How type-2 dendritic cells induce Th2 differentiation: Instruction, repression, or fostering T cell-T cell communication?

Allergic disease is caused by the activation of allergen-specific CD4+ type-2 T follicular helper cells (Tfh2) and T helper 2 (Th2) effector cells that secrete the cytokines IL-4, IL-5, IL-9, and IL-13 upon allergen encounter, thereby inducing IgE production by B cells and tissue inflammation. While it is accepted that the priming and differentiation of naïve CD4+ T cells into Th2 requires allergen presentation by type 2 dendritic cells (DC2s), the underlying signals remain unidentified. In this review we focus on the interaction between allergen-presenting DC2s and naïve CD4+ T cells in lymph node (LN), and the potential mechanisms by which DC2s might instruct Th2 differentiation. We outline recent advances in characterizing DC2 development and heterogeneity. We review mechanisms of allergen sensing and current proposed mechanisms of Th2 differentiation, with specific consideration of the role of DC2s and how they might contribute to each mechanism. Finally, we assess recent publications reporting a detailed analysis of DC-T cell interactions in LNs and how they support Th2 differentiation. Together, these studies are starting to shape our understanding of this key initial step of the allergic immune response.

IL-13 in dermal type-2 dendritic cell specialization: From function to therapeutic targeting.

Skin functions as a barrier protecting the host against physical, thermal, chemical changes as well as microbial insults. The skin is populated by several immune cell types that are crucial to host defense and to maintain self-tolerance as well as equilibrium with beneficial microbiota. Conventional dendritic cells (cDCs) are antigen-presenting cells that patrol the skin and all other nonlymphoid tissues for self or foreign antigens, and then migrate to draining lymph nodes to initiate T-cell responses. This review article describes recent developments on skin cDC specialization, focusing on the role of IL-13, a cytokine essential to allergic immune responses that is also secreted at steady state by type-2 innate lymphoid cells in healthy skin, and is required for dermal cDC differentiation. Furthermore, we contextualize how different therapeutics that block IL-13 signaling and were recently approved for the treatment of atopic dermatitis might affect cDCs in human skin.

Patients with previous immediate hypersensitivity reactions to polyethylene glycol can safely receive the BNT162b2 mRNA COVID-19 vaccine.

Previous anaphylaxis or immediate allergic reaction to polyethylene glycol (PEG; also known as macrogol) is considered a contraindication to the BNT162b2 mRNA COVID-19 vaccine, which contains 50 ug of PEG at a molecular weight of 2000, and this component is thought to account for the higher rate of anaphylaxis seen with this vaccine (4.7 per million doses) than with other non-mRNA vaccines. However, there is evidence that both anaphylaxis to PEG and anaphylaxis to the Pfizer COVID-19 reaction may not be IgE-mediated, with patients with anaphylaxis to first dose of the Pfizer COVID-19 vaccine receiving their second dose of vaccine without no or milder reactions in a high-risk clinic setting. In New Zealand, non-PEG-containing COVID-19 vaccines were not available until late 2021. Therefore, we offered patients with known or suspected PEG anaphylaxis their first dose of Pfizer COVID-19 vaccine in a high-risk hospital clinic. Eleven patients with previous hypersensitivity to PEG (including eight with anaphylaxis) successfully received their first dose with mild or no reactions; all have now had their second doses in the community without significant reaction. Record review also showed that most patients with previous hypersensitivity reactions to pegylated asparaginase have also been successfully vaccinated. This demonstrates that previous PEG hypersensitivity, including anaphylaxis, does not exclude immunisation with the Pfizer COVID-19 vaccine.

Prevalence of clinic-defined food allergy in early adolescence: The SchoolNuts study.

