Low serum IgE is associated with an increased risk of chronic lymphocytic leukemia: a large retrospective cohort study.

Background: Autoimmune diseases can occur at any time in patients with common variable immunodeficiency (CVID). However, the relationship between low immunoglobulin E (IgE) levels and autoimmune diseases in patients with CVID remains poorly understood. Objective: We aimed to determine the relationship between autoimmunity and low IgE in patients with CVID. Methods: This retrospective cohort study was conducted by using data that had been collected from 62 adult patients with CVID between April 2012 and December 2021. Serum basal IgE levels were compared between patients with and patients without autoimmune disease. Results: Overall, 23 of the 62 patients with CVID (37.1%) had at least one autoimmune disease (CVID-O). Autoimmune cytopenias, mainly immune thrombocytopenic purpura, were observed in half of all the patients. Other autoimmune diseases present among the patients included rheumatological diseases, inflammatory bowel diseases, lymphoma, granulomatous lymphocytic interstitial lung disease, autoimmune hepatitis, alopecia, and multiple sclerosis. Serum IgE levels were measured at the time of diagnosis; IgE was undetectable (<2.5 IU/mL) in 82.6% of the patients with CVID-O (n = 19). The median (interquartile range) serum IgE value in the patients with CVID-O was 2 IU/mL (1-16 IU/mL), which was significantly lower than the median serum IgE value in patients with CVID and without autoimmune disease (p < 0.001). Low IgE levels in patients with CVID-O were an independent risk factor for the development of autoimmune disease in patients with CVID (odds ratio 3.081 [95% confidence interval, 1.222-7.771]; p = 0.017). Conclusion: Low serum IgE levels were associated with the development of autoimmune disease in patients with CVID. The monitoring of serum IgE levels in patients with CVID may be useful in the early diagnosis and treatment of autoimmune diseases.

Characteristics of patients with low serum IgE levels and selective IgE deficiency: Data from an immunodeficiency referral center

