Association of tumour necrosis factor-alpha -308 G/A polymorphism with primary open-angle glaucoma.

BACKGROUND: Tumour necrosis factor-alpha (TNF-α) is an important proinflammatory cytokine driving axonal degeneration and retinal ganglion cell apoptosis in glaucoma. The aim of the study was to evaluate the association of TNF-α -308 G/A and -238 G/A polymorphisms with primary open-angle glaucoma (POAG). DESIGN: A prospective, case-control study, university hospital setting. PARTICIPANTS: Eighty-six POAG patients and 193 healthy unrelated controls. METHODS: TNF-α polymorphisms were screened by using direct gene sequencing. MAIN OUTCOME MEASURES: Frequency of TNF-α -308 G/A and TNF-α -238 G/A promoter polymorphisms in glaucoma and healthy subjects. RESULTS: The frequencies of TNF-α -308 GA genotype and 'A' allele were higher in patients with POAG (22.1% and 12.2%, respectively) in comparison with the control group (10.9% and 6%, respectively) (P = 0.046 and 0.02, respectively), with odds ratios of 2.45 (P = 0.01, 95% CI = 1.23-4.87) and 2.19 (P = 0.013, 95% CI = 1.18-4.08), respectively. Genotype distribution of the TNF-α -238 variants did not yield a statistically significant difference between the two groups (P = 0.87). CONCLUSION: TNF-α -308 G/A polymorphism seems to be associated with POAG in Turkish population. However, population-based studies with large number of subjects and long-term follow-up are needed to verify the association of TNF-α -308 G/A polymorphism with glaucoma susceptibility.

The role of human leucocyte antigens in children with hydatid disease: their association with clinical condition and prognosis.

Hydatid disease (HD) is a parasitosis caused by Echinococcus granulosus, which is still an important health problem worldwide, and our country is an endemic region for HD. There is little information regarding the role of human leucocyte antigen (HLA) in genetic susceptibility or resistance to HD. In this study, we aimed to investigate the HLA profile of Turkish children with HD and to compare them with healthy individuals. We also planned to investigate whether HLAs have a potential role in the predisposition to or prevention of the occurrence of HD and to study the relationship between the clinical features of HD and the HLA profile of the patients. The study included 81 children (25 boys, 56 girls) with HD aged between 3 and 18 years. All the patients' and control subjects' HLA class I and II antigens were examined, antigen allele frequencies were calculated, and clinical characteristics were also evaluated. The frequency of HLA-B18, -DR1, and -DR15 alleles were significantly different between the patients and healthy groups; HLA-DR15 antigen might be associated with HD occurrence, and the presence of HLA-B18 and HLA-DR1 antigens might be associated with HD resistance. Compared with the healthy group, patients with lung HD had a significant increase in HLA-B44 frequency, and liver HD patients had a significant increase in HLA-DR15 antigen frequency. Furthermore, presence of HLA-DR11 was found to be a significant factor associated with cure of the disease. We concluded that HLA types have significant impact on the development of HD and clinical course of disease.

Clinical features of chronic granulomatous disease: a series of 26 patients from a single center.

Chronic granulomatous disease is a genetically determined immunodeficiency disorder affecting phagocytic cells rendering them unable to kill certain bacteria and fungi. The present study is a single-center retrospective study that aimed to document the clinical course of 26 children, with a median age of 2.5 years, from 21 families diagnosed as chronic granulomatous disease from 1989-2008. A median delay of 39 months was observed between the onset of infections and age at diagnosis. Pneumonia was the most common initial manifestation of the disease followed by lymphadenitis, skin abscess and diarrhea. An AR inheritance was predominant in the study group. All patients received antibacterial and antifungal prophylaxis, resulting in a marked decrease in the incidence of infections. Overall mortality was 19.2%. These results showed that all features in our group (clinical, progression and outcome) were similar to the literature except for the predominance of autosomal recessive form.

Acquired factor VIII deficiency associated with a novel primary immunodeficiency suggestive of autosomal recessive hyper IgE syndrome.

Primary immunodeficiency diseases (PID) are associated with various autoimmune complications and several manifestations of autoimmunity can be seen in the disorders of T cells, B cells, phagocytes, and complement components. Acquired hemophilia is a rare entity in childhood. Although autoantibodies may develop in various forms of PID, Factor VIII (FVIII) inhibitors have not been described before. Herein, we present a case of acquired hemophilia resulting from FVIII inhibitors who had underlying undefined PID features suggestive of autosomal recessive hyper IgE syndrome. Our patient responded to corticosteroid treatment rather well and quickly, with an increased FVIII level and decreased FVIII inhibitors. However, FVIII inhibitor reappeared 7 months later, and disappeared spontaneously 4 months ago. Long-term and close follow-up is needed to observe the long-term prognosis in this child.

