Low ige levels cancer

Low ige levels cancer DEFAULT

The other side of the coin: IgE deficiency, a susceptibility factor for malignancy occurrence

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Decreased Level of IgE is Associated with Breast Cancer and Allergic Diseases

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AllergoOncology: ultra-low IgE, a potential novel biomarker in cancer—a Position Paper of the European Academy of Allergy and Clinical Immunology (EAACI)

  • D. FerastraoaruORCID: orcid.org/1,
  • H. J. BaxORCID: orcid.org/2,3,
  • C. BergmannORCID: orcid.org/4,
  • M. CapronORCID: orcid.org/5,
  • M. Castells6,
  • D. DombrowiczORCID: orcid.org/7,
  • E. FiebigerORCID: orcid.org/8,
  • H. J. GouldORCID: orcid.org/X9,10,
  • K. HartmannORCID: orcid.org/11,
  • U. Jappe12,13,
  • G. JordakievaORCID: orcid.org/14,
  • D. H. JosephsORCID: orcid.org/2,3,
  • F. Levi-SchafferORCID: orcid.org/15,
  • V. MahlerORCID: orcid.org/16,
  • A. Poli17,
  • D. RosenstreichORCID: orcid.org/1,
  • F. Roth-WalterORCID: orcid.org/18,
  • M. ShamjiORCID: orcid.org/19,
  • E. H. Steveling-KleinORCID: orcid.org/20,
  • M. C. TurnerORCID: orcid.org/21,22,23,24,
  • E. UntersmayrORCID: orcid.org/X25,
  • S. N. KaragiannisORCID: orcid.org/2,26 &
  • E. Jensen-JarolimORCID: orcid.org/18,25

Clinical and Translational Allergyvolume 10, Article number: 32 () Cite this article

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Abstract

Elevated serum IgE levels are associated with allergic disorders, parasitosis and specific immunologic abnormalities. In addition, epidemiological and mechanistic evidence indicates an association between IgE-mediated immune surveillance and protection from tumour growth. Intriguingly, recent studies reveal a correlation between IgE deficiency and increased malignancy risk. This is the first review discussing IgE levels and links to pathological conditions, with special focus on the potential clinical significance of ultra-low serum IgE levels and risk of malignancy. In this Position Paper we discuss: (a) the utility of measuring total IgE levels in the management of allergies, parasitosis, and immunodeficiencies, (b) factors that may influence serum IgE levels, (c) IgE as a marker of different disorders, and d) the relationship between ultra-low IgE levels and malignancy susceptibility. While elevated serum IgE is generally associated with allergic/atopic conditions, very low or absent IgE may hamper anti-tumour surveillance, indicating the importance of a balanced IgE-mediated immune function. Ultra-low IgE may prove to be an unexpected biomarker for cancer risk. Nevertheless, given the early stage of investigations conducted mostly in patients with diseases that influence IgE levels, in-depth mechanistic studies and stratification of malignancy risk based on associated demographic, immunological and clinical co-factors are warranted.

Highlights

  1. 1.

    Elevated IgE is a robust biomarker in atopy, allergy and parasitic infestations, but the implications of ultra-low IgE levels are not understood.

  2. 2.

    Epidemiologic analyses and in vitro and in vivo studies indicate that natural IgE has a surveillance function in cancer, and recombinant anti-cancer IgE is under investigation in a human trial.

  3. 3.

    IgE immunodeficiency correlates with a significantly elevated risk of malignancy development, prompting the need for further research to evaluate ultra-low IgE levels as a new biomarker in oncology.

Methods

This Position Paper was prepared by the EAACI Task Force (TF) for AllergoOncology, an expert panel of immunologists, allergists, physicians, biochemists and epidemiologists. In the first meeting, topics were identified and prior to the second workshop, a PubMed literature search of specific topics was conducted by individual TF members. The compiled manuscript was extensively revised by the second workshop attendees to obtain consensus on text, tables and figures. Although no evidence-based recommendations were made, due to the limited number of published studies on IgE deficiency, future directions were discussed. The manuscript was recirculated for review to all TF members, compiled and again recirculated for complete consensus. The final manuscript was read and approved by all authors and represents an expert consensus opinion with recommendations summarized in the “Highlights box”.

Data sources, search strategy and study selection

Published peer reviewed studies in English were identified from PubMed. The following key words were used in the search strategy: (allergy* OR atopy* OR *IgE) AND (tumor/tumour OR cancer OR malignancy) AND (IgE OR IgE deficiency). References published within the timeframe that had not been otherwise identified in the initial search were added where relevant. We reviewed approximately published studies relevant to this paper.

Part 1. Intro: a brief history of IgE in atopy/allergy, parasitosis and cancer

Immunoglobulin E (IgE) was isolated in and recognized as the immunoglobulin isotype involved in allergic reactions [1]. Earlier, two groups worked independently on γE antibody (K. and T. Ishizaka) and IgND (recognized initially as a new myeloma protein by SGO Johansson and H. Bennich), which were found to represent the same IgE molecule [2]. Thousands of publications have since shaped our understanding of the role of IgE not only in type I hypersensitivity reactions, but also in parasitosis and other specific immunologic disorders, and more recently in tumour surveillance (Historic milestones are summarized in Table 1).

Full size table

Allergic diseases, which are widespread throughout the world, are driven by a T helper 2 (Th2) immune response to allergens, resulting in production of Th2 cytokines and class-switching to IgE. Th2 responses are actually thought to have originally evolved to control extra‐cellular parasites. Nearly one-third of the global population has some type of helminth infection which triggers an immune response characterized by elevated Th2 cytokines, IgE and eosinophilia [3]. Many questions regarding the immunological similarities between allergic and anti-parasitic immunity have been raised, and molecular similarity between some allergenic proteins and those encoded by parasitic genomes have been reported [4, 5]. It has been hypothesized that, since the rate of parasitic infection is significantly lower in most humans today, the specialized Th2 immune system which primarily evolved to recognize parasite antigens, now reacts to innocuous allergens causing atopic disorders [6,7,8].

Recently, another new role of IgE in tumour immune surveillance has been suggested by many epidemiological studies and in vitro and in vivo studies in murine models [9,10,11]. In human populations, early epidemiological studies reported inverse associations between self-reported atopy, anti-histamine use and pancreatic cancer incidence in a population aged > 70 years [12], as well as between physician-diagnosed chronic allergy/atopy and brain tumour incidence [13]. In addition, self-reported asthma and fatal prostate cancer risk [14], as well as self-reported asthma/hay fever and colorectal cancer mortality [15], have been reported to correlate inversely. However, one study of postmenopausal women showed no association between self-reported environmental allergies and incident myeloid or lymphoid malignancies [16]. These findings suggest that the relationship between atopy and malignancy is complex and probably depends on specific tumour types and the individual studied populations.

Most of the initial epidemiological studies assessed the association between self-reported allergies and malignancy, which may produce different types of biases. However, once it was recognized that the IgE molecule might be the link between allergies and cancer, different population studies began to examine the association between total or allergen-specific IgE levels and cancer incidence. For example, results from a large Swedish cohort demonstrated an inverse correlation between elevated specific IgE and overall cancer risk, specifically for melanoma, breast and gynaecological cancers [17]. Another prospective study reported that high total serum IgE was associated with a lower risk of developing chronic lymphocytic leukaemia and multiple myeloma [18]. Similarly, higher pre-diagnostic serum IL-4 levels [19], higher total IgE levels [20] and respiratory allergen-specific IgE [21] were associated with a lower risk of developing glioma. However, this was not confirmed in another meta-analysis [22]. Importantly, patients diagnosed with glioma and multiple myeloma with elevated serum IgE experienced longer survival [23, 24]. Despite some mixed results, a review tabulating the body of epidemiological evidence of the relationship between atopy and cancer risk since , suggested that atopy was associated with a reduced cancer risk [9]. These observations, along with recent murine studies showing that IgE is important in tumour surveillance [11, 25, 26], raise questions on how the incidence and risk of malignancy are affected by ultra-low IgE levels in the clinical practice. To our knowledge, this is the first review that discusses not only consequences of elevated IgE levels, but also the potential clinical significance of ultra-low serum IgE. Figure 1 provides an overview of the diverse role of IgE in atopy, parasitosis and cancer, mechanisms that will be discussed later in this review.

