Mechanism underlying polyvalent IgG-induced regulatory T cell activation and its clinical application: Anti-idiotypic regulatory T cell theory for immune tolerance

The regulatory T (Treg) cells constitute a functionally defined subpopulation of T cells that modulate the immune system and maintain immune tolerance through suppression of the development of autoimmune responses to self-antigens and allergic reactions to external antigens. Reduction in the number or function of Treg cells has been suggested as a key immune abnormality underlying the development of autoimmune and allergic diseases. In vitro studies have demonstrated that purified polyvalent immunoglobulin G (IgG) from multiple healthy blood donors can exert immunomodulatory effects on Treg cells. Incubation of polyvalent human IgG with purified CD4+CD25high T cells increased the intracellular expression of interleukin (IL)-10. Intravenous administration of polyvalent human IgG induced significant expansions of CD4+ Foxp3+ Treg cells and clinical improvements in patients with autoimmune diseases. In human clinical trials, intramuscular administration of autologous total IgG significantly increased the percentage of IL-10-producing CD4+ Treg cells in the peripheral blood of healthy subjects and provided significant clinical improvements in patients with atopic dermatitis. These results suggest a clinical usefulness of polyvalent IgG-induced activation of Treg cells in human subjects. This review proposes a new hypothesis for immune tolerance mechanism by integrating the pre-existing “idiotypic network theory” and “Treg cell theory” into an “anti-idiotypic Treg cell theory.” Based on this hypothesis, an “active anti-idiotypic therapy” for allergic and autoimmune diseases using autologous polyvalent IgG (as immunizing antigens) is suggested as follows: (1) Intramuscular or subcutaneous administration of autologous polyvalent IgG produces numerous immunogenic peptides derived from idiotypes of autologous IgG through processing of dendritic cells, and these peptides activate anti-idiotypic Treg cells in the same subject. (2) Activated anti-idiotypic Treg cells secrete IL-10 and suppress Th2 cell response to allergens and autoimmune T cell response to self-antigens. (3) These events can induce a long-term clinical improvements in patients with allergic and autoimmune diseases. Further studies are needed to evaluate the detailed molecular mechanism underlying polyvalent IgG-induced Treg cell activation and the clinical usefulness of this immunomodulatory therapy for autoimmune and allergic diseases

Inibição da resposta de hipersensibilidade do Tipo I da prole de camundongos mediada pela imunização materna com o ácaro Dermatophagoides pteronyssinus

The early life exposure to allergens associated with the tendency of newborns to develop Th2-biased responses, may contribute to the development of allergy during infancy. The effect of preconception immunization of A/Sn females with the dust mite Dermatophagoides pteronyssinus (Dp), were analysed on the hybrid offspring’s type I hypersensitivity response. The kinetics of Dp immunization was followed from newborn to adult age. Offspring from immune mothers did not show evidence of pre or postnatal allergen priming at humoral level. Immunization with Dp in very early life and in the postweaning period revealed a marked inhibition of offspring anti-Dp IgE and IgG1 Ab production, which remained decreased upon secondary allergenic challenge. The maternal influence on the offspring’s Ab response was specific to Dp, since their immunization with a heterologous antigen led to a normal IgE response. Taken together, maternal immunization to Dp seems to be protective in regard to the early development of allergy.A exposição precoce a alérgenos associada a tendência dos neonatos a desenvolverem respostas do tipo Th2 pode contribuir com o desenvolvimento da alergia durante a infância. O efeito da imunização de camundongos fêmeas A/Sn pré concepção com o ácaro Dermatophagoides pteronyssinus (Dp), foi analisado na resposta de hipersensibilidade tipo I da prole híbrida. A cinética da imunização dos filhotes com Dp foi avaliada da idade neonatal até a adulta. As proles de mães imunes não demonstraram evidência de sensibilização pré ou pós natal ao alérgeno pela análise dos alótipos de anticorpos. A imunização com Dp das proles derivadas de mães imunizadas no período neonatal e após o desmame revelou uma significativa inibição da produção de anticorpos IgE e IgG1 anti-Dp, permanecendo diminuída mesmo após os desafios alergênicos secundários. A inibição da resposta foi específica para o Dp considerando que a imunização com antígeno heterólogo induziu similar produção de anticorpos IgE ao grupo de proles controles. A imunização materna com Dp sugere proteger o desenvolvimento precoce de alergia nos filhotes

Reatividade cutânea a alérgenos alimentares em habitantes da cidade de São Paulo: uma possível relação com animais domésticos

