Marek Jutel

Classification and prediction of clinical Alzheimer's diagnosis based on plasma signaling proteins

A molecular test for Alzheimers disease could lead to better treatment and therapies. We found 18 signaling proteins in blood plasma that can be used to classify blinded samples from Alzheimers and control subjects with close to 90% accuracy and to identify patients who had mild cognitive impairment that progressed to Alzheimers disease 2–6 years later. Biological analysis of the 18 proteins points to systemic dysregulation of hematopoiesis, immune responses, apoptosis and neuronal support in presymptomatic Alzheimers disease.

Histamine regulates T-cell and antibody responses by differential expression of H1 and H2 receptors

Many pathological processes, including those causing allergies and autoimmune diseases, are associated with the presence of specialized subsets of T helper cells (TH1 and TH2) at the site of inflammation. The diversity of TH1 and TH2 function is not predetermined but depends on signals that drive the cells towards either subset. Histamine, released from effector cells (mast cells and basophils) during inflammatory reactions can influence immune response. Here we report that histamine enhances TH1-type responses by triggering the histamine receptor type 1 (H1R), whereas both TH1- and TH2-type responses are negatively regulated by H2R through the activation of different biochemical intracellular signals. In mice, deletion of H1R results in suppression of interferon (IFN)-γ and dominant secretion of TH2 cytokines (interleukin (IL)-4 and IL-13). Mutant mice lacking H2R showed upregulation of both TH1 and TH2 cytokines. Relevant to T-cell cytokine profiles, mice lacking H1R displayed increased specific antibody response with increased immunoglobulin-ε (IgE) and IgG1, IgG2b and IgG3 compared with mice lacking H2R. These findings account for an important regulatory mechanism in the control of inflammatory functions through effector-cell-derived histamine.

Anaphylaxis: guidelines from the European Academy of Allergy and Clinical Immunology

Anaphylaxis is a clinical emergency, and all healthcare professionals should be familiar with its recognition and acute and ongoing management. These guidelines have been prepared by the European Academy of Allergy and Clinical Immunology (EAACI) Taskforce on Anaphylaxis. They aim to provide evidence‐based recommendations for the recognition, risk factor assessment, and the management of patients who are at risk of, are experiencing, or have experienced anaphylaxis. While the primary audience is allergists, these guidelines are also relevant to all other healthcare professionals. The development of these guidelines has been underpinned by two systematic reviews of the literature, both on the epidemiology and on clinical management of anaphylaxis. Anaphylaxis is a potentially life‐threatening condition whose clinical diagnosis is based on recognition of a constellation of presenting features. First‐line treatment for anaphylaxis is intramuscular adrenaline. Useful second‐line interventions may include removing the trigger where possible, calling for help, correct positioning of the patient, high‐flow oxygen, intravenous fluids, inhaled short‐acting bronchodilators, and nebulized adrenaline. Discharge arrangements should involve an assessment of the risk of further reactions, a management plan with an anaphylaxis emergency action plan, and, where appropriate, prescribing an adrenaline auto‐injector. If an adrenaline auto‐injector is prescribed, education on when and how to use the device should be provided. Specialist follow‐up is essential to investigate possible triggers, to perform a comprehensive risk assessment, and to prevent future episodes by developing personalized risk reduction strategies including, where possible, commencing allergen immunotherapy. Training for the patient and all caregivers is essential. There are still many gaps in the evidence base for anaphylaxis.

Update on allergy immunotherapy: American Academy of Allergy, Asthma & Immunology/European Academy of Allergy and Clinical Immunology/PRACTALL consensus report

Allergy immunotherapy (AIT) is an effective treatment for allergic asthma and rhinitis, as well as venom-induced anaphylaxis. In addition to reducing symptoms, AIT can change the course of allergic disease and induce allergen-specific immune tolerance. In current clinical practice immunotherapy is delivered either subcutaneously or sublingually; some allergens, such as grass pollen, can be delivered through either route, whereas others, such as venoms, are only delivered subcutaneously. Both subcutaneous and sublingual immunotherapy appear to have a duration of efficacy of up to 12 years, and both can prevent the development of asthma and new allergen sensitivities. In spite of the advances with AIT, safer and more effective AIT strategies are needed, especially for patients with asthma, atopic dermatitis, or food allergy. Novel approaches to improve AIT include use of adjuvants or recombinant allergens and alternate routes of administration. As part of the PRACTALL initiatives, the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma & Immunology nominated an expert team to develop a comprehensive consensus report on the mechanisms of AIT and its use in clinical practice, as well as unmet needs and ongoing developments in AIT. This resulting report is endorsed by both academies.

Prevention and treatment of hymenoptera venom allergy: guidelines for clinical practice.

Based on the knowledge of the living conditions and habitat of social Aculeatae a series of recommendations have been formulated which can potentially greatly minimize the risk of field re‐sting. After a systemic sting reaction, patients should be referred to an allergy specialist for evaluation of their allergy, and if necessary venom immunotherapy (VIT). An emergency medical kit should be supplied, its use clearly demonstrated and repeatably practised until perfected. This should be done under the supervision of a doctor or a trained nurse. Epinephrine by intramuscolar injection is regarded as the treatment of choice for acute anaphylaxis. H1‐antihistamines alone or in combination with corticosteroids may be effective in mild to moderate reactions confined to the skin and may support the value of treatment with epinephrine in full‐blown anaphylaxis. Up to 75% of the patients with a history of systemic anaphylactic sting reaction develop systemic symptoms once again when re‐stung. Venom immunotherapy is a highly effective treatment for individuals with a history of systemic reaction and who have specific IgE to venom allergens. The efficacy of VIT in yellow jacket venom allergic patients has been demonstrated also by assessing health‐related quality of life. If both skin tests and serum venom specific IgE turn negative, VIT may be stopped after 3 years. After VIT lasting 3–5 years, most patients with mild to moderate anaphylactic symptoms remain protected following discontinuation of VIT even with positive skin tests. Longer term or lifelong treatment should be considered in high‐risk patients. Because of the small but relevant risk of re‐sting reactions, in these patients, emergency kits, including epinephrine auto‐injectors, should be discussed with every patient when stopping VIT.

