Excerpt from Immunoglobulin A Deficiency

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Background

Selective immunoglobulin A deficiency (SIgAD) is a primary immunodeficiency disease and is the most common of the primary antibody deficiencies (Bonilla, 2005). Total immunoglobulin A deficiency (IgAD) is defined as an undetectable serum immunoglobulin A (IgA) level at a value of 5 mg/dL (0.05 g/L) in humans. Partial IgAD refers to detectable but decreased IgA levels that are more than 2 standard deviations below normal age-adjusted means (Daele, 2000).

IgAD is commonly associated with normal B lymphocytes in peripheral blood, normal CD4⁺ and CD8⁺ T cells, and, usually, normal neutrophil and lymphocyte counts. Anti-IgA autoantibodies may be present. Peripheral blood may also be affected by autoimmune cytopenias, eg, autoimmune thrombocytopenia (Spickett, 1991; Longhurst, 2002).

IgA was first identified by Graber and Williams in 1952; ten years later, the first patients with IgAD were described.

IgAD is a complex disorder, and the results of intensive study are beginning to elucidate the genetic loci and molecular pathogenesis of this disorder. Several lines of evidence support a common pathogenesis for IgAD and common variable immunodeficiency (CVID), which is discussed further in Pathophysiology. Family studies show variable inheritance patterns. Familial inheritance of IgAD occurs in approximately 20% of cases (Hammarstrom, 2000), and, within families, IgAD and CVID are associated (Vorechovsky, Am J Hum Genet, 1999; Vorechovsky, J Immunol, 1999).

Associated conditions reported in some IgAD patients include (1) deficits in one or more immunoglobulin G (IgG) subclasses (20-30% of IgA-deficient patients) and (2) a deficient antibody response to pneumococcal immunization. Some patients with IgAD later develop CVID.

Primary IgAD is permanent, and below-normal levels have been noted to remain static and persist after 20 years of observation (Koskinen, 1994).

Environmental factors such as drugs or infections can cause IgAD, but this form is reversible in more than half the cases (see Causes).

Although individuals with IgAD have largely been considered healthy, recent studies indicate a higher rate of symptoms. A 20-year follow-up study that compared 204 healthy blood donors with incidentally identified IgAD to 237 healthy subjects with normal IgA levels demonstrated that 80% of IgAD donors and 50% of control subjects had episodes of infections, drug allergy, or autoimmune or atopic disease. Severe respiratory tract infections occurred in 26% of IgAD subjects, in 24% of subjects with decreased IgA levels, and in 8% of control subjects; however, the incidence of life-threatening infections was not increased. IgAD is more common in adult patients with chronic lung disease than in healthy age-matched control subjects (International Union of Immunological Societies, 1999).

Patients with IgAD are at a high risk of developing severe reactions after receiving blood products (Sazama, 1990; Rogers, 1998; Sanz, 1999). IgA-deficient patients with immunoglobulin E (IgE)–class anti-IgA antibodies are at risk for anaphylaxis if they receive blood or intravenous immunoglobulin. Only intravenous immunoglobulin depleted of IgA should be used in patients with confirmed or probable IgE anti-IgA antibodies. A history devoid of previous blood product administration does not exclude the possibility of anti-IgA antibodies or adverse reactions. Fortunately, appropriate precautions can significantly reduce morbidity (see Treatment).

Pathophysiology

IgA is the second most common immunoglobulin in human serum (after IgG) and is the predominant immunoglobulin found in mucosal secretions.

Structurally, IgA has 2 different forms. Serum IgA is a monomer, and secretory IgA is a dimer; it is this property that makes this unique immunoglobulin resistant to the proteolytic enzymes found in many human secretions.

Secretory IgA antibodies can neutralize viruses, bind toxins, agglutinate bacteria, prevent bacteria from binding to mucosal epithelial cells, and bind to various food antigens, thus preventing their entry into the general circulation. The role of serum IgA is unclear.

IgAD is a primary immunodeficiency disease presumed to result from a failure of terminal differentiation in IgA-positive B cells. Multipotent hematopoietic stem cells give rise to progenitors of T cells, B cells, and natural killer cells.

The development of B-lineage cells begins in the fetal liver. B-lineage cell development then transfers to the bone marrow when it becomes the major hematopoietic organ. Pre–B cells become immature immunoglobulin M (IgM)–positive B cells and then migrate from the bone marrow to lymph node germinal centers. After leaving the bone marrow, the B cells mature and express immunoglobulin D receptors, respond to antigens, and, with the help of T cells (CD4⁺), undergo proliferation and plasma cell differentiation (International Union of Immunological Societies, 1999).

