IgG4-Related Fibrotic Diseases from an Immunological Perspective: Regulators out of Control?

Patients with autoimmune pancreatitis have a striking polyclonal elevation of total IgG4 in serum. This observation has been confirmed and extended to other fibrotic conditions (that are therefore called IgG4-related disease) but as yet remains unexplained. The affected tissue contains many IgG4-producing plasma cells embedded in a fibrotic matrix originating from activated mesenchymal (stellate) cells. We propose that the process results from an unusual interaction between two regulatory systems: the regulatory arm of the immune system (including Bregs) and the tissue repair regulatory components orchestrated by the activated stellate cell. This interaction results in ongoing mutual activation, generating TGFbeta, IL10, and vitamin D. This environment suppresses most immune reactions but stimulates the development of IgG4-producing plasma cells

Метаморфозы философской иронии: от Сократа к постмодерну

В статье исследуется генезис иронии как специфического метода философствования в контексте смены социокультурных парадигм. Показана связь между конкретно-историческими условиями развития философских идей и характером и направленностью иронизирования. Выявляются эвристическая, гносеологическая, аналитическая, медиационная и другие функции иронии в философском дискурсе.У статті досліджується генезис іронії як специфічного методу філософування в контексті зміни соціокультурних парадигм. Показано зв’язок між конкретно-історичними умовами розвитку філософських ідей і характером й спрямованістю іронізування. Виявляються евристична, гносеологічна, аналітична, медіаційна та інші функції іронії у філософському дискурсі.In the article genesis of irony is probed as a specific method of philosophizing in the context of changing of sociocultural paradigms. Intercommunication is shown between the concretely-historical terms of development of philosophical ideas and character and orientation of mocking. The heuristic, gnosiological, critical, analytical, mediational function of irony in philosophical discourse are revealed

Еволюція підходів до виділення факторів зміцнення конкурентних позицій підприємств

В статье исследовано развитие теоретической базы дисциплин, которые рассматривают конкурентное позиционирование предприятий. На основе обобщения дисциплинарных подходов к определению факторов укрепления конкурентных позиций предприятий выделено и охарактеризовано этапы развития последних. Сформулированы выводы относительно пригодности использования различных подходов для формирования адекватного современным условиям функционирования предприятий механизма достижения, поддержки и укрепления их конкурентных позиций.У статті досліджено розвиток теоретичної бази дисциплін, що розглядають конкурентне позиціонування підприємств. На основі узагальнення дисциплінарних підходів до визначення факторів зміцнення конкурентних позицій підприємств виділено та охарактеризовано етапи розвитку останніх. Сформульовано висновки відносно придатності використання різних підходів для формування адекватного сучасним умовам функціонування підприємств механізму досягнення, підтримки і зміцнення їх конкурентних позицій.Development of theoretical base of disciplines which examine the competition positioning is explored in the article. On the basis of generalization of disciplinary approaches to determination of factors of competition positions of enterprises it is selected and described the stages of development of it. Conclusions are formulated in relation to the fitness of the use of different approaches for forming of functioning of enterprises of mechanism of achievement, support and strengthening of their competition positions adequate to the modern terms

Mite and pet allergen levels in homes of children born to allergic and nonallergic parents: the PIAMA study.

The Prevention and Incidence of Asthma and Mite Allergy (PIAMA) study is a birth cohort study that investigates the influence of allergen exposure on the development of allergy and asthma in the first several years of life. The objectives of this study were to investigate the relationship between a family history of allergy and/or asthma and exposure of newborn children to mite and pet allergen and to study the influence of different home and occupant characteristics on mite allergen exposure. Dust was sampled from the child's mattress and the parental mattress at 3 months after birth of the index child and analyzed for mite and pet allergens. Subjects were divided in groups according to history of asthma and allergy in their parents, and allergen exposure was studied in the different groups. Cat allergen exposure was significantly lower on parental mattresses in families with allergic mothers, but dog allergen exposure was not different. Mite allergen exposure was lower on parental mattresses in families with allergic mothers. Use of mite allergen-impermeable mattress covers reduced mite allergen exposure. Some other characteristics such as age of home and mattress were also found to influence mite allergen exposure. Parental mattresses in homes of allergic mothers had lower cat and mite (but not dog) allergen loadings than mattresses in homes of nonallergic parents. Paternal (as opposed to maternal) allergy seemed to have little influence

