Eduardo Talesnik

IRF8 Mutations and Human Dendritic-Cell Immunodeficiency

BACKGROUND The genetic analysis of human primary immunodeficiencies has defined the contribution of specific cell populations and molecular pathways in the host defense against infection. Disseminated infection caused by bacille Calmette-Guérin (BCG) vaccines is an early manifestation of primary immunodeficiencies, such as severe combined immunodeficiency. In many affected persons, the cause of disseminated BCG disease is unexplained. METHODS We evaluated an infant presenting with features of severe immunodeficiency, including early-onset disseminated BCG disease, who required hematopoietic stem-cell transplantation. We also studied two otherwise healthy subjects with a history of disseminated but curable BCG disease in childhood. We characterized the monocyte and dendritic-cell compartments in these three subjects and sequenced candidate genes in which mutations could plausibly confer susceptibility to BCG disease. RESULTS We detected two distinct disease-causing mutations affecting interferon regulatory factor 8 (IRF8). Both K108E and T80A mutations impair IRF8 transcriptional activity by disrupting the interaction between IRF8 and DNA. The K108E variant was associated with an autosomal recessive severe immunodeficiency with a complete lack of circulating monocytes and dendritic cells. The T80A variant was associated with an autosomal dominant, milder immunodeficiency and a selective depletion of CD11c+CD1c+ circulating dendritic cells. CONCLUSIONS These findings define a class of human primary immunodeficiencies that affect the differentiation of mononuclear phagocytes. They also show that human IRF8 is critical for the development of monocytes and dendritic cells and for antimycobacterial immunity. (Funded by the Medical Research Council and others.).

First Report of the Hyper-IgM Syndrome Registry of the Latin American Society for Immunodeficiencies: Novel Mutations, Unique Infections, and Outcomes

Hyper-IgM (HIGM) syndrome is a heterogeneous group of disorders characterized by normal or elevated serum IgM levels associated with absent or decreased IgG, IgA and IgE. Here we summarize data from the HIGM syndrome Registry of the Latin American Society for Immunodeficiencies (LASID). Of the 58 patients from 51 families reported to the registry with the clinical phenotype of HIGM syndrome, molecular defects were identified in 37 patients thus far. We retrospectively analyzed the clinical, immunological and molecular data from these 37 patients. CD40 ligand (CD40L) deficiency was found in 35 patients from 25 families and activation-induced cytidine deaminase (AID) deficiency in 2 unrelated patients. Five previously unreported mutations were identified in the CD40L gene (CD40LG). Respiratory tract infections, mainly pneumonia, were the most frequent clinical manifestation. Previously undescribed fungal and opportunistic infections were observed in CD40L-deficient patients but not in the two patients with AID deficiency. These include the first cases of pneumonia caused by Mycoplasma pneumoniae, Serratia marcescens or Aspergillus sp. and diarrhea caused by Microsporidium sp. or Isospora belli. Except for four CD40L-deficient patients who died from complications of presumptive central nervous system infections or sepsis, all patients reported in this study are alive. Four CD40L-deficient patients underwent successful bone marrow transplantation. This report characterizes the clinical and genetic spectrum of HIGM syndrome in Latin America and expands the understanding of the genotype and phenotype of this syndrome in tropical areas.

Higher latitude and lower solar radiation influence on anaphylaxis in Chilean children

Recent studies suggest an association between higher latitude, a proxy of vitamin D (VD) status, and allergic diseases. Chile provides an ideal setting to study this association due to its latitude span and high rates of VD deficiency in southern regions. The aim of this study is to explore the associations of latitude and solar radiation with anaphylaxis admission rates.

time Course of Antibody Response to Tetanus Toxoid and Pneumococcal Capsular Polysaccharides in Patients Infected With Hiv

The temporal course of the humoral immune response to T-cell-dependent and T-cell-independent type 2 antigens was evaluated in HIV-infected patients. In all, 26 seropositive patients were vaccinated with tetanus toxoid and 23-valent pneumococcal vaccines; total IgG and IgG1 antibodies to tetanus toxoid (Ttox) and total IgG and IgG2 antibodies against 23 Streptococcus pneumoniae capsular antigens (PPS) were measured at baseline, 2 months, and 12 months after vaccination. For the Ttox, baseline levels of IgG1 (Ttox-IgG1) increased from 11.0 to 19.5 mg/L at 2 months postimmunization. Overall only 6 patients (23%) showed a significant response. At 12 months postvaccination, Ttox-IgG and T-tox-IgG1 were significantly lower than baseline levels (Ttox IgG basal; 11.0 mg/L, 12 months; 0.8 mg/L, Ttox IgG1 baseline; 13.1 mg/L, Ttox IgG1 12 months; 2.4 mg/L) and in 10 patients, antibodies that fell below protective levels (0.6 mg/L). In contrast with PPS, a significant response was observed at 2 and 12 months (PPS-IgG basal; 35.9 U/ml, 2 months; 151.4 U/ml, 12 months; 59.7 U/ml; PPS-IgG2 baseline 20.3 U/ml, 2 months; 113.2 U/ml, 12 months; 51.9 U/ml). Overall, 19 patients (76%) showed an immune response to pneumococcal polysaccharides antigens. Immunization with the Ttox T-cell-dependent antigen fails to elicit a significant immune response and may induce inhibition of antibody production in HIV-infected patients. In contrast, immunization with a T-cell-independent type 2 antigen can cause the pneumococcal polysaccharides to induce significant immune response in a high proportion of HIV-infected patients.