Chronic lymphocytic leukaemia (CLL) is a monoclonal expansion of neoplastic mature B lymphocytes with >5 × 109 CLL cells/l peripheral blood.1 The disease is preceded by the premalignant condition called monoclonal B-cell lymphocytosis (MBL) increasing in prevalence with age, reaching >10% prevalence in males aged >65 years with ~1% of cases progressing to CLL per year.2, 3 In the present study, we explore the presence of CLL clones decades before the diagnosis of CLL by using the Copenhagen City Heart Study (CCHS) and the Copenhagen General Population Study (CGPS) to analyse pre-diagnostic peripheral blood samples obtained at visits in the time period 1992–2014 from healthy individuals subsequently diagnosed with CLL in the period 2001–2019. We assessed CLL clonal DNA by analysis for minimal residual disease (MRD) according to EuroMRD guidelines.4 For additional information on methods see the supplement. A total of 247 individuals with a diagnosis of CLL registered after participation in the CCHS or CGPS from 1992 to 2014 were identified (Fig S1). In all, 22 of these patients had immunoglobulin heavy-chain variable-region (IGHV) mutational status analysis performed at the Department of Hematology at Rigshospitalet, Copenhagen from 2001 to 2017 at time of the diagnosis of CLL and had a >5 years latency from CCHS or CGPS participation until diagnosis of CLL. The study was manually supplemented with an additionally eight cases who either had IGHV mutational status performed at Rigshospitalet and <5 years latency (two cases) or IGHV mutational status performed at Rigshospitalet in 2018 and 2019 and >10 years latency (six cases). A total of 10 patients were excluded either due to lack of sufficient full blood DNA material in the biobanks, or incorrect diagnosis of CLL (patients with small lymphocytic lymphoma). Furthermore, three patients were excluded due to technically insufficient analysis. The final cohort consisted of samples from 17 patients. Characteristics are listed in Table I and are comparable with other patients with early-stage disease. A total of 13 of the 17 patients (76%) had a detectable clone in their pre-diagnostic sample. The median (range) time between the pre-diagnostic sample and the diagnosis of CLL was 13·9 (3·3–26·8) years (Table SI, Fig 1). Lymphocytosis with an absolute lymphocyte count above the upper limit of the reference range was present at time of the pre-diagnostic sample for four out of 14 patients (28%, three patients with no data, Table SI). No specific CLL characteristics were noted for the four (24%) patients without detectable pre-diagnostic CLL clones; two of those patients had normal fluorescence in situ hybridisation (FISH) while two had del(13q), one was IGHV unmutated. Six of the 13 patients (46%) with a pre-diagnostic CLL clone had an elevated C-reactive protein (CRP) of >10 mg/l at one or more occasions before the diagnosis of CLL. However, none of the patients had hospital admissions due to infections prior to the diagnosis of CLL that was registered in the National Danish Patient Registry. Of note, none of the four patients without a detectable pre-diagnostic CLL clone had an elevated CRP level or hospital admissions due to infections in the latency period. The patients all had a low comorbidity burden at the time of the pre-diagnostic sample with a median (range) Charlson score5 of 0 (0–3), data not shown. Based on patient-specific allele-specific oligonucleotide quantitative polymerase chain reaction (ASO-qPCR) we could quantify tumour-specific DNA in 16 out of 20 samples analysed from the 17 patients with CLL (Fig 1). For three patients, two pre-diagnostic samples were available. For one of these, only DNA from the most recent sample was quantifiable. Thus, the CLL clone was detectable 8 years and not 18 years prior to the diagnosis of CLL for this patient (CLL no. 6, Table SI, Fig 1). CLL clones were detected more than a decade prior to diagnosis for both patients with unmutated and mutated IGHV. In support of our present findings, other population based studies found B-cell clones up to 6·4 and 7·4 years before the diagnosis of CLL using RNA-based IGHV mutational status analysis and flow cytometry,6, 7 while yet another study found white blood cells with CLL-like DNA methylation patterns up to 15·9 years prior to the diagnosis of CLL.8 Furthermore, our group has recently shown the use of anti-microbials increases 6 years before the diagnosis of CLL in a large Danish nation-wide register study.9 Markers of progression and the understanding of the mechanisms implicated in progression from the dormant B-cell clone through MBL to CLL are warranted and also in patients with early-stage solid cancers. Only a few studies of genomic, transcriptome, and methylation profiles have been published.8, 10-12 However, plasma markers would be preferable from a logistic perspective; in the CCHS and CGPS a high plasma total immunoglobulin E (IgE) level has been associated with decreased risk of CLL.13 Thus, differences in immunoglobulin levels among other plasma markers could serve as a potential marker for CLL and hypothetically MBL. Strengths of the present study include it being based on a population from a geographical area where population-based studies of healthy individuals have been ongoing for several decades. Furthermore, due to the Danish national registries and the unique patient-specific number, we could identify patients from cohorts at the hospitals in the population-based studies. Thus, the study could be repeated in patients who develop solid cancers if warranted. The 17 patients are representative of patients with early-stage CLL and selection bias should be limited as IGHV mutational analyses have been performed at Rigshospitalet since 2001 for a defined population-based cohort of patients with CLL. By combining a population-based, consecutive CLL patient cohort with registers and biobanks from two large population-based studies covering the same population, we succeeded in detecting CLL clones in asymptomatic individuals more than two decades prior to diagnosis of CLL applying the most recently standardised IGHV mutational status methodology based on DNA14 and the EuroMRD-validated MRD analysis.4 Identification of predictive markers of progression, immune dysfunction and infectious complications are warranted before considering the institution of screening for MBL, and development of clinical trials testing pre-emptive interventions in this population. We acknowledge the participating patients, Dr Lisbeth Enggaard and the Department of Hematology at Herlev hospital. Fie J. Vojdeman performed data analyses and wrote the first draft of the paper. Fie J. Vojdeman, Jens Helby, Stig E. Bojesen, Børge G. Nordestgaard, Michael A. Andersen and Carsten U. Niemann designed the study and wrote the final version of the paper. Lone B. Pedersen performed laboratory analyses and Christian Brieghel performed data analysis. Stig E. Bojesen, Børge G. Nordestgaard and Jens Helby were responsible for collection of biobank samples. Fie J. Vojdeman, Christian Brieghel, Michael A. Andersen, Lone B. Pedersen, Jens Helby, Stig E. Bojesen and Børge G. Nordestgaard have no conflicts of interest to disclose. Carsten U. Niemann has received funding from the Novo Nordisk Foundation (NNF; grant NNF16OC0019302), research grants, travel grants and/or personal fees outside this work from Abbvie, Janssen, AstraZeneca, Gilead, Roche, CSL Behring, Takeda and Sunesis. Data can be accessed by request to the corresponding author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Finnish and Russian Karelian children have a highly contrasting occurrence of asthma and allergy. In these two environments, we studied associations between total serum immunoglobulin E (IgE) with methylation levels in cluster of differentiation 14 (CD14). Five hundred Finnish and Russian Karelian children were included in four groups: Finnish children with high IgE (n = 126) and low IgE (n = 124) as well as Russian children with high IgE (n = 125) and low IgE (n = 125). DNA was extracted from whole blood cells and pyrosequenced. Three CpG sites were selected in the promoter region of CD14. Methylation levels in two of the three CpG sites were higher in the Finnish compared to Russian Karelian children. In the promoter area of CD14, the Finnish compared to Russian children with low IgE had a significant (p < 0.0001) increase in methylation levels at the Amp5Site 2. Likewise, the Finnish compared to Russian children with high IgE had a significant (p = 0.003) increase in methylation levels at the Amp5Site 3. In Russian children with low vs. high IgE, there were significant differences in methylation levels, but this was not the case on the Finnish side. In the regression analysis, adding the methylation variation of CD14 to the model did not explain the higher asthma and allergy risk in the Finnish children. The methylation levels in the promoter region of CD14 gene were higher in the Finnish compared to Russian Karelian children. However, the methylation variation of this candidate gene did not explain the asthma and allergy contrast between these two areas.

