Immunoglobulin E in primary immunodeficiency diseases

Immunoglobulin E (IgE) was discovered in the late 1960s (1,2). Since then, aberrations of IgE synthesis have been noted in allergic diseases, in certain bacterial, fungal and parasitic infections, in graft-versus-host disease, and in certain acquired and primary immunodeficiency disorders (PID). However, the exact biological role of IgE under these conditions is unclear. This review will focus on IgE abnormalities in PID in which either deficiency or excess of IgE production is associated with increased susceptibility to infection. Particular emphasis will be put on the hyper-IgE syndrome, the Wiskott–Aldrich syndrome, the Omenn syndrome and the Comèl–Netherton syndrome (Table 1). At birth, serum levels of IgE are usually undetectable, rising to 8–200 IU/ml in healthy nonatopic children during the first 5 years of life (3). In childhood, IgE levels depend on factors such as age and genetic background, as well as environmental factors including allergen exposure and parasitic diseases. IgE has a very short half-life, less than 1 day, and is present in lower concentrations in serum than any other immunoglobulin. Despite the low blood levels, IgE is extremely biologically active. This is because IgE binds to high-affinity receptors on the surface of mast cells and basophils, making these cells highly sensitive to stimulation by IgE antibody–allergen interaction. This reaction is the key to IgE-mediated allergy (4). Moreover, the expression of these high-affinity receptors is probably up-regulated by IgE itself (5, 6, 7). Therefore, the concentration of circulating IgE does not reflect its true activity. T cells play an important role in immune and inflammatory pathways. CD4+ T cells regulate or organize most types of immune responses to foreign proteins by secreting cytokines such as interleukins and interferons; they can be categorized as Th0, Th1, and Th2 cells on the basis of their products. Th1 cells are primarily involved in classic delayed hypersensitivity and have been proposed to inhibit Th2-driven processes. In contrast, the Th2 class releases primarily IL-4 and IL-5, and to some extent IL-13, which induce the Ig switch to IgE production, stimulate eosinophilopoiesis, regulate eosinophil functions, and promote the growth of mucosal-type mast cells, thus enabling immediate allergic response. The so called “switch factor” IL-4 has a wide variety of functions, including up-regulation of cell-surface major histocompatibility complex (MHC) class II molecules and CD23, the low affinity IgE receptor, and promotion of the growth of T and B cells, and mast cells (8). IL-13 also causes B cells to isotype-switch for IgE production independent of IL-4 (9, 10, 11). It is difficult to define IgE deficiency, since in most routine laboratories normal values range from 0 to about 200 IU/ml. In 1970, Levy and Chen encountered an IgE-deficient person who was apparently healthy (12). Immunoglobulin deficiency, including IgE deficiency can be found in transient hypogammaglobulinemia of infancy, common variable immunodeficiency, X-linked agammaglobulinemia, X-linked immunodeficiency with hyper-IgM, severe combined immunodeficiency disease, and ataxia-telangiectasia. In all of these diseases, IgE deficiency is accompanied by a profound deficiency in IgG production. The latter is most likely responsible for the increased susceptibility to infections, since therapy with intravenous IgG, which contains no IgE, helps to reduce substantially the morbidity (13). The biological need for IgE antibodies is still debated. It has been proposed that resistance to parasitic infections is mediated by chemotactic factors for eosinsophils produced by IgE-sensitized mast cells. These factors include histamine, eosinophilic chemotactic factors, platelet activating factor, and leukotriene B2. The eosinophils attracted by this are capable of killing schistosomula of Schistosoma mansoni by both IgE- and IgG-dependent, as well as complement-dependent, mechanisms (14, 15). However, the precise mechanism(s) of killing have not been established. In 1977, Juhlin and Michaelsson (16) reported a man in whom eosinophils and basophils were absent. He had a lifelong history of repeated otitis, sinusitis, and pneumonia. As an adult, he had numerous warts and chronic scabies. The definition of excessive IgE production varies. IgE is one of a handful of laboratory values with a logarithmic range. Monoclonal production of IgE is rarely found in plasmocytoma and has not been reported in children (17). Polyclonal increases of serum IgE in developed countries are most frequently caused by an allergen-specific IgE antibody response, as in atopic eczema/dermatitis syndrome (AEDS) (18). In AEDS, IgE levels are usually around 1000 IU/ml, but may be as high as 10 000 IU/ml. In undeveloped countries polyclonal IgE elevation is commonly due to parasitic infections. IgE levels in patients with parasites exceed 1000 IU/ml in only exceptionally rare cases. However, polyclonal IgE elevations can also be seen after viral infections such as cytomegalovirus (CMV) (19), intrauterine infections (20), “chemical” stimulation from substances like cigarette smoke (21), or major immunologic events like bone-marrow transplantation and graft-versus-host disease (GVHD) (22). The