Regulation and dysregulation of immunoglobulin E: a molecular and clinical perspective
© Pate et al; licensee BioMed Central Ltd. 2010
Received: 21 December 2009
Accepted: 23 February 2010
Published: 23 February 2010
Altered levels of Immunoglobulin E (IgE) represent a dysregulation of IgE synthesis and may be seen in a variety of immunological disorders. The object of this review is to summarize the historical and molecular aspects of IgE synthesis and the disorders associated with dysregulation of IgE production.
Articles published in Medline/PubMed were searched with the keyword Immunoglobulin E and specific terms such as class switch recombination, deficiency and/or specific disease conditions (atopy, neoplasia, renal disease, myeloma, etc.). The selected papers included reviews, case reports, retrospective reviews and molecular mechanisms. Studies involving both sexes and all ages were included in the analysis.
Both very low and elevated levels of IgE may be seen in clinical practice. Major advancements have been made in our understanding of the molecular basis of IgE class switching including roles for T cells, cytokines and T regulatory (or Treg) cells in this process. Dysregulation of this process may result in either elevated IgE levels or IgE deficiency.
Evaluation of a patient with elevated IgE must involve a detailed differential diagnosis and consideration of various immunological and non-immunological disorders. The use of appropriate tests will allow the correct diagnosis to be made. This can often assist in the development of tailored treatments.
Molecular Regulation of IGE Production
The Physiological Properties of Immunoglobulin E
Molecular weight: 190,000 Da (170 kDa protein; 20 kDa Carbohydrate)
Does not fix complement
Does not cross the placental barrier
Half-life: 2 days
Isoforms: Secreted and membrane bound IgE
Structure: Two light chains (κ or λ) and 2 heavy chains (ε)
Binds to High affinity IgE receptor (FcεRI) and degranulates mast cells and basophils
IgE-mediated antigen presentation via FcεRI
Cell-Cell Interactions in IgE Synthesis
IgE Class-Switch Recombination
A two-step process of DNA excision and ligation are required for assembly of a functional IgE. In the primary response, characterized by expression of membrane IgM and IgD, VDJ (heavy chain) and VJ (light chain) recombination occurs in fetal tissue (liver and bone marrow). This is both an antigen and a T cell-independent process. In the secondary immune response, which results in formation of the isotypes IgG, IgA and IgE, class switch recombination (CSR) occurs in secondary lymphoid tissues (lymphoid tissue, spleen and tonsils). This is T cell/cytokine dependent and an antigen dependent process. This results in high affinity antibodies, further modified by the process of somatic hypermutation (SHM). SHM results from missense mutations in the V regions of the immunoglobulin molecule.
First, during the pre-B cell stage, the individual heavy chain variable (VH), diversity (D) and joining (JH) exons randomly combined to form a VH(D)JH cassette that encodes an antigen-specific VH domain. This cassette is upstream of the constant μ exons and allows for the assembly of complete VDJ exons that encode an antigen-binding VH domain which produces intact μ heavy chains. The second step, class-switch recombination, is required for mature B cells to alter the isotope of their antibodies, while retaining their antigen specificity. This involves tightly regulated and irreversible exchange of the various isotope's VHJ cassette to construct different heavy chains . The Cε locus of IgE is similar to other CH loci. The 5' region of each heavy chain isotope gene includes switch regions with tandem repeats, known as Sε and μ. In CSR, two switch regions, Sε and μ are combined, which allows the joining of the VH(D)JH and Cε regions. This joining generates a functional gene encoding IgE. CSR leading to IgE production is induced by cytokines IL-4 or IL-13 secreted by T helper 2 (TH2) cells .
The Role of T cells, Cytokines and Tregs
Normal levels of IgE are highly variable in the population. Factors regulating IgE levels include age, gene-by-environment interactions, genetic factors (such as certain polymorphisms), racial factors (higher levels are seen in African Americans and persons of Filipino descent), sex (males tending to have higher levels) and season (IgE levels may increase during pollen season in allergic individuals).