Benralizumab efficacy by atopy status and serum immunoglobulin E for patients with severe, uncontrolled asthma

Chronic lymphocytic leukemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

To evaluate the association between maternal asthma (MA) and obstetric complications, while considering subdivided total serum immunoglobulin E (IgE) levels. Data of the participants enrolled in the Japan Environment and Children's Study between 2011 and 2014 were analyzed. In total, 77,131 women with singleton live births at and after 22weeks of gestation were included. MA was defined based on a self-administered questionnaire. Women with MA were stratified based on the quartile of total serum IgE levels during pregnancy as follows: low IgE levels (< 52.40IU/mL), moderate IgE levels (52.40-331.00IU/mL), and high IgE levels (> 331.00IU/mL). The adjusted odds ratios (aORs) for preterm births (PTB), small for gestational age (SGA) infants, gestational diabetes mellitus, and hypertensive disorders of pregnancy (HDP) were calculated using multivariable logistic regression, while considering women without MA as reference and maternal socioeconomic factors as confounders. The aORs for SGA infants and HDP in women with MA and high total serum IgE levels were 1.26 (95% confidence interval [CI], 1.05-1.50) and 1.33 (95% CI, 1.06-1.66), respectively. The aOR for SGA infants among women with MA and moderate total serum IgE levels was 0.85 (95% CI, 0.73-0.99). The aOR for PTB among women with MA and low total serum IgE levels was 1.26 (95% CI, 1.04-1.52). MA with subdivided total serum IgE levels was associated with obstetric complications. Total serum IgE level may be a potential prognostic marker to predict obstetric complications in pregnancies with MA.