Inverse correlation between allergy markers and Helicobacter pylori infection in children is associated with elevated levels of TGF-β.

Objectives We evaluated allergy/hypersensitivity clinical markers and their correlation with Helicobactor pylori infection in children and adults to analyze how early acquisition of H. pylori could modulate allergic disorder expression. Patients and methods H. pylori presence was assessed by the rapid urease test and histology of antrum biopsies in 165 patients. Skin tests, serum IgE, and two clinical allergy questionnaires were performed. Allergy severity was operationally defined using a combined score. Findings were correlated with H. pylori status and cytotoxin-associated gene A presence in pediatric and adult patients. Transforming growth factor &bgr; (TGF-&bgr;) levels were measured by an enzyme-linked immunosorbent assay in serum and gastric biopsies of H. pylori (+) patients. Results H. pylori (−) children had more positive skin tests to a higher number of antigens than H. pylori (+) children (P<0.05). Operationally defined allergy inversely correlates with H. pylori infection in children, but not in adults. The percentage of H. pylori infection was lower in children with severe allergy (32.3%) compared with children with mild allergy (43.4%) or no allergy (64.3%) (P<0.05). Colonization with virulent strains (cytotoxin-associated gene A+) showed a nonsignificant inverse correlation with severity of allergies in pediatric patients. H. pylori-infected children, but not adults, without allergy markers showed increased levels of TGF-&bgr; compared with allergic children both in serum and gastric mucosa (P<0.05). Conclusion There was a strong inverse correlation between allergy markers and H. pylori infection in pediatric patients associated with elevated levels of TGF-&bgr; locally and systemically. H. pylori-associated chronic gastritis might downregulate clinical allergy expression.

TRAPS, un síndrome autoinflamatorio: Casos cínicos

Tumor Necrosis Factor Receptor Associated Periodic Syndrome (TRAPS) is an autoinflammatory disorder associated to a mutation of the Tumor Necrosis Factor Receptor 1 (TNFR1) whose clinical presentation consists on recurrent episodes of prolonged fever, abdominal pain, myalgias, migratory cutaneous erythema, conjunctivitis or periorbitary edema. The diagnosis is confirmed by genetic analysis of the TNFR1 gene. Its main complication is amyloidosis and the treatment is based on the use of corticosteroids or anti-TNF antibodies. We report a 17 year-old male and 23 year-old female with the syndrome. Both cases had heterozygous mutations of the TNFR1 gene, C30R in the first case and T50M in the second case.

Azathioprine as Monotherapy for Scleritis in Relapsing Polychondritis

Dear Editor, Relapsing polychondritis (RPC) is a rare immunemediated condition occurring at nearly all ages. It is characterized by inflammation in cartilaginous structures and other tissues throughout the body, particularly the ears, nose, eyes, joints, and respiratory tract. Ocular disease is a frequent problem in RPC, affecting up to 22% of patients at presentation and approximately 60% at some time during the course of the disease. The most common ocular findings in RPC are scleritis, uveitis, peripheral ulcerative keratitis, conjuntival lesions, and/or proptosis.1,2 In most patients, relapsing polychondritis assumes a fluctuating but progressive course in which polycyclic bouts of inflammation eventually lead to the permanent destruction of the involved structure, resulting in a significant shortening of life expectancy.3 The goal of treatment in RPC is to abate current symptoms and to preserve the integrity of cartilaginous structures and visual function. No form of therapy has been shown to modify the natural history of the disease, although successful remission of inflammation can be achieved upon anti-inflammatory and immunosuppressive agents. The rarity of RPC has not allowed clinical trials to determine the efficacy and safety of different therapies. We present a case that may add some information about the better response to azathioprine treatment than to other immunosuppressive drugs for scleritis in RPC setting. In May 2003, a 9-year-old female was sent to our ophthalmology clinic with a 10-day history of pain, redness, and visual loss in her left eye (Figure 1). Previous medical history was unremarkable and she had no family history of autoimmune diseases. Clinical diagnosis of diffuse non-necrotizing anterior scleritis was done. At that time, physical examination was otherwise normal. Laboratory workup of autoimmune and infectious diseases was negative, including antinuclear antibodies (ANA), antineutrophil cytoplasmic antibodies (ANCA), anti DNA antibodies, rheumatoid factor, human leukocyte antigen B-27 (HLA B-27), indirect fluorescence assay (IFA) for Bartonella henselae, and enzyme-linked immunosorbent assay (ELISA) for Toxoplasma gondii. Hemogram, urinalysis, and complement levels C3 and C4 were normal. We started prednisone 20 mg/daily and complete remission was achieved in 6 months. The scleritis remained inactive for 3 years after stopping all medication. At age 12, the patient had a new episode of scleritis in her right eye. Treatment with systemic steroids and methotrexate 12.5 mg/week achieved partial response. When the steroids were tapered to 5 mg/day she had a new flare-up of the disease. Methotrexate was replaced by mycophenolate 2 g per day. Despite this treatment, recurrent episodes of scleritis persisted over the next 2 years of treatment, so mycophenolate was replaced by azathioprine 50 mg/ Ocular Immunology & Inflammation, 20(3), 235–236, 2012 Copyright

