In a follow-up study of 40 children with sIgAD, four boys showed a rise in serum IgA levels to low normal levels.165 Resolution of IgA deficiency is much more common in children under 5 years of age,166 presumably the result of a delayed maturation of the IgA system. IgA deficiency can be acquired following drug therapy or viral infection. Penicillamine,167 sulfasalazine,168 hydantoin,169,170 cyclosporine,171 fenclofenac,172 sodium valproate,173 and captopril can produce a usually reversible IgA deficiency174 (see also Box 16.1). On the other hand, congenital rubella and Epstein-Barr virus infections may result in persistent IgA deficiency.175 A unique case of acquired IgA deficiency was reported by Hammarstrom and colleagues,176 who noted that an IgA-deficient bone marrow transplant donor transferred the deficiency to the recipient, who previously had normal IgA levels. Many patients have a serum IgA level lower than expected for age (i.e., less than 2 SDs from the mean, but above 7 mg/dl), a condition that can be considered “partial” IgA deficiency. This is more common in children, presumably because of the immaturity of the IgA system. As noted earlier, such patients are more likely to undergo spontaneous remission. Partial IgA deficiency can be the result of deletions of genes controlling either the α1 or α2 chains, a condition termed selective IgA1 (or IgA2) subclass deficiency.19

Anti-IgA Antibodies A significant proportion of IgA-deficient individuals have anti-IgA antibodies in their serum.186 Anti-IgA antibodies can be directed to IgA1 (most commonly), IgA2, or the allotypic variants A2m(1) or A2m(2). These antibodies occur with a reported frequency of 9.6% to 44% in IgAdeficient subjects.187,188 Although blood or blood products

Box 16.1 Drugs that can Cause Reversible sIgAD G G G G G G G

Other Forms of IgA Deficiency: Transient, Acquired, Partial, and Selective Although IgA deficiency is generally a permanent condition,162 occasionally a spontaneous remission occurs i.e., transient IgA deficiency.163 In a few such instances of transient IgA deficiency with recovery, the original IgA

Primary Immune Deficiencies

G G

D-Pencillamine167,177 Sulfasalazine168 Hydantoin169,170 Cyclosporine171 Fenclofenac172 Gold178 Anticonvulsants179 G phenytoin180,181 G valproic acid173 G carbamazepine182 G zonisamide183 Captopril174,184 Thyroxine185

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given to IgA-deficient individuals with high titers of antiIgA antibodies can lead to severe, even fatal, transfusion reactions, such reactions are actually quite rare.189 191 Hospitalized patients, some of whom are certain to be IgA deficient, are not screened for anti-IgA antibodies prior to blood transfusions. The actual incidence of anti-IgAmediated blood infusion reactions, due to anti-IgA antibodies, has been estimated as 1.3 per million units of blood or blood products infused.192 Reactions to these blood products have also been described in CVID, and can be clinically indistinguishable from anaphylaxis.189,193,194 AntiIgA antibodies are more common in IgA-deficient individuals with undetectable IgA, but may occasionally occur when the IgA level is 10 mg/dl or higher. Ferreira and associates found that 39% of their IgA-deficient patients had anti-IgA antibodies195; 22% of those in the antibodypositive group had IgA levels between 1.1 and 5 mg/dl, and the remaining 78% had IgA levels lower than 1.1 mg/ dl. Anti-IgA antibodies are usually of the IgG1 class,196 and are more common in IgA-deficient subjects who are also IgG2 deficient.195,197 Anti-IgA antibodies may be of the IgE isotype, leading to true anaphylactic reactions115; however, the actual incidence of such antibodies is unknown, and some studies have not found them.187 Because IgA-deficient and IgG2-deficient individuals often have poor but not absent antibody responses and may require immunoglobulin treatment57 they may be at particular risk for infusion reactions, because immunoglobulin treatments contain varying amounts of IgA. IgAdepleted preparations are available and are usually well tolerated, even in patients with high titers of anti-IgA antibodies.197 Eijkhout et al. demonstrated that side effects due to anti-IgA antibodies were not observed when human immunoglobulin was given by subcutaneous infusion.198 In some patients, antibodies disappeared and therapy could be changed to intravenous Ig administration. It should be noted that there are also other factors which might influence the association of adverse reactions with anti-IgA antibodies, including the serum concentration and isotype (IgG or IgE) of the anti-IgA antibody, its specificity (class or subclass specific), the method of measurement, and the IgA content of the gammaglobulin infusion and its route of administration, which would make the role of anti-IgA antibodies in causing anaphylaxis in sIgAD received immunoglobulin treatment controversial.80