In germinal centers, antigen is presented by follicular dendritic cells with help from CD4⁺ T cells and stimulates B cells to proliferate and undergo somatic mutation and immunoglobulin class-switching. B cells that produce high antigen affinity antibodies are selected to develop into plasma cells that produce different immunoglobulin isotypes (ie, IgM, IgG, IgA, or IgE) or become recirculating memory B lymphocytes. These processes are regulated by cell interaction molecules (eg, CD40 on B cells, CD40 ligand on activated T cells), and cytokines (ie, interferon-gamma and interleukin [IL]–2, IL-4, IL-5, IL-6, IL-7, IL-10, IL-12, IL-13, IL-14, and IL-15) and their cell surface receptors (International Union of Immunological Societies, 1999).

Patients with IgAD have a normal number of B cells expressing surface IgA in their blood, but the amount of surface IgA on each B cell is markedly decreased. Based on animal studies, the failure of B cells to terminally differentiate into IgA-secreting plasma cells may be due to the lack of effects caused by cytokines such as IL-4, IL-6, IL-7, or IL-10.

Molecular analysis of B-cell differentiation in a small number of patients with selective or partial IgA deficiency indicated that a decreased expression level of alpha germline transcripts before a class switch might be critical for the pathogenesis of some patients with SIgAD. However, in patients with a partial IgA deficiency, B-cell differentiation might be disturbed after a class switch (Asano, 2004). Missense mutations in one allele of the tumor necrosis factor receptor family member TACI (transmembrane activator and calcium-modulator and cyclophilin ligand interactor) were found in 4 of 19 unrelated individuals with common variable immunodeficiency and in 1 of 16 individuals with SIgAD. The B cells from individuals with the TACI mutations expressed TACI but did not produce IgG and IgA in response to a TACI ligand, a finding thought to reflect impaired isotype switching (Castigli, 2005).

IgAD has been noted to evolve into CVID and is often observed in pedigrees containing individuals with CVID (Buckley, 1992). Evidence for a common pathogenesis of CVID and IgAD include shared susceptibility alleles major histocompatibility complex class III genes (D locus) (Cucca, 1998), a similar spectrum of IgG subclass deficiencies, a gradual decline of immunoglobulin levels in concordant siblings, and the development of CVID in some patients with IgAD.

Previous studies of multiple-case families of patients with IgAD showed a higher prevalence of CVID among close relatives than in the general population. In multiple-case families with dominant transmission of CVID and IgAD, CVID was usually present in parents, followed by IgAD in the descendants. That study indicated the presence of a predisposing locus in the proximal part of the major histocompatibility complex. The recurrence risk was found to depend on the sex of the parents transmitting the defect. Affected mothers were more likely to produce offspring with IgAD than affected fathers (Vorechovsky, Am J Hum Genet, 1999; Vorechovsky, J Immunol, 1999; Vorechovsky, 2000; Vorechovsky, 2001).

IgAD has been reported in patients with constitutional chromosome 18 abnormalities, and a case series of 83 cases of 18p- syndrome showed an increased frequency of IgAD; however, attempts to identify a specific locus on chromosome 18 have not been successful (Vorechovsky, J Immunol, 1999).

Structural lung disease such as chronic obstructive pulmonary disease (COPD) was previously thought not to impair the ability to generate antigen-specific IgA. Studies of acute exacerbations of chronic bronchitis show that new mucosal IgA to surface-exposed epitopes of the infecting Moraxella catarrhalis isolate developed in sputum supernatants after 42% of exacerbations (Bakri, 2002), and significant increases in mycoplasmal-specific IgA occurred in 85% of a group of 34 patients hospitalized for acute exacerbations of COPD. In a prospective study of 250 hospitalizations for acute exacerbations of COPD, the geometric mean serum titer for IgG and IgA against Chlamydia pneumoniae was higher, with 33% meeting criteria for chronic infection (Lieberman, 2001). In another series from India, serum and sputum IgA levels were higher in subjects with COPD than in control subjects (Chauhan, 1990).

Recent studies, however, suggest that the mucosal IgA response is impaired in COPD with deficient transport of IgA across the bronchial epithelium, possibly involving degradation of the Ig receptor involved in transepithelial routing (Pilette, 2004).

Observations that SIgAD is associated with an increased prevalence of atopy suggest a role for IgA in asthma pathogenesis. A protective role of IgA has been seen in murine models of asthma (Pilette, 2004).

Frequency

United States

At a minimum, an estimated 250,000 individuals have IgAD in the United States (Gustafson, 1997). In African Americans, the prevalence of IgAD is 1 case per 6000 persons.

International

• Factors associated with the prevalence of IgAD include a family history of IgAD and the country of origin. Family studies using IgAD blood donors as probands show that first-degree relatives have a 7.5% prevalence rate of IgAD, which is 38-fold higher than that of unrelated donors (Oen, 1982). The serological prevalence of IgAD varies 100-fold among populations. Prevalences, in decreasing order, are as follows:

• Arabian peninsula - One in 142 persons.



