Gavin Spickett

Relevance of biallelic versus monoallelic TNFRSF13B mutations in distinguishing disease-causing from risk-increasing TNFRSF13B variants in antibody deficiency syndromes

TNFRSF13B encodes transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), a B cell- specific tumor necrosis factor (TNF) receptor superfamily member. Both biallelic and monoallelic TNFRSF13B mutations were identified in patients with common variable immunodeficiency disorders. The genetic complexity and variable clinical presentation of TACI deficiency prompted us to evaluate the genetic, immunologic, and clinical condition in 50 individuals with TNFRSF13B alterations, following screening of 564 unrelated patients with hypogammaglobulinemia. We identified 13 new sequence variants. The most frequent TNFRSF13B variants (C104R and A181E; n=39; 6.9%) were also present in a heterozygous state in 2% of 675 controls. All patients with biallelic mutations had hypogammaglobulinemia and nearly all showed impaired binding to a proliferation-inducing ligand (APRIL). However, the majority (n=41; 82%) of the pa-tients carried monoallelic changes in TNFRSF13B. Presence of a heterozygous mutation was associated with antibody deficiency (P< .001, relative risk 3.6). Heterozygosity for the most common mutation, C104R, was associated with disease (P< .001, relative risk 4.2). Furthermore, heterozygosity for C104R was associated with low numbers of IgD(-)CD27(+) B cells (P= .019), benign lymphoproliferation (P< .001), and autoimmune complications (P= .001). These associations indicate that C104R heterozygosity increases the risk for common variable immunodeficiency disorders and influences clinical presentation.

Autoantibodies against type I interferons as an additional diagnostic criterion for autoimmune polyendocrine syndrome type I

CONTEXT In autoimmune polyendocrinopathy syndrome type I (APS-I), mutations in the autoimmune regulator gene (AIRE) impair thymic self-tolerance induction in developing T cells. The ensuing autoimmunity particularly targets ectodermal and endocrine tissues, but chronic candidiasis usually comes first. We recently reported apparently APS-I-specific high-titer neutralizing autoantibodies against type I interferons in 100% of Finnish and Norwegian patients, mainly with two prevalent AIRE truncations. OBJECTIVES Because variability in clinical features and age at onset in APS-I frequently results in unusual presentations, we prospectively checked the diagnostic potential of anti-interferon antibodies in additional APS-I panels with other truncations or rare missense mutations and in disease controls with chronic mucocutaneous candidiasis (CMC) but without either common AIRE mutation. DESIGN The study was designed to detect autoantibodies against interferon-alpha2 and interferon-omega in antiviral neutralization assays. SETTING AND PATIENTS Patients included 14 British/Irish, 15 Sardinian, and 10 Southern Italian AIRE-mutant patients with APS-I; also 19 other patients with CMC, including four families with cosegregating thyroid autoimmunity. OUTCOME The diagnostic value of anti-interferon autoantibodies was assessed. RESULTS We found antibodies against interferon-alpha2 and/or interferon-omega in all 39 APS-I patients vs. zero of 48 unaffected relatives and zero of 19 British/Irish CMC patients. Especially against interferon-omega, titers were nearly always high, regardless of the exact APS-I phenotype/duration or AIRE genotype, including 12 different AIRE length variants or 10 point substitutions overall (n=174 total). Strikingly, in one family with few typical APS-I features, these antibodies cosegregated over three generations with autoimmune hypothyroidism plus a dominant-negative G228W AIRE substitution. CONCLUSIONS Otherwise restricted to patients with thymoma and/or myasthenia gravis, these precocious persistent antibodies show 98% or higher sensitivity and APS-I specificity and are thus a simpler diagnostic option than detecting AIRE mutations.

