STAT3 gain-of-function mutations connect leukemia with autoimmune disease by pathological NKG2Dhi CD8+ T cell dysregulation and accumulation.

The association between cancer and autoimmune disease is unexplained, exemplified by T cell large granular lymphocytic leukemia (T-LGL) where gain-of-function (GOF) somatic STAT3 mutations correlate with co-existing autoimmunity. To investigate whether these mutations are the cause or consequence of CD8+ T cell clonal expansions and autoimmunity, we analyzed patients and mice with germline STAT3 GOF mutations. STAT3 GOF mutations drove the accumulation of effector CD8+ T cell clones highly expressing NKG2D, the receptor for stress-induced MHC-class-I-related molecules. This subset also expressed genes for granzymes, perforin, interferon-γ, and Ccl5/Rantes and required NKG2D and the IL-15/IL-2 receptor IL2RB for maximal accumulation. Leukocyte-restricted STAT3 GOF was sufficient and CD8+ T cells were essential for lethal pathology in mice. These results demonstrate that STAT3 GOF mutations cause effector CD8+ T cell oligoclonal accumulation and that these rogue cells contribute to autoimmune pathology, supporting the hypothesis that somatic mutations in leukemia/lymphoma driver genes contribute to autoimmune disease.

Human T-bet governs the generation of a distinct subset of CD11chighCD21low B cells.

High-level expression of the transcription factor T-bet characterizes a phenotypically distinct murine B cell population known as "age-associated B cells" (ABCs). T-bet-deficient mice have reduced ABCs and impaired humoral immunity. We describe a patient with inherited T-bet deficiency and largely normal humoral immunity including intact somatic hypermutation, affinity maturation and memory B cell formation in vivo, and B cell differentiation into Ig-producing plasmablasts in vitro. Nevertheless, the patient exhibited skewed class switching to IgG1, IgG4, and IgE, along with reduced IgG2, both in vivo and in vitro. Moreover, T-bet was required for the in vivo and in vitro development of a distinct subset of human B cells characterized by reduced expression of CD21 and the concomitantly high expression of CD19, CD20, CD11c, FCRL5, and T-bet, a phenotype that shares many features with murine ABCs. Mechanistically, human T-bet governed CD21loCD11chi B cell differentiation by controlling the chromatin accessibility of lineage-defining genes in these cells: FAS, IL21R, SEC61B, DUSP4, DAPP1, SOX5, CD79B, and CXCR4. Thus, human T-bet is largely redundant for long-lived protective humoral immunity but is essential for the development of a distinct subset of human CD11chiCD21lo B cells.

Review of venom immunotherapy at a regional tertiary paediatric centre.

AIM: Bee stings can result in allergic reactions, including anaphylaxis. Venom immunotherapy (VIT) is a definitive cure for bee venom allergy, but controversy surrounds whether accelerated protocols are safe in children. Our primary aim was to assess the safety profile of ultra-rush bee VIT compared with conventional bee VIT at a regional paediatric tertiary centre. We also sought to evaluate the impact of both approaches on time and resource use. METHODS: Data were collected retrospectively from 14 patients with bee venom allergy who were treated with ultra-rush or conventional bee VIT between 2013 and 2021 at John Hunter Children's Hospital. We compared VIT-associated adverse reactions and use of resources in both these groups. RESULTS: Overall, six patients received ultra-rush bee VIT and eight patients received conventional VIT. The ultra-rush group had a lower rate of systemic reaction (16%) compared with the conventional group (25%). One patient from the conventional group required adrenaline. Ultra-rush patients require fewer injections over a shorter time and fewer hospital visits to complete the protocol. Travel distance for families was significantly reduced. CONCLUSION: At our regional paediatric tertiary centre, ultra-rush bee VIT was a safe treatment option for children with bee venom allergy. It has many advantages over a conventional approach, especially for patients living in regional or remote areas.

Making a diagnosis of periodic fever syndrome: Experience from a single tertiary centre.