The IgE isotype uniquely encompasses effector function in the pathophysiologies of allergic reactions, parasitosis, and tumour defence

Full size image

Overview of medical conditions which are associated with altered serum IgE levels, ranging from ultra-low to elevated serum IgE titres

Elevated IgE (often referred to high and very high serum IgE levels) is commonly considered a serum signature for allergic/atopic conditions [27, 28]. In clinical practice, these patients are referred to Allergy clinics for suspected allergic disorders or other conditions associated with elevated IgE levels. For example, atopic dermatitis and hyper-IgE syndrome are among the disorders with the highest serum IgE levels (often IgE greater than 10, kU/L), followed by asthma, parasitosis and allergic rhinitis [29,30,31].

Total serum IgE of – kU/L is typically considered the normal upper limit in adults [28], although IgE levels < – kU/L cannot be used to exclude atopy or allergic disorders. Because of the wide range of IgE levels in non-allergic individuals and in patients with different disorders, no certain cut-offs to define “high IgE” and “very high IgE” states are established. Some studies defined IgE values of kU/L as “high IgE level”, and IgE ≥  kU/L as “very high” [32,33,34]. Others categorized serum IgE levels of – kU/L as “moderately elevated IgE levels”, while IgE > 10, kU/L was labelled as “extraordinarily high serum IgE” [29] or “extremely elevated IgE” [35]. We propose a unified classification of different total IgE cut-off levels and their possible associated pathologies (Table 2).

Full size table

While research has focused primarily on elevated IgE serum levels, the evidence presented in this Position Paper indicates that investigating the consequences of IgE deficiency (IgE <  kU/L [36] or IgE < 2 kU/L [37]) may be equally important. Current evidence suggests that IgE deficiency is associated with several types of clinical pathologies, including higher rates of malignancy [32,33,34, 37]. In selected patients suspected of a primary humoral immunodeficiency, low IgE may be a sensitive and specific marker for the presence of common variable immunodeficiency [38]. Although the pathophysiology of IgE deficiency is not completely understood, it is clear that there is a mechanistic difference between IgE deficiency (ultra-low IgE levels) and atopy (elevated IgE levels) which ultimately may be responsible for the features of these two different conditions. The purpose of this paper is to review for the first time, how different IgE serum levels (from ultra-low to very high) are suggestive of specific pathological conditions, focusing on the less-appreciated anti-tumour role of IgE.

Part 2: IgE synthesis and regulation

B cells diversify the antibody repertoire by rearrangement, recombination and somatic mutation of immunoglobulin genes. The germline genes are transformed at two stages of B cell development: during V(D)J recombination in B cell precursors, and by somatic hypermutation (SHM) in the Ig variable (V) domains and class switch recombination (CSR) in mature B cells. CSR to IgE requires IL-4 or IL during cognate interactions between CDligand (CD40L) on the Th2 cell and CD40 on B cells, or T cell-independent (TI) stimulation of polyclonal IgE through homologues of CD40L and CD40 in mucosal tissues [39].

There are two types of IgE receptors, high (FcεRI) and low (FcεRII) affinity, that are well described in the literature. In addition, soluble isoforms of IgE Fc receptors (sFcεR) have been described and may form a serum sink for IgE, preventing loading of IgE to surface-expressed FcεRI. In allergic reactions, this may be part of the negative feedback loop that can shut down allergic responses by inhibiting surface binding of IgE and preventing cellular sensitization [40]. On the other hand, the same mechanism could be responsible for preventing IgE-mediated anti-cancer responses and might therefore be considered a feature of tumour evasion. The low affinity receptor for IgE, FcεRII/CD23, which is mainly expressed by B lymphocytes and involved in regulation of IgE production, is expressed on monocytes and follicular dendritic cells that participate in antigen presentation by internalization of IgE-antigen immune complexes. CD23 is expressed in some malignancies (e.g. chronic B cell lymphoma) and serum levels of sCD23 have been described as potential biomarker for cancer progression [41].

Part 3: Elevated IgE, a biomarker in allergies

Definition of atopy, allergic sensitization, and allergy

As last published in , “atopy” is defined as “a personal and/or familial tendency, usually in childhood or adolescence, to become sensitized and produce IgE antibodies in response to ordinary exposures to allergens, usually proteins. As a consequence, these persons can develop typical symptoms of asthma, rhinoconjunctivitis, or eczemas” [42]. Despite extensive research to find a genetic signature for atopic individuals, no clear genetic fingerprint has yet emerged. An individual with high total or specific serum IgE is considered sensitized, though may not suffer from an allergic disease [43]. The clinical relevance of IgE levels in different type I hypersensitivity disorders is summarized below and in Table 3.

Full size table

IgE and other markers used in the clinical diagnosis of allergic reactions

Specific environmental, food or drug allergen provocation tests remain the gold standard for the clinical diagnosis of IgE-mediated reactions. However, there are certain conditions under which provocation tests should not be performed, depending on the type of reaction, the results of additional tests and history, and the clinician’s familiarity with this procedure. Therefore, in clinical practice, different tools are used to diagnose IgE-mediated reactions, in addition to detailed history and examination.

Commonly, serum total and allergen-specific IgE (sensitization is defined as serum specific IgE (ssIgE) >  kU/L) are considered important biomarkers in allergy, atopy and asthma [44,45,46] (detailed below). Increased mast cell degranulation and clinical symptoms are the result of a number of factors including a high IgE affinity for allergens [47], increased concentration of allergen-specific IgE titers relative to IgE that is not specific for any known allergen, increased serum total IgE, and increased number of epitopes recognized by the IgE repertoire [48].

For some allergens, dominant allergenic proteins have been identified, purified, and incorporated into diagnostic in vitro tests, termed “component-resolved diagnosis” (CRD). Apart from the fact that CRD is often more sensitive than whole allergen extract diagnosis, the presence of specific IgE to certain allergen components is a predictive biomarker for the severity of allergic reactions [49].

Similarly, positive skin tests are considered to be a reliable method for diagnosing inhalant, food, drug or venom allergies [50]. Measuring tryptase levels, during and after an allergic reaction, can differentiate between IgE-mediated hypersensitivity and primary mast cell disorders [51]. Secondary eosinophilia (>  cells/µl) may also be found in different atopic/allergic conditions, [52] and periostin might identify asthmatic patients with an IL—dependent Th2 phenotype [53]. The basophil activation test, which uses the surface expression of CD63 and/or CDC following allergen stimulation [54], is emerging as a promising tool to differentiate between true IgE-mediated allergy and allergic sensitization.

Total and specific IgE measurements as biomarkers in respiratory allergies

Total serum IgE >  kU/L was associated with new‐onset asthma in a longitudinal analysis of the European Community Respiratory Health Survey [45], while IgE levels of  IU/mL had 93% sensitivity and 91% specificity for asthma diagnosis in another study [55]. This evidence supports the use of anti-IgE as additional therapy in asthma. The dose and frequency of administration of omalizumab, a recombinant humanized IgG1 monoclonal antibody that binds IgE with high affinity, are based on baseline total serum IgE levels (30– IU/ml depending on age), patients’ weight, and sensitization status [56].

Allergic bronchopulmonary aspergillosis (ABPA) is the only allergic disease for which total IgE levels are part of the diagnostic criteria (IgE >  kU/L in asthmatics; IgE >  kU/L in cystic fibrosis patients). A 35–50% decrease in total IgE levels in response to treatment suggests remission, while doubling of the baseline IgE levels suggest ABPA relapse [44].

Regarding the utility of performing skin tests and/or measuring specific IgE for diagnosis of environmental allergies, it was shown that, regardless of the allergen tested, every third to fourth patient would have been misdiagnosed as non-sensitized for a particular allergen if diagnosis relied exclusively on serum specific IgE or skin prick testing. These data support the importance of combining skin tests with measurements of ssIgE for diagnostic purposes, and suggested that the two testing methods should be used in a complementary fashion [57]. Nevertheless, other studies showed that levels of ssIgE to dust mites may predict the severity of allergic rhinitis: patients with mild intermittent symptoms had significantly-lower dust mite-specific IgE (median, kU/L) compared with those with mild persistent symptoms (median,  kU/L) and those with moderate-to-severe persistent symptoms (median,  kU/L) [46].

Importantly, patients with IgE deficiency can also suffer from allergic rhinitis, chronic sinusitis-like symptoms, or asthma [32, 36, 37, 58]. It has been speculated that baseline IgE production might have a protective mucosal effect [59], so its absence would contribute to the severity of the above-mentioned conditions. Despite very low or undetectable serum IgE titres, local IgE production could explain tissue-specific allergic responsiveness which should be explored in patients with IgE deficiency who present with symptoms consistent with environmental allergies.

