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Objective: To measure azithromycin (AZM) concentrations in serum and bronchial secretions in patients with cystic fibrosis (CF) and chronic Pseudomonas aeruginosa pulmonary infection. Patients and Methods: 10 CF patients (four male, six female; mean age 29 ± 10 years) with chronic P. aeruginosa pulmonary infection were randomised to receive either 500 or 1000mg of AZM (five patients per group) orally once daily for 5 days. Concentrations of AZM in serum and bronchial secretions (obtained after physiotherapy) were evaluated every 24 hours for the 5 days of administration and the following 6 days. Main Outcome Measures and Results: High AZM concentrations were found in bronchial secretions, persisting after drug administration had ended. Mean concentrations were ≥ 4 mg/L for the 1000 mg/day dose from day 2 to 11 and >2 mg/L for the 500 mg/day dose from day 2 to day 10. Serum AZM concentrations were much lower (<0.4 mg/L for the 1000 mg/day, and <0.2 mg/L for the 500 mg/day, dosage). Conclusions: These data appear to indicate the possibility of obtaining in vivo AZM concentrations previously shown to inhibit production of virulence factors in P. aeruginosa in vitro. We consider that clinical trials evaluating prolonged administration of AZM to CF patients would be both useful and justifiable. [ABSTRACT FROM AUTHOR]

Seventeen adult volunteers were vaccinated orally with the live attenuated Salmonella typhi mutant strain Ty21a. Their peripheral blood mononuclear cells were tested at different times after vaccination for direct cell-mediated activity against bacteria, employing a simple short-term in vitro assay. It was observed that 16/17 of the vaccinated subjects acquired the capacity to express specific cellular immunity against S. typhi which lasted from 15 days to at least 3 years. The effector cell of the in vitro antibacterial activity was preliminarily characterized as a non-adherent T3+,T8-,T4+ lymphocyte. In parallel, mice immunized orally with S. typhimurium and proving resistant to reinfection were tested employing the same in vitro assay. Also in this case peripheral and, most important, intestinal lymphocytes were able to express cellular immunity against the agent of murine typhoid. It is concluded that administration of live oral vaccine against S. typhi results in the induction of specific cellular immunity which is expressed at the peripheral and, probably, also at the intestinal level. [ABSTRACT FROM AUTHOR]

Fibroblasts from a patient with ICF syndrome were grown in the presence of excess of nucleotides, in media with different amounts of folic acid, and with caffeine in an attempt to induce the chromosomal anomalies observed in lymphocytes. We induced despiralisation and breakages in the centromeric heterochromatin of chromosomes 1 and 16 but not associations and multibranching. We suggest that the absence of the major chromosomal anomalies in fibroblasts from patients with ICF might be the result of both a longer G2 in these cells and differential patterns of interphase heterochromatin associations in the two tissues. [ABSTRACT FROM PUBLISHER]

Mutations of forkhead box p3 (FOXP3), the master gene for naturally occurring regulatory T cells (nTregs), are responsible for the impaired function of nTregs, resulting in an autoimmune disease known as the immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. The relevance of other peripheral tolerance mechanisms, such as the presence and function of type 1 regulatory T (Tr1) cells, the major adaptive IL-10-producing Treg subset, in patients with IPEX syndrome remains to be clarified. FOXP3(mutated) Tr1-polarized cells, differentiated in vitro from CD4(+) T cells of four IPEX patients, were enriched in IL-10(+) IL-4(-) IFN-γ(+) T cells, a cytokine production profile specific for Tr1 cells, and expressed low levels of FOXP3 and high levels of Granzyme-B. IPEX Tr1 cells were hypoproliferative and suppressive, thus indicating that FOXP3 mutations did not impair their function. Furthermore, we isolated Tr1 cell clones from the peripheral blood of one FOXP3(null) patient, demonstrating that Tr1 cells are present in vivo and they can be expanded in vitro in the absence of WT FOXP3. Overall, our results (i) show that functional Tr1 cells differentiate independently of FOXP3, (ii) confirm that human Tr1 and nTregs are distinct T-cell lineages, and (iii) suggest that under favorable conditions Tr1 cells could exert regulatory functions in IPEX patients., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is an autoimmune genetic disorder caused by mutation of the forkhead box protein 3 gene (FOXP3), a key regulator of immune tolerance., Objective: We sought to provide clinical and molecular indicators that facilitate the understanding and diagnosis of IPEX syndrome., Methods: In 14 unrelated affected male subjects who were given diagnoses of IPEX syndrome based on FOXP3 gene sequencing, we determined whether particular FOXP3 mutations affected FOXP3 protein expression and correlated the molecular and clinical data., Results: Molecular analysis of FOXP3 in the 14 subjects revealed 13 missense and splice-site mutations, including 7 novel mutations. Enteropathy, generally associated with endocrinopathy and eczema, was reported in all patients, particularly in those carrying mutations within FOXP3 functional domains or mutations that altered protein expression. However, similar genotypes did not always result in similar phenotypes in terms of disease presentation and severity. In addition, FOXP3 protein expression did not correlate with disease severity., Conclusion: Severe autoimmune enteropathy, which is often associated with increased IgE levels and eosinophilia, is the most prominent early manifestation of IPEX syndrome. Nevertheless, the disease course is variable and somewhat unpredictable. Therefore genetic analysis of FOXP3 should always be performed to ensure an accurate diagnosis, and FOXP3 protein expression analysis should not be the only diagnostic tool for IPEX syndrome.