AIM: This study aims to evaluate the utility of genetic testing of patients diagnosed with periodic fever syndromes and to assess the validity of existing scoring criteria. METHODS: This study retrospectively reviewed the clinical history of patients diagnosed with periodic fever syndromes at Queensland Children's Hospital between November 2014 and June 2018. RESULTS: Forty-three patients were diagnosed with periodic fever syndromes. Diagnoses in the cohort included periodic fever, adenitis, pharyngitis and aphthous stomatitis (10), tumour necrosis factor receptor-associated periodic syndrome (9), cryopyrin-associated periodic syndrome (6), mevalonate kinase deficiency (4) while 14 remained unspecified. No presenting symptoms were uniquely associated with any particular diagnosis. Genetic testing of between 1 and 26 genes was performed in 26 (60%) patients. Two (7.7%) patients had pathogenic variants identified. Variants of uncertain significance which were insufficient to confirm a monogenic disorder were identified in a further 7 (27%) patients. The Eurofever classification criteria correlated with clinical diagnosis for patients diagnosed with cryopyrin-associated periodic syndrome (P = 0.046) and tumour necrosis factor receptor-associated periodic syndrome (P = 0.025) but not for patients diagnosed with mevalonate kinase deficiency (P = 0.47); however, the Eurofever classification criteria were often positive for more than one diagnosis in these patients. CONCLUSION: The European classification criteria can form a potentially useful tool to guide diagnosis; however, clinical judgement remains essential, because the score is often positive for multiple diagnoses. The diagnostic yield of genetic testing in this cohort was low and genetic testing may be more useful to confirm a strong clinical suspicion than to clarify a diagnosis for patients with less clear symptoms.

Optimising immunisation in children with 22q11 microdeletion.

BACKGROUND: The condition known as 22q11 microdeletion syndrome has a broad phenotypic spectrum, with many affected individuals experiencing mild-to-moderate immunodeficiency. Currently, there are significant variations in live vaccine practices and immunological testing prior to live vaccine administration due to safety concerns and limited established guidelines. METHODS: Queensland Children's Hospital (QCH) Child Development Unit, offers a state-wide 22q11 microdeletion clinic. This is a retrospective single-centre review, capturing the majority of children with 22q11 microdeletion in Queensland, Australia. We describe the live vaccination status of 134 children, age 0 to 18 years under our care between 2000 and 2018, adverse events following immunisation (AEFI) and the proportion of children who received additional pneumococcal coverage. An immunological investigation pathway prior to live vaccine administration is proposed. RESULTS: Of the 134 children, 124 were eligible for live vaccinations as per the Australian National Immunisation Program: 82% had received dose one of measles, mumps and rubella (MMR) vaccine, 77% had completed MMR dose two and 66% had completed varicella immunisation. There were no AEFI notifications reported. Of the total sample of children, 18% received a fourth dose of conjugate pneumococcal vaccine (Prevenar 7 or 13) and 16% received a dose of Pneumovax 23 from 4 years of age. Immunology workup practices were demonstrated to vary widely prior to live vaccine administration. Most patients' immune profiles were consistent with mild-to-moderate immunodeficiency. CONCLUSION: We propose an immunological investigation and vaccination pathway with the aim of providing guidance and consistency to clinicians caring for children with 22q11 microdeletion.

Diagnosis and management of severe combined immunodeficiency in Australia and New Zealand.

This consensus document outlines the recommendations from the Australasian Society of Clinical Immunology and Allergy Transplantation and Primary Immunodeficiency group for the diagnosis and management of patients with severe combined immunodeficiency. It also provides a proposed framework for the early investigation, management and supportive care prior to haematopoietic stem cell transplantation.

Change in exhaled nitric oxide during peanut challenge is related to severity of reaction.

BACKGROUND: Peanut allergy affects 3% of Australian children and has a higher risk of anaphylaxis than most food allergies. Predicting who is likely to develop anaphylaxis is still an inexact science. The fraction of exhaled nitric oxide (FeNO) shows promise as a biomarker involved in peanut allergy, as nitric oxide plays a role in inhibiting mast cell degranulation which is relevant in anaphylaxis, where mast cell degranulation plays a mediator role. The aim of this study was to assess the change in FeNO in children during peanut challenge. METHODS: Thirty-six children aged from 5 to 17 years were recruited for open-labelled peanut challenge. Participants had skin prick test to peanut performed, and serum collected for Ara h2 specific IgE and peanut specific IgE. FeNO was measured by portable device (NIOX VERO) prior to and throughout the peanut challenge. RESULTS: When grouped according to reaction type at peanut challenge (anaphylaxis, clinical allergy not anaphylaxis and tolerant), there were significant differences in the mean change in FeNO measurement between the anaphylaxis group and the clinical allergy, not anaphylaxis group (p = 0.005), and between the anaphylaxis group and tolerant group (p < 0.0001). CONCLUSIONS: FeNO decreased more significantly in those who subsequently developed anaphylaxis than in those with clinical allergy, not anaphylaxis or negative peanut challenge (tolerance). As a bedside test that can be used in children, it has potential for further research into mechanisms of anaphylaxis in food allergy and potentially assists in predicting an imminent anaphylactic reaction in some patients.Trial registration ClinicalTrials.gov: PEAnut Anaphylaxis Predictors (PEAAP) NCT02424136.