Specific IgE as a biomarker in food allergies

Considerable efforts have been made to define 95% predictive cut-off specific IgE levels (diagnostic decision points (DDPs)) for egg (7 kU/L), milk (15 kU/L), peanut (14 kU/L), soy (65 kU/L), wheat (80 kU/L), and fish (20 kU/L) [60]. However, anaphylaxis was also reported to occur in patients with low or even undetectable specific IgE. In these cases, CRD is helpful in diagnosing and predicting IgE-mediated food allergies [61, 62]. Additional allergy-enhancing co-factors must be taken into consideration when interpreting the results of specific IgE and CRD in food allergy diagnosis.

Relevance of total and specific IgE in venom and drug allergies

In patients who have experienced venom anaphylaxis despite having negative skin prick tests, venom-specific IgE is used as an alternative test to support decisions for initiating venom immunotherapy. Interestingly, total IgE levels may predict venom allergy severity: individuals with low total IgE levels (< 50 kU/L) had higher rates of loss of consciousness than those with IgE >  kU/L [63]. Using CRD may be helpful to differentiate between honeybee and yellow jacket sensitivity in those with double positivity [63].

Although ssIgE to different drugs can be measured, clear evidence to justify their use in the diagnosis of IgE-mediated drug allergies is lacking, because results do not correlate with the outcomes of drug challenges [64]. However, penicillin-specific IgE may be useful in patients with recent anaphylaxis to penicillin [65]. Sensitization to alpha-Gal is associated with IgE-mediated anaphylaxis to the anti-EGFR therapeutic antibody Cetuximab (used in the treatment of certain solid tumours), due to alpha-Gal moiety on the Fab portion of the heavy chain [66], as well as with allergic reactions occurring more than 2 h after ingestion of mammalian meat in those patients previously sensitized [67]. Evidence that IgE is involved in immediate-type drug allergies is supported by the observation that the off-label use of anti-IgE antibody, omalizumab, effectively prevents such reactions during drug desensitization protocols [68, 69].

Part 4. Total and specific IgE as biomarkers in parasitic infestations

For > 40 years, a protective role of IgE in helminth infections has been postulated: IgE binding to the parasite attracts IgE-receptor bearing cells to the site, resulting in parasite killing [3, 70] (Fig. 1). Similarly to the atopic/allergic status, the response to parasitic infections is also associated with the induction of strong Th2 immune responses, leading to eosinophilia, elevated Th2 cytokines and increased serum IgE (e.g. in a cohort of patients with Ascaris infection, total IgE levels reached 13, kU/L) [71, 72]. Moreover, total IgE levels significantly decrease after treatment for E. histolytica, H. nana or A. lumbricoides [73].

The role for IgE in fighting parasites was also illustrated by the fact that genetically engineered, IgE-deficient mice infected with T. spiralis had significantly increased intestinal and muscular worm burden, compared with infected wild-type mice [74]. However, it is not known if humans with IgE deficiency have higher rates or risk of developing parasitic infections. One retrospective study showed similar rates of positive serologies for Strongyloides, Toxacara and Trichinella in patients with IgE-deficiency (IgE <  kU/L), compared with those with IgE ≥  kU/L. However, the number of performed serologic tests was small [32]. In support of a positive correlation of serum IgE and parasitic defense, Omalizumab therapy has been associated with a modest increase in helminth infection incidence [75].

Part 5. IgE and its role in tumour surveillance

Evidence for a physiological role of IgE in cancer protection and cancer treatment

Host defense against parasites is widely considered to be the most significant beneficial function of IgE. However, a growing body of evidence strongly suggests that IgE plays key roles in tumour immune surveillance. Solid tumours are infiltrated by immune cells that express IgE receptors, resulting in anti-tumor antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cell-mediated phagocytosis (ADCP) [10]. Additionally, IgE-mediated cross-presentation of different tumour cell antigens by dendritic cells induces anti-tumour cell cytotoxic T cell activation [26] (Fig. 1).

A higher abundance of IgE-expressing cells was reported in head and neck tumours compared with normal mucosa [76]. Patient-derived pancreatic tumour-specific serum IgE potentiated anti-tumour effector functions in vitro [77], supporting the role of IgE in tumour surveillance. Furthermore, expression of the high-affinity IgE receptor gene MS4A2 by tumour-infiltrating mast cells in lung cancer was associated with a favourable prognosis and correlated with innate anti-tumour immune responses [78].

In a therapeutic context, the very high affinity of IgE for its cognate Fcε receptors and lack of inhibitory IgE Fc receptors suggests the potential for long-lasting and efficient anti-neoplastic effector cell responses, and this has stimulated interest in the clinical application of anti-tumour IgE in cancer treatment [79]. The first phase I clinical trial of a cancer-associated antigen-specific IgE in patients with advanced solid tumours (NCT) is ongoing and promising interim data from this trial were recently presented. Ultimately, further clinical evaluations should provide important information about the anti-tumour functions of IgE [80].

Very low total serum IgE levels, a potential novel biomarker in malignancies

One clinical question, arising from the findings that IgE and atopy are protective against malignancy, is whether the opposite is also true, that individuals with very low or undetectable IgE levels have a higher prevalence and risk of developing malignancy. In several epidemiological studies assessing the relationship between IgE levels and cancer, patients with higher IgE levels were found to have a lower risk of chronic lymphocytic leukaemia, multiple myeloma or glioma compared with individuals in the lowest IgE level tertile [18] or with those with IgE <  kU/L. [20] Other retrospective studies, focusing specifically on the relationship between ultra-low IgE levels and malignancy, found that IgE-deficient individuals (IgE <  kU/L) had higher rates and risk of having a diagnosis of any type of malignancy compared with non-IgE deficient individuals (IgE ≥  kU/L) [32, 33, 37]. Another prospective, longitudinal study found that IgE deficient patients had, after a median month follow up, significantly higher rates and risk of developing new malignancy (%) compared with those with IgE levels – kU/L (%) and with those with IgE ≥  kU/L (0%) [34]. Presently, we do not know if the very low or absent IgE levels are caused by the malignancy but develop before the malignancy becomes clinically apparent, or if IgE deficiency develops for other, unknown reasons, and the low IgE levels cause or are part of an immunomodulatory response associated with increased malignancy susceptibility.

The fact that ultra-low IgE levels may be associated with higher malignancy risk is also supported by different murine studies. For example, in a recent study, IgE-, FcεRI- and ILdeficient mice developed skin cancers significantly faster than wild-type mice after skin exposure to a known carcinogen. The same study showed that skin exposure to DNA-damaging stress signals potentiated adaptive immune responses that favoured B cell class switching to IgE and restricted tumour growth [25]. Similarly, mammary carcinomas grew significantly faster in low-IgE ΔM1M2 mice lacking the transmembrane/cytoplasmic domain of the IgE-receptors of B-cells, mimicking a reduced serum IgE level phenotype [81]. In striking contrast, tumour growth was inhibited in high-IgE KN1 mice which have four to sixfold increase in serum IgE levels compared to wild type strains. Moreover, tumour challenge following immunization with irradiated cancer cells caused delayed tumour growth in wild-type but not in IgE-knockout mice. Importantly, mice with higher levels of IgE-secreting B cells were completely protected from tumour growth [81]. In another study, HER-2 overexpressing D2F2E2 cells were grafted into mice with different IgE levels and the immune and survival benefits were compared following treatment with anti-HER-2 antibody trastuzumab [11]. Notably, in this study, the innate immune effects of high-IgE levels in the high-IgE KN1 mice were at least as impressive as the effects of an antigen-specific HER-2 vaccine. The KN1 model may, therefore, recapitulate the epidemiologic observations that total IgE levels in atopic individuals appeared protective against tumour growth.

In summary, these studies point to beneficial immune surveillance roles for IgE in cancer, and to a potential link between absent or very low serum IgE levels and malignancy risk. Although in clinical practice omalizumab is designed to decrease serum IgE levels, there is insufficient evidence to determine whether omalizumab influences development or progression of malignancy in the studied populations [82].

Part 6: Other conditions affecting IgE levels

Other medical conditions associated with elevated or ultra-low IgE levels

Several immunodeficiencies are associated with very high and extremely high IgE levels due to regulatory T cell dysfunction, T cell oligoclonality and increased IL-4 production (Table 3) [83]. Some of these rare primary immunodeficiencies caused by STAT3 mutations [31, 84] are characterized by extremely high serum IgE levels (often above 10, kU/L) and are associated with a pruritic eczematous skin rash, eosinophilia and impairments of other organ systems including intelligence and motor function. These human hyper-IgE syndromes (HIES) include the autosomal dominant Job´s syndrome and autosomal recessive PGM3 (phosphoglucomutase 3) and SPINK5 (Serine Peptidase Inhibitor Kazal Type 5) syndromes, that can be successfully treated with anti-IgE antibody therapy [85] or stem cell transplantation [86].

