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Biomedical subjects

D Maurer

Publications and source records attributed to D Maurer.

At least 55 records · Page 3Linked to original sources
PubMed1998

Molecular characterization of an autoallergen, Hom s 1, identified by serum IgE from atopic dermatitis patients.

Atopy is a genetically determined disorder that affects 10%-20% of the population. Many symptoms of patients with atopy (allergic rhinitis, conjunctivitis, asthma, and anaphylaxis) result from events occurring after crosslinking of cell-bound IgE by per se innocuous environmental antigens. The frequently raised hypothesis that autosensitization can also be a pathogenetic factor in atopy, gained support by our recent demonstration of IgE antibodies against human proteins in atopic dermatitis patients. To unravel the molecular nature of IgE-defined autoantigens, we used serum IgE from atopic dermatitis patients to screen a human epithelial cDNA expression library. One of the cDNA-encoding IgE-reactive products contained 1501 bp of a 2274 bp open-reading frame finally identified by sequence analysis of two additional cDNA clones resulting from oligonucleotide screening. The IgE-defined autoantigen, designated Hom s 1, exhibited an almost complete sequence identity with a recently described antigen recognized by cytotoxic T cells of a squamous cell carcinoma patient. Purified recombinant Hom s 1 specifically bound IgE from patients with severe atopy. When used as immunogen in rabbits, recombinant Hom s 1 gave rise to an anti-serum that reacted with a cytoplasmic protein exhibiting a broad cellular and tissue reactivity (skin, lung >> gastrointestinal tract >> muscle, brain) and identified a 55 kDa protein in blotted serum IgE preparations. The attractive possibility remains that the Hom s 1-triggered IgE response contributes to the events resulting in allergic tissue inflammation. If so, the respective recombinant molecule may serve as a paradigmatic tool for the diagnosis and treatment of patients with "intrinsic" atopy.

Allergens↗
PubMed1997

The high-affinity receptor for IgE is the predominant IgE-binding structure in lesional skin of atopic dermatitis patients.

While the skin of most patients with atopic dermatitis (AD) is known to contain IgE-bearing cells, the contribution of the various IgE-binding structures to this phenomenon is not fully understood. To address this issue, we eluted cell-bound IgE from cryostat sections of lesional AD skin by acid treatment and performed reconstitution experiments with IgE in the absence or presence of reagents directed against the currently known IgE-binding structures. We found that incubation of acid-treated sections, with either chimeric or serum IgE, resulted in the appearance of sizable numbers of anti-IgE-reactive cells. This cellular IgE loading could be entirely prevented by preincubation of the sections with the anti-Fc epsilonRI alpha MoAb 15-1 but not with either antibodies against Fc epsilonRII/CD23 and Fc gammaRII/CD32 or with alpha-lactose. To exclude the possibility that acid treatment of tissue sections may have adversely influenced the IgE-binding capacity of IgE receptors other than Fc epsilonRI, we performed an identical series of experiments on AD skin samples that, as an exception, were essentially devoid of anti-IgE-reactive cells. Again, no IgE loading was detected when these sections were preincubated with anti-Fc epsilonRI alpha MoAbs. In contrast, preincubation of the sections with alpha-lactose and/or MoAbs against Fc epsilonRII/CD23 or Fc gammaRII/CD32 did not affect IgE loading. Together with the observations that anti-Fc epsilonRI alpha-reactive and IgE-binding cells are largely overlapping populations and include cells of the Langerhans cell/dendritic cell lineage, mast cells, and a few dermal dendrocytes and eosinophils, our results demonstrate that Fc epsilonRI is the predominant and, perhaps, the only biologically relevant IgE-binding structure on histogenetically and functionally diverse cell populations of AD skin.

Adult↗
PubMed1997

The outcome of unrelated donor bone marrow transplantation in patients with hematologic malignancies using tacrolimus (FK506) and low dose methotrexate for graft-versus-host disease prophylaxis.

