Maria N. Sato

Maternal–fetal interaction: preconception immunization in mice prevents neonatal sensitization induced by allergen exposure during pregnancy and breastfeeding

Allergen exclusion measures during pregnancy and lactation have been given consideration in studies of primary allergy prevention but complete avoidance of mother/neonatal allergen exposure has proven to be a difficult procedure. To evaluate a strategy to prevent allergen sensitization in early life in mice, we first established a neonatal model with ovalbumin sensitization through maternal allergen exposure during pregnancy or breastfeeding. The modulatory potential of preconception immunization was investigated on the neonatal development of subsequent allergic responses to maternal allergen exposure. Herein, we demonstrate that immunized mothers exposed to antigen during pregnancy or breastfeeding underwent intense vertical transmission of antibodies, including immunoglobulin G (IgG) in complex with ovalbumin and IgG1 antibody with anaphylactic function. It was further shown that maternal immunization efficiently decreased the passage of free antigens through breastfeeding and inhibited the enhanced IgE antibody response after postnatal antigen exposure. In addition, antenatal immunization decreased the antigen‐specific proliferative response of immunized neonates, in parallel with profound downmodulatory effects on both the activation and differentiation of T and B cells after a non‐specific stimulus and cytokine production. These findings showed that early life sensitization, subsequent to maternal allergen exposure during both the prenatal and postnatal periods, could be avoided by preventive vaccination of the mother.

Maternal immunization with ovalbumin prevents neonatal allergy development and up-regulates inhibitory receptor FcγRIIB expression on B cells

BackgroundPreconception allergen immunization prevents neonatal allergen sensitization in mice by a complex interaction between regulatory cells/factors and antibodies. The present study assessed the influence of maternal immunization with ovalbumin (OVA) on the immune response of 3 day-old and 3 week-old offspring immunized or non-immunized with OVA and evaluated the effect of IgG treatment during fetal development or neonatal period.ResultsMaternal immunization with OVA showed increased levels of FcγRIIb expression in splenic B cells of neonates, which were maintained for up to 3 weeks and not affected by additional postnatal OVA immunization. Maternal immunization also exerted a down-modulatory effect on both IL-4 and IFN-γ-secreting T cells and IL-4 and IL-12- secreting B cells. Furthermore, immunized neonates from immunized mothers showed a marked inhibition of antigen-specifc IgE Ab production and lowered Th2/Th1 cytokine levels, whereas displaying enhanced FcγRIIb expression on B cells. These offspring also showed reduced antigen-specific proliferative response and lowered B cell responsiveness. Moreover, in vitro evaluation revealed an impairment of B cell activation upon engagement of B cell antigen receptor by IgG from OVA-immunized mice. Finally, in vivo IgG transference during pregnancy or breastfeeding revealed that maternal Ab transference was able to increase regulatory cytokines, such as IL-10, in the prenatal stage; yet only the postnatal treatment prevented neonatal sensitization. None of the IgG treatments induced immunological changes in the offspring, as it was observed for those from OVA-immunized mothers.ConclusionMaternal immunization upregulates the inhibitory FcγRIIb expression on offspring B cells, avoiding skewed Th2 response and development of allergy. These findings contribute to the advancement of prophylactic strategies to prevent allergic diseases in early life.

The Role of Exercise in a Weight-Loss Program on Clinical Control in Obese Adults with Asthma A Randomized Controlled Trial

Rationale: Clinical control is difficult to achieve in obese patients with asthma. Bariatric surgery has been recommended for weight loss and to improve asthma control; however, the benefits of nonsurgical interventions have been poorly investigated. Objectives: To examine the effect of exercise training in a weight‐loss program on asthma control, quality of life, inflammatory biomarkers, and lung function. Methods: Fifty‐five obese patients with asthma were randomly assigned to either a weight‐loss program plus exercise (WL + E group, n = 28) or a weight‐loss program plus sham (WL + S group, n = 27), where the weight‐loss program included nutrition (caloric restriction) and psychological therapies. The WL + E group incorporated aerobic and resistance muscle training, whereas the WL + S group incorporated breathing and stretching exercises. Measurements and Main Results: The primary outcome was clinical improvement in asthma control over 3 months. Secondary outcomes included quality of life, lung function, body composition, aerobic capacity, muscle strength, and inflammatory/antiinflammatory biomarkers. After 3 months, 51 patients were analyzed. Compared with the WL + S group, the WL + E group demonstrated improved clinical control scores (median [25th to 75th percentile], −0.7 [−1.3 to −0.3] vs. −0.3 [−0.9 to 0.4]; P = 0.01) and greater weight loss (mean ± SD, −6.8% ± 3.5 vs. −3.1% ± 2.6; P < 0.001) and aerobic capacity (median [25th to 75th percentile], 3.0 [2.4 to 4.0] vs. 0.9 [−0.3 to 1.3] ml O2 × kg−1 × min−1; P < 0.001). These improvements in the WL + E group were also accompanied by improvements in lung function, antiinflammatory biomarkers, and vitamin D levels, as well as reductions in airway and systemic inflammation. Conclusions: Adding exercise to a short‐term weight‐loss program should be considered as a useful strategy for achieving clinical control of asthma in obese patients. Clinical trial registered with www.clinicaltrials.gov (NCT 02188940).