Elevated IgE levels may be also found in patients with IgG4-related disease. A total IgE >  IU/mL at diagnosis distinguished patients with IgG4-related disease from control subjects with 86% specificity, while IgE >  IU/mL identified patients with disease relapse with 88% specificity [87]. Contrastingly, although elevated IgE levels in asthmatic patients with eosinophilia may suggest a diagnosis of EGPA (Eosinophilic granulomatosis with polyangiitis (Churg–Strauss syndrome)), IgE levels alone are not a good predictor of EGPA disease activity [88]. Elevated IgE levels have been reported in patients infected with the human immunodeficiency virus (HIV), specifically in advanced stages, possibly attributed to polyclonal stimulation of B cells [89].

In addition to patients with selective IgE deficiency (IgE <  kU/mL, but normal IgG, IgA and IgM levels), ultra-low IgE levels may also be found in patients with common variable immunodeficiency (CVID) [38], hyper-IgM syndrome and XLA agammaglobulinemia, due to defects in B cell lineage and IgE-isotype class switching.

Demographic and lifestyle factors influencing IgE levels

A wide variety of factors affect allergy development and may therefore influence IgE levels (Table 4). In a non-selected Austrian adolescent cohort, male gender was associated with higher sensitization frequency (%) compared to females, while family size and growing up on a farm inversely-correlated with ssIgE levels [90]. After multivariant adjustment in a random sample of Danish children, positive skin prick test, airway hyperresponsiveness, atopic dermatitis, and parental predisposition remained significant predictors of total serum IgE [91]. Smokers and those with occupational dust or gas exposure have higher mean logarithmic IgE values than non‐smokers and unexposed individuals [92]. Similarly, in Korean adults, a larger proportion of individuals with total IgE ≥  kU/L and ssIgE ≥  kU/L to D. farinae were ex- or current smokers [93] and high-risk drinkers [94]. Among a U.S. population cohort aged ≥ 6 years, median IgE levels were higher: for males ( kU/L) than for females ( kU/L); for non-Hispanic Blacks (kU/L) and Mexican-Americans ( kU/L) than for non-Hispanic whites (kU/L); for persons with < 12th grade education ( kU/L), increased poverty ( kU/L) or higher BMIs (body mass index) ( kU/L) [95]. In the – NHANES (National Health and Nutrition Examination Survey) cohort, there were significantly more Caucasian females with IgE deficiency than non-IgE deficient individuals [33].

Full size table

Therapeutic manipulations affecting total IgE levels

Total serum IgE may be influenced by medications (Table 4). Omalizumab is targeted therapeutically to reduce free IgE to <  IU/mL [96]. Assessing changes in total IgE levels pre- and post-omalizumab administration has been challenging because of broad variations of these changes (–%), the assay used, and the molar ratio of omalizumab/total IgE [97]. Currently, there is no accurate technique to measure free IgE levels in omalizumab-treated patients. In clinical practice, an initial increase in total IgE after omalizumab administration (e.g. % increase over baseline at 16 weeks in paediatric patients [98]) is observed and can be explained by the increased half-life of IgE-omalizumab immune complexes. Additionally, omalizumab may activate IgE-positive memory B cells and induce IgE production [99]. After an initial increase, IgE levels decrease despite omalizumab continuation (e.g. from % increase to % decrease at 48 weeks [98], or from % increase to 74% decrease []), likely because of slow elimination of IgE-expressing lymphoblasts and memory cells due to downregulation of IgE receptors []. Presently, no clear consensus has been established among experts on how to utilize total pre- and post-omalizumab IgE levels regarding disease monitoring and response. It is yet to be reported how the new humanized IgG1 monoclonal anti-IgE antibody (ligelizumab) could influence IgE levels, since it binds with higher affinity to the IgE Cε3 domain and is designed to achieve superior IgE suppression [].

Dupilumab, a fully-humanized monoclonal antibody targeting the interleukin-4 receptor α (IL-4Rα) subunit, which is approved for the treatment of asthma, atopic dermatitis and chronic rhinosinusitis with nasal polyps, decreases serum total IgE levels by a mean of 50% at 16 weeks compared with baseline []. The implication of this finding for clinical practice remain to be evaluated.

Corticosteroids are used to control different allergic disorders. Since IgE is a biomarker of “allergies”, one would expect that corticosteroids would decrease IgE levels. However, the decrease in IgE does not occur since corticosteroids polarize the immune system towards a Th2 predominance by suppressing IFN-γ (which normally inhibits Th2 differentiation) and inducing IL production (which normally promotes Th1 cytokines), as well as by increasing IgE production by enhancing the expression of CD40 ligand [].

Allergen immunotherapy induces an initial increase in serum specific and total IgE, followed by a gradual decrease over months or years of treatment [].

Other medical conditions in which IgE might play a pathophysiological role

A higher proportion of patients with chronic urticaria (34%) have total IgE >  IU/mL compared with controls [] and multiple IgE autoantigens were found in patients with chronic spontaneous urticaria (CSU) []. Additionally, some patients with refractory CSU respond well to anti-IgE therapies, although the exact mechanism remains unclear []. The therapeutic success of anti-IgE treatment in CSU suggests a role for IgE in urticaria pathophysiology.

Different antigenic targets of IgE have been described in several medical conditions, including systemic lupus, bullous pemphigoid, pemphigus vulgaris, autoimmune uveitis, rheumatoid arthritis, multiple sclerosis, autoimmune pancreatitis, which led to the new research field of IgE-mediated autoimmunity []. However, IgE is not considered a biomarker in any of these diseases.

Lastly, significant experimental evidence points to the role of vitamin D as a regulator of various immune pathways, and hypovitaminosis D might be associated with elevated total IgE levels and a higher rate of different allergic disorders [].

Microbiota influences on IgE levels

Different mechanisms, about how microbiota may influence and regulate the innate and adaptive immune responses with emphasis on the Th2 pathway, have been reviewed in detail in our previous AllergoOncology Position Paper []. One study showed that germ-free mice have elevated total IgE levels, resulting in higher susceptibility to anaphylaxis than non-germ free mice, and demonstrating the difficulty of achieving oral tolerance in animals with altered microbiota []. In humans, low inferior turbinate bacterial diversity was associated with allergic rhinitis and total serum IgE >  IU/mL []. Asthmatics with small intestine bacterial overgrowth (SIBO) had higher mean IgE levels ( ±  IU/mL) which significantly decreased after SIBO treatment, compared with non-SIBO asthmatics []. Presently, our observations predominantly describe correlations rather than causations between microbiota alterations, IgE levels, and allergic reactions. Whether altered microbiomes are a cause or effect of allergies requires further in-depth investigations.

Conclusion

In clinical practice, attention should be paid not only to patients with high IgE levels, but also to those with very low or absent serum IgE. IgE-deficient individuals have higher rates and risk of malignancy, and attention to this observation will close knowledge gaps with regards to questions such as: (1) Should we check serum total IgE levels in all patients? (2) Which assays should we use to monitor patients with ultra-low IgE levels and what are the ethical implications of not monitoring them? (3) What IgE levels protect from malignancies or, maybe even more importantly, which IgE titres are associated with the risk of developing cancer?

Longer prospective studies are needed to delineate the exact clinical consequence of very low or absent serum IgE levels and to assess if ultra-low IgE will emerge as a clinical biomarker for malignancy susceptibility. While the anti-tumour role of IgE and the potential of IgE-based therapy begins to be recognised, the immunological mechanisms causing IgE deficiency are not yet understood. Dysregulated pathways involved in the IgE class-switching process might not only be responsible for the low serum IgE levels but perhaps also for some impaired anti-tumour activity. Based on the available data, we conclude that low IgE may be a novel, unrecognized biomarker for cancer development. However, substantial effort and interactive research by immunologists, allergists, and oncologists will be necessary to determine the exact role of IgE in malignancy susceptibility and whether there is a specific threshold for serum IgE that determines malignancy susceptibility.

Box 1: Unmet needs to define very low/absent IgE as biomarker in cancer

  • The exact IgE level threshold that confers protection versus risk for malignancy occurrence remains to be defined.