A case of interleukin-12 receptor beta-1 deficiency with recurrent leishmaniasis.

Interleukin-12 receptor beta-1 (IL-12Rbeta1) defect is generally associated with selective susceptibility to weakly pathogenic mycobacteria and Salmonella species. Patients rarely experience infections caused by other organisms. We report a 5-year-old patient with IL-12Rbeta1 deficiency who developed recurrent visceral leishmaniasis 6 months apart. The patient responded to lyposomal amphotericin B treatment reasonably well.

Presentation of interleukin-12/-23 receptor beta1 deficiency with various clinical symptoms of Salmonella infections.

Clinical disease caused by weakly pathogenic mycobacterial species, Mycobacterium bovis Bacille Calmette-Guérin (BCG) and non-tuberculous environmental mycobacteria (EM), which is known as Mendelian susceptibility to mycobacterial disease (MSMD), is a rare entity defined recently. Infections with the more virulent Mycobacterium species, M. tuberculosis, may have largely gone unnoticed in these patients due to early death. Mutations in five proteins (IFNgammaR1, IFNgammaR2, IL-12/IL-23Rbeta1, IL-12/IL-23p40 and STAT1) have been found in MSMD. These patients are prone to surprisingly few other infectious diseases mainly to salmonellosis. Here we present three IL-12/IL-23Rbeta1 deficient patients from three different families and with different genetic mutations, who presented exclusively with Salmonella infections. Bacteremia and lymph node involvement were common clinical expressions. Leukocytoclastic vasculitis developed in one of these patients. Two patients were not inoculated with BCG, the third patient did not develop BCG infection although BCG vaccine had been given twice at ages of 1 and 7 years. All three patients responded well to antibiotic treatment. In conclusion, patients with chronic, recurrent or complicated Salmonella infections should be screened for MSMD, particularly for IL-12/IL-23p40/IL-12R/-23Rbeta1 deficiency. Conversely, in patients with genetic IL-12/-23Rbeta1 deficiency a full evaluation for Salmonella infection is required. IL-12/IL-23p40/IL-12R/IL-23Rbeta1 deficiency seem to be underdiagnosed in patients with salmonellosis, and since such patients need prolonged therapy, diagnosis is important.

A novel mutation leading to a deletion in the SH3 domain of Bruton's tyrosine kinase.

X-linked agammaglobulinemia (XLA) is a primary B cell immunodeficiency disorder, caused by a defect in the Bruton tyrosine kinase (BTK) gene. Here, we describe a novel four base pair mutation (838delGAGT) in intron 9 of the BTK gene leading to the skipping of exon 9 in a 2.5-year-old boy with this disorder.

The efficacy of immunoglobulin replacement therapy in the long-term follow-up of the B-cell deficiencies (XLA, HIM, CVID).

Immunoglobulin replacement therapy is the essential treatment of B-cell deficiencies. Because of the high expense of therapy, optimal dose, infusion intervals and serum IgG levels should be well defined. Data of 19 X-linked agammaglobulinemia (XLA), 7 hyper-IgM syndrome (HIM) and 20 common variable immunodeficiency (CVID) patients were analyzed. Infection frequencies and hospitalization requirements were correlated with the immunoglobulin doses used and serum IgG levels achieved. The characteristics before diagnosis and after treatment were compared among the XLA, HIM and CVID groups. By using a median dose of 370 mg/kg/month immunoglobulin, which maintained serum IgG levels at a median concentration of 440 mg/dl, the annual incidence of infections dropped from 12.4 to 3.2 and annual hospitalization requirements decreased from 1.6 to 0.16 per patient. Serum IgG levels of 300-500 mg/dl were found to be satisfactory, except in the CVID group. Increasing the level over 500 mg/dl neither prevented pneumonia further nor decreased the need for hospitalization. Monthly replacement was found to be adequate, except for XLA patients. Serum IgG levels between 300-500 mg/dl are sufficient for effective treatment of hypogammaglobulinemias. These concentrations can be maintained with 300-400 mg/kg/month doses. Higher doses and IgG levels are not needed.

Long-term survival in severe combined immune deficiency: the role of persistent maternal engraftment.