Initial studies of FK506 combined with methotrexate (MTX) in patients receiving unrelated donor BMT have demonstrated a possible-decrease in the incidence of severe GVHD but high rates of severe stomatitis and nephrotoxicity. With this background, we undertook a pilot study evaluating FK506 in combination with a lower than usual dose of MTX in an attempt to improve the tolerability of this immunoprophylaxis regimen. Between July 1993 and October 1994, 26 consecutive adults receiving unrelated donor BMT at Emory University Hospital were enrolled on this study. All patients received FK506 intravenously at an initial dose of 0.03 mg/kg/day beginning day -1 and continuing until oral FK506 was tolerated. Patients also received MTX intravenously at 5 mg/m2 on days 1, 3, 6, and 11. The preparative regimen administered to all but one patient included cyclophosphamide at 200 mg/kg over 4 days followed by total body irradiation (TBI) at 1400 cGy in twice daily fractions over 4 days. The median age of patients was 31 years (range: 19 to 52). Sixteen donor/recipient pairs were matched for HLA-A, -B, and -DR by serology and molecular typing. Ten paris were minor mismatches at either class I or class II. Twenty-two of 26 patients (85%) completed four doses of MTX on schedule. Nephrotoxicity was the most common adverse event associated with the administration of FK506: 88% of patients experienced a doubling of their serum creatinine. One patient died of central nervous system hemorrhage prior to engraftment. Twenty-four of the remaining 25 patients (96%) engrafted. Fourteen of 24 patients (50%) evaluable developed grades 2-4 acute GVHD. The rate of severe (grades 3-4) acute GVHD was 25%. Chronic GVHD developed in 11 of 20 (55%) evaluable patients. At a median follow-up of 461 days, 14 patients (54%) are alive. All are relapse-free with a median Karnofsky performance status of 90% (range: 70-100%). The cumulative probability of 2-year disease-free survival is 50% (95% confidence interval [CI]: 0.33 to 0.77); for low risk patients 67% (95% CI: 0.47 to 0.95) and for high risk patients 23% (95% CI: 0.049 to 1.00). These preliminary data indicate that FK506-based immunosuppression following unrelated donor BMT is effective in preventing severe acute GVHD and warrants comparison to CSA-based regimens.

Adult↗
PubMed1996

Peripheral blood dendritic cells express Fc epsilon RI as a complex composed of Fc epsilon RI alpha- and Fc epsilon RI gamma-chains and can use this receptor for IgE-mediated allergen presentation.

Originally limited to basophils and mast cells, the spectrum of high affinity IgE receptor (Fc epsilon RI-bearing cells has expanded recently to include Langerhans cells, dermal dendritic cells (DC), monocytes, and eosinophils. As a result of studies on the distribution, structure, and function of Fc epsilon RI on APCs, we discovered a minor nonbasophil, nonmonocyte PBMC population that can bind IgE via Fc epsilon RI. This receptor occurs on the surface of these cells as a multimeric structure containing Fc epsilon RI alpha- and Fc epsilon RI gamma-chains but, unlike its counterpart on basophils, lacking Fc epsilon RI beta. Further experiments revealed that these Fc epsilon RI alpha gamma-expressing cells closely resemble peripheral blood DC by immunophenotype (HLA-DRhigh, HLA-DQhhigh; CD4+, CD11a+, CD32+, CD33+, B7/2 (CD86)+; CD11blow, CD14low, CD40low, CD54low, CD64low) and cell morphology. These features allowed us to isolate Fc epsilon RI-expressing DC from the peripheral blood and to investigate their immunostimulatory properties. We found Fc epsilon RI-positive DC to be efficient stimulators of both primary (allogeneic MLR) and Fc epsilon RI/IgE-dependent, secondary T cell responses at low cell numbers. Thus, Fc epsilon RI-expressing DC may not only amplify established type I allergic immune reactions but, unlike Fc epsilon RI-positive semiprofessional APCs, may be able to prime naive T cells to common and/or cryptic epitopes of IgE-reactive Ags.