  • It is not yet clear whether ultra-low/undetectable serum IgE is truly a risk factor for developing malignancy, or if IgE levels are low in response to undetected cancer progression. It is possible that an aberrant and unknown immune pathway causes low IgE levels in response to malignancy.

  • There is a need for large prospective studies as well as in vitro experiments and in vivo models to further delineate the role of ultra-low IgE as a putative biomarker for malignancy.

Box 2: Pending questions in the field, future directions

  • Is antigen-specific and/or total serum IgE involved in cancer surveillance?

  • Is an IgE-related immune score helpful to predict malignancy occurrence? What demographic, clinical and/or immunological factors should this score include?

  • New genetic and genomic evaluations are needed to determine if there is a familial risk for IgE deficiency.

  • Is the prevalence of IgE deficiency age-dependent?

  • Should patients at risk of developing malignancy be treated with specific anti-tumour IgE or total IgE to achieve higher anti-tumour surveillance? Is passive intravenous IgE (IVIGE) or IL-4 a safe option?

Box 3: Recommendations for patients with IgE deficiency

  • Due to current minimal information in the field, we cannot specify screening tests or establish recommendations for patients with IgE deficiency. However, with the goal of understanding the role of diminished IgE in the general population, certain clinical findings (e.g. presence of lymphadenopathy, splenomegaly) and laboratory tests (e.g. presence of tumour markers [], C-reactive protein level [], DNA methylation test [], cell frequency detection [], proteome and miRNome profiling [], presence of circulating exosomes []) may be considered as directions for future studies in these patients.

Availability of data and materials

Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.

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Sours: https://ctajournal.biomedcentral.com/articles//sw
The Various Hyper IgE Syndromes (HIES)

Abstract

Previous epidemiological studies suggest an inverse association between allergies, marked by elevated immunoglobulin (Ig) E levels, and non-Hodgkin lymphoma (NHL) risk. The evidence, however, is inconsistent and prospective data are sparse. We examined the association between prediagnostic total (low: <20; intermediate: 20–; high > kU/l) and specific IgE (negative: <; positive ≥ kU/I) concentrations against inhalant antigens and lymphoma risk in a study nested within the European Prospective Investigation into Cancer and Nutrition cohort. A total of incident cases and matched controls of NHL, multiple myeloma (MM) and Hodgkin lymphoma with a mean follow-up time of 7 years were investigated. Multivariate-adjusted odds ratios (ORs) with 95% confidence intervals (CI) were calculated by conditional logistic regression. Specific IgE was not associated with the risk of MM, B-cell NHL and B-cell NHL subtypes. In contrast, total IgE levels were inversely associated with the risk of MM [high level: OR = (95% CI = –)] and B-cell NHL [intermediate level: OR = (95% CI = –); high level: OR = (95% CI = –)], largely on the basis of a strong inverse association with chronic lymphocytic leukemia [CLL; intermediate level: OR = (95% CI = –); high level: OR = (95% CI = –)] risk. The inverse relationship for CLL remained significant for those diagnosed 5 years after baseline. The findings of this large prospective study demonstrated significantly lower prediagnostic total IgE levels among CLL and MM cases compared with matched controls. This corresponds to the clinical immunodeficiency state often observed in CLL patients prior to diagnosis. No support for an inverse association between prediagnostic levels of specific IgE and NHL risk was found.

Introduction

Lymphomas constitute a heterogeneous group of malignancies involving lymphocytes. They represent the fifth most common cause of cancer incidence among women and the sixth among men (1). Epidemiologic observations point to important associations between lymphoma development and deregulation of immune responses (2). For non-Hodgkin lymphomas (NHLs) and less so for Hodgkin lymphoma, strongly increased risks have been observed among immunosuppressed organ transplant recipients and certain autoimmune diseases were associated with lymphoma risk (3,4). In contrast, epidemiologic data, especially from case-control studies, suggest a possible inverse relationship between the risk of NHL and atopic conditions, such as hay fever, allergic asthma and allergic reactions against high-molecular-weight allergens in occupational exposure settings (2,5,6). Atopic conditions, including those against occupational allergens (7), are caused by hypersensitivity to environmental allergens and are characterized by an immune response shifted towards an increased type 2 (relative to type-1) T-helper cell activity and increased immunoglobulin (Ig) E production (8,9). It has been speculated that this type of increased immune response could be linked to stronger immune surveillance and host defense against malignant disease (‘immune surveillance hypothesis’) (10).

These observations have led to speculations that a relatively large proportion of NHL occurrences could be related to comparatively minor, and potentially subclinical, variations in immune function (2). However, considerable debate still exists as to whether the association of NHL with atopic conditions and related variations in immune response reflect a cause or an effect of lymphoma development (11–13). To date, only a few prospective studies have assessed specific and/or total IgE levels in relation to subsequent lymphoma diagnosis (12,14,15). Two Swedish cohorts, which measured individuals for total IgE, found no association with either the risk of cancer in general or with lymphoma (14,15). In a Finnish cohort of pregnant women, no association between NHL and specific IgE reactivity was found, except in women who developed NHL <5 years after the blood samples were drawn, again suggesting that reduced antibody levels could be a consequence rather than a cause of NHL development (12). Finally, in several cohort studies, contrary to many case-control studies, no protective effect was found (3,14,16–21), and some studies even observed an increase in lymphoma risk in association with a self-reported history of allergies (3,16,18,20,21).

To further clarify the prospective relationship between atopy-related immune response and the risk of lymphoma and its main subtypes, we measured plasma levels of total IgE and specific IgE against inhalant allergens in incident cases of lymphoma and matched controls, within the European Prospective Investigation into Cancer and Nutrition (EPIC).

Materials and methods

EPIC is a large prospective cohort study with over participants enrolled from 23 centers in Denmark, France, Germany, Greece, Italy, the Netherlands, Norway, Spain, Sweden and the United Kingdom (22). In most EPIC study centers, study participants were recruited from the general population of the local geographical areas. Exceptions were the Utrecht subcohort in the Netherlands and the Florence subcohort in Italy, where participants were recruited among women participating in a population-based breast cancer screening program, and the French subcohort, which was based on women who were members of the health insurance system or state-school employees. In addition, the five Spanish subcohorts, and the Turin and Ragusa subcohorts in Italy included high proportions (46–%) of blood donors. Between and , standardized lifestyle and personal history questionnaires were collected from all study participants, and for over participants, a blood sample was also collected at first recruitment. Blood samples were stored in a central bio-repository at the International Agency for Research on Cancer (Lyon, France, −°C in liquid nitrogen) for all countries except Denmark (−°C in nitrogen vapor) and Sweden (in −80°C freezer). All participants gave written informed consent to participate in the study. The research was approved by the local ethics committees in the participating countries and by the internal review board of the International Agency for Research on Cancer (Lyon, France).

Follow-up for cancer incidence and vital status

Data on vital status in EPIC are collected through record linkage with regional and/or national mortality registries, except in Germany and Greece, where data are collected through active follow-up and checks through municipal population registries. Cancer incidence is determined through record linkage with regional cancer registries (Denmark, Italy, the Netherlands, Norway, Spain, Sweden and the United Kingdom; complete, for the present report, up to December ) or via a combination of methods, including the use of health insurance records, contacts with pathology registries, and active follow-up through participants and their next of kin (France, Germany and Greece complete up to December ). Cases with lymphoid cancers were originally classified according to the Second revision of the International Classification of Diseases for Oncology (ICD-O-2), but were subsequently reclassified according to the WHO classification of hematopoietic and lymphoid tissue cancers, third edition (23), using a program available on the United States National Cancer Institute Surveillance, Epidemiology and End Results website (http://seer.cancer.gov/) and the expertise of pathologists. If the ICD-O-2 codes could not be exactly translated to ICD-O-3, a patient was categorized as ‘lymphoma, not otherwise specified’. Participants of the French cohort (n = 24 ) with available blood samples) were excluded from the study because of incomplete coding for lymphoid neoplasms, when the present project was started. From the remaining individuals, we excluded cases who had any form of cancer at time of blood draw except benign skin tumors (n = 27 ). The final analyses included lymphoma cases available for matching.

Nested case-control design and participant selection

For each lymphoma case, one control was selected by incidence density sampling from a total of eligible controls available, who were alive and without a cancer diagnosis cancer at the time a corresponding index case with lymphoma had been diagnosed. Matching criteria were study centre, sex, blood donor status, age at blood collection (±12 months at blood collection), date (±3 months) and time of blood collection. Following further exclusion of individuals with missing measurements, data from subjects ( matched case-control pairs) were available for analysis. Cases included Hodgkin lymphoma (n = 54), B-cell NHL (n = ), T-cell NHL (n = 36), multiple myeloma (MM; n = ) and lymphoma not otherwise specified (n = 71; collectively referred as NOS). The B-NHL subtypes included diffuse large B-cell lymphoma (DLBCL; n = ), follicular lymphoma (FL; n = ) and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (n = ). Due to their limited sample size, Hodgkin lymphoma and T-cell NHL were not considered in the analysis.