Two siblings with severe combined immune deficiency, one with maternal engraftment and detectable immunologic functions who was alive at the age of 8 years are presented. Both patients had the same JAK3 gene mutation, suggesting that maternal engraftment may result in immune competence leading to long-term survival in patients with severe combined immune deficiency.

Defective anti-polysaccharide antibody response in patients with ataxia-telangiectasia.

The immunodeficiency in ataxia-telangiectasia (A-T) patients involves both cellular and humoral immunity; however, the specific antibody response is not well defined. Frequent respiratory infections are a prominent feature in A-T. Streptococcus pneumoniae is a common pathogen responsible for these infections. Defective B cell membrane signaling has been reported in A-T cells. These observations prompted us to investigate the B cell response to six frequently encountered pneumococcal serotypes in A-T patients. We found defective IgG antibody production to all studied serotypes (3, 6B, 7F, 14, 19F, and 23F) in 22 of 31 A-T patients (71%) who were immunized with a polyvalent pneumococcal vaccine. The impaired antibody responses did not correlate with either history of infection or serum immunoglobulin isotype levels. In addition, we did not observe any correlation between the pneumococcal antibody production and a specific mutation or level of intracellular ATM (ataxia-telangiectasia mutated) protein in lysates of lymphoblastoid cell lines from these patients. Our results suggest that the extent and severity of the recurrent sinopulmonary infections may depend not only on the immunological defects but also on other ATM-dependent physiological responses.

Antioxidant enzymes in red blood cells and lymphocytes of ataxia-telangiectasia patients.

Toxic oxygen metabolites may contribute to the development of tissue damage, and play a role in the pathogenesis of malignancies, some acute and chronic pulmonary diseases, and in cell damage by radiomimetic agents, which can be seen in patients with ataxia-telangiectasia (A-T). Oxidative stress resulting from increased free radical production and/or defects in antioxidant defences is also involved in neurodegenerative disorders. Thus, oxidative stress could account for several aspects of the pleiotropic phenotype of A-T patients. The aim of this study was to determine the activities of the enzymes involved in cellular antioxidant metabolism in A-T patients to see if there is any defect which may result in constant oxidative stress. Superoxide dismutase (SOD) and catalase activities of erythrocytes, in contrast to lymphocytes, were found to be significantly higher in patients than in healthy controls. Our results may be another indication for the presence of constant oxidative stress in A-T patients as suggested previously.

Malignant solid tumors associated with congenital immunodeficiency disorders.

This objective of this study was to evaluate patients with immunodeficiency syndromes who had developed malignant solid tumors and to examine survival rates and prognosis with respect to type of immunodeficiency disease. Twenty-two patients who were diagnosed with malignant solid tumors and immunodeficiency syndromes between January 1972 and February 2003 were analyzed retrospectively. There were 12 (55%) patients with non-Hodgkin lymphoma, 8 (37%) with Hodgkin disease, 1 (5%) with mucinous adenocarcinoma of the colon, and 1 (5%) with brain stem glioma. Fifteen (68%) patients had ataxia-telangiectasia, 3 (14%) had common variable immunodeficiency disease, 2 (9%) had Bloom syndrome, 1 (5%) had combined immunodeficiency, and 1 (5%) had selective immunoglobulin A deficiency. Out of the 15 patients with ataxia-telangiectasia 9 patients had non-Hodgkin lymphoma, 5 had Hodgkin disease, and 1 had brain stem glioma. Two patients with common variable immunodeficiency disease had non-Hodgkin lymphoma and 1 had Hodgkin disease. One of the patients with Bloom syndrome had Hodgkin disease and 1 had colon carcinoma. The overall survival for the whole group was 24%. Overall survival rates in non-Hodgkin lymphoma, Hodgkin disease, colon carcinoma, and brain stem glioma were 17, 44, 0, and 0% (p =.25), respectively. Overall survival in ataxia-telangiectasia patients was 20%. In this series, most of the patients had ataxia-telangiectasia (68%). The survival rates of the malignant diseases were very poor in immunodeficiency. Overall survival in non-Hodgkin lymphoma patients was relatively worse than Hodgkin disease patients.

Antibody response to a seven-valent pneumococcal conjugated vaccine in patients with ataxia-telangiectasia.