BACKGROUND: Rising rates of food-induced anaphylaxis have recently been shown in the adolescent age group, following earlier descriptions of a rise in children younger than 5 years. However, few population-based studies have examined the prevalence of food allergy in adolescence using objective measures such as oral food challenge (OFC). OBJECTIVE: We sought to determine the prevalence of food allergy among a population-based sample of 10- to 14-year-old adolescents using clinical evaluation including OFC to confirm the diagnosis. METHODS: Schools were randomly selected from greater metropolitan Melbourne, Australia. Students aged 10 to 14 years, and their parents, were asked to complete a questionnaire regarding the adolescent's food allergy or food-related reactions. Clinic evaluation, which consisted of skin prick tests and OFC where eligible, was undertaken if students were suspected to have current food allergy from parent response. Among 9816 students assessed, 5016 had complete parent response and clinic evaluation when eligible. An additional 4800 students had student questionnaires only. RESULTS: The prevalence of clinic-defined current food allergy based on history, sensitization data, and OFC results was 4.5% (95% CI, 3.9-5.1), with the most common food triggers being peanut, 2.7% (95% CI, 2.3-3.2), and tree nut, 2.3% (95% CI, 1.9-2.8). Among the additional group of 4800 adolescents who had only self-reported food allergy status available, the prevalence of self-reported current food allergy was 5.5% (95% CI, 4.9-6.2), with peanut, 2.8% (95% CI, 2.3-3.3), and tree nut, 2.3% (95% CI, 1.9-2.8), the most common. CONCLUSIONS: Approximately 1 in 20 10- to 14-year-old school students in Melbourne has current food allergy. This high prevalence suggests that the previously reported rise in food-induced anaphylaxis in this age group may reflect an increasing prevalence of food allergy rather than simply increased reporting of anaphylaxis.

Identification of germinal centres in the lymph node of a patient with hyperimmunoglobulin M syndrome associated with congenital rubella.

BACKGROUND: The hyper immunoglobulin M syndrome (HIM) associated with congenital rubella infection (rHIM) is an extremely rare disorder, where patients have elevated serum IgM in association with reduced IgG and IgA. We have previously shown that in contrast to X-linked HIM (XHIM), a patient with well-characterised rHIM is able to express functional CD40 ligand, undergo immunoglobulin isotype switching and to generate memory B cells. Here we describe the ultrastructural features of an excised lymph node from this patient. METHODS: An inguinal lymph node was surgically removed and examined histologically as well as by immunohistochemistry. It was then stained with multiple fluorescent dyes to visualize the cellular interactions within the node. Flow cytometry was undertaken on a cellular suspension from the node. FINDINGS: Our patient has normal lymph node architecture by light microscopy. Immunohistochemistry studies showed the presence of scattered germinal centres. Polychromatic immunofluorescence staining showed disruption of the architecture with mostly abnormal germinal centres. A small number of relatively intact germinal centres were identified. Both IgM and IgG bearing cells were identified in germinal centres. INTERPRETATION: In contrast to XHIM where germinal centres are absent, the presence of small numbers of relatively normal germinal centres explain our previous identification of isotype switched memory B cells in rHIM.

The SARS-CoV-2 neutralising antibody profile of New Zealand adults in 2023: Impact of vaccination and infection.

The successive dominance of SARS-CoV-2 omicron sublineages presents challenges for vaccination strategies with respect to the antigenic content of boosters. New Zealand's COVID-19 elimination strategy (2020-2021) ensured the major vaccination campaign (Pfizer-BioNTech BNT162b2) was completed pre-omicron in an infection-naive population, providing a unique setting to explore the impact of omicron infection waves on vaccine responses. This study compared neutralising antibodies (NAb) to eight SARS-CoV-2 omicron sublineages 28-days and 11-months after a third dose. Participants (n = 219) were classified by antigen exposure in the intervening 10 months including additional vaccinations and/or infections. Both vaccination and infection boosted NAb levels to all sublineages. Antigenic maps showed infection had a major impact on NAb breadth, despite all participants being vaccinated with an ancestral-based vaccine. While vaccination remains an important tool to boost immunity, the breadth of NAbs observed suggest that attempts to match booster specificity with current circulating variants may not always be necessary.

Robust immunogenicity of a third BNT162b2 vaccination against SARS-CoV-2 Omicron variant in a naïve New Zealand cohort.

