B cell development and longevity of IgE plasma cells.

IgE and IgG antibodies to penicillins can have different specificities. However, this response, including the recognition of the different parts of penicillin, has never been studied in the same subject. Study of the specificity of IgE and IgG antibodies and the relevant parts of the penicillin molecule that contribute to the hapten binding site in sera from human. Specific IgE antibodies were determined by RAST and specific IgG antibodies by ELISA. The recognition of the different molecules was studied by inhibition studies. Seven sera with IgG and IgE antibodies to amoxicillin and benzyl penicillin were analyzed. IgE antibodies recognized mainly two different epitopes: in one, the side chain was a relevant part of the epitope, in the other, it was the nuclear portion. IgG antibodies recognized the nuclear portion in all instances. In the same subject, antibodies of different isotype and specificity were found. Subjects who develop simultaneously IgE and IgG antibodies to penicillins show different specificities. This proves that different populations of antibodies recognize different epitopes.

Analysis Of 4,610 Patients With Elevated Serum Immunoglubulin E

Immunoglobulin E (IgE) is a key driver of type 1 hypersensitivity reactions and allergic disorders, which are globally increasing in number and severity. Although eliminating pathogenic IgE may be a powerful way to treat allergy, no therapeutic strategy reported to date can fully ablate IgE production. Interleukin-4 receptor α (IL-4Rα) signaling is required for IgE class switching, and IL-4Rα blockade gradually reduces, but does not eliminate, IgE. The persistence of IgE after IL-4Rα blockade may be due to long-lived IgE+ plasma cells that maintain serological memory to allergens and thus may be susceptible to plasma cell-targeted therapeutics. We demonstrate that transient administration of a B cell maturation antigen x CD3 (BCMAxCD3) bispecific antibody markedly depletes IgE, as well as other immunoglobulins, by ablating long-lived plasma cells, although IgE and other immunoglobulins rapidly rebound after treatment. Concomitant IL-4Rα blockade specifically and durably prevents the reemergence of IgE by blocking IgE class switching while allowing the restoration of other immunoglobulins. Moreover, this combination treatment prevented anaphylaxis in mice. Together with additional cynomolgus monkey and human data, our studies demonstrate that allergic memory is primarily maintained by both non-IgE+ memory B cells that require class switching and long-lived IgE+ plasma cells. Our combination approach to durably eliminate pathogenic IgE has potential to benefit allergy in humans while preserving antibody-mediated immunity.

Description Antibody-secreting plasma cells (PCs) play both protective and pathogenic roles across various disease contexts. The lifespan of PCs ranges from days to decades, and they exhibit diverse functionality including antibody secretion, cytokine production, and immunoregulation. Currently, we cannot identify, ascribe function to, nor manipulate distinct human PC subsets, preventing targeted therapeutic intervention and selective induction. To discover and characterize human PC subsets, we paired a systems immunology approach with a suite of functional assays investigating cellular identity and behavior. To identify cell surface markers expressed by human PCs, we quantified the expression of hundreds of surface proteins on millions of PCs from healthy human tissues. We then developed a bespoke PC-focused antibody panel and applied it to healthy human bone marrow in a tri-modal single-cell sequencing assay measuring surface protein expression, transcriptomics, and chromatin accessibility. We identified distinct PC subsets and dissected their molecular and epigenetic features. We sorted PC subsets and evaluated their morphology, antibody secretion rates, cytokine production, and longevity. Overall, our deep phenotypic and functional profiling has revealed unappreciated PC subsets and provided the highest resolution assessment of human PC identity reported to date. Our findings promise to enhance the identification, monitoring, and therapeutic manipulation of PCs in clinical settings. Funding Sources Cancer Research Institute Irvington Postdoctoral Fellowship American Society of Hematology Fellow Scholar Award Fred Hutchinson Cancer Center Translational Data Science Integrated Research Center Pilot Award Allen Institute for Immunology Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)

The objective of this study was to investigate the correlation of symptoms in patients with presumed allergic rhinitis on the basis of their medical history and physical examination with the levels of total immunoglobulin E (IgE) and specific IgE, and to question the necessity of these tests in diagnosis. The records of 295 patients, who had at least two complaints of nasal itching, nasal obstruction, runny discharge and sneezing, and/or presumed as allergic rhinitis on physical examination findings were retrospectively screened. The correlation between the levels of IgE, specific inhalant IgE, and food-specific serum IgE were evaluated in these patients. A total of 70 cases (23.7%) were determined to have a total value of IgE under 20 U/ml, 113 cases (38.3%) with IgE values between 20 U/ml and 100 U/ml, and 100 cases with IgE values above 100 U/ml. Results of total IgE could not be obtained in 12 (4.06%) patients. Dermatophagoides farinae was the most common allergy in this group with 74 (68.5%) cases. The determination of IgE in allergic rhinitis is a supportive method. However, it cannot be recommended for routine use because of the time loss and high cost.

