An Atypical Autoinflammatory Disease Due to an LRR Domain NLRP3 Mutation Enhancing Binding to NEK7.

The NLRP3 inflammasome is a vital mediator of innate immune responses. There are numerous NLRP3 mutations that cause NLRP3-associated autoinflammatory diseases (NLRP3-AIDs), mostly in or around the NACHT domain. Here, we present a patient with a rare leucine-rich repeat (LRR) domain mutation, p.Arg920Gln (p.R920Q), associated with an atypical NLRP3-AID with recurrent episodes of sore throat and extensive oropharyngeal ulceration. Unlike previously reported patients, who responded well to anakinra, her oral ulcers did not significantly improve until the PDE4 inhibitor, apremilast, was added to her treatment regimen. Here, we show that this mutation enhances interactions between NLRP3 and its endogenous inhibitor, NIMA-related kinase 7 (NEK7), by affecting charge complementarity between the two proteins. We also demonstrate that additional inflammatory mediators, including the NF-кB and IL-17 signalling pathways and IL-8 chemokine, are upregulated in the patient's macrophages and may be directly involved in disease pathogenesis. These results highlight the role of the NLRP3 LRR domain in NLRP3-AIDs and demonstrate that the p.R920Q mutation can cause diverse phenotypes between families.

Oral hairy leukoplakia in a patient on long-term anticonvulsant treatment with lamotrigine.

We describe a case of oral hairy leukoplakia that presented with an atypical appearance in a patient on long-term anticonvulsant treatment with an aromatic antiepileptic, lamotrigine. Recent medical history was also significant for recurrent respiratory tract infections requiring treatment with oral antibiotics. Immunologic investigations revealed inverted CD4/CD8 ratio, mild hypogammaglobulinemia, and poor specific antibody titers. Combined immune deficiency caused by long-term treatment with lamotrigine was suspected after other known factors and conditions (including retroviral infection) leading to acquired immune deficiency were excluded. Withdrawal of lamotrigine resulted in complete resolution of oral hairy leukoplakia. There was no significant improvement in immunoglobulin levels. The effect of lamotrigine and other aromatic antiepileptics on the immune system should be considered in a patient presenting with otherwise unexplained oral hairy leukoplakia.

Practical management of antibiotic allergy in adults.

This review looks at the main issues around immediate hypersensitivity and the role and limitations of testing. The majority of literature on antibiotic hypersensitivity relates to ß-lactam antibiotics, mainly because of the heavy usage of this class of drugs. Concerns around cross-reactivity always worry clinicians, particularly in the emergency situation. Reasonable data now exist in relation to ß-lactam antibiotics and derivatives, which enable appropriate risk management to be undertaken. The available literature for other classes of antibiotics is also discussed.

Methotrexate, rheumatoid arthritis and infection risk: what is the evidence?

Low-dose MTX administered weekly remains a mainstay in the therapy of RA. There is a belief amongst rheumatologists that RA patients taking MTX have both an increased risk and severity of infection. Here we review the published data on the risks of infection associated with the use of MTX in patients with RA and make some recommendations for managing MTX in patients with infection.

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 > or = 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.

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.

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.

Reduced anti-PRP antibody response to Hib immunisation in preterm (<32 weeks) UK infants who received inactivated polio (eIPV).

A vaccine containing inactivated polio (eIPV) (Pediacel) is now used in the UK. The effect of the eIPV on other components is not well understood. We studied Haemophilus influenzae type b (Hib) and tetanus responses in preterm infants, <32 weeks gestation at birth, immunised with the (then) standard UK primary vaccines and either oral polio vaccine (OPV) or eIPV and analysed the effect showing reduced Hib responses with eIPV.

An unusual cause of granulomatous disease.

BACKGROUND: Chronic granulomatous disease (CGD) is an inherited disorder of phagocytic cells caused by an inability to generate active microbicidal oxygen species required kill certain types of fungi and bacteria. This leads to recurrent life-threatening bacterial and fungal infections with tissue granuloma formation. CASE PRESENTATION: We describe a case of X-linked Chronic granulomatous disease (CGD) diagnosed in an 18-year-old male. He initially presented with granulomatous disease mimicking sarcoidosis and was treated with corticosteroids. He subsequently developed Burkholderia cepacia complex pneumonia and further investigation confirmed a diagnosis of CGD. CONCLUSION: Milder phenotypes of CGD are now being recognised. CGD should be considered in patients of any age with granulomatous diseases, especially if there is a history of recurrent or atypical infection.

