Duration of allergen immunotherapy for inhalant allergy Purpose of review We evaluated the time-course of clinical and immunologic changes that occur during and after cessation of sublingual and subcutaneous allergen immunotherapy for inhalant allergies. Recent findings Increases in production of inhibitory cytokines, such as IL-10 and allergen-specific IgE and IgG4 antibodies are induced within weeks of starting immunotherapy for both seasonal and perennial allergens. In general, 2–4 months’ immunotherapy is needed for onset of efficacy whereas maximal clinical effect is achieved within 1–2 years of treatment. Therefore, assuming optimal patient selection, good compliance and at least moderate allergen exposure, if immunotherapy is ineffective at 2 years, it is reasonable to discontinue the treatment. For long-term clinical efficacy, at least 3 years of either subcutaneous or sublingual immunotherapy is required and this results in clinical and immunologic tolerance -- persistence of clinical benefits and suppression of type 2 immunity for years after discontinuation of treatment. Summary Both sublingual and subcutaneous immunotherapy are effective and well tolerated for respiratory allergy. Clinical and immunological changes occur at early stages of treatment. Long-term evaluations support recommendations in international guidelines that both routes of administration should be continued for a minimum of 3 years to achieve disease modification and long-term tolerance. Correspondence to Prof Stephen R. Durham, Allergy and Clinical Immunology, Division of Respiratory Science, Imperial College London and National Heart and Lung Institute, Royal Brompton Hospital. Dovehouse Street, London, SW3 6LY, United Kingdom. Tel: +44 (0) 207 351 8024; e-mail: s.durham@imperial.ac.uk Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

An update on X-Linked agammaglobulinaemia: clinical manifestations and management Purpose of review X-linked agammaglobulinaemia (XLA) is a congenital defect of development of B lymphocytes leading to agammaglobulinaemia. It was one of the first primary immunodeficiencies described, but treatment has remained relatively unchanged over the last 60 years. This summary aims to outline the current outcomes, treatments and future research areas for XLA. Recent findings Immunoglobulin therapy lacks IgA and IgM, placing patients at theoretical risk of experiencing recurrent respiratory tract infections and developing bronchiectasis despite best current therapy. Recent cohort studies from Italy and the USA conform that bronchiectasis remains a major burden for this group despite best current efforts. However, gene therapy offers a potential cure for these patients with proven proof of concept murine models. Summary The potential limitations of current immunoglobulin therapy appear to be confirmed by recent cohort studies, and therefore further work in the development of gene therapy is warranted. Until this is available, clinicians should strive to reduce the diagnostic delay, regularly monitor for lung disease and individualize target immunoglobulin doses to reduce infection rates for their patients. Correspondence to Benjamin Martin James Shillitoe, MBBS, MRCPCH, Paediatric Immunology, Floor 4, Block 2, Clinical Resource Building, Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne NE1 4LP, UK. E-mail: Benjamin.shillitoe@nhs.net Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Manufacturing and quality assessment of allergenic extracts for immunotherapy: state of the art Purpose of review The recent developments in the manufacturing and quality assessment of allergenic extracts in Europe are summarized. Recent findings Quality assessment has always been a fundamental part of allergen product evaluation. New analytical methods have been reported that fill currently existing gaps in the characterization of commonly used allergen products. New types of products require innovative considerations and concepts for their assessment. Advanced standardization efforts aim at increasing reliability and comparability of analytical tools applied for allergen product characterization. In consequence, regulatory requirements are updated in line with such developments. Summary Current demands on the quality of allergen products ensure production of well characterized products of consistent quality. While experience with manufacturing processes and successful product characterization approaches increase, accompanying and continuous re-evaluation of underlying quality control and assessment concepts is being performed. Correspondence to Stefan Vieths, PhD, Paul-Ehrlich-Institut, Federal Institute for Vaccines and Biomedicines, Paul-Ehrlich-Str. 51-59, 63225 Langen, Germany. Tel: +49 6103 77 2000; e-mail: stefan.vieths@pei.de Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Rheumatologic