PROLONGED HYPEREOSINOPHILIA IN RETT SYNDROME PATIENT SECONDARY TO ENVIRONMENTAL ALLERGY

Seasonal changes in IgE antibodies and their relationship to IgG antibodies were studied in 52 patients with ragweed hay fever and 10 normal controls. Allergic patients received either no immunotherapy, preseasonal immunotherapy, or high dose perennial immunotherapy with aqueous-mixed ragweed extract. Serums were collected before, during, just after, and 4 mo after the ragweed pollination season. IgE antibodies to ragweed antigen E (AgE) were measured using the radioallergosorbent test, and IgG antibodies were measured by radioimmunoprecipitation.IgE antibodies to AgE were elevated in all allergic patients, and rose during the ragweed pollination season. The magnitude of the rise in IgE antibody was a function of the preseasonal IgE antibody level. IgE antibody production in the treated groups was the same as in the untreated group when patients were matched on the basis of their preseasonal IgE antibody levels. Thus, we were not able to confirm previous reports that immunotherapy suppresses the seasonal rise in IgE antibodies. Furthermore, there was a close relationship between the levels of IgE and IgG antibodies in the high dose group. This finding is contrary to what one would expect were IgG antibodies acting to suppress the formation of IgE antibodies. Rather, it suggests that in certain patients either humoral immunological reactivity to ragweed antigens in the IgG and IgE classes is low to begin with or that this reactivity may wane after treatment with high doses of ragweed extract.

Since the discovery of immunoglobulin E (IgE) antibodies thirty-six years ago, our understanding of the mechanisms of allergy has improved to such an extent that we can now better differentiate allergy from non-allergic hypersensitivity, and allergic/atopic from intrinsic/non-atopic bronchial asthma. IgE antibodies are crucial immune mediators of airway inflammation in allergic atopic asthma and IgE-mediated hypersensitivity reactions are the likely mechanisms of allergen-induced airway obstruction. In addition, IgE may cause chronic airway inflammation in asthma through effector cells activated via high-affinity (Fcepsilon RI) or low-affinity (Fcepsilon RII) IgE receptors. Therapeutic anti-IgE antibodies able to reduce free IgE levels and to block the binding of IgE to Fcepsilon RI without cross-linking IgE and triggering degranulation of IgE-sensitised cells have been developed. This non-anaphylactogenic anti-IgE monoclonal antibody (rhuMAb-E25; omalizumab) binds IgE at the same site as these antibodies bind Fcepsilon RI and Fcepsilon RII. As a consequence, omalizumab inhibits IgE effector functions by blocking IgE binding to high-affinity receptors on IgE effector cells and does not cause mast cell or basophil activation because it cannot bind to IgE on cell surfaces where the Fcepsilon R1 receptor already masks the anti-IgE epitope. Studies in patients with atopic asthma demonstrated that omalizumab decreases serum IgE levels and allergen-induced bronchoconstriction during both the early and late-phase responses to inhaled allergen. In several clinical controlled trials omalizumab resulted to be able to reduce asthma-related symptoms, to decrease corticosteroid use and to improve quality of life of asthmatic patients. The anti-IgE approach to asthma treatment has several advantages, including concomitant treatment of other IgE-mediated diseases (allergic rhinitis, allergic conjunctivitis, atopic dermatitis and food allergies), a favourable side-effect profile and a twice-monthly dosing frequency.