Immune Dysregulation Associated with IGE Deficiency
IgE hypogammaglobulinemia is currently defined as a significant decrease in serum levels of IgE (<2.5 IU/mL) in a patient whose other immunoglobulin levels are normal (selective IgE deficiency) or diminished (mixed IgE deficiency). It is a laboratory finding that does not necessarily equate to a clinical disorder.
Prevalence of IgE Hypogammaglobulinemia
Common associated deficiencies*
AIC patients (N = 974)
IgG4, IgG1, IgG2 & IgG3
RP patients (N = 155)
IgA2, IgA1, IgG2, IgG4
RC donors (N = 500)
Prevention and control of infection
Several early reports suggested that isolated deficiencies in IgE predisposed to chronic sinopulmonary disease [12, 13], whereas others found no such association [10, 14]. At the time, there was no standard methodology in use for measuring IgE levels, nor did the authors of the reports use a common definition of what constitutes a true deficiency in this immunoglobulin. However, more recent reports using standardized technologies indicate that IgE antibody may play a protective role in some parasitic, bacterial, and viral infections in humans [15–19], and possess anti-tumor properties in vitro [20, 21].
Secord and associates reported that the incidence of opportunistic infection and failure to thrive was lower in children with HIV-1 infection and high IgE levels than it was in HIV-1 infected children with low or normal IgE levels and similar decreases in CD4+ T lymphocyte counts; IgE anti-HIV antibody was detected in 43% of the children with high IgE levels. Pellegrino and associates found that all members of a group of long-term pediatric survivors with maternally transmitted HIV infection had elevated total serum IgE levels and made anti-HIV-1 IgE capable of inhibiting HIV replication in vitro; the inhibitory effect was reversed when IgE was removed using immunoaffinity columns or anti-IgE antibody.
In a study involving 700 asymptomatic subjects from Tanzania, Bereczky and associates found that high IgE (but not IgG) anti-P. falciparum antibody was associated with a reduced risk for subsequent development of clinically evident malaria . Duarte et al also found that P. falciparum-specific IgE responses contributed to the control of malaria, particularly in asymptomatic individuals . There are also reports that IgE antibody can provide immunity against B. burgdorferi infection in children that lasts throughout adulthood , and contribute to the expulsion of intestinal parasites such as N. americanus . The authors have found that IgE deficiency predisposes to sinopulmonary infection with common respiratory pathogens, including Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis in patients of their allergy-immunology clinic .
Protection against autoimmune disease
IgE is predominantly a mucosal immunoglobulin. Hence, as is postulated with IgA, it is possible that IgE protects against autoimmunization by preventing the systemic absorption of mucosal antigens . A lack of antigen exclusion at the mucosal barrier could allow exogenous antigens to induce autoimmune responses by stimulating autoreactive lymphocytes through molecular mimicry [24, 25]; by promoting immune complex formation ; by super-antigen-induced polyclonal activation of lymphocytes ; by inducing a perturbation of the idiotypic network ; and/or by aberrant induction of MHC class II antigens .
Evidence also indicates that rather than merely priming mast cells to respond to specific antigen, IgE, in the absence of cross-linking agents, favorably influences mast cell survival, receptor expression, and mediator release, and hence, has an important and active role in facilitating immune responses . Mast cells have been shown to be essential intermediaries in Treg induced allograft tolerance in mice ; it is possible, therefore, that IgE deficiency predisposes to autoimmunity by adversely effecting mast cell survival and function. It is also possible that common genetic factors predispose an individual to both IgE deficiency and autoimmune disease, or that low levels of IgE merely reflect an imbalance between Th1 and Th2 lymphocyte activity. That, in turn, favors the development of Th1-mediated autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis [32, 33]. Systemic lupus erythematosus also may be related to Treg dysregulation, auto-antibody or anti-apoptotic defect.
