Hepatitis B virus e antigen (HBeAg) may have a negative effect on dendritic cell generation

Hepatitis B virus (HBV) continues to be a serious worldwide health problem despite the use of protective HBV vaccines and therapeutic regimens against chronic HBV infection. Chronic HBV patients cannot induce sufficient immune responses against the virus. HBV and its antigens are believed to suppress immune responses during chronic infection. Hence, studying the role of HBV in immune suppression is very important for the development of alternative therapeutic strategies for HBV infections.     

Effects of the cysteinyl leukotriene receptor antagonists pranlukast and zafirlukast on tracheal mucus secretion in ovalbumin-sensitized guinea-pigs in vitro

1. We investigated the inhibitory effects of the cysteinyl leukotriene (CysLT₁) receptor antagonists, pranlukast and zafirlukast, on ³⁵SO₄ labelled mucus output, in vitro, in guinea-pig trachea, induced by leukotriene D₄ (LTD₄) or by antigen challenge of sensitized animals. Agonists and antagonists were administered mucosally, except in selected comparative experiments where drugs were administered both mucosally and serosally to assess the influence of the epithelium on evoked-secretion.
2. LTD₄ increased ³⁵SO₄ output in a concentration-related manner with a maximal increase of 23 fold above controls at 100 μM and an approximate EC₅₀ of 2 μM. Combined mucosal and serosal addition of LTD₄ did not significantly affect the secretory response compared with mucosal addition alone. Neither LTC₄ nor LTE₄ (10 μM each) affected ³⁵SO₄ output. Pranlukast or zafirlukast significantly inhibited 10 μM LTD₄-evoked ³⁵SO₄ output in a concentration-dependent fashion, with maximal inhibitions of 83% at 10 μM pranlukast and 78% at 10 μM zafirlukast, and IC₅₀ values of 0.3 μM for pranlukast and 0.6 μM for zafirlukast. Combined mucosal and serosal administration of the antagonists (5 μM each) gave degrees of inhibition of mucosal-serosal 10 μM LTD₄-evoked ³⁵SO₄ output similar to those of the drugs given mucosally. Pranlukast (0.5 μM) caused a parallel rightward shift of the LTD₄ concentration-response curve with a pK_B of 7. Pranlukast did not inhibit ATP-induced ³⁵SO₄ output.
3. Ovalbumin (10–500 μg ml⁻¹) challenge of tracheae from guinea-pigs actively sensitized with ovalbumin caused a concentration-related increase in ³⁵SO₄ output with a maximal increase of 20 fold above vehicle controls at 200 μg ml⁻¹. The combination of the antihistamines pyrilamine and cimetidine (0.1 mM each) did not inhibit ovalbumin-induced ³⁵SO₄ output in sensitized guinea-pigs. Neither mucosal (10 μM or 100 μM) nor mucosal-serosal (100 μM) histamine had any significant effect on ³⁵SO₄ output.
4. Pranlukast or zafirlukast (5 μM each) significantly suppressed ovalbumin-induced secretion in tracheae from sensitized guinea-pigs by 70% and 65%, respectively.
5. We conclude that LTD₄ or ovalbumin challenge of sensitized animals provokes mucus secretion from guinea-pig trachea in vitro and this effect is inhibited by the CysLT₁ receptor antagonists pranlukast and zafirlukast. These antagonists may be beneficial in the treatment of allergic airway diseases in which mucus hypersecretion is a clinical symptom, for example asthma and allergic rhinitis.

     

Immunoglobulin E synthesis in parasite infection.