The ability of a third dose of the Pfizer-BioNTech BNT162b2 SARS-CoV-2 vaccine to stimulate immune responses against subvariants, including Omicron BA.1, has not been assessed in New Zealand populations. Unlike many overseas populations, New Zealanders were largely infection naïve at the time they were boosted. This adult cohort of 298 participants, oversampled for at-risk populations, was composed of 29% Maori and 28% Pacific peoples, with 40% of the population aged 55+. A significant proportion of the cohort was obese and presented with at least one comorbidity. Sera were collected 28 days and 6 months post second vaccination and 28 days post third vaccination. SARS-CoV-2 anti-S IgG titres and neutralising capacity using surrogate viral neutralisation assays against variants of concern, including Omicron BA.1, were investigated. The incidence of SARS-CoV-2 infection, within our cohort, prior to third vaccination was very low (<6%). This study found a third vaccine significantly increased the mean SARS-CoV-2 anti-S IgG titres, for every demographic subgroup, by a minimum of 1.5-fold compared to titres after two doses. Diabetic participants experienced a greater increase (∼4-fold) in antibody titres after their third vaccination, compared to non-diabetics (increase of âˆ¼ 2-fold). This corrected for the deficiency in antibody titres within diabetic participants which was observed following two doses. A third dose also induced a neutralising response against Omicron variant BA.1, which was absent after two doses. This neutralising response improved regardless of age, BMI, ethnicity, or diabetes status. Participants aged ≥75 years consistently had the lowest SARS-CoV-2 anti-S IgG titres at each timepoint, however experienced the greatest improvement after three doses compared to younger participants. This study shows that in the absence of prior SARS-CoV-2 infection, a third Pfizer-BioNTech BNT162b2 vaccine enhances immunogenicity, including against Omicron BA.1, in a cohort representative of at-risk groups in the adult New Zealand population.

Vaccine mandates in the time of Omicron.

Nil.

Immunogenicity of BNT162b2 COVID-19 vaccine in New Zealand adults.

BACKGROUND: There is very little known about SARS-CoV-2 vaccine immune responses in New Zealand populations at greatest risk for serious COVID-19 disease. METHODS: This prospective cohort study assessed immunogenicity in BNT162b2 mRNA vaccine recipients in New Zealand without previous COVID-19, with enrichment for Maori, Pacific peoples, older adults ≥ 65 years of age, and those with co-morbidities. Serum samples were analysed at baseline and 28 days after second dose for presence of quantitative anti-S IgG by chemiluminescent microparticle immunoassay and for neutralizing capacity against Wuhan, Beta, Delta, and Omicron BA.1 strains using a surrogate viral neutralisation assay. RESULTS: 285 adults with median age of 52 years were included. 55% were female, 30% were Maori, 28% were Pacific peoples, and 26% were ≥ 65 years of age. Obesity, cardiac and pulmonary disease and diabetes were more common than in the general population. All participants received 2 doses of BNT162b2 vaccine. At 28 days after second vaccination, 99.6% seroconverted to the vaccine, and anti-S IgG and neutralising antibody levels were high across gender and ethnic groups. IgG and neutralising responses declined with age. Lower responses were associated with age ≥ 75 and diabetes, but not BMI. The ability to neutralise the Omicron BA.1 variant in vitro was severely diminished but maintained against other variants of concern. CONCLUSIONS: Vaccine antibody responses to BNT162b2 were generally robust and consistent with international data in this COVID-19 naïve cohort with representation of key populations at risk for COVID-19 morbidity. Subsequent data on response to boosters, durability of responses and cellular immune responses should be assessed with attention to elderly adults and diabetics.

The case for a national service for primary immune deficiency disorders in New Zealand.

Primary immune deficiency disorders (PIDs) are rare conditions for which effective treatment is available. It is critical these patients are identified at an early stage to prevent unnecessary morbidity and mortality. Treatment of these disorders is expensive and expert evaluation and ongoing management by a clinical immunologist is essential. Until recently there has been a major shortage of clinical immunologists in New Zealand. While the numbers of trained immunologists have increased in recent years, most are located in Auckland. The majority of symptomatic PID patients require life-long immunoglobulin replacement. Currently there is a shortage of subcutaneous and intravenous immunoglobulin (SCIG/IVIG) in New Zealand. A recent audit by the New Zealand Blood Service (NZBS) showed that compliance with indications for SCIG/IVIG treatment was poor in District Health Boards (DHBs) without an immunology service. The NZBS audit has shown that approximately 20% of annual prescriptions for SCIG/IVIG, costing $6M, do not comply with UK or Australian guidelines. Inappropriate use may have contributed to the present shortage of SCIG/IVIG necessitating importation of the product. This is likely to have resulted in a major unnecessary financial burden to each DHB. Here we present the case for a national service responsible for the tertiary care of PID patients and oversight for immunoglobulin use for primary and non-haematological secondary immunodeficiencies. We propose that other PIDs, including hereditary angioedema, are integrated into a national PID service. Ancillary services, including the customised genetic testing service, and research are also an essential component of an integrated national PID service and are described in this review. As we show here, a hub-and-spoke model for a national service for PIDs would result in major cost savings, as well as improved patient care. It would also allow seamless transition from paediatric to adult services.