pathophysiology by which excessive production of IgE might adversely affect host defence is not known. One hypothesis is that with an underlying partial T cell deficiency, patients may have increased Th2 cells or cytokines, or a deficiency of Th1 type cells or cytokines, driving B cells to isotype-switch for IgE production via IL-4 (8, 23, 24). This might explain both the infection susceptibility and the augmented production of IgE. In DiGeorge syndrome (chromosome 22q11.2 deletion syndrome) (25), which is characterized by thymic hypoplasia, meta-analyses of small cohorts revealed elevated serum IgE in 11 out of 35 patients (26–30). Allergic signs or symptoms, however, were not common in these infants. Elevated serum IgE concentrations may be related to the degree of thymic hypoplasia. Patients with complete DiGeorge anomaly may not have sufficient T-helper cell function to initiate IgE formation. On the other hand, those with the more common partial form of DiGeorge anomaly (31), who have some T cell function, may be more likely to have increased IgE production because they may have sufficient Th2-type cells or cytokines but a deficiency of Th1-type cells or cytokines. Another characteristic shared by many patients with immunodeficiency who have elevated IgE levels is a tendency to be infected with staphylococci. This raises the issue of whether excessive IgE levels are permissive for Staphylococcus aureus infections, or whether staphylococcal infections stimulate excessive production of IgE. The latter is contradicted by the fact that most patients with chronic granulomatous disease or with cystic fibrosis have relatively normal IgE concentrations, despite frequent staphylococcal infections (32; and Holland, unpublished data). “So went Satan forth from the presence of the Lord, and smote Job with sore boils from the sole of his foot unto his crown.” From this citation (Job II:7) Davis, Schaller and Wedgewood coined the term Job's syndrome in 1966 (33). They described two red-haired, fair-skinned girls who had frequent sinopulmonary infections, severe dermatitis, and recurrent staphylococcal skin infections that were remarkable for their lack of surrounding warmth, erythema, or tenderness. The syndrome was further defined and clarified by Buckley et al. in 1972 (34) who noted similar infectious problems in two boys with severe dermatitis, characteristic facies, and elevated IgE levels, leading to the term Buckley syndrome. Following this report, elevated levels of IgE and a defect in neutrophil chemotaxis were identified in the two girls from the initial report showing that Job's syndrome and Buckley syndrome represented the same condition (35). To avoid further confusion, the name “hyperimmunoglobulin E recurrent infection syndrome” (HIE or HIES) is now widely accepted. In 1999, our group at the National Institutes of Health further defined the phenotype of HIES. The incidence of 20 clinical features associated with HIES was published, based on a cohort of 30 patients with clear-cut HIES (36). It became clear that the hyper-IgE recurrent infection syndrome (Online Mendelian Inheritance in Man (OMIM) database #147060, #243700) is a rare primary immunodeficiency characterized by recurrent staphylococcal skin abscesses, pneumonias with pneumatocele formation, extreme elevations of serum IgE, eosinophilia, and distinct abnormalities of the connective tissue, skeleton, and dentition (33–39). Most cases are sporadic. However, there have been reports of autosomal dominant kindreds (36, 39–45) and autosomal recessive inheritance in consanguineous families (Renner et al. submitted). Eczema, abscesses, pneumonia, mucocutaneous candidiasis, elevated serum IgE, and eosinophilia are the most common features of immunodeficiency and immune dysregulation in HIES patients. Some degree of eczema is seen in almost all HIES patients, although moderate-to-severe eczema is seen in only 71%, but may be as severe as documented in Fig. 1A. It usually manifests in the first few days or weeks of life, it is typically pruritic, and often lichenified (in a distribution not necessarily typical for AEDS because of the frequent involvement of the back, buttocks, and scalp). A newborn rash (Fig. 1B) is seen in 78% of HIES patients. Skin infections typically include staphylococcal furunculosis and cellulitis. The abscesses may occur anywhere but are most common around the face and trunk. The abscesses are well walled off in most cases, filled with pus, and almost always grow S. aureus. Surgery to treat these lesions is common and they typically resolve without spreading through the dermis and fascia. Although “cold” abscesses have been said to be pathognomonic of HIES, they are not essential to the diagnosis. Following use of almost any prophylactic antibiotics, recurrent cutaneous abscesses are rare. In some patients, abscesses may be frequent early in life, but recently we have mostly seen impetiginized eczema. In our cohort, 89% of HIES patients had recurrent skin abscesses, and 81% had more than four recurrences. A. Impetiginized eczema in an 11-year-old girl with the hyper-IgE syndrome. The lesions responded well to systemic treatment with antistaphylococcal antibiotics and low-dose corticosteroids. B. 6-week-old infant with the autosomal dominant form of the hyper-IgE syndrome. Erythematous