Unrelated donor and HLA-identical sibling haematopoietic stem cell transplantation cure chronic granulomatous disease with good long-term outcome and growth

Chronic granulomatous disease (CGD) causes recurrent infection and inflammatory disease. Despite antimicrobial prophylaxis, patients experience frequent hospitalisations and 50% mortality by 30 years. Haematopoietic stem cell transplantation (HSCT) can cure CGD with resolution of infection and colitis. This study reports the survival and long‐term outcome in 20 conditioned patients treated between 1998 and 2007, using 10 matched sibling (MSD) and 10 unrelated donors (URD). Age at HSCT, graft‐versus‐host disease (GvHD), growth, and outcome were analysed. Fourteen had ≥1 invasive infection, 10 had colitis and seven had growth failure before HSCT. Median age at transplantation was 75 months (range 15 months–21 years). Eighteen (90%) were alive 4–117 months (median 61) after HSCT with normal neutrophil function. Two died from disseminated fungal infection. Two experienced significant chronic GvHD, with continuing sequelae in 1. Colitis resolved within 8 weeks of HSCT. Mean weight and height for age Z scores on recovery from HSCT rose significantly (P < 0·001). HSCT with MSD or URD gave excellent engraftment and survival, remission of colitis and catch‐up growth, with low incidence of significant GvHD. Transplant‐associated complications were restricted to those with pre‐existing infection or inflammation, supporting the argument for early HSCT for more CGD patients with a well matched donor.

Lymphoproliferative disease in antibody deficiency: a multi-centre study

We have undertaken a retrospective study of antibody deficient patients, with and without lymphoma, and assessed the ability of specific polymerase chain reaction (PCR) primers to determine if the detection of clonal lymphocyte populations correlates with clinical and immunohistochemical diagnosis of lymphoma. We identified 158 cases with antibody deficiency presenting during the past 20 years. Paraffin‐embedded biopsy specimens or slides were available for analysis in a cohort of 34 patients. Of these patients, 29 had common variable immunodeficiency, one X‐linked agammaglobulinaemia, one X‐linked immunoglobulin deficiency of uncertain cause and three isolated IgG subclass deficiency. We have confirmed that lymphoma in antibody deficiency is predominantly B cell in origin. Clonal lymphocyte populations were demonstrated in biopsies irrespective of histology (16/19 with lymphoma and 11/15 without). Isolated evidence of clonality in biopsy material is therefore an insufficient diagnostic criterion to determine malignancy. Furthermore, our data suggest that clonal expansions are rarely the result of Epstein–Barr virus‐driven disease.

Immunodeficiency and Autoimmunity in 22q11.2 Deletion Syndrome

22q11.2 deletion syndrome is the commonest chromosome deletion syndrome. 22q11.2 deletion may result in variable clinical phenotypes which may differ even between patients with identical deletions. Abnormal pharyngeal arch development results in defects in the development of the parathyroid glands, thymus and conotruncal region of the heart. Defective thymic development is associated with impaired immune function. ‘Complete’ DiGeorge syndrome with total absence of the thymus and a severe T‐cell immunodeficiency accounts for <0.5% of patients. The majority of patients with 22q11.2 deletion syndromes have ‘partial’ defects with impaired thymic development rather than complete absence with variable defects in T‐cell numbers. Immunodeficiency in these patients is not solely due to T‐cell deficiency and abnormalities of T‐cell clonality or impairment of proliferative responses may play a role. Humoral deficiencies including defects in the B‐cell compartment have also been identified in these patients. 22q11.2 deletion syndrome patients are at increased risk of a variety of autoimmune diseases. A number of immune defects may predispose to the development of autoimmunity in these patients including increased infection, impaired development of natural T‐regulatory cells and impaired thymic central tolerance.

Lymphocyte subsets in term and significantly preterm UK infants in the first year of life analysed by single platform flow cytometry

This observational study describes the ranges observed for lymphocyte subsets for significantly preterm infants (<32 weeks) in the first year of life, measured by single platform flow cytometry and compared to identically determined subsets in term infants. After ethical approval 39 term and 28 preterm infants had lymphocyte subset analysis before and after their primary immunization series. Median values with 5th and 95th percentiles of absolute counts and percentages are presented for total lymphocytes, T cells, NK cells, B cells, cytotoxic T cells, helper T cells, dual positive T cells, activated T cells, activated T helper cells (including T regulatory cells), pan memory T cells, pan naïve T cells, memory helper T cells, naïve helper T cells and the T helper/suppressor ratio. The lymphocyte profile of the preterm infants differed from that of the term infants.