Agammaglobulinemia is a rare primary immunodeficiency characterized by an early block of B cell development in the bone marrow, resulting in the absence of peripheral B cells and low/absent immunoglobulin serum levels. So far, mutations in Btk, mu heavy chain, surrogate light chain, Igalpha, and B cell linker have been found in 85-90% of patients with agammaglobulinemia. We report on the first patient with agammaglobulinemia caused by a homozygous nonsense mutation in Igbeta, which is a transmembrane protein that associates with Igalpha as part of the preBCR complex. Transfection experiments using Drosophila melanogaster S2 Schneider cells showed that the mutant Igbeta is no longer able to associate with Igalpha, and that assembly of the BCR complex on the cell surface is abrogated. The essential role of Igbeta for human B cell development was further demonstrated by immunofluorescence analysis of the patient's bone marrow, which showed a complete block of B cell development at the pro-B to preB transition. These results indicate that mutations in Igbeta can cause agammaglobulinemia in man.

A questionnaire-based retrospective clinical and immunological survey was conducted in 73 males with a definite diagnosis of X-linked agammaglobulinemia based on BTK sequence analysis. Forty-four were sporadic and 29 familial cases. At December 2000, the patients' ages ranged from 2 to 33 years; mean age at diagnosis and mean duration of follow-up were 3.5 and 10 years respectively. After the mid-1980s all but 2 were on intravenous immunoglobulin (IVIG) substitution therapy, with residual IgG >500 mg/dl in 94% of the patients at the time of enrollment. Respiratory infections were the most frequent manifestation both prior to diagnosis and over follow-up. Chronic lung disease (CLD) was present in 24 patients, in 15 already at diagnosis and in 9 more by 2000. The cumulative risk to present at diagnosis with CLD increased from 0.17 to 0.40 and 0.78 when the diagnosis was made at the ages of 5, 10, and 15 years respectively. For the 9 patients who developed CLD during follow-up, the duration of follow-up, rather than age at diagnosis; previous administration of intramuscular immunoglobulin; and residual IgG levels had a significant effect on the development of CLD. Chronic sinusitis was present in 35 patients (48%), in 15 already at diagnosis and in 20 by 2000. Sistemic infections such as sepsis and meningitis/meningoencephalitis decreased over follow-up, probably due to optimal protection provided by high circulating IgG levels reached with IVIG.

20 CF patients, aged from 16.5 to 31.7 years, with chronic pulmonary infection due to Pseudomonas, were included in an open trial to study the efficacy of ciprofloxacin on respiratory exacerbation. Ciprofloxacin was given orally at the dose of 1500 mg/die for ten days. 16 patients concluded the entire treatment with clear clinical improvement, based on a score including 11 parameters. There has also been a significant improvement in the pulmonary function tests, and a tendency of Rx score to decrease. 4 patients interrupted the treatment on the fifth day because of clinical inefficacy. There was no increase of Pseudomonas resistance to ciprofloxacin at the end of the treatment; 30 days after no strain of pseudomonas was found resistant. We observed side-effects in 5 patients, but in no case it was necessary to discontinue the treatment. Ciprofloxacin may be considered as a good alternative to the more established antibiotic strategy in the treatment of Pseudomonas lung exacerbations in CF.

Defects of neutrophil chemotaxis are usually accompanied by recurrent or chronic infections of the skin and the respiratory tract. The onset of clinical symptoms may occur early in infancy; infections tend to be severe and they are generally due by organisms which are of relatively low pathogenicity in the healthy subject. Abnormalities of neutrophil chemotaxis were classified and described as humoral, cellular and unclassified defects. The relevance of neutrophil chemotaxis in the single clinical entities was discussed, taking in particular account the most recent views on the argument. Some details on practical and theoretical therapeutic approaches were also reviewed.

Neutrophil chemotaxis is a complex orchestration of biochemical and morphologic events that requires the integrity and coordination of a complicated series of cellular functions. Different substances (both endogenous and exogenous) with chemotactic activity for human neutrophils were described; their interaction with specific receptors on neutrophil cell membrane is requested to induce a directional motility. The ligand-receptor interaction causes the activation of intracellular metabolic pathways and the modification of cytoskeletal structures involved in the chemotactic response. Neutrophil chemotaxis may be studied, for clinical purpose, by in vitro and in vivo methods. The two approaches of investigation are complementary, and, if properly used, they may give a valuable help in defining the nature of the chemotactic defect.

Neutrophil motility and superoxide anion production and serum immunoglobulin levels were assessed in 51 children with recurrent infections of the lower respiratory tract and chronic bronchial suppuration, not due to anatomic or functional cause. In 26 children (50.9%), a significant defect of the immunologic defenses, likely to be responsible for the disease, was observed. A precocious diagnosis and an adequate therapy could result, at least in some patients, in the prevention of progressive lung damage.

Five patients with recurrent infections of the lower respiratory tract, chronic bronchial suppuration and significant defect of polymorphonuclear granulocyte (PMN) motility were studied. Clinical evaluation and in vitro studies of PMN motility were performed before, during and after the treatment with levamisole chlorhydrate (2.5 mg/Kg twice a week). Clinical improvement was obtained in all the patients, together with a significant increase in the chemotactic response of PMN. No side effects were reported. After a follow-up of 7-18 months PMN chemotaxis remained normal in all the patients and a reappearance of respiratory symptoms was observed only in one subject.

Two episodes of acute iron deficiency anemia with blood-stained sputum and symptoms of severe acute pulmonary exacerbation were observed in a child with cystic fibrosis (CF). Hemosiderin laden macrophages (siderophages) were repeatedly found in sputum and gastric juice, suggesting the coexistence of pulmonary hemosiderosis (PH). The possibility that pulmonary immune-mediated mechanisms characteristic of CF may have played a role in the development of PH is considered.