Laboratory analysis

Circulating plasma total and specific IgE antibody concentration were determined by an automated fluorescence enzyme immunoassay with the ImmunoCAP (Thermo Fisher Scientific, Phadia, GmbH, Freiburg, Germany). The following specific IgE antibodies against the eight most common allergens (with their international allergen codes) were quantified: g6-timothy grass, gcultivated rye, t3-common silver birch, w6-mugwort, d1-Dermatophagoides pteronyssinus, e1-cats epithelium and dander, e5-dog dander and m2-Cladosporium herbarum. Analyses were performed in the Division of Cancer Epidemiology of the German Cancer Research Center in Heidelberg. Laboratory personnel were blinded to the case or control status of participants. Plasma samples from each case-control set were assayed within the same analytical batch. About 40 µl of plasma was required for each assay. Two plasma quality control samples were analyzed within each batch. The intra-assay coefficients of variation were % (at kU/l) and % (at kU/l) for total IgE and % (at kU/l) and % (at kU/l) for specific IgE. The interassay coefficients of variation were % (at kU/l) and % (at kU/l) for total IgE and % (at kU/l) and % (at kU/l) for specific IgE.

Statistical analysis

Differences between cases and controls in IgE levels and continuous baseline covariates were tested by paired t-tests for each case-control set. Group differences in geometric mean IgE levels by baseline covariates were identified using pairwise t-tests and analysis of variance. For all further analyses, total IgE was categorized into three levels: reference (<20 kU/l; probability of allergic symptoms low), intermediate (20– kU/l; probability of allergic symptoms moderate) and high (> kU/l; probability of allergic symptoms high) (24). Likewise, specific IgE was categorized into ‘negative’ (< kU/l) and ‘positive’ (≥ kU/l) (25), and in additional analyses was further categorized into a ‘negative’ reference category (< kU/l) and tertiles for positive values (≥ kU/l) based on the distribution of IgE levels in the controls (first tertile, – kU/l; second tertile, – kU/l; third tertile ≥ kU/l). Conditional logistic regression, stratified by the case-control set, was used to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs) of lymphoma risk in relation to total and specific IgE levels. Statistical adjustments were made for smoking status (categorical: life-long non-smoker, current smoker, ex-smoker), alcohol consumption at the time of recruitment (g/d), highest school level [categorical: none, primary school completed, technical/professional school, secondary school, longer education (including university degree)].Test for linear trend was conducted by assigning ordinal scores (1–3) to each of the categories and treating the variable as continuous in the regression model. Missing value categories were added to the various confounding variables in order to retain all of the observations in the analysis (Table I). All analyses were also performed after the exclusion of the individuals with missing values in any of the variables (n = ). The results obtained from the two approaches did not differ meaningfully. Stratified analysis by time to diagnosis (<2/≥2; <3/≥3; <5/≥5 years after baseline) were conducted to evaluate the influence of time on the investigated associations. The likelihood ratio χ2 test was used to assess heterogeneity in the association between total and specific IgE levels and all main variables. All analyses were performed using SAS version (SAS Institute, Cary, NC). All tests of statistical significance were two-sided, and P-values < were considered significant.

Table I.

Distribution and geometric mean of prediagnostic specific and total IgE levels

Specific IgE (kU/l) . Total IgE (kU/l) . 
Controls (n = ) . Cases (n = ) . Controls (n = ) . Cases (n = ) . 
N (%) . Mean . PaN (%) . Mean . PN (%) . Mean . PN (%) . Mean . P
Sex 
 Male  (52)   (52)    (52)   (52)  
 Female  (48)   (48)   (48)   (48)  
Age at recruitment 
 <40 31 (3)   31 (3)   31 (3)   31 (3)   
 40–49  (14)   (14)   (14)   (14)  
 50–59  (45)   (44)   (45)   (44)  
 ≥60  (39)   (38)   (39)   (38)  
Season of blood donation 
 Spring  (29)    (29)    (29)    (29)   
 Summer  (18)   (18)   (18)   (18)  
 Autumn  (30)   (29)   (30)   (29)  
 Winter  (24)   (24)   (24)   (24)  
Smoking history 
 Life-long non-smoker  (43)    (41)    (43)   (41)  
 Current smoker  (20)   (19)   (20)   (19)  
 Ex-smoker  (30)   (33)   (30)   (33)  
 Missing information 70 (7)  73 (7)  70 (7)  73 (7)  
Alcohol at recruitment 
 0g/day  (11)    (14)   (11)    (14)  
 <5g/day  (30)   (28)   (30)   (28)  
 5–29g/day  (42)   (41)   (42)   (41)  
 ≥30g/day  (17)   (17)   (17)   (17)  
 Missing information 6 (1)  5 (0)  6 (1)  5 (0)  
Highest school level 
 None 40 (4)   40 (4)  40 (4)   40 (4)   
 Primary school  (35)   (33)   (35)   (33)  
 Technical/professional school  (27)   (27)   (27)   (27)  
 Secondary school  (12)   (14)   (12)   (14)  
 University  (18)   (18)   (18)   (18)  
 Missing information 44 (4)  50 (5)  44 (4)  50 (5)  
Specific IgE (kU/l) . Total IgE (kU/l) . 
Controls (n = ) . Cases (n = ) . Controls (n = ) . Cases (n = ) . 
N (%) . Mean . PaN (%) . Mean . PN (%) . Mean . PN (%) . Mean . P
Sex 
 Male  (52)   (52)    (52)   (52)  
 Female  (48)   (48)   (48)   (48)  
Age at recruitment 
 <40 31 (3)   31 (3)   31 (3)   31 (3)   
 40–49  (14)   (14)   (14)   (14)  
 50–59  (45)   (44)   (45)   (44)  
 ≥60  (39)   (38)   (39)   (38)  
Season of blood donation 
 Spring  (29)    (29)    (29)    (29)   
 Summer  (18)   (18)   (18)   (18)  
 Autumn  (30)   (29)   (30)   (29)  
 Winter  (24)   (24)   (24)   (24)  
Smoking history 
 Life-long non-smoker  (43)    (41)    (43)   (41)  
 Current smoker  (20)   (19)   (20)   (19)  
 Ex-smoker  (30)   (33)   (30)   (33)  
 Missing information 70 (7)  73 (7)  70 (7)  73 (7)  
Alcohol at recruitment 
 0g/day  (11)    (14)   (11)    (14)  
 <5g/day  (30)   (28)   (30)   (28)  
 5–29g/day  (42)   (41)   (42)   (41)  
 ≥30g/day  (17)   (17)   (17)   (17)  
 Missing information 6 (1)  5 (0)  6 (1)  5 (0)  
Highest school level 
 None 40 (4)   40 (4)  40 (4)   40 (4)   
 Primary school  (35)   (33)   (35)   (33)  
 Technical/professional school  (27)   (27)   (27)   (27)  
 Secondary school  (12)   (14)   (12)   (14)  
 University  (18)   (18)   (18)   (18)  
 Missing information 44 (4)  50 (5)  44 (4)  50 (5)  

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Table I.