Diagnostics When IgA deficiency is identified in a healthy person with no significant medical history, no further evaluation is needed. Usually, quantitative immunoglobulins have been ordered because a significant clinical problem has emerged. In these cases, especially when significant infections have been present, IgG subclass levels should

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be performed. A combined IgA IgG2 subclass-deficient patient may have a normal IgG levels because of an elevation of other IgG subclasses; such individuals may have a history of serious or even life-threatening illness. Many of these patients may not respond to vaccination with pneumococcal polysaccharides. For these patients Ig replacement is sometimes indicated, but anti-IgA antibodies can be present in such patients. Whether anti-IgA antibodies should be determined in all IgA-deficient patients is debatable. Although anti-IgA antibodies can produce serious anaphylactic reactions if blood or blood products (including Ig) are infused, the likelihood of such a reaction is low. Some IgA-deficient patients have persistent allergic symptoms. An allergic evaluation, including skin and or radioallergosorbent testing, may be indicated. Serum immunoglobulin levels on family members to ascertain the inheritance pattern, although of scientific interest, are not usually indicated unless a family member has symptoms. Similarly, HLA typing in patients or their families, except for research purposes, is not indicated unless a family member has symptoms. IgA-deficient patients with certain HLA types are not more likely to have specific medical problems. Quantitation of IgA1 and IgA2 levels in the partially IgA-deficient patient is difficult and expensive, and not informative. Although there is an association between IgA deficiency and autoimmune disease, the likelihood of an autoimmune disease developing in an individual IgA-deficient patient is probably low. Thus, extensive screening for autoantibodies is not indicated in the asymptomatic IgAdeficient patient.

Management There is no specific treatment for IgA deficiency because there are no drugs that activate IgA-producing B cells. A preliminary ex vivo study demonstrates an initial basis for a potential therapeutic role of IL-21 to reconstitute Ig production.199 Intermittent or continuous prophylactic antibiotics may be helpful in patients with recurrent respiratory tract infections, particularly those with chronic asthma, bronchitis, or sinusitis. For the IgA-deficient individual with concomitant IgG2 subclass deficiency, or impaired antibody responses to bacterial or vaccine antigens, immunoglobulin replacement may be warranted, especially when lung damage is present or recurrent infections are prominent.71 Ig replacement in the usual therapeutic doses (300 400 mg/kg body weight, every 3 to 4 weeks) is indicated. In some cases, one might elect to use a product low in IgA to decrease the risk of sensitization, but the utility of this is unknown. Subcutaneous infusions of immunoglobulin can

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also be used safely under these circumstances.198,200 Transfusions with other blood products containing IgA (whole blood, red blood cells, platelets, fresh frozen plasma, cryoprecipitate, or granulocytes) may sensitize the selective IgA-deficient patient, or may cause an anaphylactic reaction in a sensitized patient with anti-IgA antibodies.201 Lactose intolerance is not uncommon in sIgAD, and milk should be avoided in lactose-intolerant IgA-deficient patients. IgA-deficient subjects with milk precipitins are not instructed to avoid milk, because there is no clear association with disease. Management of Secondary Complications Associated diseases in sIgAD are treated conventionally using standard therapies, and the results in most cases are the same as in non-immunodeficient patients.

Prognosis SIgAD in children usually persists,97,164 whereas partial IgAD in children may resolve over time.163,166 SIgAD can progress to common variable immunodeficiency, which tends to occur in adolescence or young adulthood.202,203 The prognosis of sIgAD diagnosed in adulthood has not been well studied.

Selective IgM Deficiency Definition Selective IgM deficiency is an isolated absence or profound deficiency of serum IgM associated with infections, atopic manifestations, autoimmunity, or malignant conditions, but it may also be asymptomatic. There are no other underlying immunodeficiencies. Serum IgM levels are less than 10 15 mg/dl in infants and children and less than 20 30 mg/dl in adults. Other immunoglobulin levels and T cell immunity are usually normal.

