M. D. Tarzi

The effect of Fel d 1-derived T-cell peptides on upper and lower airway outcome measurements in cat-allergic subjects

Background:  We previously showed that overlapping Fel d 1‐derived T‐cell peptides inhibited surrogate markers of allergy (i.e. early and late‐phase skin reactions and T‐cell function) in cat allergic subjects. The present pilot study was designed to determine whether this treatment affected clinically relevant outcome measurements such as the allergen‐induced nasal and bronchial reactions, and asthma/rhinitis quality of life (QOL).

Common Variable Immunodeficiency: An Update on Etiology and Management

Common variable immunodeficiency (CVID) represents a heterogeneous group of primary antibody deficiency disorders characterized by recurrent infection and by inflammatory, granulomatous, and autoimmune complications. Recently, there have been significant advances in understanding the pathogenesis of the disease, with five genetic mutations identified in patients who have a CVID phenotype. Clinical care also has progressed with refinements in treatment and the development of classification schemes for prognostic and research purposes. Significant delays in diagnosis remain, however. It is likely that more genetic defects will be identified in the future, further shrinking the pool of patients who have CVID of unknown cause.

A UK national audit of hereditary and acquired angioedema

Hereditary angioedema (HAE) and acquired angioedema (AAE) are rare life‐threatening conditions caused by deficiency of C1 inhibitor (C1INH). Both are characterized by recurrent unpredictable episodes of mucosal swelling involving three main areas: the skin, gastrointestinal tract and larynx. Swelling in the gastrointestinal tract results in abdominal pain and vomiting, while swelling in the larynx may be fatal. There are limited UK data on these patients to help improve practice and understand more clearly the burden of disease. An audit tool was designed, informed by the published UK consensus document and clinical practice, and sent to clinicians involved in the care of HAE patients through a number of national organizations. Data sets on 376 patients were received from 14 centres in England, Scotland and Wales. There were 55 deaths from HAE in 33 families, emphasizing the potentially lethal nature of this disease. These data also show that there is a significant diagnostic delay of on average 10 years for type I HAE, 18 years for type II HAE and 5 years for AAE. For HAE the average annual frequency of swellings per patient affecting the periphery was eight, abdomen 5 and airway 0·5, with wide individual variation. The impact on quality of life was rated as moderate or severe by 37% of adult patients. The audit has helped to define the burden of disease in the UK and has aided planning new treatments for UK patients.

Outcome of allogeneic stem cell transplantation in adults with common variable immunodeficiency

induction, making a role for secreted mediators unlikely (not shown). Another factor influencing FOXP3 induction is the strength of the T-cell receptor (TCR) signal and costimulation. In our settings the TCR signal was standardized by plate-bound anti-CD3, but costimulation is provided by the APCs. High costimulation through CD28 signaling prevents the upregulation of FOXP3. We therefore investigated the role of the CD28 ligands CD80 and CD86 on APCs. We observed no difference in the expression of these molecules. When blocking antibodies toward CD80, CD86, or both were added to the cultures, this did not result in a difference in FOXP3 expression (Fig 2, A). This finding was confirmed by adding increasing concentrations of cytotoxic T lymphocyte–associated antigen 4-immunoglobulin (CTLA4Ig) to the cultures, blocking both CD80 and CD86, which had no obvious effect (data not shown). Inhibition of downstream signaling pathways of TCR and CD28 on T-cell activation is able to promote FOXP3 induction as well. The phosphoinositide 3-kinase/protein kinase B (PKB) pathway is central in T-cell differentiation. Prevention of activation of this pathway by limited costimulation or signaling through inhibitory molecules, such as programmed death 1 (PD-1), promotes FOXP3 upregulation. We hypothesized that differential downstream signaling on activation might be pivotal to the high levels of FOXP3 found on day 6 of activation and onward (Fig 1, D). We therefore investigated the role of PD-1 and PKB in the induction of FOXP3 in CB-naive T cells. On activation, CB CD4 T cells have an increased expression of the PD-1 molecule compared with APB (Fig 2, B). When we blocked the interaction between PD-1 and its ligand PD-L1 by including a blocking mAb to PD-L1 in the culture, a significant reduction in the percentage of FOXP3 T cells was observed (Fig 2, C), isotype mAb had no effect (not shown). A PD-1–blocking mAb showed comparable results. As a consequence, the phosphorylation status of PKB on activation by different concentrations of anti-CD3 was lower for CB than APB cells (Fig 2, D). Additionally, CB T cells required approximately 10-fold more TCR triggering than APB T cells before an increase in PKB phosphorylation was observed. Shortly after birth, the immune system of the newborn encounters all kinds of neoantigens. The low percentages of Treg cells found ex vivo in CB are not likely to play a major role in maintaining tolerance to these neoantigens. However, we here show that PD-1 signaling in CB T cells facilitates their differentiation into induced functional FOXP3 Treg cells through a mechanism involving reduced PKB signaling. This phenomenon might well represent a mechanism that is developed to ensure active tolerance in the neonatal immune system. Sytze de Roock, MSc* Sanne B. E. A. Hoeks, MD* Linda Meurs Anouk Steur Maarten O. Hoekstra, MD, PhD Berent J. Prakken, MD, PhD Marianne Boes, PhD Ism e M. de Kleer, MD, PhD

