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Biomedical subjects

J N Fink

Publications and source records attributed to J N Fink.

At least 19 recordsLinked to original sources
PubMed2005

The costimulatory molecules CD80, CD86 and OX40L are up-regulated in Aspergillus fumigatus sensitized mice.

Aspergillus fumigatus (Af) is a fungus associated with allergic bronchopulmonary aspergillosis (ABPA) and other allergic diseases. Immune responses in these diseases are due to T and B cell responses. T cell activation requires both Af-specific engagement of the T-cell-receptor as well as interaction of antigen independent costimulatory molecules including CD28-CD80/CD86 and OX40-OX40L interactions. Since these molecules and their interactions have been suggested to have a potential involvement in the pathogenesis of ABPA, we have investigated their role in a model of experimental allergic aspergillosis. BALB/c mice were primed and sensitized with Af allergens, with or without exogenous IL-4. Results showed up-regulation of both CD86 and CD80 molecules on lung B cells from Af-sensitized mice (79% CD86+ and 24% CD80+) and Af/rIL-4-treated mice (90% CD86+ and 24% CD80+) compared to normal controls (36% and 17%, respectively). Lung macrophages in Af-sensitized mice treated or not with IL-4 showed enhanced expression of these molecules. OX40L expression was also up-regulated on lung B cells and macrophages from both Af-sensitized and Af/rIL-4 exposed mice as compared to normal controls. All Af-sensitized animals showed peripheral blood eosinophilia, enhanced total serum IgE and allergen-specific IgG1 antibodies and characteristic lung inflammation. The up-regulation of CD80, CD86 and OX40L molecules on lung B cells and macrophages from Af-allergen exposed mice suggests a major role for these molecules in the amplification and persistence of immunological and inflammatory responses in ABPA.

Allergens↗
PubMed2005

Detection of focal cerebral hemisphere lesions using the neurological examination.

OBJECTIVE: To determine the sensitivity and specificity of clinical tests for detecting focal lesions in a prospective blinded study. METHODS: 46 patients with a focal cerebral hemisphere lesion without obvious focal signs and 19 controls with normal imaging were examined using a battery of clinical tests. Examiners were blinded to the diagnosis. The sensitivity, specificity, and positive and negative predictive values of each test were measured. RESULTS: The upper limb tests with the greatest sensitivities for detecting a focal lesion were finger rolling (sensitivity 0.33 (95% confidence interval, 0.21 to 0.47)), assessment of power (0.30 (0.19 to 0.45)), rapid alternating movements (0.30 (0.19 to 0.45)), forearm rolling (0.24 (0.14 to 0.38)), and pronator drift (0.22 (0.12 to 0.36)). All these tests had a specificity of 1.00 (0.83 to 1.00). This combination of tests detected an abnormality in 50% of the patients with a focal lesion. In the lower limbs, assessment of power was the most sensitive test (sensitivity 0.20 (0.11 to 0.33)). Visual field defects were detected in 10 patients with a focal lesion (sensitivity 0.22 (0.12 to 0.36)) and facial weakness in eight (sensitivity 0.17 (0.09 to 0.31)). Overall, the examination detected signs of focal brain disease in 61% of the patients with a focal cerebral lesion. CONCLUSIONS: The neurological examination has a low sensitivity for detecting early cerebral hemisphere lesions in patients without obvious focal signs. The finger and forearm rolling tests, rapid alternating movements of the hands, and pronator drift are simple tests that increase the detection of a focal lesion without greatly increasing the length of the examination.

Adult↗
PubMed2001

T cell proliferation and cytokine secretion to T cell epitopes of Asp f 2 in ABPA patients.

