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Granulomas may develop as a response to a local antigenic trigger, leading to the activation of macrophages and T-lymphocytes. Primary immunodeficiency (PID) is associated with the development of extensive cutaneous granulomas, whose aetiology remains unknown. We performed high-throughput sequencing of the transcriptome of cutaneous granuloma lesions on two consecutive index cases, and RT-PCR in a third consecutive patient. The RA27/3 vaccine strain of rubella virus-the core component of a universally used paediatric vaccine-was present in the cutaneous granuloma of these three consecutive PID patients. Controls included the healthy skin of two patients, non-granulomatous cutaneous lesions of patients with immunodeficiency, and skin biopsy samples of healthy individuals, and were negative. Expression of viral antigens was confirmed by immunofluorescence. Persistence of the rubella vaccine virus was also demonstrated in granuloma lesions sampled 4-5 years earlier. The persistence of the rubella virus vaccine strain in all three consecutive cutaneous granuloma patients with PID strongly suggests a causal relationship between rubella virus and granuloma in this setting., (© 2014 The Authors Clinical Microbiology and Infection © 2014 European Society of Clinical Microbiology and Infectious Diseases.)

Genetic mutations cause primary immunodeficiencies (PIDs) that predispose to infections. Here, we describe activated PI3K-δ syndrome (APDS), a PID associated with a dominant gain-of-function mutation in which lysine replaced glutamic acid at residue 1021 (E1021K) in the p110δ protein, the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ), encoded by the PIK3CD gene. We found E1021K in 17 patients from seven unrelated families, but not among 3346 healthy subjects. APDS was characterized by recurrent respiratory infections, progressive airway damage, lymphopenia, increased circulating transitional B cells, increased immunoglobulin M, and reduced immunoglobulin G2 levels in serum and impaired vaccine responses. The E1021K mutation enhanced membrane association and kinase activity of p110δ. Patient-derived lymphocytes had increased levels of phosphatidylinositol 3,4,5-trisphosphate and phosphorylated AKT protein and were prone to activation-induced cell death. Selective p110δ inhibitors IC87114 and GS-1101 reduced the activity of the mutant enzyme in vitro, which suggested a therapeutic approach for patients with APDS.

DNA polymerase ε (Polε) is a large, four-subunit polymerase that is conserved throughout the eukaryotes. Its primary function is to synthesize DNA at the leading strand during replication. It is also involved in a wide variety of fundamental cellular processes, including cell cycle progression and DNA repair/recombination. Here, we report that a homozygous single base pair substitution in POLE1 (polymerase ε 1), encoding the catalytic subunit of Polε, caused facial dysmorphism, immunodeficiency, livedo, and short stature ("FILS syndrome") in a large, consanguineous family. The mutation resulted in alternative splicing in the conserved region of intron 34, which strongly decreased protein expression of Polε1 and also to a lesser extent the Polε2 subunit. We observed impairment in proliferation and G1- to S-phase progression in patients' T lymphocytes. Polε1 depletion also impaired G1- to S-phase progression in B lymphocytes, chondrocytes, and osteoblasts. Our results evidence the developmental impact of a Polε catalytic subunit deficiency in humans and its causal relationship with a newly recognized, inherited disorder.

We report the clinical description and molecular dissection of a new fatal human inherited disorder characterized by chronic autoinflammation, invasive bacterial infections and muscular amylopectinosis. Patients from two kindreds carried biallelic loss-of-expression and loss-of-function mutations in HOIL1 (RBCK1), a component of the linear ubiquitination chain assembly complex (LUBAC). These mutations resulted in impairment of LUBAC stability. NF-κB activation in response to interleukin 1β (IL-1β) was compromised in the patients' fibroblasts. By contrast, the patients' mononuclear leukocytes, particularly monocytes, were hyper-responsive to IL-1β. The consequences of human HOIL-1 and LUBAC deficiencies for IL-1β responses thus differed between cell types, consistent with the unique association of autoinflammation and immunodeficiency in these patients. These data suggest that LUBAC regulates NF-κB-dependent IL-1β responses differently in different cell types.

We report the first prospective study describing the prevalence and clinical consequences of norovirus infection in hospitalized children with primary immunodeficiencies. Fecal samples from 62 children were systematically screened for virus. Norovirus was the most frequent pathogen (11 of 24 positive samples) found in both combined and humoral immunocompromised children. Norovirus shedding was associated with gastrointestinal symptoms and concomitant viremia in 54.5% and 25% of cases, respectively. Norovirus excretion was prolonged: 57.1% of fecal samples were still positive after a median of 9.5-months follow-up. Further large longitudinal studies are needed to evaluate the clinical consequences of norovirus shedding in patients with primary immunodeficiencies.