Allergens↗
PubMed1996

Generation of human dendritic cells/Langerhans cells from circulating CD34+ hematopoietic progenitor cells.

Human Langerhans cells (LC) are CD1a+ dendritic cells (DC) that function as potent antigen-presenting cells for primary and secondary immune responses. Limitations in DC/LC numbers, imposed by difficult and tedious isolation procedures, have so far precluded their use as immunogens in the generation and/or augmentation of host responses against various pathogens. Therefore, we have developed a procedure for the generation of human DC/LC from CD34+ hematopoietic progenitor cells (HPC) isolated (mean: 0.7 x 10(6)/ buffy coat and 2.6 x 10(6)/leukapheresis product) and purified ( > 95%) from the peripheral blood of healthy adults. In vitro stimulation of these cells with granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor (TNF)-alpha led to their vigorous proliferation and differentiation resulting in the emergence of CD45+/CD68+/CD3-/CD19-/CD56- leukocytes some of which (mean: 12%) express CD1a and exhibit anti-CD4 and anti-major histocompatibility complex (MHC) class II reactivity. These CD1a- leukocytes include (1) LC as evidenced by the presence of Birbeck granules (BG), (2) CD14+ monocytes, and (3) Birbeck granule-negative cells with a dendritic morphology. Addition of interleukin (IL)-4 to the cytokine cocktail interfered with the development of monocytes and led to a reduction in the overall yield but, on the other hand, resulted in an increased percentage of CD1a+ cells (mean: 24%) among all cells generated. In vitro generated CD1a+, but not CD1a- HPC-derived cells are potent stimulators of the primary mixed leukocyte reaction and, as such, promising candidates for vaccination purposes.

Adult↗
PubMed1996

Anti-IgE and anti-Fc epsilon RI autoantibodies in clinical allergy.

Autoantibodies recognizing critical effector molecules of type I allergic reactions have been identified. Anti-IgE autoantibodies occur at high frequencies not only in atopic diseases but also in healthy individuals and, depending on their epitope specificities, may promote or prevent the elicitation of allergic symptoms. In contrast, anti-Fc epsilon RI autoantibodies with basophil/mast cell activating properties were selectively found in patients with chronic urticaria, a condition characterized by the continuous degranulation of mast cells. Thus, humoral anti-Fc epsilon RI autoreactivity defines a distinctive subset of chronic urticaria and may well be the causative and pathogenetic principle in this disease.

Animals↗
PubMed1996

Immunoglobulin E response to human proteins in atopic patients.

The demonstration that human IgE recognizes both exogenous allergens and structurally related human proteins has led to the hypothesis that IgE autoreactivity may be a pathogenic factor in atopic diseases. To determine the frequency of occurrence as well as the disease specificity of this phenomenon, we tested sera from patients with atopic diseases and, for control purposes, from persons with immunologically mediated disorders for serum IgE reactivity with nitrocellulose-blotted human proteins. We found that 12 of 20 sera from atopic patients with pronounced skin lesions contained Western blot-detectable IgE antibodies. Patients suffering predominantly from allergic rhinoconjunctivitis as well as control individuals failed to display serum IgE autoreactivity, but occasionally exhibited elevated serum IgE levels. The molecular weights of the IgE-defined autoantigens ranged predominantly from 10 to 100 kDa. Whereas some of these were expressed in only certain cell types, others were detected in histogenetically different cells. Our results suggest that IgE autoimmunity occurs frequently in atopic dermatitis patients and may be of pathogenic relevance for the chronicity of skin manifestations typical of this disease.

Antibody Specificity↗
PubMed1996

Intelligibility and spectral differences in high-pitched vowels.