The pathogenesis of allergic bronchopulmonary aspergillosis (ABPA) involves specific cytokines secreted by lymphocytes in response to Aspergillus fumigatus (Af) allergens. To gain information about the lymphoproliferative response and cytokine production against a major Af allergen, Asp f 2, we studied Asp-f-2-specific T cell clones (TCCs) from ABPA patients. TCCs were stimulated with rAsp f 2, its deletion mutants, and synthetic peptides to identify the T cell epitope(s) and to understand cytokine production. PBMCs from four of five ABPA patients showed proliferation in response to Asp f 2. Three TCCs from one patient showed higher IL-5 secretion compared to IL-4 and IFN-gamma. Two TCCs from the second patient showed a mixed Th1/Th2 response, as evidenced by production of IL-4, IL-5, and IFN-gamma. An epitope from the N-terminal region of Asp f 2 induced only IL-5 secretion. High IL-5 secretion might explain the marked eosinophilia observed in ABPA patients.

Amino Acid Sequence↗
PubMed2001

Anaphylaxis to celecoxib.

BACKGROUND: Adverse reactions such as urticaria, angioedema, asthma, and anaphylaxis are known to be associated with nonsteroidal anti-inflammatory agents (NSAIDs). Celecoxib (Pfizer/Searle, Caguas, PR) is a new NSAID that differs in structure and mechanism of action of other similar drugs of this class. OBJECTIVE: Evaluation of a case of anaphylaxis to celecoxib (Celebrex). METHODS AND RESULTS: This report describes a 55-year-old woman who experienced the acute onset of pruritus, urticaria, respiratory distress, and hypotension minutes after ingesting a celecoxib capsule. She had taken the drug a previous time for tendonitis without difficulty. Treatment with epinephrine, corticosteroids, and intravenous fluids was successful. An IgE mechanism could not be detected. She has avoided the drug and has had no further problems. CONCLUSIONS: This is the first patient report of anaphylaxis attributable to celecoxib, a new NSAID. This suggests that physicians and other health care professionals should be aware of the potential serious side effects of this drug.

Anaphylaxis↗
PubMed2001

Cloning and expression of Aspergillus fumigatus allergen Asp f 16 mediating both humoral and cell-mediated immunity in allergic bronchopulmonary aspergillosis (ABPA).

BACKGROUND: Aspergillus fumigatus, a ubiquitous fungus, is responsible for a number of lung disorders in atopic and non-atopic individuals. Standardized, pure, and relevant allergens are desirable for reliable immunodiagnosis of the disease and to understand the structural and functional properties of these allergens and the role they play in causing ABPA. OBJECTIVE: Molecular cloning and characterization of a relevant allergen from A. fumigatus cDNA library. MATERIALS AND METHODS: A cDNA library was constructed from 96 h old mycelium of A. fumigatus using lambda ZAP expression vector. A novel gene encoding an A. fumigatus allergen was identified by screening the library with sera from ABPA patients. The gene was cloned and the allergen over-expressed in Escherichia coli. This recombinant allergen, Asp f 16, was evaluated in ELISA and Western blots using sera from patients and normal subjects and peripheral blood mononuclear cells (PBMC) for antigen-induced stimulation. RESULTS: Seventy percent of the patients with ABPA demonstrated high levels of serum IgE antibodies to Asp f 16, a 43-kDa protein, whereas patients with allergic asthma, Aspergillus skin test-positive asthmatics without clinical evidence of ABPA, and normal controls failed to show Asp f 16-specific IgE binding by ELISA. The deduced amino acid sequences of Asp f 16 showed extensive sequence homology to 30.6-kDa Asp f 9 at the N-terminal region of the protein. PBMC from the majority of patients with ABPA exhibited significant proliferation with the recombinant Asp f 16 allergen. CONCLUSION: Specific humoral and cell-mediated immune responses of Af-sensitized patients against Asp f 16 suggest its usefulness in the immunodiagnosis of hypersensitivity diseases due to Af and understanding the pathophysiology of ABPA.

Allergens↗
PubMed2000

Antibody binding of deletion mutants of Asp f 2, the major Aspergillus fumigatus allergen.

