Biomedical subjects
Publications and source records attributed to Huda Mussaffi.
This pictorial review illustrates the findings in the sonographic examination of the male genital tract in children with cystic fibrosis (from newborn to age 12 years). We illustrate the variability in appearance and discuss the differences in findings from those in adult males with cystic fibrosis.
Chemokines play a pivotal role in homeostatic and inflammatory migration of naive and activated natural killer (NK) subsets. Recent studies have shown that aberrant chemokine receptor expression on certain immune cells underlies the pathogenesis of clinical conditions in which recruitment of such cells is altered. Progressive accumulation of activated NK cells, subsequently resulting in the formation of chronic granulomatous lesions in the respiratory tract and the skin, has been described in a number of patients with transporter associated with antigen processing 2 (TAP-2) deficiency in the later stages of disease. Therefore, the goal of the present study was to elucidate whether the dysregulation of chemoattracting receptor expression on NK cells could explain abnormal navigation of these cells in TAP-2 deficiency. High-throughput proteomic comparison, followed by verification with flow cytometry, revealed that chronically activated NK cells derived from 3 newly identified patients with TAP-2 deficiency consistently expressed aberrant levels of CC chemokine receptor 2 (CCR2) chemokine receptor in vitro and in vivo. This expression pattern translated into specific responsiveness of chronically activated NK cells derived from patients with TAP-2 deficiency to multiple ligands of CCR2. Moreover, the in vivo elevated levels of interleukin-2 (IL-2) and monocyte chemoattractant protein-1 (MCP-1) detected in serum and bronchoalveolar lavage samples derived from these patients highlight the potential involvement of the CCR2 pathway in aberrant NK-cell retention at chronic inflammatory sites.
Interactions of natural killer (NK) cells with MHC class I proteins provide the main inhibitory signals controlling NK killing activity. It is therefore surprising to learn that TAP2-deficient patients suffer from autoimmune manifestations only occasionally in later stages of life. We have previously described that the CEACAM1-mediated inhibitory mechanism of NK cytotoxicity plays a major role in controlling NK autoreactivity in three newly identified TAP2-deficient siblings. This novel mechanism probably compensates for the lack of MHC class I-mediated inhibition. The CEACAM1 protein can also be present in a soluble form and the biological function of the soluble form of CEACAM1 with regard to NK cells has not been investigated. Here we show that the homophilic CEACAM1 interactions are abrogated in the presence of soluble CEACAM1 protein in a dose-dependent manner. Importantly, the amounts of soluble CEACAM1 protein detected in sera derived from the TAP2-deficient patients were dramatically reduced as compared to healthy controls. This dramatic reduction does not depend on the membrane-bound metalloproteinase activity. Thus, the expression of CEACAM1 and the absence of soluble CEACAM1 observed in the TAP2-deficient patients practically maximize the inhibitory effect and probably help to minimize autoimmunity in these patients.
The killing of natural killer (NK) cells is regulated by activating and inhibitory NK receptors that recognize mainly class I major histocompatibility complex (MHC) proteins. In transporter associated with antigen processing (TAP2)-deficient patients, killing of autologous cells by NK cells is therefore expected. However, none of the TAP2-deficient patients studied so far have suffered from immediate NK-mediated autoimmune manifestations. We have previously demonstrated the existence of a novel class I MHC-independent inhibitory mechanism of NK cell cytotoxicity mediated by the homophilic carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) interactions. Here, we identified 3 new siblings suffering from TAP2 deficiency. NK cells derived from these patients express unusually high levels of the various killer cell inhibitory receptors (KIRs) and the CEACAM1 protein. Importantly, the patients' NK cells use the CEACAM1 protein to inhibit the killing of tumor and autologous cells. Finally, we show that the function of the main NK lysis receptor, NKp46, is impaired in these patients. These results indicate that NK cells in TAP2-deficient patients have developed unique mechanisms to reduce NK killing activity and to compensate for the lack of class I MHC-mediated inhibition. These mechanisms prevent the attack of self-cells by the autologous NK cells and explain why TAP2-deficient patients do not suffer from autoimmune manifestations in early stages of life.
BACKGROUND: Cystic fibrosis is no longer a terminal illness of childhood and mean survival is now over 30 years. Adult patients with atypical CF are increasingly being diagnosed. In Israel, all patients are still followed in pediatric centers. OBJECTIVES: To describe our experience with adult CF, stressing the importance of adult-related health and psychosocial issues. METHODS: Twenty-five CF patients aged 20-50 years, constituting 44% of the 57 patients followed at our center, were analyzed for pulmonary and extrapulmonary features and management. RESULTS: Nineteen were diagnosed as children and 6 as adults. Nineteen were pancreatic-insufficient and 6 were pancreatic-sufficient, including 5 diagnosed as adults. Pulmonary status was usually stable, with forced expiratory volume in 1 second 66.3 +/- 21% (mean +/- SD) and no difference between pancreatic-sufficient and insufficient patients. The latter had more hemoptysis, Pseudomonas infection, intestinal obstruction, liver disease and diabetes. Two patients died of malignancy and two of advanced lung disease. A majority received continuous inhaled and oral antibiotics, bronchodilators, Dnase, physiotherapy and periodic home intravenous antibiotics. Psychosocial functioning was excellent: 60% were employed, 36% were married and 40% had children (none with CF). Patients diagnosed as adults had mild multisystem disease or isolated severe lung disease. CONCLUSIONS: CF adults generally have a good quality of life. Advances in understanding the CF defect and a plethora of new treatment modalities bode well for the future. Patients must be maintained in optimal condition to reap the benefits, and there is an urgent necessity for adult physicians to develop expertise in CF.
OBJECTIVES: Lung lesions are increasingly diagnosed since the advent of routine prenatal ultrasound. These lesions seem to involute in 15% to 30% of cases. Postnatal evaluation is frequently limited, particularly when repeated ultrasound or initial chest radiographs are normal. As careful follow-up or resection may be required, accurate diagnosis is essential. The objective of this study was to determine whether prenatal lung lesions that seem to resolve are still present when evaluated more closely. METHODS: We followed 24 cases of prenatally diagnosed lung lesions at our center, using repeated chest radiographs and chest computerized tomography (CT). RESULTS: Some lesions caused mild mediastinal shift, but none showed hydrops fetalis. In 7 cases, the last prenatal ultrasound was negative. In 15 cases, initial postnatal chest radiograph was normal and in only 4 of these, the lesion was seen on later chest radiographs. This apparently high rate of resolution was, however, misleading. In 22 of the 23 cases in which CT was performed, lung cysts or lobar overinflation was clearly demonstrated. CONCLUSIONS: Apparent involution of lung lesions on serial prenatal ultrasounds or neonatal chest radiograph can be misleading. We strongly recommend repeated radiographs and chest CT for definitive diagnosis in all cases.
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