The first formant frequency of most German vowels can be 'oversung' in the sense of vocalizations with pitch frequencies above F1 of normal speech. Investigations of sung and synthesized vowels suggested that, with rising F0, either the vowel loses its identity and its spectral characteristics, or changes in the vocal effort and the speaker group are perceived. This study presents high-pitched vocalizations by untrained men, women and children, apart from singing or shouting. Three main results were found: (i) vowel identity can be maintained at high pitches (F0 = 660-870 Hz); (ii) clear spectral differences in high-pitched vowels are demonstrated; (iii) high pitched vowels can be found within one speaker group, apart from changes in the perceived speaker group. Both the F0 dependence of the lower formants and a possible relationship between phonation and articulation are discussed.

Adult↗
PubMed1996

High-speed imaging of vocal fold vibrations and larynx movements within vocalizations of different vowels.

Theoretic investigations of the "source-filter" model have indicated a pronounced acoustic interaction of glottal source and vocal tract. Empirical investigations of formant pattern variations apart from changes in vowel identity have demonstrated a direct relationship between the fundamental frequency and the patterns. As a consequence of both findings, independence of phonation and articulation may be limited in the speech process. Within the present study, possible interdependence of phonation and phoneme was investigated: vocal fold vibrations and larynx position for vocalizations of different vowels in a healthy man and woman were examined by high-speed light-intensified digital imaging. We found 1) different movements of the vocal folds for vocalizations of different vowel identities within one speaker and at similar fundamental frequency, and 2) constant larynx position within vocalization of one vowel identity, but different positions for vocalizations of different vowel identities. A possible relationship between the vocal fold vibrations and the phoneme is discussed.

Adult↗
PubMed1995

The high affinity IgE receptor (Fc epsilon RI) mediates IgE-dependent allergen presentation.

The discovery that the high affinity IgE receptor (Fc epsilon RI) is expressed on APCs of patients with atopic diseases raised the possibility that the functional importance of Fc epsilon RI in the pathogenesis of atopy may extend beyond its role in type I allergic reactions. Here we show that, following removal of in vivo-bound IgE by lactic acid treatment, targeting of allergens to monocytes by Ag-specific IgE critically depends on Fc epsilon RI expression. Even more importantly, lactic acid-treated, monocyte-enriched PBMCs present allergen to T cells 100- to 1000-fold more effectively if the allergen has been targeted to Fc epsilon RI on these cells via allergen-specific IgE. This mechanism may critically lower the atopic individual's threshold to mount allergen-specific T cell responses capable of promoting IgE production and delayed-type hypersensitivity reactions.

Allergens↗
PubMed1995

Cardiac myxomas: a long term study.

From 1980 to 1992 we followed 12 patients with cardiac myxomas for an average of 4.4 years (8 months-11 years). Presenting symptoms were neurological in four patients (hemiparesis, aphasia, visual field deficits, progressive dementia or vertigo), progressive dyspnoea in six, pulmonary embolism in one, and peripheral arterial or renal emboli in three. The diagnosis was suspected clinically in 11 patients. It was confirmed by echocardiography in ten and by thoracic CT in one. All these patients had cardiac surgery. One diagnosis was made at autopsy; the patient died unexpectedly during surgery for emboli to the leg arteries. At follow-up, two additional patients had died, one from myocardial infarction and one from rhabdomyosarcoma. Only one of the nine surviving patients had recurrent symptoms after cardiac surgery. His dementia continued to progress. The patients without new symptoms after cardiac surgery had normal MRI of the brain or residual ischaemic lesions. MRI of the patient with progressive dementia showed multiple cerebral lesions with a bright centre and a dark rim on T1- and T2-weighted spin-echo images. On CT there were many calcified lesions. CT, MR angiography and contrast angiography revealed multiple fusiform aneurysms. The rare occurrence of progressive neurological symptoms after myxoma resection with multiple cerebral lesions and aneurysms should suggest myxoma metastases to the brain.

Adult↗
PubMed1995

Immunoglobulin E-binding structures on antigen-presenting cells present in skin and blood.