Association of IL13 with total IgE: evidence against an inverse association of atopy and diabetes.

BACKGROUND: Atopic illnesses, related to high circulating IgE levels, and the autoimmune disease type 1 diabetes, have been reported to be inversely associated. One possible explanation is that susceptibility alleles for one disease provide protection for the other. OBJECTIVE: Using the largest sample sizes reported so far for the identification of genetic determinants of circulating IgE levels, we investigated associations between total serum IgE (log-transformed) and single nucleotide polymorphisms in 8 genes that are candidate susceptibility loci for IgE levels/atopic illness (IL13, IL4, IL4RA, FCER1B, IL12B, TBET) and/or type 1 diabetes (CTLA4, PTPN22, IL2RA). METHODS: As many as 4570 DNA samples obtained from members of the British 1958 Birth Cohort were genotyped for 51 candidate variants, and the associations of alleles and genotypes with log-transformed serum IgE levels were evaluated by regression modeling. RESULTS: We obtained evidence of association between IL13 variants and total serum IgE levels (P = .00002, explaining 0.59% of phenotypic variance). However, there was no evidence of association of the confirmed type 1 diabetes susceptibility genes CTLA4 and PTPN22 and the candidate gene IL2RA with IgE levels. CONCLUSION: Allelic variation in the IL-13 gene is robustly confirmed as a contributor to the variance of IgE levels but has no detectable effect in type 1 diabetes. CLINICAL IMPLICATIONS: Although the allelic variation at the confirmed IL-13 locus explains too little of the between-individual variation of circulating IgE to be of use for clinical prediction on its own, the discovery of additional susceptibility loci in the future may aid in the stratification of atopic subjects and improve risk assessment.

Haemophilus influenzae type b immunization in infants in the United Kingdom: effects of diphtheria/tetanus/acellular pertussis/Hib combination vaccine, significant prematurity, and a fourth dose.

OBJECTIVE: To measure anti-polyribosylribitolphosphate (PRP) antibody and anti-tetanus toxoid (TT) antibody responses in UK infants to explore the effects of (1) immunization with an acellular diphtheria/tetanus/pertussis/Haemophilus influenzae type b (DTPHib) combination vaccine, (2) significant preterm delivery, and (3) a fourth dose of conjugated Hib vaccine (PRP-T) in those with a low anti-PRP antibody (<1.0 microg/mL) after primary immunization. METHODS: A prospective study was conducted in 4 tertiary neonatal units at a time when 2 types of DTPHib vaccines were used interchangeably in the United Kingdom for primary immunization: acellular (DTPaHib) and whole cell. Timing and type of all vaccine doses were as per standard UK practice. Blood was taken before and after immunization. A total of 166 preterm and 45 term infants completed the study; 97 (15 term) infants who had anti-PRP antibody <1.0 microg/mL were offered a fourth dose of PRP-T; 61 (55 preterm) then had repeat antibody measurements. Anti-PRP and anti-TT antibody after primary immunization relative to gestation and number of whole cell vaccine doses received was measured, as well as anti-PRP antibody after a fourth dose of PRP-T. RESULTS: A total of 49% of preterm and 33% of term infants had anti-PRP antibody <1.0 microg/mL after full primary immunization. Receipt of 1 or more acellular vaccine doses was associated with lower anti-PRP antibody, a dose response effect being observed. Preterm infants were less likely to have anti-PRP antibody >1.0 microg/mL compared with term infants. A total of 93% of infants who were given a fourth dose had anti-PRP antibody >1.0 microg/mL. Anti-TT antibody responses were satisfactory for all infants but also reduced by each DTPaHib dose received. CONCLUSION: Infants who receive DTPaHib, are significantly preterm, or who do not receive a fourth dose of conjugated Hib vaccine may be at increased risk for Hib disease.