• Spain - One in 170 persons



• Eastern Nigeria - One in 255 persons



• Finland - One in 396 persons



• Czech Republic - One in 408 persons



• Basque regions of Spain and France - One in 521 persons



• Iceland - One in 533 persons



• England - One in 875 persons



• Brazil - One in 965 persons



• France - One in 3040 persons



• China (Han) - One in 2600 persons



• China (Zhuang) - One in 5300 persons



• Japan - One in 14,850-18,500 persons



• Sweden - Approximately 20,000 persons affected



• United Kingdom - Approximately 120,000 persons affected (Gustafson, 1997)

Isolated IgAD is present in a minority of cases of transient hypogammaglobulinemia of infancy. Of a series of 40 patients presenting with recurrent responsive infections, otitis media, bronchitis or bronchial asthma, or recurrent gastroenteritis when aged 4-29 months, only 1 had isolated IgAD, 10 had reduced IgG and IgA levels, and 6 had diminished IgA and IgM levels. The majority recovered immunoglobulin levels by age 3 years, but 3 had persistently low IgG and IgA levels.

A study performed by Weber-Mzell et al (2004) on 7293 healthy white volunteers demonstrated an IgAD prevalence of 0.21% (definition of IgAD was level <0.07g/L). The same study showed seasonal fluctuations of serum IgA (SIgA) concentration; levels of SIgA increased in winter.

Mortality/Morbidity

IgAD is more frequent in adult subjects with chronic lung disease than in a healthy, age-matched control subjects (International Union of Immunological Societies, 1999).

The 20-year longitudinal study of healthy blood donors with incidental findings of IgAD used questionnaires and medical record reviews to demonstrate a 3-fold increase in rates of severe childhood respiratory conditions (9% vs 3%), a 4-fold increase in rates of severe adult respiratory conditions (16% vs 4%), a similar increase in recurrent mild respiratory tract infections, and a significant increase in rates of recurrent viral infections (16% vs 1%).

This study also noted a 4-fold increase in the rate of autoimmune conditions (23% in subjects with SIgAD vs 5% in control subjects); a 2.5-fold increase in the rate of abdominal symptoms caused by milk (16% vs 6%); and slight increases in the rates of atopic eczema (8% vs 5%), drug allergy (9% vs 5%), and food hypersensitivity (3% vs 1%). A slight decrease was observed in the rate of allergic rhinitis and/or eczema (11% vs 17%).

In previous reports, most individuals with IgAD (ie, 60-90%) were asymptomatic. A longitudinal design may have been needed to appreciate the cumulative burden of this disorder.

Patients with SIgAD commonly present with anaphylactic transfusion reactions (patients with anti-IgA antibodies) or autoimmune antibodies, autoimmune disorders, or both.

When IgAD is associated with one or more IgG subclass deficiencies or an impaired polysaccharide responsiveness, some individuals with IgAD may develop recurrent sinopulmonary infections, especially in patients with concurrent IgG type 2 subclass deficiency; GI tract infections and disorders in patients with absent secretory IgA; or an increased incidence of cancer. Lack of secretory IgA has been hypothesized to compromise the defense against infection with Helicobacter pylori, which is thought to be a cause of stomach cancer.

The risk for cancer among 562 Danish and Swedish subjects with CVID or IgA was compared with that of 2017 relatives for the period 1958-1996. Among 176 subjects with CVID, the incidence of cancer (all sites) was increased (standardized incidence ratio [SIR], 1.8; 95% confidence interval [CI], 1-2.9). Stomach cancer was increased (SIR, 10.3; 95% CI, 2.1-30.2), and malignant lymphoma was increased (SIR, 12.1; 95% CI, 3.3-31). Among 386 subjects with IgAD, the incidence of cancer (all sites) was not increased (SIR, 1); however, the incidence of stomach cancer was increased, albeit to an insignificant degree (SIR, 5.4; CI, 0.7-19.5) (Mellemkjaer, 2002). The same study did not show an increase in lymphoid malignancies (non-Hodgkin lymphoma, Hodgkin disease) in IgAD subjects, even though some evidence in the literature indicates that the risk of developing a lymphoid malignancy is increased (Cunningham-Rundles, 1993).

Patients with IgAD who have a compensatory increase in secretory monomeric IgM in their upper respiratory tract secretions and GI fluids tend to be less symptomatic. Note that patients with total IgAD are more symptomatic than patients partial IgAD.