Consensus Statement on the Pathology of IgG4-Related Disease

IgG4-related disease is a newly recognized fibro-inflammatory condition characterized by several features: a tendency to form tumefactive lesions in multiple sites; a characteristic histopathological appearance; and—often but not always—elevated serum IgG4 concentrations. An international symposium on IgG4-related disease was held in Boston, MA, on 4–7 October 2011. The organizing committee comprising 35 IgG4-related disease experts from Japan, Korea, Hong Kong, the United Kingdom, Germany, Italy, Holland, Canada, and the United States, including the clinicians, pathologists, radiologists, and basic scientists. This group represents broad subspecialty expertise in pathology, rheumatology, gastroenterology, allergy, immunology, nephrology, pulmonary medicine, oncology, ophthalmology, and surgery. The histopathology of IgG4-related disease was a specific focus of the international symposium. The primary purpose of this statement is to provide practicing pathologists with a set of guidelines for the diagnosis of IgG4-related disease. The diagnosis of IgG4-related disease rests on the combined presence of the characteristic histopathological appearance and increased numbers of IgG4+ plasma cells. The critical histopathological features are a dense lymphoplasmacytic infiltrate, a storiform pattern of fibrosis, and obliterative phlebitis. We propose a terminology scheme for the diagnosis of IgG4-related disease that is based primarily on the morphological appearance on biopsy. Tissue IgG4 counts and IgG4:IgG ratios are secondary in importance. The guidelines proposed in this statement do not supplant careful clinicopathological correlation and sound clinical judgment. As the spectrum of this disease continues to expand, we advocate the use of strict criteria for accepting newly proposed entities or sites as components of the IgG4-related disease spectrum

Structural Determinants of Unique Properties of Human IgG4-Fc

Human IgG4, normally the least abundant of the four subclasses of IgG in serum, displays a number of unique biological properties. It can undergo heavy-chain exchange, also known as Fab-arm exchange, leading to the formation of monovalent but bispecific antibodies, and it interacts poorly with FcγRII and FcγRIII, and complement. These properties render IgG4 relatively “non-inflammatory” and have made it a suitable format for therapeutic monoclonal antibody production. However, IgG4 is also known to undergo Fc-mediated aggregation and has been implicated in auto-immune disease pathology. We report here the high-resolution crystal structures, at 1.9 and 2.35 Å, respectively, of human recombinant and serum-derived IgG4-Fc. These structures reveal conformational variability at the CH3–CH3 interface that may promote Fab-arm exchange, and a unique conformation for the FG loop in the CH2 domain that would explain the poor FcγRII, FcγRIII and C1q binding properties of IgG4 compared with IgG1 and -3. In contrast to other IgG subclasses, this unique conformation folds the FG loop away from the CH2 domain, precluding any interaction with the lower hinge region, which may further facilitate Fab-arm exchange by destabilisation of the hinge. The crystals of IgG4-Fc also display Fc–Fc packing contacts with very extensive interaction surfaces, involving both a consensus binding site in IgG-Fc at the CH2–CH3 interface and known hydrophobic aggregation motifs. These Fc–Fc interactions are compatible with intact IgG4 molecules and may provide a model for the formation of aggregates of IgG4 that can cause disease pathology in the absence of antigen

A molecular sensitization map of European children reveals exposome- and climate-dependent sensitization profiles