In atopic individuals, cutaneous antigen-presenting cells (APC), i.e., Langerhans cells and dermal dendritic cells, frequently display anti-IgE reactivity. Although earlier observations suggested that this phenomenon results from the binding of (complexed) IgE to the low-affinity IgE receptor (Fc epsilon RII/CD23), we and others demonstrated recently that Langerhans cells, dermal dendritic cells, and peripheral blood monocytes from atopic individuals can bind monomeric IgE via the high-affinity receptor for IgE (Fc epsilon RI). These new observations re-stimulated investigations aiming to unravel the nature and functionality of the relevant in vivo IgE-binding moiety(-ies) on APC. New data demonstrate that Fc epsilon RI, both quantitatively and qualitatively, is the pivotal serum IgE-binding structure on APC of atopics and, even more important, that Fc epsilon RI on APC functions as an allergen-focusing molecule. Thus, it is likely that allergens may be more efficiently taken up, processed, and presented to T cells after targeting to APC via Fc epsilon RI as compared with allergen binding to APC in the conventional manner. In vivo, Fc epsilon RI-IgE-dependent allergen presentation may critically lower atopic individuals' threshold to mount allergen-specific T-cell responses. This would result in the perpetuation of allergen-specific IgE production (type I reactions) and perhaps even the occurrence of T-cell-mediated, delayed-type hypersensitivity reactions in allergen-exposed tissues.

Antigen-Presenting Cells↗
PubMed1995

Serum IgG autoantibodies directed against the alpha chain of Fc epsilon RI: a selective marker and pathogenetic factor for a distinct subset of chronic urticaria patients?

While it is well established that acute allergic urticaria is caused by degranulation of skin mast cells occurring after allergen/IgE-dependent cross-linking of high affinity IgE receptors (FcepsilonRI), the pathophysiologic mechanisms operative in chronic urticaria (CU) are less well understood. Some evidence points to the existence of histamine-releasing activity in the serum of CU patients which possibly acts via triggering of FcepsilonRI. In this study, we aimed to better characterize this anti-FcepsilonRIalpha reactivity of CU patients using affinity-purified, IgE-depleted IgG fractions of such individuals (CU-IgG). Using immobilized, recombinant soluble FcepsilonRIalpha as a a reaction target for Western blot studies, we found that 12/32 (37%) CU-IgG serum samples exhibited IgG autoreactivity against FcepsilonRI- alpha. These findings were confirmed by experiments demonstrating that immunoblot-reactive, but not immunoblot-nonreactive, CU-IgG preparations precipitated the FcepsilonRIalpha from FcepsilonRI- alphagamma-transfected cells. No anti-FcepsilonRIalpha reactivity was observed in IgG fractions from atopic dermatitis (AD) patients (0/15) or healthy control individuals (CO:0/15). As opposed to the selective occurrence of IgG anti-Fc epsilon RI alpha autoantibodies in CU patients, IgG anti-IgE antibodies were detected in all groups investigated (CU: 69%; AD: 73%; CO: 26%). While both types of autoantibodies can exhibit histamine-releasing properties, not all of the autoantibodies proved to be functional in vitro. Our results indicate that the occurrence of IgG anti-FcepsilonRIalpha reactivity defines an autoimmune-mediated subentity of CU and provide a basis for the development of new diagnostic procedures and, perhaps, therapeutic strategies for this disease.

Animals↗
PubMed1995

FO-dependence, number alteration, and non-systematic behaviour of the formants in German vowels.

In acoustic theory, formant pattern differences within one vowel identify are related to differences in the speaker groups or in the types of vocalization. Yet, studies of vowel synthesis indicate that formant patterns can also vary strongly in relation either to pitch or to formant number alterations. Within this study, natural vocalizations of nine German vowels were investigated with regard to different formant patterns representing the same vowel identity, apart from differences in speaker groups and vocalization types. The results show i) FO-dependence of the lower formants < 1.5-2 kHz; ii) occurrence of natural one-formant back and two-formant front vowels; iii) a non-systematic relationship between FO and the formants, and a non-systematic relationship between formant patterns of different formant numbers. The implications for psychophysics, physiology and perception of speech are discussed.