Protection against reactive airway disease
The authors found that the prevalence of non-allergic reactive airway disease (rhinosinusitis, bronchitis and asthma) was increased in AIC patients with IgE deficiency. However, it was unclear as to whether these findings were the result of IgE deficiency or reflected selection bias inherent in allergy practices. In a study involving 664 pregnant women, Levin and associates found that the 21 individuals with low serum IgE (<2.0 IU/mL) had a higher prevalence of symptoms of rhinosinusitis, but a lower prevalence of physician diagnosed rhinosinusitis when compared to those with normal to elevated IgE levels . Other studies on the prevalence of airway disease in IgE deficient patients are likewise inconclusive [10, 12, 34]. Experimental evidence is emerging that may provide an explanation for the occurrence of non-infectious, non-allergic airway inflammation in some IgE deficient patients. Kang and associates have demonstrated the occurrence of airway inflammation in lymphotoxin-deficient α (LTα-/-) mice, accompanied by diminished levels of IgE and reduced airway responsiveness, to both environmental and induced antigen challenge . The lung inflammation in the LTα-/- mice is Th1-mediated and alleviated by reconstitution with IgE. Depletion of IgE in wild-type mice duplicates the lung pathologies of the LTα-/- mice, which is also reversed by the administration of IgE. The authors of this article suggest that the presence of low levels of IgE impairs the ability of mast cells to respond normally to airway antigens and, consequently, to produce cytokines that favor Th2 development (IL-4, IL-13); Th1 responses to the uncleared antigens then predominate.
In our experience, the majority of IgE deficient patients seek medical advice because of persistent sinorespiratory symptoms that are often assumed to be allergic in origin . In our own Allergy Immunology clinic population, 79 IgE deficient patients have been identified. All of these patients tested negative on skin testing or in vitro allergy testing to a wide spectrum of indoor and outdoor allergens. When compared to a sex and aged-matched control group from the same clinic with normal levels of IgE, these subjects were more likely to complain of arthralgias, chronic fatigue, and symptoms suggestive of airway infection. In addition, they had a significantly higher prevalence of autoimmune disease and, as previously noted, non-allergic reactive airway disease. Sixty-two percent of the IgE deficient patients had depressed levels of other immunoglobulins, most commonly IgG4; 38 percent had selective IgE deficiencies. Not unexpectedly, serious infection involving both the upper and lower respiratory tract was more common in patients with low IgE and concomitant deficiencies in other immunoglobulins. Thus, in our experience, patients with IgE deficiency have a higher prevalence of sinopulmonary disease, chronic fatigue, arthralgias, autoimmune disease, and concomitant immunoglobulin deficiencies.
At the present time, attempts to replace IgE in persons with IgE hypogammaglobulinemia are neither feasible nor recommended. Rather, IgE deficient patients should be given standard therapy for their underlying conditions.
Immune Dysregulation Associated with High IGE Levels
Elevated IgE: Etiologies and Evaluation
Rhinitis, asthma, SAM
ST/RAST, PFT, Chest CT scan
Food ST/RAST, Challenge
RAST/Patch, biopsy, culture
Allergic Fungal Sinusitis
Mixed T and B
Flow, Immune tests
DiGeorge, WAS, HIES
Genetic, platelet, clinical
Treg cell studies
Selective IgA deficiency
IgA level, functional antibody
Pertussis, S. Aureus
Cultures, serology, clinical
Cultures, biopsy, serology
EBV, CMV, HIV
Serology, PCR, cultures
Clinical, biopsy, culture
Clinical, serology, stool exam
Clinical, blood smear
SPEP***, Bone marrow
Kawasaki, PAN*, CSS**
Rheumatoid factor, CCP****
Urine protein, biopsy
CFTR Mutation, sweat chloride
RA, burns, Nicotine
Serology, history etc
Conditions with very high IgE levels
Extreme IgE Elevation
Allergic fungal disease
Atopic Dermatitis and Food Allergy
Immune Deficiency Disease
Several immune deficiency disorders are associated with allergic manifestations. These include selective IgA deficiency and Common Variable Immunodeficiency. In addition, several primary immune deficiency disorders may demonstrate very high IgE levels. These include Hyper-IgE syndromes (HIES), Immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX), The Wiskott-Aldrich Syndrome (WAS), Omenn syndrome and some forms of DiGeorge syndrome. Hyper-IgE syndrome [37–40] is characterized by highly elevated IgE levels, skin disease and repeated infections. IgE levels tend to exceed 10,000 U/mL, although a huge variability in levels may be observed. HIES syndrome can be idiopathic, autosomal dominant (AD) or autosomal recessive (AR). Most cases appear to have a sporadic basis, but mutations in the STAT3 gene is a feature of the autosomal dominant disorder (also referred to as type 1). AD HIES is characterized by typical skeletal changes such as "coarse facies", abnormal dentition and infection (Staphylococcal pneumonia and/or a pneumatocele). In AR HIES (also known as type 2), recurrent pneumonias, severe viral infections (Molluscum, Herpes simplex), neurological disease and vasculitis may be presenting features and mutations in the TYK2 gene may be seen.