papular skin lesions appeared 4 weeks after birth and developed into eczema by age 6 weeks. Upper-respiratory infections, including sinusitis, bronchitis, otitis media, otitis externa and mastoiditis, are frequent in HIES. Seventy-one percent of patients reported four or more episodes per year. A clinical hallmark of HIES is recurrent pneumonia. Most patients (90%) had at least one episode of pneumonia in their lifetime, but 76% had three or more bouts. Frequent pathogens of acute pneumonia in HIES are S. aureus and Haemophilus influenzae. For reasons that are still unclear, pneumonias in HIES are frequently complicated. About three-quarters (77%) of HIES patients develop long-term pulmonary complications, including bronchiectasis and pneumatoceles. The cycle of infection and lung destruction is further exacerbated by superinfection of the cavities and bronchiectatic lung with Pseudomonas aeruginosa and Aspergillus fumigatus. Pulmonary infections seen less commonly in HIES include Pneumocystis carinii, Mycobacterium intracellulare, and Nocardia. Chronic candidiasis of mucosal sites and the nail beds affect 75% of HIES patients, including children. Cryptococcal infections of the esophagus and colon have also been reported in HIES (46, 47). Facial and skeletal abnormalities associated with HIES were recognized in the original reports by Davis et al. in 1966 (33) and Buckley et al. in 1972 (34). We noted hyperextensibility in 71% of patients, and the characteristic facies in 87% of all HIES patients seen at the National Institutes of Health (NIH). The facial features develop progressively and become almost universal by late adolescence. Eighty-eight percent have an increased interalar distance (nasal width) and 65% have a high arched palate. Craniosynostosis has been previously reported in HIES (49–51), and has been seen at the NIH in one patient. Recurrent pathologic fractures are further evidence of the multisystemic nature of HIES, occurring in 61% of patients. Osteopenia may be common in HIES and may be cytokine- or immune-driven (52, 53). Scoliosis has been seen in 66% of patients, arising from diverse conditions, including discrepancies in leg length, after thoracotomy (e.g. removal of a lung cyst), anomaly of the vertebral body, and idiopathic disease. Impaired deciduation of primary teeth in HIES patients was only recently recognized, but it appears to be found quite consistently. Reduced resorption of primary tooth roots may lead to prolonged retention of the primary teeth, which in turn prevents the appropriate eruption of the permanent successors (54). However, the mechanism underlying this developmental abnormality is unknown. In our cohort of HIES patients who were older than 6 years, 73% displayed delayed dental deciduation. Our current practice is to determine the developmental age of the secondary teeth by radiography. If the primary teeth are significantly delayed in deciduation, we recommend extraction of retained primary teeth, which is usually followed by normal eruption of the permanent teeth. Several malignancies have been reported in HIES, suggesting that these patients may be at some increased risk (55–61). In our cohort, two patients developed non-Hodgkin's lymphoma, and one had Hodgkin's disease. One patient developed metastatic squamous cell carcinoma of the tongue. To date, only one of our patients has developed systemic lupus erythematosus (62–65), and not one has had autoimmune vasculitis (66), dermatomyositis (67), or membranoproliferative glomerulonephritis (68) (each of which has been previously reported in HIES). The underlying cause of HIES is still unknown. Many studies have focused on the immune aspects of the disease, such as detection of eosinophilia in blood, sputum, and abscesses (51, 69), defective granulocyte chemotaxis (34, 35, 40, 70), abnormal T lymphocyte subsets (51, 71), defective antibody production (72–75), and decreased production of, or responsiveness to, cytokines such as IL-4 and interferon-gamma (IFN-γ) (76–79). Complement levels were normal when studied. Elevated levels of urinary histamine have been reported in some patients, and correlate with the extent of the eczematoid dermatitis (80). Although impaired neutrophil chemotaxis has been documented in HIES patients, this defect is inconsistently present, even in the same patient at different times (37, 81). White blood cell counts are typically in the normal range, but have been reported to range from 1700 to 60 000/µl (37, 72). Chronic leukopenia with borderline neutropenia has been observed in several patients (37). Some HIES patients also showed a defect in mixed lymphocyte culture proliferation to intrafamilial but not unrelated mononuclear cells (82). There is no association of human leukocyte antigen (HLA) with HIES (37, 72). In summary, no specific immune defect has been found consistently in all patients. The clinically validated multicomponent scoring system (45) has some benefits compared to the uncommon laboratory tests described above for the diagnosis of HIES, and it is preferred. In HIES, IgE levels of more than 10 000 IU/ml are characteristic and levels of > 50 000 IU/ml have been reported (36, 72). However, serum IgE levels are not static. Substantial fluctuations in serum IgE concentrations have been noted over time without