Asp f 2, a 268 amino acid major allergen from Aspergillus fumigatus (Af) demonstrated nine linear IgE binding regions. It is not known whether any of these linear epitopes are also conformatory epitopes. Hence, we constructed deletion mutants of Asp f 2 devoid of one or more epitopes, and the IgE binding of these proteins with sera from patients with ABPA was compared with the full-length Asp f 2 expressed in E. coli and Pichia. The Pichia expressed protein reacted weakly with IgE, but strongly with IgG of ABPA sera compared to E. coli expressed Asp f 2. Weak IgE binding only was seen when the C-terminal or N-terminal was deleted, while depletion of both ends negated all reactivity. The monoclonal antibody IL-B8 and IgE and IgG of ABPA sera bound significantly to the Asp f 2 E-4 fragment indicating that the major B-cell epitope is located at the N-terminal end of Asp f 2.

Allergens↗
PubMed2000

Detection of immunoglobulin antibodies in the sera of patients using purified latex allergens.

BACKGROUND: Latex allergy is largely an occupational allergy due to sensitization to natural rubber latex allergens present in a number of health care and household products. Although several purified allergens are currently available for study, information on the usefulness of these purified, native or recombinant allergens in the demonstration of specific immunoglobulin (Ig) E in the sera of patients is lacking. OBJECTIVE: To evaluate the purified latex allergens and to demonstrate specific IgE antibody in the sera of health care workers and spina bifida patients with clinical latex allergy. METHODS: Two radioallergosorbent and an enzyme-linked immunosorbent assay (ELISA) using latex proteins Hev b 1, 2, 3, 4, 6 and 7 along with two glove extracts and Malaysian nonammoniated latex (MNA) were evaluated to demonstrate IgE in the sera of health care workers and spina bifida with latex allergy and controls with no history of latex allergy. RESULTS: ELISA using the purified latex allergens demonstrated specific IgE in 32-65% health care workers and 54-100% of spina bifida patients with latex allergy. The corresponding figures for RAST were 13-48 and 23-85 for RAST-1 and 19-61 and 36-57 for RAST-2. These results were comparable with the results obtained with glove extracts and crude rubber latex proteins. CONCLUSIONS: When used simultaneously, latex proteins Hev b 2 and Hev b 7 reacted significantly with specific serum IgE in 80% of health care workers and 92% of spina bifida patients with latex allergy by ELISA technique, while this combination gave lower positivity when the RASTs were used. By the addition of Hev b 3, specific IgE was detected in all spina bifida patients with latex allergy. Both RASTs failed to show specific IgE in the control subjects, while the ELISA showed significant latex-specific IgE in 22% of controls.

Allergens↗
PubMed1999

Aspergillus fumigatus antigen exposure results in pulmonary airway resistance in wild-type but not in IL-4 knockout mice.

Inhalation of Aspergillus fumigatus, a ubiquitous fungus, results in the development of allergic bronchopulmonary aspergillosis, a disabling allergic lung disease. For better patient management early diagnosis is essential, and understanding of the immune mechanism is important in achieving this goal. Although animal model studies have contributed to the understanding of the disease mechanism, details on the immunopathogenesis are still lacking. In the present study, we have developed an allergic aspergillosis model in wild-type and IL-4 knockout mice and studied the immune and airway responses. The results indicate that the immune response, pulmonary pathology, and airway reactivity comparable to allergic bronchopulmonary aspergillosis are reproducible in wild mice. IL-4 knockout mice showed similar pulmonary pathology, but no increase in airway resistance, suggesting that IgE and hence IL-4 may be important in eliciting the airway response, while other factors may be involved in the inflammatory process.

Airway Resistance↗
PubMed1999

Immune responses to Aspergillus antigen in IL-4-/-mice and the effect of eosinophil ablation.