Though HDAC11 expression is confirmed in B cells and plasma cells (PC), its functions in these cells remain largely unknown. In this study, we attempted a functional analysis of HDAC11 in PC development along with its pro-tumorigenic function in multiple myeloma (MM) cells. Mouse models, including a transgenic mouse strain expressing eGFP under the regulation of the HDAC11 promoter (Tg-HDAC11-eGFP), and also an HDA11-deficient mouse (B6.HDAC11-/-) were studied to establish the importance of HDAC11 in PC biology. Pharmacologic inhibition of HDAC11 in MM cell lines was accomplished by using elevenostat (ES), a new HDAC11-selective inhibitor. Post-translational modifications and subcellular localization changes induced by ES exposure were assessed by western blotting of fractionated cell lysates, while co-immunoprecipitation (Co-IP) and proximity ligation assays (in situ PLA) were used to identify a binding partner for HDAC11. Studies in Tg-HDAC11-eGFP mice revealed that HDAC11 expression in B cell lymphopoiesis was minimally detectable prior to B cell activation but demonstrated strong induction upon maturation into a PC. Consistent with this, PC development was markedly impaired in the absence of HDAC11. Furthermore, HDAC11-selective inhibitor ES showed significant cytotoxic potential, measured by CCK-8 assay, in different MM cell lines and primary MM cells that express moderate to high level of HDAC11, with IC50 values ranging 0.6-2.0 µM. Apoptotic cell death was confirmed via detection of activated caspase-3 and annexin/propidium iodide staining by flow cytometry. Consistently, MM cell lines expressing null/very low level of HDAC11 were insensitive to ES. Moreover, combining ES with proteasome inhibitors bortezomib and carfilzomib resulted in significant synergistic effects. Furthermore, ES-treated cells showed a time-dependent alteration in the subcellular localization of HDAC11, it gradually disappeared from the nuclear fractions with simultaneous upregulation in cytoplasmic fractions. Inhibition of HDAC11 also caused downstream suppression of several pro-tumorigenic factors in MM cells, including IRF4 and c-Myc. Moreover, a novel interaction between HDAC11 and IRF4, an essential regulator of PC differentiation and MM survival, was identified by using PLA and Co-IP. HDAC11 dynamically interacts with IRF4 which can be induced by LPS and IL-6 stimulation and inhibited by ES, indicating the involvement of HDAC11 in the IRF4-mediated regulatory circuit. We also identified changes in the extent of IRF4 acetylation upon genomic or pharmacological induction/inhibition of HDAC11. Overall, we observe that targeted inhibition of HDAC11 can impair MM cell survival and overcome acquired resistance to proteasome inhibitors. Furthermore, we identify IRF4 as a nuclear binding partner of HDAC11 and propose this interaction as a candidate mechanism regulating PC maturation and survival. Citation Format: A G M MOSTOFA, Jason Brayer. Functional analysis of HDAC11 in plasma cell development and multiple myeloma survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3101.

Allergic rhinitis is diagnosed by clinical parameters with no widely accepted screening test. Measurement of total serum immunoglobulin E (IgE) has limited use in the general population due to a low negative predictive value. The value of total IgE level in select populations undergoing in vitro allergy testing remains unknown. The aim of this study is to determine the utility of total serum IgE in the in vitro diagnosis of allergic rhinitis. A retrospective chart review of patients undergoing testing for allergic rhinitis was performed. Clinical parameters, total IgE level, and enzyme-linked immunosorbent assay (ELISA) for serum-specific IgE levels were analyzed with multivariate logistic regression. The positive and negative predictive values and a receiver operating characteristic (ROC) curve were used to assess the utility of total IgE in predicting serum-specific IgE test results. Records from 1073 patients were reviewed. ROC curve for total IgE >150 IU/mL (Σ 0.88) indicates good discrimination in identifying patients with sensitization by in vitro testing, whereas low total IgE level had strong negative predictive value (0.87, IgE <10) in identifying negative specific IgE testing. Multivariate logistic regression showed that differences in covariables did not significantly change the odds of a positive in vitro allergy test panel. Serum total IgE level is useful in the in vitro diagnosis of allergic rhinitis. In vitro testing for specific IgE may be unnecessary in patients with low serum total IgE, whereas high total IgE level suggests that in vitro testing would confirm specific sensitizations in patients with allergic rhinitis.

Inflammatory Cytokines, Hyperferritinemia and IgE Are Prognostic in Patients with KSHV-Associated Lymphomas Treated with Curative Intent Therapy

