Authors Jan L. Brozek, MD, PhD – Department of Clinical Epidemiology & Biostatistics and Medicine, McMaster University, Hamilton, Canada Jean Bousquet, MD, PhD – Service des Maladies Respiratoires, Hopital Arnaud de Villeneuve, Montpellier, France, INSERM, CESP U1018, Respiratory and Environmental Epidemiology Team, France, and WHO Collaborating Center for Rhinitis and Asthma Carlos E. Baena-Cagnani, MD – Faculty of Medicine, Catholic University of Cordoba, Cordoba, Argentina Sergio Bonini, MD – Institute of Neurobiology and Molecular Medicine – CNR, Rome, Italy and Department of Medicine, Second University of Naples, Naples, Italy G. Walter Canonica, MD – Allergy & Respiratory Diseases, DIMI, Department of Internal Medicine, University of Genoa, Genoa, Italy Thomas B. Casale, MD – Division of Allergy and Immunology, Department of Medicine, Creighton University, Omaha, Nebraska, USA Roy Gerth van Wijk, MD, PhD – Section of Allergology, Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, the Netherlands Ken Ohta, MD, PhD – Division of Respiratory Medicine and Allergology, Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan Torsten Zuberbier, MD – Department of Dermatology and Allergy, Charite Universitatsmedizin Berlin, Berlin, Germany Holger J. Schunemann, MD, PhD, MSc – Department of Clinical Epidemiology & Biostatistics and Medicine, McMaster University, Hamilton, Canada

/pdf/allergic-rhinitis-and-its-impact-on-asthma-20b4c7y0pr.pdf

Allergic Rhinitis and Its Impact on Asthma

In addition to their role in binding antigen, antibodies can regulate immune responses through interacting with Fc receptors (FcRs). In recent years, significant progress has been made in understanding the mechanisms that regulate the activity of IgG antibodies in vivo. In this Review, we discuss recent studies addressing the multifaceted roles of FcRs for IgG (FcgammaRs) in the immune system and how this knowledge could be translated into novel therapeutic strategies to treat human autoimmune, infectious or malignant diseases.

/pdf/fcg-receptors-as-regulators-of-immune-responses-46isonwygz.pdf

Fcγ receptors as regulators of immune responses

IgE, mast cells, basophils, and eosinophils are essential components of allergic inflammation. Antigen-specific IgE production, with subsequent fixation of IgE to FceRI receptors on mast cells and basophils, is central to the initiation and propagation of immediate hypersensitivity reactions. Mast cells, basophils, and eosinophils are central effector cells in allergic inflammation, as well as in innate and adaptive immunity. This review highlights what is known about these components and their roles in disease pathogenesis.

/pdf/ige-mast-cells-basophils-and-eosinophils-2he7mbn0j1.pdf

IgE, Mast Cells, Basophils, and Eosinophils

Immunoglobulins are the major secretory products of the adaptive immune system. Each is characterized by a distinctive set of glycoforms that reflects the wide variation in the number, type, and location of their oligosaccharides. In a given physiological state, glycoform populations are reproducible; therefore, disease-associated alterations provide diagnostic biomarkers (e.g., for rheumatoid arthritis) and contribute to disease pathogenesis. The oligosaccharides provide important recognition epitopes that engage with lectins, endowing the immunoglobulins with an expanded functional repertoire. The sugars play specific structural roles, maintaining and modulating effector functions that are physiologically relevant and can be manipulated to optimize the properties of therapeutic antibodies. New molecular models of all the immunoglobulins are included to provide a basis for informed and critical discussion. The models were constructed by combining glycan sequencing data with oligosaccharide linkage and dynamics information from the Glycobiology Institute experimental database and protein structural data from "The Protein Data Bank."

The Impact of Glycosylation on the Biological Function and Structure of Human Immunoglobulins

T cell recognition of antigen-presenting cells depends on their expression of a spectrum of peptides bound to major histocompatibility complex class I (MHC-I) and class II (MHC-II) molecules. Conversion of antigens from pathogens or transformed cells into MHC-I- and MHC-II-bound peptides is critical for mounting protective T cell responses, and similar processing of self proteins is necessary to establish and maintain tolerance. Cells use a variety of mechanisms to acquire protein antigens, from translation in the cytosol to variations on the theme of endocytosis, and to degrade them once acquired. In this review, we highlight the aspects of MHC-I and MHC-II biosynthesis and assembly that have evolved to intersect these pathways and sample the peptides that are produced.

Pathways of Antigen Processing

The molecular defect leading to Fabry disease: structure of human alpha-galactosidase.

The initiation of immunoglobulin-E (IgE)-mediated allergic responses requires the binding of IgE antibody to its high-affinity receptor, FceRI. Crosslinking of FceRI initiates an intracellular signal transduction cascade that triggers the release of mediators of the allergic response. The interaction of the crystallizable fragment (Fc) of IgE (IgE-Fc) with FceRI is a key recognition event of this process and involves the extracellular domains of the FceRI α-chain. To understand the structural basis for this interaction, we have solved the crystal structure of the human IgE-Fc–FceRIα complex to 3.5-A resolution. The crystal structure reveals that one receptor binds one dimeric IgE-Fc molecule asymmetrically through interactions at two sites, each involving one Ce3 domain of the IgE-Fc. The interaction of one receptor with the IgE-Fc blocks the binding of a second receptor, and features of this interaction are conserved in other members of the Fc receptor family. The structure suggests new approaches to inhibiting the binding of IgE to FceRI for the treatment of allergy and asthma.

Structure of the Fc fragment of human IgE bound to its high-affinity receptor Fc epsilonRI alpha.

http://people.biochem.umass.edu/hebertlab/Lab%20Pubs/hebert%20et%20al%20TCB%202005.pdf

The glycan code of the endoplasmic reticulum: asparagine-linked carbohydrates as protein maturation and quality-control tags

Background. Fabry disease is an underdiagnosed, treatable, X-linked, multisystem disorder. Objectives. To test the hypothesis that quality of life and sweating are decreased among pediatric patients with Fabry disease, compared with control subjects, and to provide quantitative natural history data and novel clinical end points for therapeutic trials. Design. Prospective, cross-sectional, observational study. Setting. Referral to the National Institutes of Health. Participants. Twenty-five male children with Fabry disease (mean age: 12.3 ± 3.5 years) and 21 age-matched control subjects. Main Outcome Measures. Quality of life (measured with the Child Health Questionnaire) and sweating (assessed with the quantitative sudomotor axon reflex test). Results. Quality of life scores for pediatric patients 51 g/m2.7) were localized near the catalytic site of the enzyme. Conclusions. Despite the absence of major organ dysfunction, Fabry disease demonstrates significant morbidity already in childhood. We have identified important, potentially correctable or preventable, outcome measures for future therapeutic trials. Prevention of complications involving major organs should be the goal for long-term specific therapy.

https://pediatrics.aappublications.org/content/pediatrics/115/3/e344.full.pdf

Pediatric Fabry disease.

https://www.cell.com/cell/pdf/S0092-8674(00)81719-5.pdf

Scott C. Garman

Papers

The molecular defect leading to Fabry disease: structure of human alpha-galactosidase.

Structure of the Fc fragment of human IgE bound to its high-affinity receptor Fc epsilonRI alpha.

The glycan code of the endoplasmic reticulum: asparagine-linked carbohydrates as protein maturation and quality-control tags

Pediatric Fabry disease.

Crystal structure of the human high-affinity IgE receptor.