BackgroundUnderstanding differences in sensitization profiles at the molecular allergen level is important for diagnosis, personalized treatment and prevention strategies in allergy. MethodsImmunoglobulin E (IgE) sensitization profiles were determined in more than 2800 sera from children in nine population-based cohorts in different geographical regions of Europe; north [BAMSE (Sweden), ECA (Norway)], west/central [PIAMA (the Netherlands), BiB (the United Kingdom), GINIplus (Germany)], and south [INMA Sabadell and Gipuzkoa (Spain) and ROBBIC Rome and Bologna (Italy)] using the MeDALL-allergen chip. ResultsSensitization to grass pollen allergen, Phl p 1, and to major cat allergen, Fel d 1, dominated in most European regions whereas sensitization to house dust mite allergens Der p 1, 2 and 23 varied considerably between regions and were lowest in the north. Less than half of children from Sabadell which has a hot and dry climate were sensitized to respiratory allergens, in particular house dust mite allergens as compared to Gipuzkoa nearby with a more humid climate. Peanut allergen Ara h 1 was the most frequently recognized class 1 food allergen in Northern/Western Europe, while the fruit allergens Pru p 3, Act d 1 and 2 were prominent in Southern and Western/Central Europe. Ves v 5-sensitization dominated in North and West/Central Europe. ConclusionWe show regional, exposome- and climate-dependent differences in molecular IgE-reactivity profiles in Northern, Western/Central and Southern Europe which may form a molecular basis for precision medicine-based approaches for treatment and prevention of allergy

Enrichment of Sialylated IgG by Lectin Fractionation Does Not Enhance the Efficacy of Immunoglobulin G in a Murine Model of Immune Thrombocytopenia

Intravenous immunoglobulin G (IVIg) is widely used against a range of clinical symptoms. For its use in immune modulating therapies such as treatment of immune thrombocytopenic purpura high doses of IVIg are required. It has been suggested that only a fraction of IVIg causes this anti immune modulating effect. Recent studies indicated that this fraction is the Fc-sialylated IgG fraction. The aim of our study was to determine the efficacy of IVIg enriched for sialylated IgG (IVIg-SA (+)) in a murine model of passive immune thrombocytopenia (PIT). We enriched IVIg for sialylated IgG by Sambucus nigra agglutinin (SNA) lectin fractionation and determined the degree of sialylation. Analysis of IVIg-SA (+) using a lectin-based ELISA revealed that we enriched predominantly for Fab-sialylated IgG, whereas we did not find an increase in Fc-sialylated IgG. Mass spectrometric analysis confirmed that Fc sialylation did not change after SNA lectin fractionation. The efficacy of sialylated IgG was measured by administering IVIg or IVIg-SA (+) 24 hours prior to an injection of a rat anti-mouse platelet mAb. We found an 85% decrease in platelet count after injection of an anti-platelet mAb, which was reduced to a 70% decrease by injecting IVIg (p<0.01). In contrast, IVIg-SA (+) had no effect on the platelet count. Serum levels of IVIg and IVIg-SA (+) were similar, ruling out enhanced IgG clearance as a possible explanation. Our results indicate that SNA lectin fractionation is not a suitable method to enrich IVIg for Fc-sialylated IgG. The use of IVIg enriched for Fab-sialylated IgG abolishes the efficacy of IVIg in the murine PIT model

A molecular sensitization map of European children reveals exposome- and climate-dependent sensitization profiles

BACKGROUND: Understanding differences in sensitization profiles at the molecular allergen level is important for diagnosis, personalized treatment and prevention strategies in allergy. METHODS: Immunoglobulin E (IgE) sensitization profiles were determined in more than 2800 sera from children in nine population-based cohorts in different geographical regions of Europe; north [BAMSE (Sweden), ECA (Norway)], west/central [PIAMA (the Netherlands), BiB (the United Kingdom), GINIplus (Germany)], and south [INMA Sabadell and Gipuzkoa (Spain) and ROBBIC Rome and Bologna (Italy)] using the MeDALL-allergen chip. RESULTS: Sensitization to grass pollen allergen, Phl p 1, and to major cat allergen, Fel d 1, dominated in most European regions whereas sensitization to house dust mite allergens Der p 1, 2 and 23 varied considerably between regions and were lowest in the north. Less than half of children from Sabadell which has a hot and dry climate were sensitized to respiratory allergens, in particular house dust mite allergens as compared to Gipuzkoa nearby with a more humid climate. Peanut allergen Ara h 1 was the most frequently recognized class 1 food allergen in Northern/Western Europe, while the fruit allergens Pru p 3, Act d 1 and 2 were prominent in Southern and Western/Central Europe. Ves v 5-sensitization dominated in North and West/Central Europe. CONCLUSION: We show regional, exposome- and climate-dependent differences in molecular IgE-reactivity profiles in Northern, Western/Central and Southern Europe which may form a molecular basis for precision medicine-based approaches for treatment and prevention of allergy