Comparison of diagnostic criteria for common variable immunodeficiency disorder.

Common variable immunodeficiency disorders (CVIDs) are the most frequent symptomatic primary immune deficiency condition in adults. The genetic basis for the condition is not known and no single clinical feature or laboratory test can establish the diagnosis; it has been a diagnosis of exclusion. In areas of uncertainty, diagnostic criteria can provide valuable clinical information. Here, we compare the revised European society of immune deficiencies (ESID) registry (2014) criteria with the diagnostic criteria of Ameratunga et al. (2013) and the original ESID/pan American group for immune deficiency (ESID/PAGID 1999) criteria. The ESID/PAGID (1999) criteria either require absent isohemagglutinins or impaired vaccine responses to establish the diagnosis in patients with primary hypogammaglobulinemia. Although commonly encountered, infective and autoimmune sequelae of CVID were not part of the original ESID/PAGID (1999) criteria. Also excluded were a series of characteristic laboratory and histological abnormalities, which are useful when making the diagnosis. The diagnostic criteria of Ameratunga et al. (2013) for CVID are based on these markers. The revised ESID registry (2014) criteria for CVID require the presence of symptoms as well as laboratory abnormalities to establish the diagnosis. Once validated, criteria for CVID will improve diagnostic precision and will result in more equitable and judicious use of intravenous or subcutaneous immunoglobulin therapy.

Primary immune deficiency disorders in the South Pacific: the clinical utility of a customized genetic testing program in New Zealand.

Primary immune deficiency disorders (PIDs) are a group of diseases associated with a genetic susceptibility to recurrent infections, malignancy, autoimmunity, and allergy. The molecular basis of many of these disorders has been identified in the last two decades. Most are inherited as single gene defects. As discussed in this paper, identifying the underlying genetic defect plays a critical role in many areas-including patient management, diagnosis, identifying atypical presentations, family studies, providing prognostic information, prenatal diagnosis, and defining new diseases. New Zealand is a geographically isolated, developed country in the South Pacific. We have introduced a dedicated customized genetic testing service for PID patients in New Zealand. This accredited diagnostic program offers rapid turnaround times for genetic tests and minimizes the risk of laboratory errors. Here we review the clinical indications for genetic testing for PIDs based on cases referred to the molecular immunology diagnostic service at Auckland City Hospital.

Adverse reactions to food in New Zealand children aged 0-5 years.

AIM: The aim of this study was to describe parent/caregiver-reported adverse reactions to food in children aged 0-5 years in New Zealand. METHOD: A cross-sectional survey was undertaken in clinics conducted by the Royal New Zealand Plunket Society, which is the major healthcare provider for New Zealand's Well Child programme. Parents/caregivers of 110 (65%) children participated. RESULTS: Of the 44 children who experienced an adverse reaction to food, only four were clinically evaluated and had undergone diagnostic testing. Two other children were hospitalised following systemic symptoms. Neither was tested for food allergy. 18 (16%) children had physician diagnosed eczema. CONCLUSION: Within the limitations of this small study, the data indicated adverse reactions to foods are a public health concern in New Zealand and may be under investigated even in children with severe symptoms. These children remain at increased risk of continued morbidity. Based on this preliminary study further research on food allergy in New Zealand is warranted.

The changing epidemiology of food allergy--implications for New Zealand.

Food allergy (FA) is recognised as an important public health problem in developed countries. Recent studies suggest a significant proportion of the general population has a definable FA. The methods used to study FA influence published estimates of incidence and prevalence. In particular, studies relying on self-assessment are likely to overestimate the condition compared to studies using a comprehensive approach including symptoms, allergy testing, rigorously conducted laboratory tests, and food challenges. Currently there are no reliable data on the prevalence of FA in New Zealand. This has had several adverse consequences including the lack of public hospital services for patients with severe allergies. In this article we summarise the epidemiological data on FA and discuss the implications for New Zealand.