Distribution and geometric mean of prediagnostic specific and total IgE levels

Specific IgE (kU/l) . Total IgE (kU/l) . 
Controls (n = ) . Cases (n = ) . Controls (n = ) . Cases (n = ) . 
N (%) . Mean . PaN (%) . Mean . PN (%) . Mean . PN (%) . Mean . P
Sex 
 Male  (52)   (52)    (52)   (52)  
 Female  (48)   (48)   (48)   (48)  
Age at recruitment 
 <40 31 (3)   31 (3)   31 (3)   31 (3)   
 40–49  (14)   (14)   (14)   (14)  
 50–59  (45)   (44)   (45)   (44)  
 ≥60  (39)   (38)   (39)   (38)  
Season of blood donation 
 Spring  (29)    (29)    (29)    (29)   
 Summer  (18)   (18)   (18)   (18)  
 Autumn  (30)   (29)   (30)   (29)  
 Winter  (24)   (24)   (24)   (24)  
Smoking history 
 Life-long non-smoker  (43)    (41)    (43)   (41)  
 Current smoker  (20)   (19)   (20)   (19)  
 Ex-smoker  (30)   (33)   (30)   (33)  
 Missing information 70 (7)  73 (7)  70 (7)  73 (7)  
Alcohol at recruitment 
 0g/day  (11)    (14)   (11)    (14)  
 <5g/day  (30)   (28)   (30)   (28)  
 5–29g/day  (42)   (41)   (42)   (41)  
 ≥30g/day  (17)   (17)   (17)   (17)  
 Missing information 6 (1)  5 (0)  6 (1)  5 (0)  
Highest school level 
 None 40 (4)   40 (4)  40 (4)   40 (4)   
 Primary school  (35)   (33)   (35)   (33)  
 Technical/professional school  (27)   (27)   (27)   (27)  
 Secondary school  (12)   (14)   (12)   (14)  
 University  (18)   (18)   (18)   (18)  
 Missing information 44 (4)  50 (5)  44 (4)  50 (5)  
Specific IgE (kU/l) . Total IgE (kU/l) . 
Controls (n = ) . Cases (n = ) . Controls (n = ) . Cases (n = ) . 
N (%) . Mean . PaN (%) . Mean . PN (%) . Mean . PN (%) . Mean . P
Sex 
 Male  (52)   (52)    (52)   (52)  
 Female  (48)   (48)   (48)   (48)  
Age at recruitment 
 <40 31 (3)   31 (3)   31 (3)   31 (3)   
 40–49  (14)   (14)   (14)   (14)  
 50–59  (45)   (44)   (45)   (44)  
 ≥60  (39)   (38)   (39)   (38)  
Season of blood donation 
 Spring  (29)    (29)    (29)    (29)   
 Summer  (18)   (18)   (18)   (18)  
 Autumn  (30)   (29)   (30)   (29)  
 Winter  (24)   (24)   (24)   (24)  
Smoking history 
 Life-long non-smoker  (43)    (41)    (43)   (41)  
 Current smoker  (20)   (19)   (20)   (19)  
 Ex-smoker  (30)   (33)   (30)   (33)  
 Missing information 70 (7)  73 (7)  70 (7)  73 (7)  
Alcohol at recruitment 
 0g/day  (11)    (14)   (11)    (14)  
 <5g/day  (30)   (28)   (30)   (28)  
 5–29g/day  (42)   (41)   (42)   (41)  
 ≥30g/day  (17)   (17)   (17)   (17)  
 Missing information 6 (1)  5 (0)  6 (1)  5 (0)  
Highest school level 
 None 40 (4)   40 (4)  40 (4)   40 (4)   
 Primary school  (35)   (33)   (35)   (33)  
 Technical/professional school  (27)   (27)   (27)   (27)  
 Secondary school  (12)   (14)   (12)   (14)  
 University  (18)   (18)   (18)   (18)  
 Missing information 44 (4)  50 (5)  44 (4)  50 (5)  

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Results

In total, incident lymphoma cases and controls were enrolled in this study. Lymphoma cases were on average 56 years old (range: 29–78 years) and had a mean follow-up time of years (range: 2 days to years). Overall, lymphoma cases and controls showed no differences in level of formal education, smoking status, alcohol consumption or body mass index (Supplementary Table 1, available at Carcinogenesis Online). The distribution of these variables in different lymphoma subtypes is presented in Supplementary Table 1, available at Carcinogenesis Online. Although there was no statistically significant difference between cases and controls regarding specific IgE levels, controls were more likely than cases to have levels of total IgE >20 and > kU/l, which indicate moderate and high probability of allergy symptoms, respectively (P < ; Supplementary Table 1, available at Carcinogenesis Online).

Table I presents the distributions and geometric means of total and specific IgE levels against inhalant antigens in lymphoma cases and controls, and by subject characteristics. Among both cases and controls, men had higher geometric means of total as well as specific IgE compared with women. Specific IgE levels among cases and controls and total IgE levels just among cases differed by age in both groups. Total and specific IgE levels varied widely between countries. Mean levels of total IgE in controls ranged from kU/l in Norway to kU/l in Italy. Mean levels in cases followed comparable patterns. With regard to subject characteristics, current smokers at the time of recruitment had considerably elevated total IgE levels for both cases and controls, whereas specific IgE levels were just slightly increased among the controls only. Increasing levels of alcohol consumption also correlated with increasing levels of total IgE among cases and controls, and with rising levels of specific IgE in cases only.

Table II provides risk estimates for the investigated lymphoid neoplasms and subtypes in relation to categories of specific and total IgE levels, adjusted for smoking, alcohol consumption and highest school level (in addition to matching factors). Specific IgE levels against inhalant antigens did not show any significant association with the combined risk estimate of the investigated lymphoid neoplasms, MM, B-NHL nor with the risks of specific B-NHL subtypes (DLBCL, FL and CLL; Table II).

Table II.

Association of total prediagnostic IgE and specific IgE against inhalant antigens and the risk of lymphoid neoplasms overall and by subtype

Lymphoid neoplasms overall . B-NHL . DLBCL . FL . CLL . MM . 
Number of controls/cases . PNumber of controls/cases . PNumber of controls/cases . PNumber of controls/cases . PNumber of controls/cases . PNumber of controls/cases . P
ORa (95% CI) . OR (95% CI) . OR (95% CI) . OR (95% CI) . OR (95% CI) . OR (95% CI) . 
Total IgE (kU/l)b
 Low, <20 52/57 — 50/54 — 75/ — 95/ — 
      
Intermediate, 20– <45/48  50/38  75/60 91/93  
(–)  (–)  (–)  (–)  (–)  (–) 
 High, > /97 33/25  13/21  36/13  <
1
39/21 
(–)  (–) (–)  (–) (–)  (–) 
Ptrend     
Specific IgE (kU/l)b
 < — — — 96/91 — — — 
      
 – 62/66  31/41  11/13  7/6  4/7  16/15  
(–)  (–)  (–)  (–)  (–)  (–) 
 – 64/59  37/41  9/10  2/9 12/8  14/8  
(–)  (–)  (–)  (–)  (–)  (–) 
 ≥ 62/59  42/36  6/6  8/7  13/9  13/13  
(–)  (–)  (–)  (–)  (–)  (–) 
Ptrend      
Specific IgE (kU/l)b
 Negative ≤ — — 96/91 — — — 
      
 Positive >   26/29  17/22  29/24  43/36  
(–)  (–)  (–)  (–)  (–)  (–) 
Lymphoid neoplasms overall . B-NHL . DLBCL . FL . CLL . MM . 
Number of controls/cases . PNumber of controls/cases . PNumber of controls/cases . PNumber of controls/cases . PNumber of controls/cases . PNumber of controls/cases . P
ORa (95% CI) . OR (95% CI) . OR (95% CI) . OR (95% CI) . OR (95% CI) . OR (95% CI) . 
Total IgE (kU/l)b
 Low, <20 52/57 — 50/54 — 75/ — 95/ — 
      
Intermediate, 20– <45/48  50/38  75/60 91/93  
(–)  (–)  (–)  (–)  (–)  (–) 
 High, > /97 33/25  13/21  36/13  <
1
39/21 
(–)  (–) (–)  (–) (–)  (–) 
Ptrend     
Specific IgE (kU/l)b
 < — — — 96/91 — — — 
      
 – 62/66  31/41  11/13  7/6  4/7  16/15  
(–)  (–)  (–)  (–)  (–)  (–) 
 – 64/59  37/41  9/10  2/9 12/8  14/8  
(–)  (–)  (–)  (–)  (–)  (–) 
 ≥ 62/59  42/36  6/6  8/7  13/9  13/13  
(–)  (–)  (–)  (–)  (–)  (–) 
Ptrend      
Specific IgE (kU/l)b
 Negative ≤ — — 96/91 — — — 
      
 Positive >   26/29  17/22  29/24  43/36  
(–)  (–)  (–)  (–)  (–)  (–) 

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Table II.