Immunodeficiency is a characteristic feature of ataxia-telangiectasia (A-T). Humoral immunodeficiency generally consists of hypogammaglobulinemia and impaired antibody response to bacterial and viral antigens. We previously observed defective antibody response to 23-valent pneumococcal polysaccharide vaccine (PPV) in 96% of 29 patients with A-T. In this study, we investigated the antibody response to a seven-valent pneumococcal conjugate vaccine, PCV7, in 14 patients with A-T. IgG antibody levels to four pneumococcal serotypes, 6B, 14, 19F, 23F, which were included in PCV7, were measured by ELISA in pre- and postimmunization serum samples. Antibody titers against each individual Streptococcus pneumoniae serotype was considered to be positive when serotype specific pneumococcal antibody titer was higher than 10% (>10 U/mL) of the reference plasma pool level. However, when the fold increase (FI) in postimmunization antibody titer was less than two, the subject was determined to be unresponsive to the given serotype. The values were compared with the results obtained in age- and ethnic-matched children after one dose of PPV. Only two patients produced antibodies to one serotype each; one to serotype 19 with a fold increase of <2, and the other to serotype 23F with a fold increase of 5.7 based on the above criteria, although the differences between pre- and postvaccine antibody titers for serotypes 14, 19, and 23 appeared to be statistically significant. In conclusion, A-T patients failed to respond to one dose of PCV7 vaccine. Two or more doses of conjugated vaccine may be required to recruit the help of T lymphocytes in A-T patients.

Immune function in children with classical phenylketonuria and tetrahydrobiopterin deficiencies.

BACKGROUND: An increased susceptibility to infections has been observed in some patients with phenylketonuria (PKU), which is not well known whether it is due to alterations of plasma essential amino acid concentrations or to some other factors. OBJECTIVE: This study is designed to establish B cell and T cell functions in 44 children with classical PKU and tetrahydrobiopterin (BH4) deficiencies and the effects of too high plasma phenylalanine (PA) concentrations (16.53 to 30.54 mg/dL) on the same parameters. DESIGN: B and T cell functions of 33 children with classical PKU (divided into two groups based on fasting mean plasma PA concentrations: Group-I = 20.9 +/- 3.7 mg/dL, Group-II = 3.8 +/- 1.02 mg/dL), and 11 children with BH4 deficiencies (Group III) were studied. The results were compared between the groups and referenced with previously reported values from healthy controls. RESULT: Delayed type skin hypersensitivity responses to purified protein derivative (PPD) in Group I and phytohaemagglutinin (PHA) in Group I, III were lower than the other groups and healthy controls. Plasma IgG and IgM concentrations of Group I was lower than the reference values. Although mean serum zinc and iron levels of all patients were lower than published values of healthy children, zinc and iron deficiencies in Group I, III were much more prominent as compared to Group II. CONCLUSION: The somewhat low plasma IgG concentrations in Group I may be related to the very high plasma PA levels, however the role of zinc deficiency as a causal factor can not be ruled out. BH4 metabolism defects do not appear to affect the same parameters. Impaired delayed skin hypersensitivity responses in Group I and III can be explained by severe serum zinc deficiency. In the light of this study, we conclude that in order to establish a causal relationship between PKU and immune functions, further studies need to be conducted after the correction of micro-nutrient status of such children.

Griscelli syndrome restricted to hypopigmentation results from a melanophilin defect (GS3) or a MYO5A F-exon deletion (GS1).

Griscelli syndrome (GS) is a rare autosomal recessive disorder that associates hypopigmentation, characterized by a silver-gray sheen of the hair and the presence of large clusters of pigment in the hair shaft, and the occurrence of either a primary neurological impairment or a severe immune disorder. Two different genetic forms, GS1 and GS2, respectively, account for the mutually exclusive neurological and immunological phenotypes. Mutations in the gene encoding the molecular motor protein Myosin Va (MyoVa) cause GS1 and the dilute mutant in mice, whereas mutations in the gene encoding the small GTPase Rab27a are responsible for GS2 and the ashen mouse model. We herein present genetic and functional evidence that a third form of GS (GS3), whose expression is restricted to the characteristic hypopigmentation of GS, results from mutation in the gene that encodes melanophilin (Mlph), the ortholog of the gene mutated in leaden mice. We also show that an identical phenotype can result from the deletion of the MYO5A F-exon, an exon with a tissue-restricted expression pattern. This spectrum of GS conditions pinpoints the distinct molecular pathways used by melanocytes, neurons, and immune cells in secretory granule exocytosis, which in part remain to be unraveled.

The effect of mannose-binding protein gene polymorphisms in recurrent respiratory system infections in children and lung tuberculosis.

