Scott Hackett

Immunodeficiency and severe susceptibility to bacterial infection associated with a loss-of-function homozygous mutation of MKL1

Megakaryoblastic leukemia 1 (MKL1), also known as MAL or myocardin-related transcription factor A (MRTF-A), is a coactivator of serum response factor, which regulates transcription of actin and actin cytoskeleton-related genes. MKL1 is known to be important for megakaryocyte differentiation and function in mice, but its role in immune cells is unexplored. Here we report a patient with a homozygous nonsense mutation in the MKL1 gene resulting in immunodeficiency characterized predominantly by susceptibility to severe bacterial infection. We show that loss of MKL1 protein expression causes a dramatic loss of filamentous actin (F-actin) content in lymphoid and myeloid lineage immune cells and widespread cytoskeletal dysfunction. MKL1-deficient neutrophils displayed reduced phagocytosis and almost complete abrogation of migration in vitro. Similarly, primary dendritic cells were unable to spread normally or to form podosomes. Silencing of MKL1 in myeloid cell lines revealed that F-actin assembly was abrogated through reduction of globular actin (G-actin) levels and disturbed expression of multiple actin-regulating genes. Impaired migration of these cells was associated with failure of uropod retraction likely due to altered contractility and adhesion, evidenced by reduced expression of the myosin light chain 9 (MYL9) component of myosin II complex and overexpression of CD11b integrin. Together, our results show that MKL1 is a nonredundant regulator of cytoskeleton-associated functions in immune cells and fibroblasts and that its depletion underlies a novel human primary immunodeficiency.

Inflammatory and autoimmune manifestations in X-linked carriers of chronic granulomatous disease in the United Kingdom

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Anaphylaxis and ethnicity: higher incidence in British South Asians.

The incidence of anaphylaxis in South Asians (Indian, Pakistani and Bangladeshi ethnicity) is unknown. Birmingham is a British city with a disproportionately large population of South Asians (22.5%) compared with the rest of the UK (4.9%). The main aims of this study were to determine the incidence and severity of anaphylaxis in this population and to investigate the differences between the South Asian and White populations.

Degos disease: a new simulator of non-accidental injury

Recent high‐profile cases have made paediatricians very aware of the serious implications of either missing or wrongly diagnosing non‐accidental injury. Subdural fluid collections in non‐mobile infants usually represent haemorrhage caused by non‐accidental injury. We report a 6‐month‐old male who presented to the Accident and Emergency Department of Birmingham Heartlands Hospital with bilateral subdural fluid collections and skin ulcers resembling cigarette burns. Non‐accidental injury was considered to be the most likely diagnosis. However, while under observation in hospital, the child’s neurological condition deteriorated with progressive cerebral infarctions, and serial photographs of the skin lesions showed failure to heal. The revised diagnosis, confirmed histologically, was Degos disease, an extremely rare and often fatal occlusive vasculopathy. The child was treated palliatively and died 8 weeks after presentation. This report informs doctors of a new simulator of non‐accidental injury to be considered in infants with otherwise unexplained subdural fluid collections.

Systemic reactions and anaphylaxis with an acute serum tryptase ≥14 μg/L: retrospective characterisation of aetiology, severity and adherence to National Institute of Health and Care Excellence (NICE) guidelines for serial tryptase measurements and specialist referral

Aims To characterise patients with systemic reactions and anaphylaxis with an acute serum tryptase of ≥14 μg/L against recently published World Allergy Organisation (WAO) diagnostic criteria. To also perform a clinical audit to assess adherence to National Institute of Health and Care Excellence (NICE) guideline recommendations regarding serial tryptase measurements and specialist referral. Methods A systematic retrospective survey (2006–2010) was carried out (n=171; males=86; mean age±SD 48±20 years) and data were extracted from emergency department and specialist allergy clinic records. Results 34 patients (20%) had a grade 1 reaction, 61 (36%) grade 2, 46 (27%) grade 3 and 6 patients (4%) grade 4 (24 patients (13%) could not be graded due to lack of adequate clinical details) and 6% developed a biphasic response. Serial tryptase measurements were not available in 117 (69%) of the cohort. 97 (57%) patients were referred for specialist assessment, and 72 (74%) attended. 50% of cases were diagnosed with idiopathic systemic reactions/anaphylaxis and 28%, 14% and 8% triggered by drugs, foods and other allergies including disorders of mast cell overload, respectively. A weak positive correlation was detected between acute serum tryptase and severity. Conclusions The correlation between acute serum tryptase and severity of anaphylaxis/systemic reactions is weak. A significant proportion of patients with raised acute serum tryptase had mild reactions which did not meet WAO criteria for anaphylaxis and this may reduce the specificity of the test. The commonest aetiology in this cohort was idiopathic followed by drug and food allergies. NICE guidelines relating to serial tryptase measurements and specialist referral were not followed, and there is an urgent need to raise the awareness among clinicians involved in the management of anaphylaxis.