BACKGROUND: Exposure to Aspergillus fumigatus allergens results in enhanced total serum IgE and peripheral blood eosinophils in mice. The associated pulmonary inflammation and immunologic responses are comparable to those detected in human allergic bronchopulmonary aspergillosis. Allergen-induced cytokines are thought to regulate the inflammatory and immune responses in these animals. METHODS: In the present study, we exposed C57BL/6 and BALB/c mice to A. fumigatus antigen. Both wild-type and IL-4 knockout phenotypes of animals of both strains were used. Some animals were also treated with anti-IL-5 or anti-IFN-gamma. Total serum IgE, Aspergillus species IgG subclass, peripheral blood eosinophils, and lung histology were studied. RESULTS: The results demonstrate similar lung inflammation in all wild-type and IL-4-/- animals exposed to A. fumigatus antigen. Similarly, in spite of the diverse immune response produced by the anticytokine treatment, no major differences were detected among any of the animal groups studied. CONCLUSIONS: It can be concluded that A. fumigatus exposure in an immunologically unaltered host is predominantly of a Th2 type, and that depletion of the Th2 cytokine leads to a similar lung inflammation but with a characteristic Th1 response, suggesting that the pathogenesis of allergic aspergillosis is the result of multiple induction pathways.

Animals↗
PubMed1999

Conformational and linear B-cell epitopes of Asp f 2, a major allergen of Aspergillus fumigatus, bind differently to immunoglobulin E antibody in the sera of allergic bronchopulmonary aspergillosis patients.

Asp f 2 is a major Aspergillus fumigatus allergen involved in allergic bronchopulmonary aspergillosis. Knowledge of the B-cell epitopes may contribute to the understanding of immunoregulation and immunodiagnosis. To elucidate the immunoglobulin E (IgE) binding epitopes in the linear sequence of Asp f 2, we synthesized decamer peptides spanning the whole molecule of Asp f 2 on derivatized cellulose membranes and evaluated IgE binding in ABPA patient and control sera. Peptides three to five amino acids long were synthesized based on amino acid sequences within the IgE binding regions and evaluated for the specificity of epitope antibody interactions. Nine IgE binding regions were recognized in this protein of 268 amino acid residues. Of the nine epitopes, seven (ATQRRQI, RKYFG, HWR, YTTRR, DHFAD, ALEAYA, and THEGGQ) are present in the hydrophilic regions of Asp f 2. Immunologic evaluation of the three recombinant fragments, Asp f 2A encompassing the N-terminal epitope region, Asp f 2B without N- and C-terminal regions of the protein, and Asp f 2C representing C-terminal epitopes, revealed that either the N- or C-terminal region of the protein is essential for the correct folding and conformation for IgE antibody binding.

Allergens↗
PubMed1999

Purified and recombinant latex proteins stimulate peripheral blood lymphocytes of latex allergic patients.

BACKGROUND: Natural rubber latex proteins have been implicated in severe allergy in individuals exposed to latex products, particularly health care workers. Until recently, only crude antigens were available to study the immune response in these patients. In recent years a number of relevant allergens have been purified, but few have been used in lymphocyte studies. Hence, to better understand the immunological mechanisms involved in latex allergy, we investigated the response of peripheral blood mononuclear cells (PBMCs) to various purified natural rubber latex allergens. METHODS: Using conventional protein purification methods and gene cloning, we have obtained 6 natural rubber latex proteins. We studied allergen-specific IgE levels and PBMC responses to these allergens along with 3 crude latex antigen preparations. RESULTS: Of the 28 latex-allergic health care workers studied, 16 reacted to one or more of the allergens studied, but PBMCs from controls failed to respond to these antigens. Serum IgE to the antigens was detected in 11-90% of the patients. CONCLUSION: Fifty-seven percent of the latex-allergic patients demonstrated PBMC responses to at least one of the latex allergens tested, but there was no direct correlation between serum IgE levels and PBMC responses. However, since none of the control subjects showed any PBMC stimulation, this may prove useful in determining sensitization to latex. Among the allergens studied, the predominant mononuclear cell responses were directed against Hev b 2, while serum IgE against rHev b 6 was demonstrable in the greatest number of patients. The crude latex allergens were toxic to PBMCs and hence, the purified allergens may be of greater value in demonstrating sensitization of patients to latex allergens.

Allergens↗