Introduction: Allergic hypersensitivity reaction to food proteins (food allergies) is a major public health problem. This type of reaction can affect the quality of life and its treatment entails high costs. Aim: In this study, we aimed to identify the pattern of skin allergic reactivity of volunteers to inform them about their potential for the development of food allergies and to identify factors that may be related to this type of allergy. Methods: With this purpose, 35 volunteers residing in the city of São Paulo were submitted to the prick-test and a socio-demographic interview. Individual skin reactivity was tested against allergens with origin in milk, eggs, Brazil nuts, peanuts, shrimp, and pork. Results: It was possible to verify that the food allergen that presented the highest frequency of reactivity was the shrimp followed by pork, milk, egg, Brazil nuts, and peanuts. In addition, we found that volunteers are mainly reactive to only one allergen and are not aware of their potential for developing food allergies. Finally, we observed that the number of pets may be related to the individual allergic potential. Conclusions: In conclusion, it was possible to update the description of the food allergic reactivity profile in individuals living in the city of São Paulo and to suggest an unprecedented relationship with the number of pets.Fundamentos: As reações alérgicas contra proteínas alimentares constituem um problema de saúde pública que tem se agravado em todo o mundo. Este tipo de reação afeta a qualidade de vida e seu tratamento implica em altos custos. Objetivos: Neste trabalho, objetivamos identificar o padrão de reatividade alérgica cutânea de indivíduos voluntários residentes na cidade de São Paulo e identificar fatores sociodemográficos que possam ter relação com este tipo de alergia. Metodologia: 35 voluntários foram submetidos ao teste cutâneo de puntura (TCP) e a um questionário sócio demográfico. Foi testada a reatividade cutânea contra alérgenos do leite, ovos, castanha, amendoim, camarão e carne suína. Principais resultados: Foi possível constatar que o alérgeno que apresentou maior frequência de reatividade foi o camarão seguido por carne suína, leite, ovo, castanha do Pará e amendoim.  Além disso, constatamos que geralmente os voluntários apresentam reatividade a apenas um alérgeno e que não tem conhecimento sobre seu potencial para desenvolver alergias alimentares. Por fim, ainda observamos que a quantidade de animais domésticos pode estar relacionada ao potencial alérgico individual. Conclusões: Em conclusão, foi possível atualizar a descrição do perfil de reatividade alérgica alimentar em indivíduos residentes na cidade de São Paulo e sugerir uma inédita relação com a quantidade de animais domésticos

Maternal immunization with ovalbumin or Dermatophagoides pteronyssinus has opposing effects on FcγRIIb expression on offspring B cells

Abstract\ud \ud Background\ud Over the last decade, our group has demonstrated that murine preconception immunization with allergens has a protective effect on allergy development in offspring. The murine model used in the present study allowed us to compare allergy induction by ovalbumin (OVA) and dust mite extract from Dermatophagoides pteronyssinus (Dp).\ud \ud \ud Findings\ud Female mice were immunized with OVA or Dp. Pups from immunized and non-immune mothers were immunized at 3 days old (do) with the same antigen used for the maternal immunization. The offspring were analyzed at 20 do. Preconceptional immunization with OVA or Dp did not increase maternal IgE serum levels, although the immunizations induced an increase in allergen-specific IgG1 Ab levels. Offspring serum analyses revealed that maternal immunization with OVA suppressed IgE production only in offspring immunized with OVA. Both preconception immunization protocols inhibited cellular influx into the airways of immunized offspring compared with controls. Similar frequencies of offspring IgM + B cells were found in the OVA- and Dp-immunized groups compared with their respective control groups. Moreover, preconception immunization with OVA enhanced FcγRIIb expression on OVA-immunized offspring B cells. In contrast, decreased FcγRIIb expression was detected on Dp-immunized offspring B cells compared with cells from the offspring of non-immune mothers.\ud \ud \ud Conclusions\ud Together, these results show that preconception OVA immunization and Dp immunization can inhibit allergy development but have opposite effects on FcγRIIb expression on offspring B cells.The authors would like to thank the Fundação de Amparo à Pesquisa\ud de São Paulo (FAPESP 2010/13262-5) and the LIM HC-FMUSP for their\ud financial support

Azimuthal anisotropy of charged jet production in root s(NN)=2.76 TeV Pb-Pb collisions

We present measurements of the azimuthal dependence of charged jet production in central and semi-central root s(NN) = 2.76 TeV Pb-Pb collisions with respect to the second harmonic event plane, quantified as nu(ch)(2) (jet). Jet finding is performed employing the anti-k(T) algorithm with a resolution parameter R = 0.2 using charged tracks from the ALICE tracking system. The contribution of the azimuthal anisotropy of the underlying event is taken into account event-by-event. The remaining (statistical) region-to-region fluctuations are removed on an ensemble basis by unfolding the jet spectra for different event plane orientations independently. Significant non-zero nu(ch)(2) (jet) is observed in semi-central collisions (30-50% centrality) for 20 <p(T)(ch) (jet) <90 GeV/c. The azimuthal dependence of the charged jet production is similar to the dependence observed for jets comprising both charged and neutral fragments, and compatible with measurements of the nu(2) of single charged particles at high p(T). Good agreement between the data and predictions from JEWEL, an event generator simulating parton shower evolution in the presence of a dense QCD medium, is found in semi-central collisions. (C) 2015 CERN for the benefit of the ALICE Collaboration. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Peer reviewe