The infection of rats with Nippostrongylus brasiliensis (Nb) larvae enhanced IgE synthesis prior to the formation of IgE antibody specific for parasite antigens. As early as the eighth to tenth day of infection, IgE-bearing lymphocytes appeared in lymph nodes and spleen. At this time, even bone marrow contained IgE-bearing blast cells. The IgE-forming plasma cells were detected in the lymph nodes and spleen at the tenth day and their number reached maximum at the fourteenth day. The proliferation of IgE-bearing lymphocytes in the lymphoid tissues was observed in neonatally thymectomized animals, indicating that T cells are not essential for the development of IgE-B cells in the infected animals. It appears, however, that T cells are involved in the differentiation of IgE-B cells to IgE-forming plasma cells. Nonspecific proliferation of IgE-B cells and their differentiation to IgE-forming plasma cells may explain potentiation of IgE antibody formation against unrelated antigens after infection with N. brasiliensis (Nb). It was also found that T cells specific for parasite antigens were primed by infection with Nb. Evidence was obtained tht Nb-specific T cells raised by the infection collaborated with hapten-specific IgE-B cells and IgG-B cells for the secondary antihapten antibody responses. By contrast, T cells primed by immunization with parasite antigen included in alum exerted the helper function for IgG antibody response but failed to collaborate with IgE-B cells. Dissociation between the helper function for IgE and IgG antibody response indicated that parasite infection generated a favorable condition for priming T cells for the IgE antibody response.     

Antigen-presenting capacity of guinea pig B lymphocytes in T cell proliferative response in vitro

The capacity of normal (unprimed) B cells and keyhole-limpet-hemocyanin(KLH)-primed B cells to present the antigen KLH to KLH-primed T cells in the guinea pig was examined with in vitro assay of lymphocyte proliferative response. Antigen-pulsed B-lymphocyte population, extensively devoid of macrophages (M phi), induced the proliferative response of KLH-primed T lymphocytes, although less effectively than the peritoneal M phi. The antigen presentation was antigen-specific. There was no substantial difference between the magnitude of T-cell response induced by KLH-primed B-cell population and that stimulated by unprimed, normal B-cell population. The antigen-presenting capacity of the B-cell population was abrogated by pretreatment with anti-guinea pig immunoglobulin (Ig) or anti-I-region-associated (Ia) antigen antiserum and complement, whereas it was not affected with anti-guinea pig M phi antiserum and complement. From studies using strain 2 and strain 13 guinea pigs, histocompatibility requirement between antigen-pulsed B cells and antigen-reactive T cells was suggested: B lymphocytes, as well as M phi, did elicit proliferative response to specific antigen, KLH or purified protein derivative of tuberculin (PPD), in syngeneic, but not in allogeneic, T cells. These results suggest that the Ia-positive, surface-Ig-bearing guinea-pig B lymphocytes - not only KLH-primed B cells but also unprimed B cells - are capable of presenting antigen to primed T cells in a major histocompatibility complex(MHC)-restricted fashion.     

In utero exposure to second‐hand smoke activates pro‐asthmatic and oncogenic miRNAs in adult asthmatic mice

Exposures to environmental pollutants contribute to dysregulated microRNA (miRNA) expression profiles, which have been implicated in various diseases. Previously, we reported aggravated asthmatic responses in ovalbumin (OVA)‐challenged adult mice that had been exposed in utero to second‐hand smoke (SHS). Whether in utero SHS exposure dysregulates miRNA expression patterns in the adult asthma model has not been investigated. Pregnant BALB/c mice were exposed (days 6–19 of pregnancy) to SHS (10 mg/m³) or HEPA‐filtered air. All offspring were sensitized and challenged with OVA (19–23 weeks) before sacrifice. RNA samples extracted from lung homogenates, were subjected to RNA sequencing (RNA‐seq). RNA‐seq identified nine miRNAs that were most significantly up‐regulated by in utero SHS exposure. Among these nine, miR‐155‐5p, miR‐21‐3p, and miR‐18a‐5p were also highly correlated with pro‐asthmatic Th2 cytokine levels in bronchoalveolar lavage fluid. Further analysis indicated that these up‐regulated miRNAs shared common chromosome locations, particularly Chr 11C, with pro‐asthmatic genes. These three miRNAs have also been characterized as oncogenic miRNAs (oncomirs). We cross‐referenced miRNA‐mRNA expression profiles and identified 16 tumor suppressor genes that were down‐regulated in the in utero‐exposed offspring and that are predicted targets of the up‐regulated oncomirs. In conclusion, in utero SHS exposure activates pro‐asthmatic genes and miRNAs, which colocalize at specific chromosome locations, in OVA‐challenged adult mice. The oncogenic characteristics of the miRNAs and putative miRNA‐mRNA regulatory networks suggest that the synergistic effect of in utero SHS exposure and certain adult irritants may promote an oncogenic milieu in mouse lungs via inhibition of miRNA‐regulated tumor suppressor genes. Environ. Mol. Mutagen. 57:190–199, 2016. © 2016 Wiley Periodicals, Inc.     

