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 eczema is seen in only but may be as severe as in It usually in the first or of is and a not for because of the frequent of the and is seen in of HIES patients. infections include staphylococcal and The may but are most common around the and The are well in most with and almost to these is common and they the and have been to be of they are not to the Following of almost any recurrent are In some patients, may be frequent in but have seen In our of HIES patients had recurrent skin abscesses, and had more than eczema in an with the hyper-IgE syndrome. The well to with and with the autosomal dominant form of the hyper-IgE syndrome. skin after and developed eczema by age infections, including sinusitis, and are frequent in HIES. of patients reported or more clinical of HIES is recurrent pneumonia. Most patients had at one of in their but had or more of in HIES are aureus and that are still pneumonias in HIES are frequently of HIES patients including and The of infection and is further by of the and with and infections seen less commonly in HIES include and of and the affect of HIES patients, including infections of the and have also been reported in HIES and abnormalities associated with HIES were in the reports by et al. in 1966 and Buckley et al. in 1972 noted in of patients, and the characteristic in of all HIES patients seen at the National Institutes of Health The features and almost by late have an increased and have a high has been reported in HIES and has been seen at the in one are further of the of in of patients. may be common in HIES and may be or has been seen in of patients, from including in after of a anomaly of the and of primary in HIES patients was only but to be found of primary may to of the primary which in the of the However, the underlying this is In our cohort of HIES patients who were than delayed is to the age of the by the primary are delayed in of primary which is usually by normal of the have been reported in that these patients may be at some increased In our two patients developed and one had One developed cell of the To only one of our patients has developed and not one has had or of which has been reported in The underlying of HIES is still have on the immune of the disease, such as of eosinophilia in and chemotaxis T antibody production and production or cytokines such as IL-4 and levels were normal Elevated levels of have been reported in some patients, and with the extent of the neutrophil chemotaxis has been in HIES patients, this defect is in the same at blood cell are in the normal but have been reported to range from to with has been in patients Some HIES patients also a defect in to but not cells is no of with HIES In no immune defect has been found in all patients. The has some to the laboratory described for the of and is In IgE levels of more than 10 000 IU/ml are characteristic and levels of 000 IU/ml have been reported (36, However, serum IgE levels are not in serum IgE concentrations have been noted any in the clinical an IgE of 10 the normal has been as a The of the elevated IgE in HIES is still unclear. high of the IgE in HIES binds to aureus and was not seen in other patients infected frequently with that this is and not However, are also seen in patients with and are not of HIES HIES patients have normal levels of aureus IgG and elevated levels of aureus levels are low in HIES patients and is also et al. reported immune 000 of IgG Buckley and found low antibody to and only one out of 11 patients to a However, and responses in to the and have been In contrast, responses to and in have been low or absent. In to IgE eosinophilia is seen in all patients with HIES. The eosinophilia is at two and is usually there is no the of eosinophilia and the elevation of IgE. Moreover, the of serum IgE is not with disease or (36). The of IgE production and in HIES is still IgE is elevated during most of an HIES life (36, 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 that IgE dysregulation may be IgE levels may IU/ml, or the normal range. In of 30 patients reported in the IgE and they 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 of the driving this is still but is not to cytokines in Buckley and that B cells from HIES patients had of IgE synthesis in that not be augmented by exposure to However, with the IgE synthesis by HIES B cells in The IgE were in the These that the of IgE in HIES in the of IgE not in the synthesis of IgE et al. that IgE was in which may to the elevation as the of and the of IL-4 on cell and of synthesis In HIES patients, there to be a in either or However, synthesis of and IL-4 to be elevated in IgE synthesis and production in T cells has been found in HIES patients et al. not of IgE synthesis by but that T mechanisms of IgE were et al. the of on HIES blood cell production of IgE in and in They to patients with HIES for IgE production in and in in most of their patients, as was seen blood 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 patients no in serum IgE. had any clinical from the of et al. that although both and IgE 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 of or of and IgE production in HIES cells in et al. described production in in the cells were with staphylococcal They that there is a a Th2-type response, which may in production and promote IL-5, IL-13 and IgE production. However, have not seen production in in to that this may be and Holland, unpublished Despite the in abnormalities related to IgE, the complex of this disease and its on and infection an 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 in and is with small platelet This is responsible for the such as after and in the of are a frequent of in of the immune in include IgE-mediated allergy with and susceptibility to severe and recurrent infections, and increased incidence of Eczema, either and or severe and is a of classic It is and from that of classic for present at of In eczema in of the patients but is not present at the of However, patients with the phenotype have either and transient eczema or at may play an important role in the of chronic since the eczema of patients to with skin with and frequently for allergic are in of patients The eczema to be in families with an atopic the of eczema may be by associated with or by factors and and with eczema in an with Wiskott–Aldrich syndrome. are the most frequent of in infections may be or The immune dysregulation may also as disease, including inflammatory and inflammatory disease including and are responsible for of In however, both and are The defect has been in to the of T cells in these patients infancy, the of circulating is However, by years of due to a of T is This may be as a of