Distinct natural killer cells in HIV-exposed seronegative subjects with effector cytotoxic CD56(dim) and CD56(bright) cells and memory-like CD57⁺NKG2C⁺CD56(dim) cells.

Background:Innate immunity, including natural killer (NK) cells, may play a significant role in maintaining natural resistance to infection in highly HIV-exposed seronegative (HESN) subjects. The differences between NK-cell subsets, regarding their activating/maturing marker expression and their memory markers, in HESN subjects are not fully defined. Methods:We have conducted an analysis of the activating/memory markers and intracellular CD107a and interferon &ggr; (IFN-&ggr;) expression in NK-cell subsets from HESN and HIV-infected and healthy subjects. Results:HESN individuals showed an increased expression of activating markers, such as NKG2D in CD56bright and CD56dim NK cells, and an increased frequency of CD56brightCD127+ and fully mature CD56dimCD57+ NK cells compared with HIV-infected patients and healthy control subjects. Of note, HESN individuals showed an increased frequency of memory CD56dimCD57+ NK cells, and this is known to be expanded on cytomegalovirus infection, as evidenced by their high rate of cytomegalovirus seropositivity. Simultaneous expression of the CD94, NKG2A, NKG2C, and NKG2D receptors on CD56bright NK cells was detected in HESN subjects, whereas in the HIV-1 group, the expression of these 4 receptors was enhanced in CD56dim NK cells. It was also found that CD56bright and CD56dim NK cells in HESN subjects showed increased CD107a and/or IFN-&ggr; expression. Conclusions:The NK cells from HESN individuals presented a unique activation profile, with increased expression of NKG2D, CD107a, and IFN-&ggr; and “memory” CD57+CD56dim NK cells. The complex network of functional NK-cell activities in HESN individuals may be exploited for long-term protection through vaccination.

Single Session to Infrared Low Level Diode Laser on TNF-alpha. and IL-6 Cytokines Release by Mononuclear Spleen Cells in Mice: A Pilot Study

The results of low‐level infrared laser (LLL) systemic action on inflammatory modulation process, specifically diminishing pro‐inflammatory and producing anti‐inflammatory cytokines are extremely controversial in the literature. More studies are necessary to clarify the biomodulation process. The main objective was to investigate the effect of a single session of an AsGaAl laser on spleen cells interleukin‐6 (IL‐6) and tumor necrosis factor ‐ alpha (TNF‐α) release, in vivo, in mice.

Staphylococcal enterotoxin B induces specific IgG4 and IgE antibody serum levels in atopic dermatitis

Atopic dermatitis (AD) is a chronic recurrent inflammatory disease, with prevalence of about 10–20% in children and 1–3% in adults. Staphylococcus aureus is present in 80–100% of skin from atopic patients and is related to worsening of the disease by the action of enterotoxins. The aim of this study was to evaluate the profile of anti‐Staphylococcus aureus enterotoxin B (SEB) antibody isotypes and IgG subclass levels in adult AD.

CpG-Induced Th1-Type Response in the Downmodulation of Early Development of Allergy and Inhibition of B7 Expression on T Cells of Newborn Mice

IntroductionSeveral differences have been described between neonatal and adult immune responses. The predisposition in early life to Th2-type response or tolerance makes it a susceptible period for infections and allergic sensitization.ObjectiveThe aim of this work was to evaluate the effects of CpG-containing oligodeoxynucleotides on neonatal and adult immunization with ovalbumin and Blomia tropicalis extract and compare the CpG effects on B and T cells of neonatal and adult mice.Results and DiscussionMice that received CpG showed reduced immunoglobulin E (IgE) antibody production in both neonatal and adult periods, in parallel to increased IgG2a antibody levels. We observed that spleen cells of mice that received CpG in early life produced increased amounts of interferon-γ upon anti-CD3 stimulation. Negative regulation of IgE response was more pronounced in adult than neonate mice; further, CpG decreased anaphylactic antiovalbumin IgG1 only in adults. Also, an upregulation of toll-like receptor 9 expression was detected in adult B cells, but not in neonatal, upon CpG stimuli. Neonatal B cells showed enhanced interleukin (IL)-10 expression and decreased IL-6 levels than adult B cells in response to CpG. When we analyzed in vitro activation of CD4+ T cells, an increased expression of B7 molecules on T cells in neonates was suppressed by CpG.ConclusionAltogether, we verified qualitative and quantitative evidences regarding CpG effect on neonatal and adult allergens immunizations, which points to the importance of understanding neonatal immune system to establish immunomodulatory strategies for prevention of allergic diseases.