Clinical Immunology Review Series: An approach to the management of pulmonary disease in primary antibody deficiency

The sinopulmonary tract is the major site of infection in patients with primary antibody deficiency syndromes, and structural lung damage arising from repeated sepsis is a major determinant of morbidity and mortality. Patients with common variable immunodeficiency may, in addition, develop inflammatory lung disease, often associated with multi‐system granulomatous disease. This review discusses the presentation and management of lung disease in patients with primary antibody deficiency.

Peptide immunotherapy for allergic disease

The only disease-modifying treatment available for IgE-mediated disease is specific immunotherapy, but the retention of B cell epitopes in whole allergen preparations confers a risk of IgE-mediated systemic reactions to their administration. Compelling evidence for the central role of T cells in allergic disease suggests that IgE-binding epitopes could be removed from such therapy, improving safety without affecting efficacy. Short, allergen-derived peptides lack the conformational determinants required for IgE crosslinking and are, therefore, an attractive therapeutic possibility. However, human leukocyte antigen (HLA) polymorphism means that T cell peptide epitopes present a huge diversity, which makes the design of peptide-based vaccines problematic. Over the past 10 years, advances in our understanding of epitope selection and major histocompatibility complex (MHC)–peptide–T cell receptor interactions have taken this therapy forward to early clinical trials with human volunteers.

High‐titre circulating tissue transglutaminase‐2 antibodies predict small bowel villous atrophy, but decision cut‐off limits must be locally validated

Numerous studies suggest that high levels of circulating immunoglobulin (Ig)A tissue transglutaminase (TTG2) antibodies predict coeliac disease with high specificity. Accordingly, it has been suggested that duodenal biopsy may not be required routinely for diagnostic confirmation where quantitative serology identifies the presence of high antibody titres. However, defining a cut‐off TTG2 threshold is problematic, as the multiple available assay methods are not harmonized and most studies have been focused on the paediatric population. Recent paediatric guidelines proposed a TTG2 antibody diagnostic cut‐off at 10 × the upper limit of normal (ULN) for the method; however, concerns remain about errors of generalization, between both methods and laboratories. In this study, we used retrospective laboratory data to investigate the relationship between TTG2 antibody levels and Marsh 3 histology in the seropositive population of adults and children at a single centre. Among 202 seropositive patients with corresponding biopsies, it was possible to define a TTG2 antibody cut‐off with 100% specificity for Marsh 3 histology, at just over 10 × ULN for the method. However, UK National External Quality Assurance Scheme returns during the study period showed a wide dispersion of results and poor consensus, both between methods and between laboratories using the same method. Our results support the view that high‐titre TTG2 antibody levels have strong predictive value for villous atrophy in adults and children, but suggest that decision cut‐offs to guide biopsy requirement will require local validation. TTG2 antibody assay harmonization is a priority, in order to meet the evolving requirements of laboratory users in this field.

C1 inhibitor deficiency: 2014 United Kingdom consensus document

C1 inhibitor deficiency is a rare disorder manifesting with recurrent attacks of disabling and potentially life‐threatening angioedema. Here we present an updated 2014 United Kingdom consensus document for the management of C1 inhibitor‐deficient patients, representing a joint venture between the United Kingdom Primary Immunodeficiency Network and Hereditary Angioedema UK. To develop the consensus, we assembled a multi‐disciplinary steering group of clinicians, nurses and a patient representative. This steering group first met in 2012, developing a total of 48 recommendations across 11 themes. The statements were distributed to relevant clinicians and a representative group of patients to be scored for agreement on a Likert scale. All 48 statements achieved a high degree of consensus, indicating strong alignment of opinion. The recommendations have evolved significantly since the 2005 document, with particularly notable developments including an improved evidence base to guide dosing and indications for acute treatment, greater emphasis on home therapy for acute attacks and a strong focus on service organization.