Características clínicas asociadas a colitis eosinofílica en lactantes con rectorragia persistente

UNLABELLED The most common presentation of cows milk protein allergy (CMP) in infants is known as eosinophilic colitis (EC). The aim of this study is to evaluate EC characteristics in infants evaluated with colonoscopy due to the presence of rectorrhagia. PATIENTS AND METHODS A retrospective case-control study. Left-sided colonoscopy records of infants with persistent rectal bleeding, conducted between January 2006 and March 2011, were reviewed. The cases corresponded to infants with rectal biopsy compatible with EC and controls with negative biopsy. Telephone questionnaires to parents were conducted, evaluating personal and family history. RESULTS Complete records were obtained in 61 (79%) of the 77 procedures. 33 (54%) of them were males. Examination average age was 6.3 ± 5.9 months. 25 (41%) patients had EC on their histology. Between cases and controls, no significant difference in gestational age, birth weight and gender, only regarding age at the time of rectal bleeding, were observed. There was also no difference in personal history regarding obstructive bronchitis, allergic rhinitis, family history of asthma, allergic rhinitis or other food allergies. Those who received artificial feeding did not presented greater risk of EC. The most common symptoms in the cases did not differ significantly from the controls. CONCLUSIONS The prevalence of EC in the children studied was 40.9%. Our results show that there are groups of patients with persistent rectal bleeding in which there is no personal or family history that helps diagnosing EC. An endoscopic study could be considered in these patients to establish a correct diagnosis of this condition, avoid unnecessary diets and not to delay the detection of other diseases.

A126: Clusters of Autoimmune Diseases in Children and the Role of PTPN22 C1858T Gene Polymorphism in Pediatric Polyautoimmunity

Autoimmune diseases (AIDs) have familial aggregation and frequently share a common genetic background, but few studies have evaluated autoimmune clusters in children with AIDs and their families. Children with more than one AID (pediatric polyautoimmunity) may have a stronger genetic component than children with a single AID. The objectives of this study were to identify clusters of AIDs in children and their first‐degree relatives and to evaluate the association of PTPN22 C1858T gene polymorphism with pediatric polyautoimmunity.

Rising incidence of Kawasaki disease in Chile: analysis of national discharge databases between 2001 and 2007

Results Seven hundred eighty-six hospitalizations attributable to KD were identified between 2001 and 2007, representing 0.03% of hospitalizations in children younger than 18 years. Median age of diagnosis was 1 year (range 0-17). Twenty-five percent of patients were younger than 1 year, 60% were between 1 and 4 years, 11% between 5 and 9 years, and 4% between 10 and 17 years. Male to female ratio was 1.6:1. Median length of hospital stay was 5 days (range 1-152). Highest hospitalization rates occurred in late winter and spring (August-November) with a smaller peak in summer (February-March). Sixty percent of patients had public health insurance and 30% of patients had private health insurance, which was overrepresented among KD patients. Fifty-two percent of cases were hospitalized in the Metropolitan Region (Santiago), which had the highest KD hospitalization rate in the country. Hospitalization rate attributable to KD among children younger than 5 years was 7.6 (95% CI 7.1-7.9). Hospitalization rates significantly increased from the 2001-2004 period to the 2005-2007 period: 6.3 (95% CI 5.9-6.6) to 9.3 (95% CI 8.4-10.4), (P < 0.001). Estimated incidence of KD, assuming 10% readmission rates, was 5.7 (95% CI 5.4-6.1) per 100,000 children younger than five years for the 2001-2004 period and 8.4 (95% CI 7.6-9.6) for the 2005-2007 period (P < 0.001). Two patients died during a hospitalization attributable to KD, resulting in an acute lethality rate of 0.25%.