which was found in patients with classic in the and of In contrast, patients with who not the profound immunodeficiency, not increased Moreover, T cell function is by responses to and responses to cells and antibody The defect is by low and antibody responses to and Moreover, B cells to immunologic and class B cell usually the normal range. of levels is frequently in and of low levels of normal levels of IgG, and increased levels of and IgE In the of increased serum IgE concentrations with a immunodeficiency was first noted in IgE in serum was elevated in of patients with Wiskott–Aldrich syndrome. However, only two of had allergic In one bone-marrow transplantation in partial due to of only T This partial the immune including antibody to that the antibody production in is caused by T function The on the short of the at It of and is of The a called of the has identified of the same in both and of families with or by et al. that in the first in a disease The is in the with the the cell to a defined of widely proteins involved in the of from receptors to the It to be of for the function of cells as is in all may a involved in be responsible for the of In T to stimulation the receptor, although they in to that the with normal T cells the T cell This to in T cells of since this Moreover, an important role in of by with the of These molecules to cell-surface such as B cell in B cells, and receptors in These of In has been in to the B cell The genetic of is to be responsible for the X-linked form of function is in the of T and B T to be In T cells increased of and other molecules the that a defect in may be involved in production and Omenn is a autosomal severe combined primary immunodeficiency characterized by and In patients with have and to by bone-marrow patients of infections and severe the first of life laboratory in are eosinophilia with increased serum IgE in the of hypogammaglobulinemia of IgG, and Omenn syndrome is caused by in either one of the activating 1 or that but not that the of a complete of T cell and B cell and to severe combined immune deficiency with of T and However, the identified in patients of with Therefore, abnormalities in proteins can to either or on the of the In a cohort of patients with due to had in the and in in a of patients with Omenn syndrome, had in and in cells and cells not during they not from the and The of the and the are of their In the of complete deficiency, be and are not and are not for the or the no and This the in patients with complete and In to in which eosinophilia and elevated IgE are the defect in the of some this some T cells with can the or either in the or in the and Th2-type cytokines These in may be responsible for some features of the characteristic phenotype of such as and increased IgE. in T cells of patients Th2-type cytokines IL-5, serum levels of IL-4 and are and the synthesis of and is Therefore, Th2 to be the of the underlying defect in the in for the complete patients had very low of B cells, B cells than were found in of patients with The serum levels of IgG, and are and antibody production in is but not This is also by the low but antibody to with In hypogammaglobulinemia may be due to has been a in the role of IgE in the profound of with Despite and levels of IgG, and have a with eosinophilia, and elevated serum IgE In a report by et al. patients with were patients, had 11 had and had IgE was in and was 200 in 11 of the 11 patients had the patients had of the patients with had elevated IgE an elevated IgE only in or and was to in the in in were not associated with an elevated serum IgE were in out of patients with was in of the patients with but only in two of the patients with in may the partial to elevated IgE Moreover, as B are usually in the and in the IgE in The Comèl–Netherton syndrome is a rare but severe autosomal was first reported by in and in is characterized by or with abnormalities or immune deficiency, and elevated IgE levels, the latter most likely responsible for severe IgE-mediated including and allergic at or after with by which can be difficult to from or other in with severe disease the the in most patients and which are by a that is The skin are AEDS, and an they not to The of is the and other abnormalities including and of These abnormalities during and may in In about of patients the is by to recurrent infections, and leading to and These can be and at in be to of the which may be caused by of seen in In IgG levels are low and may to the increased susceptibility to and infections. In contrast, IgE levels are This may to the characteristic allergic such as to and common The of IgE elevations in is of because of the of and immunologic abnormalities in the of a In 20 patients with the IgE was found to be and 1000 IU/ml in patients, 1000 to 10 000 IU/ml in patients, and 10 000 IU/ml in patients, the extent of IgE elevation not with the presence of severe infections. Most cases of are however, there are reports of and of in about of the families with with autosomal recessive inheritance these in a was to a on of this revealed that is caused by in the This of and a discovered is the first to be responsible for skin disease, immunodeficiency, and IgE that in of are associated with a severe phenotype play a role in the of many such as blood and of by and cell and is a of the of are Therefore, the leading to this complex disease to be wide variety of including are in the that these may be involved in cell growth and and a for the in or of the and has been described in patients, that a defect in function of the skin in may recurrent infections and in Since is highly in the expression may be to have a on T cell of T in may the of Th2 to driving the hypersensitivity and IgE This the of a distinct from and involved in the of T It is also like other is as of a expression may the to Moreover, is in cell and and some of have been to the a and the immune dysregulation seen in of of and IgE-mediated such as of IgE is associated with primary immunodeficiency disorders such as the hyper-IgE syndrome Wiskott–Aldrich syndrome Omenn syndrome Comèl–Netherton syndrome thymic and In the and and small cohort reports of patients with PID to the of the incidence and extent of IgE elevation in In the genetic revealed some causes of with elevated IgE, such as the defect in the in and the in However, because of the and of the proteins responsible for PID and IgE these have so only to the of the mechanisms of IgE production. further about the role of IgE in PID may in common but complex such as IgE-mediated allergic on the mechanisms of these genetic in IgE is are to from a to a basis for both the of these as well as the of these to The like to their to and for and and for the was by a of the and the of the