Genetics No genetic or molecular basis has been established as a cause of selective IgM deficiency.

Pathogenesis Considering the ontogeny of B cell maturation, the selective absence of IgM is difficult to explain, particularly because most patients studied have normal numbers of circulating surface IgM1 B cells and normal serum levels of IgG and IgA, which is indicative for normal B cell responses. Over the past 20 years, several in vivo and in vitro immunologic, phenotypic, and functional studies have been published, sometimes with conflicting results; these are summarized by Goldstein et al.204 and Yel et al.205 In vitro studies have

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identified B cell defects characterized by inability of B cell differentiation into IgM secreting cells206 208 with a failure of secreted Igμ messenger RNA synthesis.209 Mutations or deletions have not been observed in the IGHM gene, including the region encoding the secretory domain of IgM.210 Other studies showed that patients’ IgM-positive B cells produced normal amounts of IgM in vitro when cultured with normal T cells, whereas patients’ T cells demonstrated decreased helper activity for IgM, but also for IgG and IgA production, which would favor a defect in T-helper cell function.211 There was no indication for suppressor T cell defects that would selectively interfere with IgM synthesis.211 Some mitogen- and antigen-stimulated B cell proliferation assays show normal IgM response whilst others show a decreased response (reviewed by Goldstein et al.204).

Clinical Presentation The prevalence of selective IgM deficiency is 0.03 1% of the population.212 Between 60% and 80% of patients suffer from recurrent bacterial and viral infections. Common presentations include otitis media, bronchitis, chronic rhinosinusitis, pneumonia, and sepsis.204 Selective IgM deficiency may also be asymptomatic. Allergic disorders are also common manifestations, with presenting features such as asthma and allergic rhinitis.205,212 The association of selective IgM deficiency and atopy has already been described in earlier reports.123 Idiopathic anaphylaxis and idiopathic angioedema have been reported in a patient cohort gathered from an allergy and immunology practice.212 Autoimmune diseases, including systemic lupus erythematosus,213 Hashimoto thyroiditis,214 idiopathic thrombocytopenia purpura,215 autoimmune glomerulonephritis,215 liver cirrhosis from autoimmune hepatitis,216 and rheumatoid arthritis have been associated with selective IgM deficiency. Individual cases of malignancies i.e. sarcoma,217 lymphoma,205 and plasmacytoma have also been reported, but studies with larger samples are required to determine whether selective IgM deficient patients are really at risk of a malignancy (Goldstein et al., 2006).212 Other Causes of Decreased Serum IgM Other causes of decreased levels of serum IgM (i.e., secondary IgM deficiency) are episodes of infection, thymic hypoplasia, celiac disease, autoimmune disease, and certain adult malignancies; and other PIDs (Wiskott-Aldrich syndrome, DOCK8 deficiency, ataxia-telangiectasia, CVID, and XLA, in combination with IgG and IgA, transient hypogammaglobulinemia of infancy), and congenital disorders (Bloom syndrome and Russell-Silver syndrome).204 Primary selective IgM deficiency is less common than secondary immunodeficiency.

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403

Diagnostics Laboratory studies disclose selective IgM deficiency (,20 30 mg/dl in adults, and ,10 15 mg/dl in infants and children), when measured at least twice on separate occasions. Antibody responses to vaccination can be variable but are usually normal. Antibody responses to diphtheria, tetanus, and pneumococcal polysaccharide vaccines can be reduced despite normal serum IgG levels.218 Numbers of peripheral B cells, including IgM 1 B cells, are normal. Most, but not all, patients have normal T cell numbers and function.219 The clinical history should be explored for the presence of associated conditions, as these may ultimately explain the low levels of IgM.

Management Selective IgM patients are managed in the same fashion as for other antibody deficiencies. Ig replacement would only be given if there were a significant associated antibody deficiency. Prophylactic antibiotics and prompt treatment of febrile illness are crucial. Vaccines, particularly pneumococcal and meningococcal vaccines, should be given if there is some antibody responsiveness, and the post-vaccine response assessed.

10.

11.

12.

13. 14.

15.

16.

17.

Prognosis In some infants, selective IgM deficiency may be transient.220 For other patients insufficient data are available for a prognosis.

18.

19.

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PART | 2

Primary Immune Deficiencies

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