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.

Clozapine-associated secondary antibody deficiency Purpose of review Clozapine has recently been described as a novel cause of secondary antibody deficiency (SAD), associated with long-term therapy. Here we critically review the evidence linking clozapine use to an increased infection risk, describe immunological alterations, and discuss potential mechanisms. Recent findings Individuals with schizophrenia are at two to five times more likely to develop pneumonia than the general population, in particular, when receiving clozapine. Delayed-onset distinguishes clozapine-associated hypogammaglobulinaemia from agranulocytosis or neutropenia that occur at lesser frequency. Biomarker searches in treatment-resistant schizophrenia highlight an immune signature associated with long-term clozapine use. This includes reduction in class-switched memory B cells, echoing common variable immunodeficiency. Recent identification of a role for dopamine in T follicular helper–B cell interactions may inform future clinical studies. Summary The detrimental impact of the increased infection risk associated with clozapine necessitates a re-evaluation of the current monitoring strategies as well as further studies to better understand the underlying mechanisms of SAD in this setting. On the basis of available evidence, we suggest simple modifications to clozapine monitoring including integration of routine vaccination, smoking cessation, and assessment of humoral immunity. Further studies are required to understand the role of clozapine in neuroinflammation as well as other potentially autoantibody-mediated diseases.

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.

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.

Disorders of CTLA-4 expression, how they lead to CVID and dysregulated immune responses Purpose of review The landscape of common variable immunodeficiency disorder (CVID) is rapidly evolving as the availability of next-generation sequencing leads to the discovery of new monogenic causes with the clinical phenotype of CVID. Herein, the biology of cytotoxic T lymphocyte-associated protein four (CTLA-4), differentially expressed in FDCP6 homolog (DEF6), and lipopolysaccharide responsive beige-like anchor protein (LRBA), and their impact on the development of a dysregulated, rather than an isolated, infectious phenotype of CVID are explored. Recent findings The broad clinical phenotype associated with these monogenic forms of CVID is described, and common approaches to treatment are reviewed. Summary Knowledge of the biology, clinical manifestations, and treatment options trialed thus far in patients with CTLA-4 insufficiency, DEF6 deficiency, and LRBA deficiency are essential in the consideration and effective management of patients with CVID stemming from these monogenic causes.

Nonsevere combined immunodeficiency T-cell lymphopenia identified through newborn screening Purpose of review Although severe combined immunodeficiency (SCID) is the primary target condition for newborn screening (NBS), over 25 secondary targets, conditions other than SCID, have been identified. There is no standard method for evaluating neonates with non-SCID T-cell lymphopenia (TCL) and no standard approaches to treatment. We will describe these conditions and discuss recommendations for evaluating and follow-up of non-SCID TCL detected by NBS. Recent findings The birth prevalence of non-SCID TCL detected through SCID NBS is higher than SCID and can be a burden on NBS programs. We will present some publications discussing outcomes and comorbidities in these patients. Summary NBS for SCID has been very successful in identifying infants with SCID at birth to institute early life saving therapies. TCL due to other conditions can cause significant immune deficiency and treatment is dependent on the cause of the defect, as well as the magnitude of the immunodeficiency. Data collection from NBS programs should include assessment of various therapies and clinical outcomes. Better systems for recording long-term outcomes of SCID NBS including both SCID and non-SCID conditions should become a priority for NBS programs. This will help to advance the goal of NBS programs: improve outcomes in the most cost-effective manner.

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.

Oral and sublingual immunotherapy for food allergy Purpose of review To critically appraise the recent most relevant studies in the rapidly advancing field of food oral and sublingual immunotherapy. Recent findings Food allergen-specific immunotherapy via oral (OIT) and sublingual route (SLIT) increases the threshold of reactivity to peanut, cow's milk, egg, wheat, and many other foods in the majority of the treated individuals. This desensitized state is contingent upon the continued ingestion of the maintenance doses of the food. Permanent oral tolerance is achievable in a smaller subset of the treated individuals. The optimal duration of therapy has not been firmly established but is likely dependent on the phenotype (severity and persistence). Efficacy of food-OIT is superior compared with SLIT, whereas the safety of OIT is less favorable. Standardization of treatment protocols, maintenance dosing, duration of therapy, target populations and harmonization of the outcomes are top priorities at this stage. Summary OIT and SLIT represent two different routes of food allergen-specific immunotherapy. Although significant progress has been made in the last decade, both treatment modalities are still in the very early stages of development and further investigations are necessary to optimize the protocols and improve safety while maximizing efficacy.

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.