Background: Cartilage-hair hypoplasia (CHH) is a rare autosomal recessive disorder characterized by short-limbed skeletal dysplasia. Some patients also have defects in cell-mediated immunity and antibody production. Granulomatous inflammation has been described in patients with various forms of primary immunodeficiencies but has not been reported in patients with CHH., Objective: We sought to describe granulomatous inflammation as a novel feature in patients with CHH, assess associated immunodeficiency, and evaluate treatment options., Methods: In a retrospective observational study we collected clinical data on 21 patients with CHH to identify and further characterize patients with granulomatous inflammation., Results: Four unrelated patients with CHH (with variable degrees of combined immunodeficiency) had epithelioid cell granulomatous inflammation in the skin and visceral organs. Anti-TNF-α mAb therapy in 3 of these patients led to significant regression of granulomas. However, 1 treated patient had fatal progressive multifocal leukoencephalopathy caused by the JC polyomavirus. In 2 patients immune reconstitution after allogeneic hematopoietic stem cell transplantation led to the complete disappearance of granulomas., Conclusion: To the best of our knowledge, this is the first report of granulomatous inflammation in patients with CHH. Although TNF-α antagonists can effectively suppress granulomas, the risk of severe infectious complications limits their use in immunodeficient patients., (Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Objective: To demonstrate the feasibility of administration Tegeline at home from a point of view of efficacy, safety, tolerance, to validate the pertinence of the selection and the training of patients who could benefit from this type of administration and to assess the long term efficacy and safety., Method: This retrospective study was conducted in patients exhibiting primary immune deficiency and formerly treated with intravenous immunoglobulins at least six months in hospital settings, trained by the centre for the training of children in the home (Centre de formation au traitement à domicile de l'enfant--CFTDE) and having received at least one administration of Tegeline at home from January 1st 2000. Tegeline contains a mean of 97.6% of whole IgG (58.8% of IgG1, 34.1% of IgG2, 5.4% of IgG3 and 1.7% of IgG4)., Results: Two hundred and eighteen follow-up sheets were completed by 13 patients in whom all the eligibility criteria were fulfilled. The total number of infusions per patient ranged from 4 to 41. No difficulty in administration was reported in 10 patients, difficulties in placing the needle were encountered in 3 other patients and motivating their return to the hospital for treatment (after 6 and 10 months) in 2 cases. The infusion flow rate was usually of 2 to 3 ml/kg/h. During the follow-up period, no episode of infection was noted in 5 patients and 8 presented infections that were treated with antibiotics. Regarding safety, the security 'kits' (corticosteroids, adrenalin) that were supplied to each patient were never used. Over time, the median duration of the infusions at home was of 5 years and 6 months., Conclusion: In trained and selected patients, this study demonstrated the efficacy, safety and tolerance to the administration of Tegeline at home.

Mutations of the Activation-Induced Cytidine Deaminase (AID) gene have been found in patients with autosomal recessive hyper-IgM (HIGM) syndrome type 2. We retrospectively analyzed clinical, immunologic and genetic characteristics of 29 patients from 22 families with AID deficiency. Patients' median age at diagnosis and at last evaluation was 4.9 years (range: 0 to 53) and 14.2 years (range: 2.7 to 63), respectively. Most patients had suffered from recurrent and severe infections, however, intravenous immunoglobulin (IVIG) replacement therapy resulted in a dramatic decrease in the number of infections. Lymphoid hyperplasia developed in 22 patients and persisted in 7 at last follow-up. It is striking to note that six patients developed autoimmune or inflammatory disorders including diabetes mellitus, polyarthritis, autoimmune hepatitis, hemolytic anemia, immune thrombocytopenia, Crohn's disease and chronic uveitis. Fifteen distinct AID mutations were found but there was no significant genotype-phenotype correlation. In conclusion, AID-deficient patients are prone to infections and lymphoid hyperplasia, which may be prevented by early-onset IVIG replacement, but also to autoimmune and inflammatory disorders.

Patients with X-linked hyper-IgM syndrome [CD40 ligand (CD40L) deficiency] are prone to infections by intracellular parasites. It has been suggested that this susceptibility is caused by defective macrophage activation through the CD40L-CD40 pathway. We studied the CD40-mediated activation of monocytes and dendritic cells from patients affected with a CD40L+ hyper-IgM syndrome characterized by a defect of B lymphocyte responses to CD40 agonists. We show that the CD40-induced production of IL-6, IL-8 and TNF-alpha by monocytes, and IL-12 by dendritic cells, and expression of the activation markers CD83, the costimulatory molecules CD86 and CD80, and HLA-DR antigens were all similar in patient and control cells. This observation is consistent with the clinical characteristics of the syndrome: a defect of immunoglobulin switch but no susceptibility to opportunistic infections, as observed in CD40L-deficient patients. These observations suggest that CD40-mediated activation pathways could be, at least in part, different in B and monocytic/dendritic cell lineages.