Adult↗
PubMed1995

Development of grating acuity in children treated for unilateral or bilateral congenital cataract.

PURPOSE: To study the development of grating acuity in children treated for dense congenital unilateral or bilateral cataract and to examine how variations in treatment affect grating acuity during early childhood. METHODS: The authors used optokinetic nystagmus (OKN), preferential looking (PL), or both to measure the grating acuity of children treated for congenital cataract in one eye (n = 63) or both eyes (n = 77) whenever possible from the time of treatment until 3 years of age. At each age, the authors compared patients' monocular acuity to that of children with no history of eye disorders. RESULTS: The OKN acuity of treated eyes did not improve with age and was abnormal by 12 months of age. In contrast, PL acuity improved with age, and acuity of most treated eyes was not outside normal limits until 24 to 30 months of age. Nonetheless, at 12 months and at 3 years of age, PL acuity correlated significantly with age at treatment in children who had bilateral cataract. In children who had unilateral cataract, PL acuity correlated significantly with the number of hours per day the good eye had been patched since treatment. Children whose good eye was patched fewer than 3 hours per day did significantly worse than children treated at a comparable age for bilateral congenital cataract. However, children whose good eye was patched at least 3 hours per day had PL acuities similar to those of children treated at a comparable age for bilateral congenital cataract. CONCLUSIONS: Children treated for congenital cataract show deficits in grating acuity, with the deficit apparent earlier in OKN acuity than in PL acuity. At least by 1 year of age, visual development has begun to be influenced by the age at treatment and, in children treated for unilateral cataract, by patching of the good eye.

Aging↗
PubMed1994

Expression of functional high affinity immunoglobulin E receptors (Fc epsilon RI) on monocytes of atopic individuals.

Suggestive evidence indicates that immunoglobulin E (IgE)-dependent activation of mononuclear phagocytes plays an important pathogenic role in allergic tissue inflammation. Prevailing opinion holds that low affinity IgE receptors are the relevant IgE-binding structures on monocytes/macrophages and that functional events occurring after cross-linking of membrane-bound IgE on these cells are mediated by these receptors. Here we demonstrate that peripheral blood monocytes can bind monomeric IgE via the high affinity IgE receptor (Fc epsilon RI) and that Fc epsilon RI expression on these cells is upregulated in atopic persons. Further, we demonstrate that, upon monocyte adherence to substrate, bridging of monocyte Fc epsilon RI is followed by cell activation. We propose that direct interaction of multivalent allergen with Fc epsilon RI(+)-bound IgE on mononuclear phagocytes results in cell signaling via Fc epsilon RI and that the biological consequences of this event may critically influence the outcome of allergic reactions.

Animals↗
PubMed1994

Differential polymerase chain reaction assay of cyclin D1 gene amplification in esophageal carcinoma.

The cyclin D1 gene, located on chromosome 11q13, is frequently rearranged in parathyroid neoplasms and amplified in some carcinomas of other organs. Recent studies have detected amplification of cyclin D1 and other markers on chromosome 11q13 (evaluated by Southern or slot blot assays) in approximately 25-50% of squamous cell carcinomas of the esophagus and noted that amplification was associated with lessened survival time. We applied the technique of differential polymerase chain reaction to the evaluation of cyclin D1 gene amplification in squamous cell carcinomas of the esophagus. Cyclin D1 was found to be amplified in 10 of 45 (22%) primary tumors and three of 12 (25%) lymph node metastases. Lymph node metastases tended to be more common in patients with cyclin D1 amplification (70%) than in those without amplification (37%). In 36 patients with follow-up, cyclin D1 amplification was associated with decreased 1 year survival (28% vs. 59%). Cyclin D1 gene amplification in esophageal carcinomas can be evaluated by differential polymerase chain reaction and may provide useful prognostic information.

Base Sequence↗