To observe the clinical efficacy of modified painless wheat-grain blistering moxibustion for allergic rhinitis (AR) of lung deficiency and cold attacking, and to explore its effects on serum immunoglobulin E (IgE) and interleukin-10 (IL-10). Ninety-eight patients of perennial AR with lung deficiency and cold attacking were randomly divided into an observation group (49 cases, 2 dropped out) and a control group (49 cases, 2 dropped out). The control group received mometasone furoate nasal spray treatment. The observation group received modified painless wheat-grain blistering moxibustion at bilateral Feishu (BL 13), Gaohuang (BL 43), Zusanli (ST 36), and Shenzhu (GV 12) in addition to the control group's treatment. Moxibustion at Shenzhu (GV 12) was applied once every other day, 3 grains each time, forming moxibustion sores after about one week. After sores formed, moxibustion was applied once every other 2 days. For Feishu (BL 13), Gaohuang (BL 43), and Zusanli (ST 36), moxibustion was applied on one side first, every other day, 3 grains each time, until sores formed, then on the other side, alternating sides in a cycle. Both groups were treated for 4 weeks. The total nasal symptoms score (TNSS), nasal symptom visual analogue scale (VAS), and rhinoconjunctivitis quality of life questionnaire (RQLQ) scores were observed before and after treatment, and after 4 and 12 weeks of treatment completion (follow-ups). Serum IgE and IL-10 levels were measured before and after treatment, and treatment efficacy and recurrence rates at follow-ups were recorded. Compared before treatment, TNSS, VAS, and RQLQ scores in both groups were reduced after treatment and at follow-ups (P<0.05), and these scores in the observation group were lower than those in the control group (P<0.05). Except for TNSS scores in the control group at the follow-ups, and in the observation group at the 4-week follow-up, all scores at follow-ups in both groups were higher than those after treatment (P<0.05). Compared before treatment, serum IgE levels in both groups were decreased (P<0.05), and serum IL-10 levels were increased (P<0.05) after treatment. The observation group had lower serum IgE levels and higher IL-10 levels than the control group (P<0.05). The total effective rate in the observation group was 93.6% (44/47), higher than 74.5% (35/47) in the control group (P<0.05). The recurrence rates after 4 and 12 weeks of treatment completion in the observation group were lower than those in the control group (4.5% [2/44] vs 22.9% [8/35], 9.1% [4/44] vs 40.0% [14/35], P<0.05). On the basis of mometasone furoate nasal spray, modified painless wheat-grain blistering moxibustion could improve clinical symptoms in patients of AR with lung deficiency and cold attacking, and provide more sustained long-term efficacy, possibly through the regulation of serum IgE and IL-10 levels.

Background Thirty-four single nucleotide polymorphisms (SNPs) are associated with CLL risk to-date. Moreover, family history (FH) of hematological malignancy has been consistently found to be associated with CLL, with an 8.5-fold increased risk of CLL among first-degree relatives. However, there has not been an evaluation of the interactive effects among genetic factors and FH with CLL risk. Methods We pooled data from 8 CLL case-control studies within the InterLymph Consortium (1499 CLL cases and 2601 controls). We computed a polygenic risk score (PRS), a weighted average of the number of risk alleles across the 34 SNPs, with the weights being the log of the previously reported odds ratio (OR) for each SNP. We categorized the PRS by quintiles using the cutoff points based on the distribution of all InterLymph controls (N=8228). Self-reported FH data was available for 60% of cases and 73% of controls. FH was defined as any hematological malignancy in one or more first-degree relative. Logistic regression was used to estimate ORs and 95% confidence intervals (CIs) adjusted for age, sex, socioeconomic status and study. Results The median age at diagnosis of CLL was 63 years and median age of consent was 60 years in the controls. 67% were male in CLL cases and 57% in controls. As expected, FH was associated with CLL risk (OR= 2.14, CI= 1.60-2.86). The median PRS in the cases was 0.40 and in the controls was -0.36 with the frequency of CLL cases in the upper PRS quintile as 48% while in the lowest quintile only 6%. The PRS was strongly associated with CLL risk (OR= 2.90, CI= 2.35-3.56 for upper versus middle quintile). When jointly modeling FH with PRS, a significant interaction was observed (P=0.03). When stratifying by FH, the upper quintile of the PRS had an 11.8-fold (CI= 3.97-34.8) increased risk relative to those in the middle quintile in the FH+ strata, while a 3.11-fold (CI= 2.35-4.10) increased risk was observed in the FH- strata. Conclusions Our data suggest that the PRS has a strong association with CLL risk and this association varies with FH status. Among those with FH-, the risk of CLL was 3-fold for those with many inherited variants while the CLL risk was much higher than that in those with a FH+. Studies are needed to see whether this PRS stratifies risk among those with monoclonal B-cell lymphocytosis, the CLL precursor condition that affects 5-7% of the general population. Citation Format: Geffen Kleinstern, Silvia de Sanjosé, Nicola Camp, Claire M. Vajdic, Timothy G. Call, Mark Liebow, Dennis Robinson, Neil E. Kay, Julie Cunningham, Yolanda Benavente, Alain Monnereau, John Spinelli, James R. Cerhan, Susan L. Slager. Association of polygenic risk scores and family history with the risk of chronic lymphocytic leukemia (CLL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4267. doi:10.1158/1538-7445.AM2017-4267