Immune regulation by histamine

Histamine is a potent bioamine with multiple activities in various pathological and physiological conditions. In addition to its well-characterised effects in the acute inflammatory and allergic responses, histamine regulates several aspects of antigen-specific immune response development. Histamine affects the maturation of dendritic cells and alters their T cell-polarising capacity. Histamine also regulates antigen-specific T helper 1 and T helper 2 cells, as well as related antibody isotype responses. Apparently, diverse effects of histamine on immune regulation are because of differential expression of four types of histamine receptors and their distinct intracellular signals.

Histamine, histamine receptors and their role in immune pathology

The important roles of histamine in body physiology and various pathologic events have been well established, whereas new and exciting findings are still being uncovered. Histamine is not only the major mediator of the acute inflammatory and immediate hypersensitivity responses, but has also been demonstrated to affect chronic inflammation and regulate several essential events in the immune response. The diverse effects of histamine on immune regulation are due to the differential expression and regulation of four histamine receptors (HR) and their distinct intracellular signals. Differences in the affinities of these receptors are highly decisive on the biological effects of histamine and agents that target HRs. In particular, the discovery of reciprocal regulation of T cell activity by H1 and H2 receptor activation indicating histamine‐cytokine cross‐talk, as well as the characterization of the fourth histamine receptor (HR4) and its expression on numerous immune and inflammatory cells have prompted a re‐evaluation of the actions of histamine. This accounts for a new potential for HR antagonists and agonists in targeting various immunopathologic conditions.

Immunological mechanisms of allergen-specific immunotherapy

To cite this article: Jutel M, Akdis CA. Immunological mechanisms of allergen‐specific immunotherapy. Allergy 2011; 66: 725–732.

EAACI Molecular Allergology User's Guide

The availability of allergen molecules (‘components’) from several protein families has advanced our understanding of immunoglobulin E (IgE)‐mediated responses and enabled ‘component‐resolved diagnosis’ (CRD). The European Academy of Allergy and Clinical Immunology (EAACI) Molecular Allergology Users Guide (MAUG) provides comprehensive information on important allergens and describes the diagnostic options using CRD. Part A of the EAACI MAUG introduces allergen molecules, families, composition of extracts, databases, and diagnostic IgE, skin, and basophil tests. Singleplex and multiplex IgE assays with components improve both sensitivity for low‐abundance allergens and analytical specificity; IgE to individual allergens can yield information on clinical risks and distinguish cross‐reactivity from true primary sensitization. Part B discusses the clinical and molecular aspects of IgE‐mediated allergies to foods (including nuts, seeds, legumes, fruits, vegetables, cereal grains, milk, egg, meat, fish, and shellfish), inhalants (pollen, mold spores, mites, and animal dander), and Hymenoptera venom. Diagnostic algorithms and short case histories provide useful information for the clinical workup of allergic individuals targeted for CRD. Part C covers protein families containing ubiquitous, highly cross‐reactive panallergens from plant (lipid transfer proteins, polcalcins, PR‐10, profilins) and animal sources (lipocalins, parvalbumins, serum albumins, tropomyosins) and explains their diagnostic and clinical utility. Part D lists 100 important allergen molecules. In conclusion, IgE‐mediated reactions and allergic diseases, including allergic rhinoconjunctivitis, asthma, food reactions, and insect sting reactions, are discussed from a novel molecular perspective. The EAACI MAUG documents the rapid progression of molecular allergology from basic research to its integration into clinical practice, a quantum leap in the management of allergic patients.

Mechanisms of allergen specific immunotherapy – T‐cell tolerance and more

Specific immune suppression and induction of tolerance are essential processes in the regulation and circumvention of immune defence. The balance between allergen‐specific T‐regulatory (Treg) cells and T helper 2 cells appears to be decisive in the development of allergic and healthy immune response against allergens. Treg cells consistently represent the dominant subset specific for common environmental allergens in healthy individuals. In contrast, there is a high frequency of allergen‐specific T helper 2 cells in allergic individuals. A decrease in interleukin (IL)‐4, IL‐5 and IL‐13 production by allergen‐specific CD4+ T cells due to the induction of peripheral T cell tolerance is the most essential step in allergen‐specific immunotherapy (SIT). Suppressed proliferative and cytokine responses against the major allergens are induced by multiple suppressor factors, such as cytokines like IL‐10 and transforming growth factor (TGF)‐β and cell surface molecules like cytotoxic T lymphocyte antigen‐4, programmed death‐1 and histamine receptor 2. There is considerable rationale for targeting T cells to increase efficacy of SIT. Such novel approaches include the use of modified allergens produced using recombinant DNA technology and adjuvants or additional drugs, which may increase the generation of allergen‐specific peripheral tolerance. By the application of the recent knowledge in Treg cells and related mechanisms of peripheral tolerance, more rational and safer approaches are awaiting for the future of prevention and cure of allergic diseases.