IPEX is a rare syndrome mediated by a reduced or absent Treg population [36, 41]. The syndrome manifests as early-onset enteritis (diarrhea), endocrinopathy (type 1 diabetes or hypothyroidism), elevated IgE levels and dermatitis/eczema. Hematological dyscrazias such as anemia, thrombocytopenia and eosinophilia are also observed. IPEX is secondary to mutations of the FOXP3 gene and a resultant deficiency of Treg cells. An increased Th2 response and elevated IgE levels are observed.
Wiskott-Aldrich syndrome is an X-linked disorder characterized by current infection, thrombocytopenia (with small platelets), neutropenia, eczema, high IgE levels, a very high prevalence of autoimmunity (including arthropathy, vasculitis, and inflammatory bowel disease) and malignancy. The defect lies in the WAS protein (or WASP) that is crucial to T cell, platelet and neutrophil function.
Omenn syndrome is a rare disorder presenting with recurrent infection, diarrhea, alopecia, eczema/erythroderma, lymphadenopathy, hepatosplenomegaly, eosinophilia and elevated IgE levels. Immune assessment shows elevated IgE levels in spite of deficiency in B cells numbers, panhypogammaglobulinemia, oligoclonal, nonfunctional T cell expansion and excessive Th2 skewing. The patients demonstrate one of several defects: mutations in RAG genes, Artemis gene, IL-7 receptor encoding gene and the RMRP gene (RNA component of mitochondrial RNA-processing endoribonuclease).
A subgroup of patients with DiGeorge syndrome may present not only with the profound T cell defect, seen with thymic aplasia, but also with findings consistent with Omenn syndrome (including elevated IgE levels and eosinophilia).
Elevated IgE levels have been described in a variety of bacterial, fungal, mycobacterial and viral infections (listed in Table 4). Leprosy  and tuberculosis  have rarely been associated with elevated IgE levels [44, 45]. Elevated IgE levels have also been described in viral infections (Epstein-Barr Virus and Cytomegalovirus). HIV infection is a well-recognized cause for elevated IgE levels [46–48]. Elevated IgE levels have been described in both adults and in children infected with HIV-1 , and are associated with a poorer prognosis . A hyper-IgE-like syndrome and severe eczema have also been described with advanced HIV-1 infection .
Ascaris , Capillariasis , Paragonimiasis , Fasciola hepatica [55, 56], Schistosomiasis [57, 58], Hookworm (Trichuriasis) , Echinococcus , Onchocercariasis  and Malaria  have all been associated with elevated IgE levels. Of the many parasitic disorders, only a few are directly relevant to North American and these will be reviewed below. Giardiasis, Strongyloidiasis, Trichinella spiralis and Toxocara species occur with some frequency and have certain distinct and unique presentations.
Strongyloidiasis and its systemic consequences were reviewed by the authors recently . Infection with S. stercoralis occurs when the skin of the feet contact free-living filariform larvae in the soil. The filariform larvae penetrate the skin and invade the blood vessels and subsequently enter the alveoli of the lung, where they are coughed up, swallowed and undergo maturation in the duodenum and jejunum. Over half the patients who harbor S. stercoralis have symptoms are related to the GI tract invasion, lung invasion or dissemination with strongyloid hyperinfection. The latter, usually seen in patients treated with glucocorticoids or immunosuppressive agents, can be fatal with complications such as sepsis, gram negative meningitis and/or respiratory distress [64, 65]. Treatment with ivermectin (200 μg/Kg/day) is associated with a 90% cure rate.