Mannose-binding lectin (MBL) is able to bind pathogens as an opsonin and plays an important role in the innate immunity. The aim of the present study was to determine the frequencies of the MBL gene variants in the Turkish population and to examine the presence of any association between MBL variants and development of tuberculosis (TB) in adults and recurrent respiratory tract infections in children. Two structural gene mutations in exon 1 of MBL gene (codon 54 and codon 57) were studied. The overall distribution of genotypes did not significantly differ between controls and TB patients/children with recurrent respiratory system infections. The frequency of allele B was calculated as 0.14, 0.09 and 0.06 for control, TB patients and children with recurrent respiratory system infections, respectively. It was found to be significantly lower in children with recurrent respiratory system infections than in controls (chi2: 4.68, d.f: 1, p: 0.030).

The relationship between periodontal status and peripheral levels of neutrophils in two consanguineous siblings with severe congenital neutropenia: case reports.

Congenital neutropenia is characterized by a severe reduction in absolute neutrophil counts, resulting in an almost total absence of neutrophils. It is well known that severe neutropenia affects periodontal status. Oral manifestations include ulcerations, gingival desquamation, gingival inflammation, attachment loss, and alveolar bone loss which may result in tooth loss. Treatment with granulocyte-colony stimulating factor (G-CSF) may improve this periodontal condition. This article reports the relationship between periodontal disease status and peripheral neutrophil levels in two consanguineous siblings with severe congenital neutropenia who did not receive routine G-CSF for 2 years prior to examination. Both siblings were given scaling, root planing, and periodontal prophylaxis in regular follow-up visits. This report demonstrates that periodontal therapy supported by adequate oral hygiene may result in restoration of neutrophil counts in siblings with congenital neutropenia.

Severe Mycobacterium bovis BCG infections in a large series of novel IL-12 receptor beta1 deficient patients and evidence for the existence of partial IL-12 receptor beta1 deficiency.

Cell mediated immunity plays a critical role in human host defence against intracellular bacteria. In patients with unusual, severe infections caused by poorly pathogenic species of mycobacteria and salmonellae, genetic deficiencies have been identified in key genes in the type-1 cytokine pathway, especially in IFNGR1 and IL12RB1. Here, we analyzed 11 patients originating from Turkey and suffering from unusual Mycobacterium bovis Bacille Calmette-Guerin infections following vaccination, and found that most patients (n=8) are deficient in IL-12Rbeta1 expression and function. No defects were found in patients' IFN-gammaR or IL-18R. In addition, a first patient suffering from partial IL-12Rbeta1 deficiency is described. This patient presented with an intermediate cellular and immunological phenotype: a consistent, low response to IL-12 was found, which could be further augmented by IL-18. Despite a lack of cell surface IL-12Rbeta1 expression, normal levels of intracellular IL-12Rbeta1 protein were detectable, which was not seen in the other, completely IL-12Rbeta1 deficient patients examined. Moreover, this patient had a relatively mild clinical phenotype and was the only individual with a single homozygous amino acid substitution in IL-12Rbeta1 (C198R). Collectively, our findings indicate that idiopathic, unusually severe infections due to M. bovis BCG can be caused by complete as well as partial IL-12Rbeta1 deficiency.

Trimethoprim-sulfamethoxazole induced prolonged hypoglycemia in an infant with MHC class II deficiency: diazoxide as a treatment option.

Hyperinsulinemic hypoglycemia associated with trimethoprim-sulfamethoxazole (TMP-SMX) has generally been reported in adults who had renal impairment or in patients with AIDS using high dose TMP-SMX. We present a 5 month-old infant with immunodeficiency due to major histocompatibility complex class II expression defect, developing hypoglycemic convulsion on the third day of high dose TMP-SMX administration. High insulin and C-peptide levels were documented at the time of hypoglycemia. To overcome hypoglycemia while TMP-SMX tapered off, diazoxide was administered which resolved hypoglycemia in 2 months.

Osteochondritis dissecans in a patient with hyperimmunoglobulin E syndrome.

Hyperimmunoglobulin E syndrome (hyper-IgE) is a rare immunodeficiency disease associated with recurrent pyogenic infections, chronic eczematoid dermatitis and osteopenia. We present here a 13-year-old girl with hyperimmunoglobulin E syndrome, who developed osteochondritis dissecans (OCD) of the lateral femoral condyle, which is rare. Osteopenia, which is frequently associated with hyper IgE, may predispose the patient to the development of OCD.