Immunologic defects in 22q11.2 deletion syndrome

BACKGROUND 22q11.2 Deletion syndrome, the most common congenital chromosome deletion syndrome, is associated with developmental defects including cardiac abnormalities and hypoplasia or abnormal migration of the thymus. These patients have variable defects in T-cell immunity with an increased incidence of infection and autoimmune disease. OBJECTIVE To investigate the immunologic constitution of children with 22q11.2 deletion syndrome. METHODS We characterized the immunologic constitution of 27 children with 22q11.2 deletion syndrome and 54 healthy controls by flow-cytometric analysis of peripheral blood lymphocyte populations. RESULTS Patients exhibited decreased T-cell numbers, although the normal age-related decrease in T-cell numbers was slower than in healthy children. There was a significant decrease in FoxP3(+) natural regulatory T (nTreg) cells with a strong correlation between nTreg cells and recent T-cell emigrants from the thymus, suggesting a link between the nTreg cell population and thymic function. Although total B-cell numbers were unaffected, patients showed a significantly decreased proportion of memory B cells in the B-cell pool. CONCLUSION Lower nTreg cells in patients suggest that the generation and maintenance of these cells in children is related to thymic function. In addition to T-cell abnormalities classically seen in this syndrome, subtle defects in the B-cell compartment may also be seen.

Cytokine Production Differs in Children and Adults

The susceptibility of normal, healthy children to infection has long been recognized, but the underlying mechanisms are poorly understood. As adequate cytokine production is crucial for optimal immune responses, we assessed antigen and mitogeninduced cytokine production in healthy children. Our results demonstrate that healthy children differ markedly compared with adults in their ability to produce cytokines (IL-2, interferon-γ, IL-4, and IL-6). Maximal stimulation with mitogen demonstrated impaired cytokine production with markedly lower levels of all four cytokines produced compared with adult levels. When stimulated with antigens, median levels of IL-2 and IL-4 remained lower than adult values, IL-6 production was increased as was interferon-γ, albeit not significantly. Although the study was carried out on peripheral blood mononuclear cells that represent a restricted compartment of the immune system, these data suggest that, in healthy children, cytokine production is decreased and/or altered and could result in a suboptimal immune response, which could be one of the factors underlying increased susceptibility to infection in children.

Immunodeficiency and Autoimmunity in DiGeorge syndrome

22q11.2 deletion syndrome is the commonest chromosome deletion syndrome. 22q11.2 deletion may result in variable clinical phenotypes which may differ even between patients with identical deletions. Abnormal pharyngeal arch development results in defects in the development of the parathyroid glands, thymus and conotruncal region of the heart. Defective thymic development is associated with impaired immune function. ‘Complete’ DiGeorge syndrome with total absence of the thymus and a severe T‐cell immunodeficiency accounts for <0.5% of patients. The majority of patients with 22q11.2 deletion syndromes have ‘partial’ defects with impaired thymic development rather than complete absence with variable defects in T‐cell numbers. Immunodeficiency in these patients is not solely due to T‐cell deficiency and abnormalities of T‐cell clonality or impairment of proliferative responses may play a role. Humoral deficiencies including defects in the B‐cell compartment have also been identified in these patients. 22q11.2 deletion syndrome patients are at increased risk of a variety of autoimmune diseases. A number of immune defects may predispose to the development of autoimmunity in these patients including increased infection, impaired development of natural T‐regulatory cells and impaired thymic central tolerance.

The United Kingdom Primary Immune Deficiency (UKPID) Registry: report of the first 4 years' activity 2008-2012

This report summarizes the establishment of the first national online registry of primary immune deficency in the United Kingdom, the United Kingdom Primary Immunodeficiency (UKPID Registry). This UKPID Registry is based on the European Society for Immune Deficiency (ESID) registry platform, hosted on servers at the Royal Free site of University College, London. It is accessible to users through the website of the United Kingdom Primary Immunodeficiency Network (www.ukpin.org.uk). Twenty‐seven centres in the United Kingdom are actively contributing data, with an additional nine centres completing their ethical and governance approvals to participate. This indicates that 36 of 38 (95%) of recognized centres in the United Kingdom have engaged with this project. To date, 2229 patients have been enrolled, with a notable increasing rate of recruitment in the past 12 months. Data are presented on the range of diagnoses recorded, estimated minimum disease prevalence, geographical distribution of patients across the United Kingdom, age at presentation, diagnostic delay, treatment modalities used and evidence of their monitoring and effectiveness.