Association of total prediagnostic IgE and specific IgE against inhalant antigens and the risk of lymphoid neoplasms overall and by subtype

Lymphoid neoplasms overall . B-NHL . DLBCL . FL . CLL . MM . 
Number of controls/cases . PNumber of controls/cases . PNumber of controls/cases . PNumber of controls/cases . PNumber of controls/cases . PNumber of controls/cases . P
ORa (95% CI) . OR (95% CI) . OR (95% CI) . OR (95% CI) . OR (95% CI) . OR (95% CI) . 
Total IgE (kU/l)b
 Low, <20 52/57 — 50/54 — 75/ — 95/ — 
      
Intermediate, 20– <45/48  50/38  75/60 91/93  
(–)  (–)  (–)  (–)  (–)  (–) 
 High, > /97 33/25  13/21  36/13  <
1
39/21 
(–)  (–) (–)  (–) (–)  (–) 
Ptrend     
Specific IgE (kU/l)b
 < — — — 96/91 — — — 
      
 – 62/66  31/41  11/13  7/6  4/7  16/15  
(–)  (–)  (–)  (–)  (–)  (–) 
 – 64/59  37/41  9/10  2/9 12/8  14/8  
(–)  (–)  (–)  (–)  (–)  (–) 
 ≥ 62/59  42/36  6/6  8/7  13/9  13/13  
(–)  (–)  (–)  (–)  (–)  (–) 
Ptrend      
Specific IgE (kU/l)b
 Negative ≤ — — 96/91 — — — 
      
 Positive >   26/29  17/22  29/24  43/36  
(–)  (–)  (–)  (–)  (–)  (–) 
Lymphoid neoplasms overall . B-NHL . DLBCL . FL . CLL . MM . 
Number of controls/cases . PNumber of controls/cases . PNumber of controls/cases . PNumber of controls/cases . PNumber of controls/cases . PNumber of controls/cases . P
ORa (95% CI) . OR (95% CI) . OR (95% CI) . OR (95% CI) . OR (95% CI) . OR (95% CI) . 
Total IgE (kU/l)b
 Low, <20 52/57 — 50/54 — 75/ — 95/ — 
      
Intermediate, 20– <45/48  50/38  75/60 91/93  
(–)  (–)  (–)  (–)  (–)  (–) 
 High, > /97 33/25  13/21  36/13  <
1
39/21 
(–)  (–) (–)  (–) (–)  (–) 
Ptrend     
Specific IgE (kU/l)b
 < — — — 96/91 — — — 
      
 – 62/66  31/41  11/13  7/6  4/7  16/15  
(–)  (–)  (–)  (–)  (–)  (–) 
 – 64/59  37/41  9/10  2/9 12/8  14/8  
(–)  (–)  (–)  (–)  (–)  (–) 
 ≥ 62/59  42/36  6/6  8/7  13/9  13/13  
(–)  (–)  (–)  (–)  (–)  (–) 
Ptrend      
Specific IgE (kU/l)b
 Negative ≤ — — 96/91 — — — 
      
 Positive >   26/29  17/22  29/24  43/36  
(–)  (–)  (–)  (–)  (–)  (–) 

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When the analysis was restricted to cases diagnosed within the first 2 years following blood collection, a significant inverse association between specific IgE levels and overall risk of lymphoid neoplasms was observed in individuals positive for specific IgE (≥ kU/I); OR = (95% CI = –), Ptrend = No such association was observed among those diagnosed later than 2 years after baseline (Supplementary Table 2, available at Carcinogenesis Online).

Intermediate (20– kU/l) and high (> kU/l) levels of total IgE were associated with significant 28% (P < ) and 32% (P = ) reductions in risk for all studied lymphoid neoplasms, respectively (Ptrend = ; Table II). These inverse associations were statistically significant for B-NHL [intermediate level: OR = (95% CI = –); high level: OR = (95% CI = –), Ptrend = ] and MM [high level: OR = (95% CI –), Ptrend = ; Table II]. Among the major B-NHL subtypes, the inverse relationship of cancer risk with increasing total IgE levels was restricted to CLL [intermediate level: OR = (95% CI = –); high level: OR = (95% CI = –), Ptrend = ], but not seen for the risk of DLBCL and FL (Pheterogeneity = ; Table II). In total, it is worth noting that % of the B-NHL cases, % of the CLL cases, but only % of MM cases, had total IgE levels below the 10th percentile of the control distribution (data not shown).

Table III summarizes the results for CLL and MM risk in association with total IgE levels stratified by sex and time to diagnosis after baseline. Compared with the reference category (<20 kU/l), high total IgE (> kU/l) levels were associated with a significantly reduced CLL and MM risk for men [OR = (95% CI = –), Ptrend < ; OR = (95% CI = –), respectively]. Among women, those associations lacked statistical significance (P = and P = , respectively). A significant inverse association between total IgE and CLL risk at the highest category of IgE levels compared with the reference value was observed among individuals diagnosed within 3 years of recruitment as well as those diagnosed later (<3 years: P = ; ≥3 years: P = ; Pheterogeneity = , Table III). The inverse association remained significant when analysis was restricted to those diagnosed later than 5 years following recruitment (P = ).

Table III.

Association of total prediagnostic IgE and the risk of CLL and MM stratified by sex and time to diagnosis

<20 kU/l . 20– kU/l . > kU/l . Ptrend
Controls/ cases . ORaControls/ cases . ORa (95% CI) . P-value . Controls/ cases . ORa (95% CI) . P
CLL 
 Men 33/58  38/35  (–)  30/8  (–) <
 Women 42/55  37/25  (–)  7/5  (–)   
 Cases <3 year after baseline 24/38  21/16  (–) 12/3  (–)  
 Cases ≥3 year after baseline 51/75  54/44  (–) 24/10  (–) 
 Cases <5 year after baseline 39/59  36/31  (–)  20/5  (–)  
 Cases ≥5 year after baseline 36/54  39/29  (–)  16/8  (–)  
MM 
 Men 42/54  52/54  (–)  26/12  (–)  
 Women 53/57  39/39  (–)  13/9  (–)   
 Cases <3 year after baseline 30/44  29/24  (–)  20/6  (–)  
 Cases ≥3 year after baseline 65/67  41/69  (–)  24/15  (–)   
 Cases <5 year after baseline 55/71  51/51  (–)  26/10  (–) 
 Cases ≥5 year after baseline 40/40  40/42  (–)  13/11  (–)   
<20 kU/l . 20– kU/l . > kU/l . Ptrend
Controls/ cases . ORaControls/ cases . ORa (95% CI) . P-value . Controls/ cases . ORa (95% CI) . P
CLL 
 Men 33/58  38/35  (–)  30/8  (–) <
 Women 42/55  37/25  (–)  7/5  (–)   
 Cases <3 year after baseline 24/38  21/16  (–) 12/3  (–)  
 Cases ≥3 year after baseline 51/75  54/44  (–) 24/10  (–) 
 Cases <5 year after baseline 39/59  36/31  (–)  20/5  (–)  
 Cases ≥5 year after baseline 36/54  39/29  (–)  16/8  (–)  
MM 
 Men 42/54  52/54  (–)  26/12  (–)  
 Women 53/57  39/39  (–)  13/9  (–)   
 Cases <3 year after baseline 30/44  29/24  (–)  20/6  (–)  
 Cases ≥3 year after baseline 65/67  41/69  (–)  24/15  (–)   
 Cases <5 year after baseline 55/71  51/51  (–)  26/10  (–) 
 Cases ≥5 year after baseline 40/40  40/42  (–)  13/11  (–)   

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Table III.

Association of total prediagnostic IgE and the risk of CLL and MM stratified by sex and time to diagnosis

<20 kU/l . 20– kU/l . > kU/l . Ptrend
Controls/ cases . ORaControls/ cases . ORa (95% CI) . P-value . Controls/ cases . ORa (95% CI) . P
CLL 
 Men 33/58  38/35  (–)  30/8  (–) <
 Women 42/55  37/25  (–)  7/5  (–)   
 Cases <3 year after baseline 24/38  21/16  (–) 
Sours: https://academic.oup.com/carcin/article/35/12//

Cancer low ige levels

And even more so with her own. Larisa Mikhailovna answered my mother. Covering with tender kisses, fallen in her mouth, a member of her own son.

Immunoglobulin E (IgE) Mnemonic Preview for USMLE

She was more satisfied with masturbation, closing herself in the bathroom with the presentation of a young strong body. She did not have children, but she really wanted to have them, but she didnt really want to have them, and most likely it was not possible to.

Conceive them from him. The thought that he would soon bend left her immediately after they began to live together. The man is quite strong, and looking that his parents were still alive, she realized that she would live alone with him until old age.

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Beautiful evening black dress on the floor, with a deep neckline in the form of the Latin letter "v" and with a neckline in the back, almost to the very bottom. I had to give up the bra, in this outfit it was visible both from the front and from the back, but I did not have another black. Dress, and I wanted to wear mourning for my former polyamorous relationship with the outside world.

I read a lot about that this is a dead-end branch of the feminist movement, but I did not believe sexologists and psychologists.



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