As result of finding numerous plasma cells in the omenta of rabbits injected with tuberculo-protein, a method to induce the production of large numbers of these cells has been discovered. The tissues in which they were pronouncedly increased were the subserosal connective tissues of the omentum, body wall, and intestinal wall. The precursor of the plasma cells is a primitive connective tissue cell. As this cell develops into the typical Marshalkó plasma cell there is a progressive increase in the basophilia of the cytoplasm, the nucleus becomes eccentric, a condensation of the chromatin occurs near the nuclear membrane, and there is a loss of the nucleoli. At the time when the nucleus assumes the eccentric position, the clear area appears in the center of the cytoplasm. The early cells are capable of reproducing themselves by mitosis, while the typical mature cells divide by amitosis. The mature plasma cells often have muddy, spongy cytoplasm which contains acidophilic or hyaline granules as the cells grow old or begin to degenerate. The cells with granules or hyaline bodies usually have pycnotic or fragmented nuclei. These cells are the final stage reached by some plasma cells. Others, when degenerating, show vacuoles and signs of senility. Those with the granules and hyaline bodies are the so called Russell body cells. Plasma cells developed in greatest numbers after our largest injections of tuberculo-protein. The differentiation into young, mature, and senile forms was most clearly recognizable when some days had been allowed to elapse after the last large injection of the stimulating agent. A description of the plasma cell as viewed supravitally has been given. The cells are met in the blood stream as well as in the tissues. They are characterized by their deep yellowish gray cytoplasm, indistinct eccentrically placed nuclei, and large numbers of mitochondria. The plasma cells differ from lymphocytes, in that they did not develop in large numbers after direct stimulation of the lymph nodes with tuberculo-protein. The young plasma cells also differ in morphology from the young lymphocytes. When plasma cells were found in the lymph nodes they were in the connective tissue cords. The plasma cell is a definite entity, having a maturation cycle. It is stimulated to great proliferation by certain toxic irritants.

Background: Allergic rhinitis (AR) is an IgE-mediated inflammation of nasal mucosa triggered by allergen exposure, affecting 10-40% of global population. Diagnosis relies on clinical history, symptoms like rhinorrhoea, nasal itching, sneezing, & pale bluish mucosa, & tests such nasal smear eosinophilia and elevated serum IgE. This study aimed to evaluate the diagnostic utility of these markers in clinically confirmed AR cases and assess nasal smear eosinophilia severity correlates with symptom severity. Materials & Methods:100 consenting adults (18-75 years) attending the ENT department were enrolled & divided into 50 cases (AR patients) and 50 age & sex matched controls. Nasal smears were collected from both nostrils, fixed, and stained with Leishman and H&E stains. Slides were examined under 1000X magnification; >5 eosinophils in 3-5 fields or 20-30 cells single finding indicated positivity, graded as mild, moderate, & severe. Serum IgE was measured via chemiluminescent immunoassay. Results: Mean age was 39.78?15.15 years (range 18-75). Cases had 46% males, 54% females. Mean IgE level was 364.14?339.42 IU/ml in group I vs. 100.62?34.60 in group II (p<0.001). The mean nasal smear eosinophil count was 14.56?17.43 in group I & and 1.32?8.21 in group II (p<0.001). Nasal smear eosinophilia showed 81.3% positive predictive value at >0.3/HPF. Symptom severity correlated well with eosinophilia grading. Conclusions: Nasal smear eosinophilia and serum IgE aid AR diagnosis, with serum IgE offering better sensitivity and comparable specificity. Nasal eosinophilia is highly specific and links to symptom severity, supporting its routine use.

Immunoglobulin E: Role in asthma and allergic disease: Lessons from the clinic

There is increasing epidemiological evidence for a role of allergic/atopic disorders in cancer development. However, findings have been inconsistent, which may be partly due to differences in defining allergy and the associated atopic disorders. The use of a biological marker for atopy may enhance the exploration of the association with cancer risks. To examine the association of atopy with common malignancies, we compared the prevalence of atopy in 318 patients with prostate cancer, 381 patients with breast cancer, 196 patients with lung cancer, 477 patients with colorectal cancer and 4,271 controls in a case-control analysis of participants of 2 prospective studies conducted in Saarland, Germany. Data on physician-diagnosed atopy-related diseases (asthma, hay fever and atopic dermatitis) were obtained by self-administered questionnaire. Allergen-specific immunoglobulin E (IgE) was assessed among cases and controls to define atopy. We observed a significantly increased risk of prostate cancer (odds ratio (OR) 1.35, 95% confidence interval (CI) 1.00-1.83) and a tentatively, statistically not significant increased risk of breast cancer (OR 1.20, 95% CI 0.87-1.66) and lung cancer (OR 1.29, 95% CI 0.87-1.92) with specific IgE positivity. No consistent associations were found with atopy-related diseases. Our findings are consistent with other epidemiological evidence suggesting an increased risk of prostate cancer with atopy and indicate a complex association between atopy/atopy-related diseases and cancer risk that varies by type of atopy-related disorders and the particular type of cancer under consideration. The effect on cancer risk by atopy, defined by IgE reactivity, may differ from the effect by atopy-related clinically defined diseases such as asthma, hay fever and atopic dermatitis.