any obvious change in the clinical presentation. For HIES, an IgE level of 10 times the normal limit (for adults > 2000 IU/ml) has been suggested as a reasonable diagnostic level. The tropism of the elevated IgE in HIES is still unclear. A high proportion of the IgE in HIES binds to S. aureus and Candida albicans (83). Similar binding activity was not seen in other patients infected frequently with S. aureus, indicating that this abnormality is host-driven, and not organism-driven. However, raised antistaphylococcal titers are also seen in patients with AEDS and are therefore not diagnostic of HIES (84, 85). HIES patients have normal levels of anti-S. aureus IgG and modestly elevated levels of anti-S. aureus IgM. Unexpectedly, antistaphylococcal IgA levels are low in HIES patients (74) and total salivary IgA is also reduced. Quinti et al. (86), reported high-molecular-weight immune complexes (>900 000 Da) composed of IgG anti-IgE. Buckley and Becker (72), found low antibody titers to diphtheria and tetanus, where only one out of 11 patients responded to a booster inoculation. However, cytokine and proliferative responses in vitro to the mitogens phytohemagglutinin (PHA), concanavalin A, and pokeweed mitogen (PWM) have been essentially normal. In contrast, responses to Candida and tetanus in vitro have been low or absent. In addition to IgE elevation, eosinophilia is seen in virtually all patients with HIES. The eosinophilia is at least two standard deviations above normal, and is usually above 700 cells/µl. Surprisingly, there is no correlation between the level of eosinophilia and the elevation of IgE. Moreover, the level of serum IgE is not correlated with disease activity or severity (36). The specific regulation of IgE production and metabolism in HIES is still unresolved. IgE is greatly elevated during most phases of an HIES life (36, 72). IgE elevation was noted in the blood of a to a with HIES who developed HIES Since IgE does not the this reflect synthesis of IgE suggesting that IgE dysregulation may be IgE levels may 2000 IU/ml, to, or into the normal range. In of 30 patients reported in the NIH IgE and they retained their increased susceptibility to infection (36). IgE production may be elevated in HIES due to an increased of B cells making levels of IgE The nature of the driving this abnormality is still unclear, but it is not to cytokines in Buckley and Becker showed that B cells from HIES patients had of IgE synthesis in vitro that not be augmented by exposure to However, with greatly the IgE synthesis by HIES B cells in The IgE were in the These that the abnormality of IgE in HIES in the regulation of IgE not in the synthesis of IgE per et al. showed that IgE was defective in HIES, which may to the elevation as the activity of and the of IL-4 on cell proliferation and of synthesis In HIES patients, there appears to be a in either or However, synthesis of and IL-4 appears to be normal. A correlation between elevated in vitro IgE synthesis and production in T cells has been found in HIES patients et al. not of IgE synthesis by but suggested that T mechanisms of IgE regulation were et al. the of on HIES blood mononuclear cell production of IgE in vitro and in They to treat patients with HIES for weeks. IgE production in vitro and in in most of their patients, as was seen when blood mononuclear cells were for IgE production and after However, serum IgE levels in only two of patients the other IgE levels to their levels in both three patients no in serum IgE. patient had any clinical change from the of et al. showed that although both and IgE cytokine it off in HIES cells in antibodies to IL-4 and IL-13 IgE production, of both IL-4 and IL-13 IgE production in HIES cells in addition of or of and IgE production in HIES cells in et al. described decreased production in vitro in HIES, when the cells were with staphylococcal They that there is a a Th2-type cytokine response, which may in production and promote IL-5, IL-13 and IgE production. However, we have not seen decreased production in vitro in to suggesting that this abnormality it may be and Holland, unpublished Despite the in vitro abnormalities related to IgE, the complex multisystemic nature of this disease and its on teeth, and infection an regulation of some cell or that is common to all of these such as the and its or cells. The Wiskott–Aldrich syndrome is an primary immunodeficiency with an incidence of 1 in 000 in is characterized by recurrent infections, and a high incidence of X-linked is a form of the same condition with platelet abnormalities but The most abnormality in and is with small platelet This is responsible for the typical complications, such as after and in the of are a frequent cause of in of the immune in include IgE-mediated allergy with and susceptibility to severe and recurrent infections, autoimmune and increased incidence of disease. 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Omenn is a autosomal severe combined primary immunodeficiency characterized by and early (Fig. In patients with have and to by bone-marrow patients typically of infections and severe the first of life laboratory in are eosinophilia with increased serum IgE in the of hypogammaglobulinemia of IgG, and IgM. Omenn syndrome is caused by in either one of the human activating 1 or that but not