A previously unrecognized clear association of SIgAD with recurrent parotitis of childhood (PTC) was demonstrated by Fazekas et al (2005) in an Austrian pediatric clinic population. The prevalence of PTC in IgA-deficient patients (22%) was much higher than in a large population of healthy Austrian volunteers (0.3%; Weber-Mzell, 2004).

• Recurrent sinopulmonary infections are reported. IgAD usually manifests as recurrent otitis (in children), tonsillitis, sinusitis, and bronchitis with extracellular encapsulated bacteria (eg, Haemophilus influenzae, Streptococcus pneumoniae). Severe respiratory tract infections occur more often in adult subjects with IgAD than in normal control subjects, with a cumulative prevalence rate over 20 years of 16% (see Images 1-3).
  
  The substantial risk of developing lung damage, which is often reported in patients with CVID, is not a major threat to individuals who only have SIgAD. Lung function is significantly impaired among patients who have a combination of IgAD and a deficiency of one or more IgG subclasses. A few recently published cases reported the occurrence of hypersensitivity pneumonitis in patients with SIgAD and the authors suggest that SIgAD is a risk factor for a more severe course of the disease and increased susceptibility to develop extrinsic allergic alveolitis. (Yalein, 2003; Sennekamp, 2004)



• Autoimmune disease is reported in approximately 20% of patients with CVID and is associated with IgAD. Autoantibodies are often produced but may be difficult to detect. The sera of individuals with IgAD may contain various autoantibodies that cause no disease or cause myasthenia gravis or thyroid disease. Other selective case reports indicate an association between SIgAD and type 1 diabetes mellitus, vertigo, vitiligo, and alopecia. Rheumatoid arthritis and systemic lupus erythematosus are the diseases most commonly connected with IgAD. In a survey of serum specimens from 60 healthy subjects with SIgAD, 16 of 21 different autoantibody levels were higher in IgAD subjects than in healthy control subjects (Barka, 1995).
  
  The prevalence rate of anti-IgA antibodies among white persons with IgAD is 30-40%. In patients with combined IgA-IgG type 2 deficiency, the rate is 50-60 %.
  
  IgA-deficient patients with anti-IgA antibodies may develop severe anaphylactic reactions when they are transfused with blood components that contain IgA. These autoantibodies are typically of the IgE class; however, IgG class anti-IgA antibodies can also cause anaphylactic-type reactions (Bjorkander, 1987). Although anaphylactic reactions occur in 1 in 20,000-47,000 transfusions, they constitute one of the frequent nonhemolytic causes of transfusion-related mortality.



• GI tract infections and disorders are reported. Patients with SIgAD have a 10-fold increased risk of celiac disease. Milk intolerance is common in patients with primary IgAD. Reports indicate that patients with IgAD may have IgG antibodies against cow milk and ruminant serum proteins. Patients with a high titer of antibodies to cow milk reportedly are more likely to have other autoantibodies (Cunningham-Rundles, 1981).
  
  Other conditions, such as ulcerative colitis, inflammatory bowel disease, Crohn disease, and pernicious anemia, have been described in IgA-deficient individuals. Friman et al (Microb Pathol, 2002) showed that individuals with SIgAD have an increased risk of becoming a carrier of E coli strains that have increased proinflammatory properties, and hypothesize that this may contribute to the development of gastrointestinal disorders in SIgAD patients. Mucosal infections include acute diarrhea caused by viruses, bacteria, or Giardia lamblia parasites. A higher occurrence of serum antibodies to milk antigens in patients with IgAD suggests that normal serum IgA responses protect the host from continuing exposure to environmental antigens.

Race

IgAD occurs in Asian persons at a rate of 1 case per 14,840-18,500 persons, in Arab persons at a rate of 1 case per 142 persons, in white persons at a rate of 1 case per 500-700 persons, and in African American persons at a rate of 1 case per 6000 persons.

Sex

A study of 7293 Austrian volunteers showed a greater frequency of SIgAD in men than in women (0.19% vs 0.014%) and a greater frequency of subnormal serum IgA levels (0.07-0.7 g/L) in men (2.66%) than in women (0.93%; Weber-Mzell, 2004).

Age

This disease can be diagnosed in persons of any age.

Average serum IgA levels increase 0.2 ±0.06 g/L per decade of life (Weber-Mzell, 2004).

• Those older than 6 months who have recurrent upper and lower respiratory tract infections with encapsulated bacteria (eg, H influenzae, S pneumoniae) should be evaluated for IgAD. Patients with humoral deficiencies do not usually present with recurrent infections in the first few months of life because they have circulating immunoglobulins due to placental transfer of maternal immunoglobulins.



• Children and adults present with recurrent sinopulmonary infections or GI infections or diseases. Case reports exist of severe life-threatening infections in patients with SIgAD (Gomez-Carrasco, 1994; Lantz, 2001; Chen, 2002).

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