Background: Asthma is a life-threatening immediate-type allergic disease. B cell-activating factor (BAFF) is a key regulator of B lymphocyte development and is required to generate and maintain the mature B cell pool. Objectives: To investigate the level of BAFF in the serum of asthma patients and the role of BAFF on T cells. Methods: The BAFF level was measured by enzyme-linked immunosorbent assay. Peripheral blood mononuclear cells (PBMC) from asthma patients were analyzed by flow cytometry. T8.1 cells were used to test the role of BAFF on T cell-antigen-presenting cell (APC) conjugate formation. Results: The BAFF level in patient serum was elevated relative to normal serum. Immunoglobulin E (IgE) concentration and the percentage of CD3+ T and CD19+ B cells vary according to the serum BAFF level. Patients with high BAFF and high IgE (group II) and those with high BAFF and low IgE (group III) show a high ratio of CD3+ T to CD19+ B cells, and the opposite is seen for patients with low BAFF and high IgE (group I) and those with low BAFF and low IgE (group IV). The addition of BAFF increased PBMC proliferation and T cell-APC conjugate formation. BAFF concentration in serum decreased after treatment with antiasthmatic drugs including glucocorticoids and immunosuppressants. Conclusion: These findings suggest that the serum BAFF level is high in both IgE-mediated asthma and non-IgE-mediated asthma and extend our knowledge about the fact that BAFF may play a stimulatory role on the proliferation of T cells. Thus, BAFF could be a parameter to monitor the severity of asthma symptoms.

BackgroundIt has been suggested that the proliferative capacity of cells from individuals with HIV or both HIV and helminth infections is attenuated and cytokine production is dysregulated. This study describes peripheral blood mononuclear cell proliferation capacity and cytokine profile from individuals with HIV or both HIV and helminth infections in South Africa.MethodsForty HIV-infected and 22 HIV-uninfected participants were randomly selected and stratified into different helminth infection phenotypes by egg excretion and Ascaris lumbricoides specific –immunoglobulin-E (IgE) levels. Five day cell cultures of participants, unstimulated or stimulated with Phytohaemaglutinnin, Streptokinase, HIV-1 p24 and Ascaris lumbricoides worm antigens were stained with monoclonal antibody-fluorochrome conjugates (Ki67-FITC and CTLA-APC-4). Percentage expression of Ki67 and CTLA-4 was measured to determine cell proliferation and regulation, respectively. Culture supernatants were analysed for the expression of 13 cytokines using the Bioplex (BioRad) system. Kruskal Wallis was used to test for differences in variables between helminth infected subgroups who were either having eggs in stool and high IgE (egg+IgEhi); or eggs in stool and low IgE (egg+IgElo); or no eggs in stool and high IgE (egg-IgEhi) and those without helminth infection (egg-IgElo).ResultsIndividuals excreting eggs in stool with high serum IgE (egg+IgEhi phenotype) had potent mitogen responses but consistently produced low, but statistically non-significant antigen–specific (HIV-1 p24 (p = 0.41) and Ascaris (p = 0.19) and recall antigen (Streptokinase; p = 0.31) Ki67 responses. The group also had reduced type 1 cytokines. Individuals excreting eggs in stool with low serum IgE( egg+IgElo phenotype) had a more favourable antiviral profile, characterized by higher IFNγ, IL-2, lower IL-4 and higher IL-10 production.ConclusionThe findings suggest that dual HIV/helminth infection with egg excretion and/or high Ascaris IgE phenotye may be linked with poor proliferative capacity and deleterious cytokine profile with regards to HIV control.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2334-14-499) contains supplementary material, which is available to authorized users.

Relationship between low serum immunoglobulin E levels and malignancies in 9/11 World Trade Center responders

Normal serum IgE levels and eosinophil counts exhibited during Strongyloides stercoralis infection

IgE antibody in the serum--detection and diagnostic significance.

Distress and Perceived Impact on Well-Being for Low- or Intermediate-Risk and High-Risk Patients with Chronic Lymphocytic Leukemia (CLL)