Forward-central two-particle correlations in p-Pb collisions at root s(NN)=5.02 TeV

Two-particle angular correlations between trigger particles in the forward pseudorapidity range (2.5 2GeV/c. (C) 2015 CERN for the benefit of the ALICE Collaboration. Published by Elsevier B. V.Peer reviewe

Event-shape engineering for inclusive spectra and elliptic flow in Pb-Pb collisions at root(NN)-N-S=2.76 TeV

Peer reviewe

Pseudorapidity and transverse-momentum distributions of charged particles in proton-proton collisions at root s=13 TeV

The pseudorapidity (eta) and transverse-momentum (p(T)) distributions of charged particles produced in proton-proton collisions are measured at the centre-of-mass energy root s = 13 TeV. The pseudorapidity distribution in vertical bar eta vertical bar <1.8 is reported for inelastic events and for events with at least one charged particle in vertical bar eta vertical bar <1. The pseudorapidity density of charged particles produced in the pseudorapidity region vertical bar eta vertical bar <0.5 is 5.31 +/- 0.18 and 6.46 +/- 0.19 for the two event classes, respectively. The transverse-momentum distribution of charged particles is measured in the range 0.15 <p(T) <20 GeV/c and vertical bar eta vertical bar <0.8 for events with at least one charged particle in vertical bar eta vertical bar <1. The evolution of the transverse momentum spectra of charged particles is also investigated as a function of event multiplicity. The results are compared with calculations from PYTHIA and EPOS Monte Carlo generators. (C) 2015 CERN for the benefit of the ALICE Collaboration. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Peer reviewe

Elliptic flow of muons from heavy-flavour hadron decays at forward rapidity in Pb-Pb collisions at root s(NN)=2.76TeV

The elliptic flow, v(2), of muons from heavy-flavour hadron decays at forward rapidity (2.5 <y <4) is measured in Pb-Pb collisions at root s(NN)= 2.76TeVwith the ALICE detector at the LHC. The scalar product, two- and four-particle Q cumulants and Lee-Yang zeros methods are used. The dependence of the v(2) of muons from heavy-flavour hadron decays on the collision centrality, in the range 0-40%, and on transverse momentum, p(T), is studied in the interval 3 <p(T)<10 GeV/c. A positive v(2) is observed with the scalar product and two-particle Q cumulants in semi-central collisions (10-20% and 20-40% centrality classes) for the p(T) interval from 3 to about 5GeV/c with a significance larger than 3 sigma, based on the combination of statistical and systematic uncertainties. The v(2) magnitude tends to decrease towards more central collisions and with increasing pT. It becomes compatible with zero in the interval 6 <p(T)<10 GeV/c. The results are compared to models describing the interaction of heavy quarks and open heavy-flavour hadrons with the high-density medium formed in high-energy heavy-ion collisions. (C) 2015 CERN for the benefit of the ALICE Collaboration. Published by Elsevier B.V.Peer reviewe

Regulatory mechanisms involved on the offspring type I hypersensitivity response inhibition mediated by maternal immunixation with OVA.

Avaliamos os mecanismos regulatórios desencadeados pela imunização materna na resposta alérgica da prole OVA. A imunização materna com OVA promoveu alterações como o aumento da expressão dos receptores FcgRIIb nos linfócitos B esplênicos dos neonatos aos 3 dias de idade (d.i.), o que se manteve até os 20 d.i. Com a imunização das proles no período neonatal a imunização materna inibiu a produção de anticorpos IgE anti-OVA. Além disso, foi observado na população de linfócitos B da prole o aumento da expressão dos receptores FcgRIIb e CD44. A transferência passiva de IgG de mães imunes no pós-natal mostrou uma inibição da produção de IgE, e no período pré-natal foi capaz de reduzir a expressão das moléculas CD40 e CD23 nos linfócitos B e a secreção de IL-10 em linfócitos T CD4 na prole no período neonatal. As evidências mostram que a imunização pré-concepcional com OVA induz mecanismos que regulam a resposta IgE da prole imunizada no período neonatal, o que foi parcialmente observado com a transferência passiva de anticorpos IgG durante o período pré e pós-natal.To evaluate the regulatory mechanisms triggered by maternal immunization in the immune response of the offspring, the effect of preconceptional immunization with OVA was evaluated. Maternal immunization with OVA led to early alteration with increased expression of FcgRIIb in B lymphocytes from 3 days old pups. Offspring from immune mother showed diminished percentage of CD4 T cells IL-4+. The immunization of offspring during neonatal period showed that maternal immunization inhibits the production of anti-OVA IgE antibodies. The evaluation of CD4 T cell population revealed diminished IL-4+ cells. Passive IgG transfer from immune mother during neonatal period showed inhibition in the IgE synthesis, during pregnancy showed capacity to reduce the expression of CD40 molecules in B cells from neonatal pups. These evidences show that maternal OVA immunization down regulates the IgE response of offspring including phenotypic and functional alteration in B and CD4 T cells. These alterations were partially observed with IgG transfer during pregnancy or after birth