and autoimmune manifestations in primary immune deficiency Purpose of review Here we review the rheumatologic and autoimmune features of primary immune deficiencies with a focus on recently recognized genetic diseases, the spectrum of autoimmunity in PID, and targeted therapies. Recent findings Primary immune deficiencies (PIDs) were initially described as genetic diseases of the immune system leading to susceptibility to infection. It is now well recognized that immune dysfunction and dysregulation also cause noninfectious complications including autoimmunity. The increased application of molecular testing for PID has revealed the diversity of clinical disease. Recent discoveries of diseases with prominent autoimmunity include activated phosphoinositide 3-kinase δ syndrome and PIDs caused by gain-of-function in STAT1 and STAT3. Similarly, identification of larger cohorts of patients with molecular diagnoses in more common PIDs, such as common variable immune deficiency (CVID), has led to increased understanding of the range of autoimmunity in PIDs. Understanding the molecular basis of these PIDs has the potential to lead to targeted therapy to treat associated autoimmunity. Summary Autoimmunity and rheumatologic disease can be presenting symptoms and/or complicating features of primary immunodeficiencies. Evaluation for PIDs in patients who have early-onset, multiple, and/or atypical autoimmunity can enhance diagnosis and therapeutic options. Correspondence to Megan A. Cooper, Division of Rheumatology, Department of Pediatrics, Washington University School of Medicine, St, Louis, Missouri, USA. Tel: +1 314 454 6124; e-mail: addresscooper_m@wustl.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Is immunotherapy with fungal vaccines effective? Purpose of review Although allergen immunotherapy (AIT) for fungi has been performed for many years, evidence clearly demonstrating its clinical benefit are still lacking. Here, we reviewed the available studies assessing efficacy and safety of AIT for molds. Recent findings Studies on AIT for fungi were performed only for the two predominating mold species in the external environment, namely Cladosporium and Alternaria. There is no evidence for other mold species. Recent finding in the literature are lacking; the 2 most recent studies on AIT for molds were published in 2011. Overall, 13 studies were identified (the first was published in 1986), but only nine of these compared AIT to placebo. The studies are small (median study sample size, 27 patients) and of low quality, owing to several defects leading to moderate-to-high risk of bias. Symptoms improvement and medication use reduction, which are the main outcome measures of the studies, were inconsistently demonstrated. There are some concerns about safety with Cladosporium extracts, whereas vaccines with Alternaria extracts seem to be safe and well tolerated. Summary Low strength evidence suggests that mold AIT is efficacious for the treatment of respiratory allergies. High-quality studies with an adequate sample size are needed. Correspondence to Danilo Di Bona, MD, PhD, School and Chair of Allergology and Clinical Immunology, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Piazza Giulio Cesare, 11, Bari 70124, Italy. Tel/. Fax: +0039 080 5478167; e-mail: danilo.dibona@uniba.it Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

B-cell responses in allergen immunotherapy Purpose of review The establishment of long-term clinical tolerance in AIT requires the involvement of basophils, mast cells, allergen-specific regulatory T and B cells, downregulation of effector type 2 responses, and increase in production of specific IgG, particularly immunglobulin G4 (IgG4) antibodies. This review aims to provide an overview of the role of B cells in AIT, their mechanism of action, and their potential for improving AIT. Recent findings In-depth research of B cells has paved the way for improved diagnosis and research on allergic diseases. B cells play a central role in allergy and allergen tolerance through the production of immunglobulin E (IgE)-blocking antibodies. However, an increasing body of evidence has emerged supporting a role for B cells in regulating immune responses that extends beyond the production of antibodies. Regulatory B cells play an important role in immunosuppression, mediated by secretion of anti-inflammatory cytokines. Summary Successful AIT establishes the reinstatement of immune tolerance toward allergens, reduces allergic symptoms, and improves clinical treatments in patients. B cells play a central role in this process through antibody-independent immune regulatory processes in addition to the production of IgE-blocking antibodies. Correspondence to Mübeccel Akdis, MD, Ph.D., Swiss Institute of Allergy and Asthma Research (SIAF) Herman-Burchard-Strasse 9, CH- 7265 Davos, Switzerland. Tel: +41 81 4100848; fax: +41 81 4100840; e-mail: akdism@siaf.uzh.ch Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Immunoglobulin A and microbiota in primary immunodeficiency diseases Purpose of review With the emergence of the microbiota as a potential driver of host inflammation, the role of iIgA is becoming increasingly important. This review discusses the current evidence regarding the effects of clinical IgA deficiency on the microbiota, and the possible role of microbial dysbiosis in driving inflammation in PID patients. Recent findings The gut microbiota has been investigated in selective IgA deficiency and common variable immunodeficiency, revealing an important role for IgA in maintaining gut microbiota homeostasis, with disparate effects of IgA on symbionts and pathobionts. Although IgA deficiency is associated with microbial translocation and systemic inflammation, this may be partially compensated by adequate IgG and IgM induction in IgA deficiency but not in common variable immunodeficiency. Therapeutic strategies aimed at correction of the microbiota mostly focus on fecal microbiota transplantation. Whether this may reduce systemic inflammation in PID is currently unknown. Summary Clinical IgA deficiency is associated with microbial dysbiosis and systemic inflammation. The evidence for microbiota-targeted therapies in PID is scarce, but indicates that IgA-based therapies may be beneficial, and that fecal microbiota transplantation is well tolerated in patients with antibody deficiency. Correspondence to Helen Louisa Leavis, MD, PhD, Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht, the Netherlands. Tel:+31 88 75 555 55; e-mail: h.leavis@umcutrecht.nl Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

The multiple roles of mite allergens in allergic diseases Purpose of review Mites are the most worldwide spread allergens and relevant causative of respiratory allergies. Life cycle, component allergens, biological activity and immunogenicity are discussed in depth. Recent findings It is now known that mite allergens are able to stimulate the innate immune system through different receptors, for example, TLRs and PARs. The activation of the cells in the airway mucosa is followed by type 2 polarizing cytokine production in predisposed individuals. This complex network plays a pivotal role into the promotion of Th2 differentiation. Summary This is a comprehensive review regarding all the mite allergens known so far, including their location within dust mites, composition, biological activities and binding receptors relevant to the fate of the immunological response. Correspondence to Professor Paola Parronchi, Department of Experimental and Clinical Medicine, University of Firenze, Largo Brambilla 3, 50134 Firenze, Italy. Tel: +39 0557947421; e-mail: paola.parronchi@unifi.it Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

The role of component-resolved diagnosis in Hymenoptera venom allergy Purpose of review Component-resolved diagnostics (CRD) is a new tool aiming at detecting IgE-mediated sensitizations against individual, relevant allergens. Here, we discuss recent literature on molecular diagnosis in the field of Hymenoptera venom allergy (HVA) as well as CRD strengths and weaknesses. Recent findings CRD, using single molecules or panels of allergens, may discriminate between primary sensitization and cross-reactivity in patients with double/multiple positivity in diagnostic tests with whole extracts, allowing the specialist to choose the most suitable venom for specific immunotherapy (VIT), avoiding unnecessary VIT and reducing the risk of side effects. Future availability of the cross-reactive recombinant pairs of allergens of different species may further increase the diagnostic performance. CRD may be useful in patients with negative allergy tests and a proven history of a previous systemic reaction, including those with mast cell disorders, who could benefit from VIT. In honeybee venom allergy, different sensitization profiles have been identified, which could be associated with a greater risk of VIT failure or treatment side effects. Summary CRD is undoubtedly an innovative diagnostic method that leads to a more precise definition of the sensitization profile of the HVA patient. Together with a better knowledge of the molecular composition of different venom extracts, CRD may contribute to optimize patient-tailored therapy. Correspondence to Maria B. Bilò, MD, Allergy Unit, Department of Internal Medicine, University Hospital Ospedali Riuniti di Ancona, - Department of Clinical and Molecular Sciences, Polytechnic University of Marche, Ancona 60026, Italy. Tel +39 071 5963804;. fax: +39 071 5963253; e-mail: m.b.bilo@univpm.it Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.