Toxocariasis is a well recognized zoonotic disease mediated by the nematode belonging to the genus Toxocara. Adult worms are present in the intestinal tracts of dogs (T. canis) or cats (T. cati) and human infection is caused by egg ingestion [66, 67]. Infective larvae migrate through the liver and lung and result in a plethora of allergic and inflammatory manifestations, referred to as visceral, ocular or cutaneous larva migrans. Eosinophilia, elevated IgE and involvement of brain, muscle, liver and lungs are responsible for the clinical manifestations. Treatment with albendazole or mebendazole and diethylcarbamazine may be attempted.
Trichinellosis is mediated by the nematode, Trichinella spiralis, transmitted by eating undercooked pork or larval forms present in cyst form in striated muscle . Many patients may remain asymptomatic, while some patients develop abdominal pain, diarrhea, fever and excruciating myalgia (calf or masseter muscle). During the invasive stage of the illness, allergic phenomena such as urticaria or periorbital angioedema may occur. The disease is treated with albendazole and some studies have suggested a beneficial effect for glucocorticoids during the allergic and inflammatory stages of the disease.
Giardia lamblia is a protozoan parasite that infects humans following the ingestion of infectious cysts (fecal-oral route or from contaminated food or well water). Symptoms include abdominal cramps, bloating, watery diarrhea and malabsorption. Elevated IgE levels and eosinophilia have been described . Treatment with metronidazole, tinidazole, nitazoxanide or paramomycin may be variably effective, with paramomycin reserved for infected pregnant women.
A variety of neoplastic and hematological disorders have been associated with IgE.
Solid tumors such as cancers of the lung, colon, prostate and breast have been reported to elevate IgE levels . These may be the result of dysregulation of the Th1/Th2-IgE axis . Other neoplastic conditions known to present with elevated IgE levels include IgE myeloma and malignant lymphoma. Eosinophilia and elevated IL-4 and IgE levels have been shown in both Hodgkin's disease (serum IgE as well as intracellular IgE within Reed-Sternberg cells) and malignant/non-Hodgkin's lymphoma . In multiple myeloma, polyclonal elevation of IgE is associated with improved survival .
IgE myeloma was first described in 1967 as an "atypical myeloma immunoglobulin" and since then several other cases of this rare myeloma have been reported . The presentation of IgE myeloma is similar to that of an IgG myeloma, and most patients are diagnosed between the 6th and 7th decades of life.
Many other inflammatory disorders have been associated with elevated IgE levels. These include Kawasaki syndrome , vasculitides such as polyarteritis nodosa or Churg-Strauss syndrome, Guillian-Barre syndrome [77, 78], inflammatory neuropathies , burns [80, 81], Sjogren's syndrome , certain patients with rheumatoid arthritis who may also develop IgE rheumatoid factors , graft-versus-host disease and bone marrow transplantation  and scleroderma-like syndromes . The prognostic or diagnostic role for IgE in these disorders is unknown
Several dermatological and inflammatory disorders have been associated with IgE dysregulation and elevated IgE levels. Alopecia areata [86, 87], erythema nodosum (especially due to streptococcus), acral dermatitides and blistering diseases, such as pemphigus, have been associated with IgE elevation [89, 90].
Systemic and Toxic Disorders
Alcohol ingestion has been associated with elevated IgE levels . Certain forms of nephritides demonstrate IgE elevation . The elevation of IgE in these disorders may be due to dysregulation of the IL-4-IL-13 axis. In idiopathic nephritic syndrome, IL-13 levels are elevated, while in minimal change disease, polymorphisms of the IL-4 gene have been described . Other conditions reported to show elevated IgE levels include cystic fibrosis  (with associated ABPA-like disease, probably secondary to increased airway penetration by allergen), nicotine abuse  and pulmonary hemosiderosis (Heiner's syndrome).
Major advancements have been made in our understanding of the molecular basis of IgE class switching including roles for T cells, cytokines and T regulatory cells in this process. Dysregulation of this process may result in either elevated IgE levels or IgE deficiency. Evaluation of a patient with elevated IgE must involve a detailed differential diagnosis and consideration of various immunological and non-immunological disorders. The use of appropriate tests will allow the correct diagnosis to be made. This can often assist in the development of tailored treatments.
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