IgA directly inhibits antigen-dependent B cell activation following distinctive distribution of the antigen in mice

Context: Serum IgA suppresses immune responses when exposed to antigens recognized by the antibody; however, the underlying mechanism remains unclear.

Objective: We herein clarified the relationships between changes in antigen distribution and antigen-dependent B cell activation in the presence or absence of IgA against the antigen in mice.

Materials and methods: DBA/1J and HR-1 mice were intravenously injected with ovalbumin (OVA) and anti-OVA monoclonal IgA OA-4. The distribution of the antigen and B cell responses were measured.

Results: B cell activation by injected OVA, namely, increases in anti-OVA IgG production and the populations of B220⁺GL7⁺ and B220⁺CD69^high splenocytes, was diminished by the co-injection of OA-4. Co-injected OA-4 increased OVA in the serum as well as in the bile and gut. This was coincident with its decrease in the urine due to the inhibition of OVA monomer secretion through the formation of immune complexes. The apparent similarities in the association between fluorescein isothiocyanate (FITC)-OVA and splenic B cells in the presence and absence of OA-4 in vivo appeared to be attributed to compensation between the two effects of OA-4; an increase in serum OVA in vivo and inhibition of the association between OVA and B cells, as suggested by in vitro experiments.

Discussion: Based on these results, the stimulation of B cells by OVA may be directly reduced, at least partly, by the neutralization of OVA by OA-4.

Conclusion: IgA may be an effective drug for the treatment of immune disorders due to its ability to blunt antigen-specific B cell activation.     

Detection of IgA antibodies to cat, β-lactoglobulin, and ovalbumin allergens in human milk

Background: The relationship between the development of allergy during infancy and breast-feeding remains controversial. This controversy may be due to individual variations in the composition of human milk. Antibodies to food antigens to which the mother is commonly exposed are present in the milk, but their relationship to allergy is still unknown. IgA antibodies to inhalant allergens have not been previously detected. Objective: Our purpose was to analyze secretory IgA antibody levels to cat, β-lactoglobulin, and ovalbumin allergens in colostrum and mature milk in relation to maternal allergy. Methods: Colostrum and samples of mature milk were obtained after 1 and 3 months of lactation from 53 nursing mothers (17 allergic and 36 nonallergic mothers) and were analyzed for total secretory IgA levels by ELISA and secretory IgA antibodies to cat, β-lactoglobulin, and ovalbumin by an enzyme-amplified ELISA. The specificity of the assays was confirmed by inhibition experiments. Results: Secretory IgA to cat, β-lactoglobulin, and ovalbumin allergens were detected in colostrum as well as mature milk. The levels of secretory IgA to ovalbumin were lower in colostrum from allergic mothers with P = .016, whereas the levels to β-lactoglobulin and cat were similar in the 2 groups. IgA antibodies to ovalbumin were detected in 94% of the colostrum samples from allergic and in all samples from nonallergic mothers, in 82% and 96%, respectively at 1 month, and 53% and 65% at 3 months. Fewer samples had detectable secretory IgA antibodies to β-lactoglobulin than to ovalbumin and cat, and only 33% and 10% of the samples from the allergic and nonallergic mothers, respectively, remained positive at 3 months. All the allergic mothers had detectable IgA to cat in colostrum, whereas 83% and 73% of the samples were positive at 1 and 3 months. The corresponding numbers were 93%, 81%, and 81% in the nonallergic mothers (not significant). Conclusion: Even a low level of exposure of the mucosa (eg, by inhalant allergens) can induce antibody secretion into the milk, both in allergic and nonallergic mothers. (J Allergy Clin Immunol 2000;105:1236-40.)