Reproducibility of serum IgE, Ara h2 skin prick testing and fraction of exhaled nitric oxide for predicting clinical peanut allergy in children.

BACKGROUND: Ara h2 sIgE serum levels improve the diagnostic accuracy for predicting peanut allergy, but the use of Ara h2 purified protein as a skin prick test (SPT), has not been substantially evaluated. The fraction of exhaled nitric oxide (FeNO) shows promise as a novel biomarker of peanut allergy. Reproducibility of these measures has not been determined. The aim was to assess the accuracy and reproducibility (over a time-period of at least 12 months) of SPT to Ara h2 in comparison with four predictors of clinical peanut allergy (Peanut SPT, Ara h2 specific Immunoglobulin E (sIgE), Peanut sIgE and FeNO). METHODS: Twenty-seven children were recruited in a follow-up of a prospective cohort of fifty-six children at least 12 months after an open-labelled peanut food challenge. Their repeat assessment involved a questionnaire, SPT to peanut and Ara h2 purified protein, FeNO and sIgE to peanut and Ara h2 measurements. RESULTS: Ara h2 SPT was no worse in accuracy when compared with peanut SPT, FeNO, Ara h2 sIgE and peanut sIgE (AUC 0.908 compared with 0.887, 0.889, 0.935 and 0.804 respectively) for predicting allergic reaction at previous food challenge. SPT for peanut and Ara h2 demonstrated limited reproducibility (ICC = 0.51 and 0.44); while FeNO demonstrated good reproducibility (ICC = 0.73) and sIgE for peanut and Ara h2 were highly reproducible (ICC = 0.81 and 0.85). CONCLUSIONS: In this population, Ara h2 SPT was no worse in accuracy when compared with current testing for the evaluation of clinical peanut allergy, but had-like peanut SPT-poor reproducibility. FeNO, peanut sIgE and Ara h2 sIgE were consistently reproducible despite an interval of at least 12 months between the repeated measurements.

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.

Paediatric non-IgE mediated food allergy: guide for practitioners.

AIM: Food avoidance in children is increasingly common due to concerns about allergy. We aim to review the current literature on paediatric non-IgE mediated food allergy including what is known about pathophysiology, diagnosis, management and prognosis of common and severe presentations. Considerations regarding appropriate formula selection are also presented. METHODS: Common non-IgE mediated conditions were searched through common medical databases. Thorough review of available literature was then synthesised and critically appraised. RESULTS: Current understanding of immunological mechanisms of most non-IgE mediated conditions remains elusive. Most conditions are outgrown in childhood and have a good prognosis. Dietary modification for some conditions is important to ensure safety. They are not recommended in all situations due to potentially harmful consequences. CONCLUSION: Assessment of children with concerns regarding non-IgE mediated conditions requires a thorough history and is generally not supported by reliable diagnostic tests. Caution is warranted when advising families to undertake dietary exclusions unless well supported by the evidence and ensuring benefits outweigh any potential harm.

X-linked Agammaglobulinemia With Normal Immunoglobulin and Near-Normal Vaccine Seroconversion.

We present a 22-month-old boy with X-linked agammaglobulinemia masked by normal immunoglobulin levels and vaccine seroconversion. Diagnosis was made after strong clinical suspicion of immune deficiency led to identification of markedly reduced B-cell numbers and confirmation with identification of a novel Bruton tyrosine kinase gene mutation. He was commenced on replacement immunoglobulin therapy with excellent clinical improvement. This case highlights the variability of phenotypic presentation and apparent disunity between routine immunologic investigations and severe disease in X-linked agammaglobulinemia, necessitating clinical acumen to make the diagnosis.