Pollen‐food syndrome is related to Bet v 1/PR‐10 protein sensitisation, but not all patients have spring rhinitis

The pollen-food syndrome (PFS) results from sensitisation to panallergens that are common to pollen and edible plant products, typically manifesting as oral symptoms upon exposure to Rosaceae fruits. The panallergen molecules comprise three protein clusters: Bet v 1/PR-10; profilins; non-specific lipid transfer proteins (nsLTP) (1). The sensitisation profile of PFS patients to these proteins varies geographically in Europe, with PR-10 proteins the dominant allergen in Northern Europe and nsLTP in the South (2). Anecdotally, PFS in the United Kingdom is related to birch pollinosis and sensitisation to the Bet v 1/ PR-10 cluster, but published data are lacking. Accordingly, we studied the clinical phenotype and sensitisation profile of 24 PFS patients presenting to a UK allergy clinic. The study protocol was approved by the NHS Research Ethics Service and all patients provided informed written consent. Food allergies were assessed by a standardised physician-administered questionnaire, which included 38 relevant plant-derived foods. Donor serum was analysed for IgE directed against allergen components by a solid-phase microarray assay (VBC Genomics, Vienna, Austria). The group were highly atopic, with 100% sensitised to birch pollen, 88% to grass pollens, 63% to cat dander and 50% to house dust mite; 96% reported rhinitis, 32% asthma and 6% eczema. Foods reported to cause oro-pharyngeal symptoms are displayed in order of frequency in Fig. 1. Component-resolved diagnosis demonstrated ubiquitous sensitisation to the Bet v 1/PR-10 protein cluster, with 71% of patients monosensitised to PR-10 proteins and negative for nsLTP and profilin. Despite this finding, four of 24 had no history (past or present) of spring rhinitis: of these, two had symptoms restricted to the summer months only, one had chronic rhinitis with house dust mite allergy and one had no history of rhinitis. Four of 24 donors were co-sensitised to the profilin protein cluster, 3 of 24 co-sensitised to nsLTP, but none to all three proteins. All profilin-sensitised donors were allergic to grass pollen and clinical reactions to citrus, banana and papaya were restricted to this group, consistent with previous observations (3). Patients with co-sensitisation to the profilin protein cluster reported reactions to significantly more food items than those sensitised to PR-10 proteins alone or with nsLTP (mean 13.8 foods vs 6.2 respectively, P = 0.004 by Student’s’ t-test). The clinical relevance of co-sensitisation to nsLTP in three patients of this small cohort is unclear as none described systemic reactions to peaches or any other food. Eight of 24 patients reported more severe symptoms associated with ingesSensitisation to PR-10 proteins was ubiquitous in a small group of UK pollen-food syndrome patients. ALLERGY Net

Paediatric hereditary angioedema: a survey of UK service provision and patient experience

Hereditary angioedema (HAE) is a rare disease characterized by episodes of potentially life‐threatening angioedema. For affected children in the United Kingdom, there are relatively few data regarding disease prevalence, service organization and the humanistic burden of the disease. To improve knowledge in these areas, we surveyed major providers of care for children with HAE. A questionnaire was sent to major paediatric centres to determine patient numbers, symptoms, diagnostic difficulties, management and available services. In addition, all patients at a single centre were given a questionnaire to determine the experiences of children and their families. Sixteen of 28 centres responded, caring for a total of 111 UK children. Seven children had experienced life‐threatening crises. One‐third of patients were on long‐term prophylactic medication, including C1 inhibitor prophylaxis in four children. Eight centres reported patients who were initially misdiagnosed. Broad differences in management were noted, particularly regarding indications for long‐term prophylaxis and treatment monitoring. We also noted substantial variation in the organization of services between centres, including the number of consultants contributing to patient care, the availability of specialist nurses, the availability of home therapy training and the provision of patient information. Ten of 12 patient/carer questionnaires were returned, identifying three common themes: the need to access specialist knowledge, the importance of home therapy and concerns around the direct effect of angioedema on their life. To our knowledge, this study represents the first dedicated survey of paediatric HAE services in the United Kingdom and provides useful information to inform the optimization of services.