Increased frequency of circulating Tc22/Th22 cells and polyfunctional CD38 − T cells in HIV-exposed uninfected subjects

Some individuals are resistant to HIV-1 infection despite repeated exposure to the virus, suggesting the presence of a complex antiviral response. Innate factors like IL-22 exert gut mucosal protection and polyfunctional T cells have been associated with low progression in HIV infection; therefore, we evaluated the frequencies of CD4+ and CD8+ T cell-secreting cytokines, including Tc22/Th22 cells and polyfunctional T cells in HIV-1-exposed uninfected individuals (EUs), their HIV-1-infected partners and healthy controls. EUs exhibited an increased frequency of p15 Gag CD4+ IL-22+ secreting T cells, whereas HIV-infected partners demonstrated a high frequency of CD4+ IL-17+ T cells in response to p24. Similar responses of Th22 and Tc22 cells to Gag peptides and Staphylococcal enterotoxin B (SEB) stimulation were detected in the serodiscordant couples. However, polyfunctionality in HIV subjects was associated with an HIV Gag response of CD38+ T cells, whereas polyfunctionality for EUs was induced upon SEB stimulation by CD38- T cells. EUs demonstrated the presence of Tc22/Th22 cells and polyfunctional CD38- T cells with a low activation profile. These data suggest that SEB-induced polyfunctional CD4+ and CD8+ T cells together with Tc22/Th22 cells in EU individuals can provide an immunological advantage in the response to pathogens such as HIV-1.

The spider acylpolyamine Mygalin is a potent modulator of innate immune responses

Mygalin is an antibacterial molecule isolated from the hemocytes of the spider Acanthoscurria gomesiana. It was identified as bis-acylpolyamine spermidine. We evaluated the modulator effects of synthetic Mygalin in the innate immune response. We demonstrate that Mygalin induces IFN-γ synthesis by splenocytes increasing the nitrite secretion by splenocytes and macrophages. A specific inhibitor of iNOS abrogated Mygalin-induced nitrite production in macrophages independent of IFN-γ activation. In addition, Mygalin-activated macrophages produced TNF-α but not IL-1β, demonstrating that Mygalin does not act directly on the inflammasome. Furthermore, this compound did not affect spontaneous or Concanavalin A-induced proliferative responses by murine splenocytes and did not induce IL-5 or apoptosis of splenocytes or bone marrow-derived macrophages. These data provide evidence that Mygalin modulates the innate immune response by inducing IFN-γ and NO synthesis. The combined immune regulatory and antibacterial qualities of Mygalin should be explored as a strategy to enhance immune responses in infection.

Polyfunctional natural killer cells with a low activation profile in response to Toll-like receptor 3 activation in HIV-1-exposed seronegative subjects

Natural killer (NK) cells are the main mediator of the cytotoxic response in innate immunity and may be involved in resistance to HIV-1 infection in exposed seronegative (ESN) individuals. Toll-like receptor (TLR) signalling is crucial for NK cell activation. Here, we investigated the polyfunctional NK cell response to TLR3 activation in serodiscordant couples. ESN subjects showed increased IFN-γ and CD107a expression in both NK subsets, CD56bright and CD56dim cells, in response to stimulation with a TLR3 agonist, while expression was impaired in the HIV-1-infected partners. TLR3-induced expression of IFN-γ, TNF and CD107a by polyfunctional CD56bright NK cells was more pronounced in ESN individuals than that in healthy controls. Activated NK cells, as determined by CD38 expression, were increased only in the HIV-1-infected partners, with reduced IFN-γ and CD107a expression. Moreover, CD38+ NK cells of the HIV-1-infected partners were associated with increased expression of inhibitory molecules, such as NKG2A, PD-1 and Tim-3, while NK cells from ESN subjects showed decreased NKG2A expression. Altogether, these findings indicate that NK cells of ESN individuals were highly responsive to TLR3 activation and had a polyfunctional NK cell phenotype, while the impaired TLR3 response in HIV-1-infected partners was associated with an inhibitory/exhaustion NK cell phenotype.