An audit of lymphopenia in infants under 3 months of age.

Severe combined immunodeficiency (SCID) describes a group of rare genetic disorders characterised by deficient or absent T cell immunity, with an estimated incidence of 1 in 50 000 to 1 in 500 000.1 SCID is considered a paediatric emergency, but early clues, such as lymphopenia, are often not noted.2 As a result, the UK Primary Immunodeficiency Network (UK PIN) recommends that children under 2 years of age with an absolute lymphocyte count (ALC) below 3000/μl must be screened for SCID.3 A …

UK vaccination schedule: persistence of immunity to hepatitis B in children vaccinated after perinatal exposure

Objective To assess persistence of immunity to hepatitis B (HBV) in primary school children vaccinated following perinatal exposure. Design Serological survey. Setting Five UK sites (Berkshire East, Birmingham, Buckinghamshire, Milton Keynes and Oxfordshire). Participants Children from 3 years 4 months to 10 years of age (mean age 6.2 years), vaccinated against HBV from birth following perinatal exposure. Interventions A single booster dose of the paediatric formulation of a recombinant HBV vaccine. Main outcome measures Titres of antibody against hepatitis B Surface Antigen (anti-HBs) measured immediately before and 21–35 days after the HBV vaccine booster. Results Prebooster anti-HBs titres were >10 mIU/ml in 84.6% of children (n=26; 95% CI 65.1 to 95.6%). All children (n=25, 95% CI 86.3 to 100%) had titres >100 mIU/ml after the booster. Conclusions This study of antibody persistence among UK children born to hepatitis B infected women, immunised with a 3-dose infant schedule with a toddler booster suggests sustained immunity through early childhood. These data should prompt further studies to address the need for a preschool booster. Trial registration Eudract Number 2008-004785-98.

Immune deficiencies in children: an overview

Primary immune deficiencies (PIDs) are disorders of the immune system that result in increased susceptibility to infectious disease, autoimmunity and malignancy. They are challenging to paediatricians as they can present anytime from birth to adolescence with a wide variety of signs and symptoms. It is important to diagnose PIDs promptly, especially more severe forms to prevent significant morbidity and mortality. However, significant challenges exist in deciding which children to investigate and when. We aim to give a basic understanding of the human immune system, the different presentations in a child that should alert a paediatrician about the possibility of PID and the possible underlying diagnosis. Additionally, we have developed a framework for a stepwise approach to investigating these children.

Severe/combined immunodeficiency in children – a cohort of 19 patients

Background Severe Combined Immunodeficiency (SCID/CID) is a primary immune deficiency and usually has severe defect in both T- & B-lymphocyte systems. This usually results in onset of one or more serious infections within first few months of life. Aim Review all cases presented or referred to our immunology department in the past 8 years with suspected immune deficiency. Methods Case notes, correspondence and results were reviewed for all children diagnosed with SCID/CID at Birmingham Heartlands Hospital in last 7 years. Results A total of 19 patients were reviewed: 10 males and 9 females were identified. All were born at term and had no antenatal diagnosis of SCID. 9 were born to consanguineous parents and 9 had family history of immunodeficiency. The initial age at presentation varied from 1 day to 24 months. The age at final diagnosis was 2 days to 5 years. Symptoms at presentation included chest infections, diarrhoea, failure to thrive, skin infections and complicated medical problems. 11 were referred to our department for paediatric immunological opinion from other hospitals. 18 of these children were referred for bone marrow transplant to Great Ormond Street Hospital, London or Newcastle-Upon-Tyne Hospitals and 10 have been transplanted to date. 3 are awaiting a donor. One is currently receiving gene therapy and 1 awaiting thymus transplant. 6 of these children did not survive (3 died post transplant and 3 while awaiting transplant) and rest are still under follow up. Conclusions SCID / CID is a relatively common condition in West Midlands. Presentation of infants with SCID is variable and needs to be considered. Universal screening of Guthrie card heel pricks for T-cell receptor excision circles (TRECs) would allow patients to be identified sooner and hopefully improve survival rates.