Primary immunodeficiencies affecting the function of neutrophils and other phagocytic leukocytes are notable for an increased susceptibility to bacterial and fungal infections as a result of impaired ...leukocyte recruitment, ingestion, and/or killing of microbes. The underlying molecular defects can also impact other innate immune responses to infectious and inflammatory stimuli, leading to inflammatory and autoimmune complications that are not always directly related to infection. This review will provide an update on congenital disorders affecting neutrophil function in which a combination of host defense and inflammatory complications are prominent, including nicotinamide dinucleotide phosphate oxidase defects in chronic granulomatous disease and β2 integrin defects in leukocyte adhesion deficiency.
The ret/PTC rearrangements (PTC-1, PTC-2, and PTC-3) are characteristic of papillary thyroid cancer (PTC). In adults, PTC-1 is common and may be associated with an aggressive clinical course. The ...incidence and significance of ret/PTC mutations are less well understood in children. We examined spontaneous PTC from 33 patients (23 females and 10 males) with a median age of 18 yr (range, 6-21 yr) and a median follow-up of 3.5 yr (range, 0-13.4 yr). The ret/PTC mutations were identified in 15 tumors (45%), including 8 PTC-1 (8 of 15, 53%), 2 PTC-2 (2 of 15, 13%), 2 PTC-3 (2 of 15, 13%), and 3 (3 of 15, 20%) combined PTC mutations (PTC-1 and PTC-2). This distribution is significantly different (P = 0.001, by chi2 analysis) from that reported for children with radiation-induced PTC. There was no correlation between the presence or type of ret/PTC mutation and patient age, tumor size, focality, extent of disease at diagnosis, or recurrence. We conclude that ret/PTC mutations are 1) common in sporadic childhood PTC, 2) predominantly PTC-1, 3) frequently multiple, and 4) of different distribution than that reported for children with radiation-induced PTC.
•We developed recommendations for DTC surveillance in CAYAC survivors.•At-risk survivors should be counseled about options for DTC surveillance.•It is recommended to use palpation or ultrasonography ...as a screening modality.•Consultation with a thyroid specialist is recommended for survivors with a thyroid nodule.
Radiation exposure to the thyroid gland during treatment of childhood, adolescent and young adult cancer (CAYAC) may cause differentiated thyroid cancer (DTC). Surveillance recommendations for DTC vary considerably, causing uncertainty about optimum screening practices. The International Late Effects of Childhood Cancer Guideline Harmonization Group, in collaboration with the PanCareSurFup Consortium, developed consensus recommendations for thyroid cancer surveillance in CAYAC survivors. These recommendations were developed by an international multidisciplinary panel that included 33 experts in relevant medical specialties who used a consistent and transparent process. Recommendations were graded according to the strength of underlying evidence and potential benefit gained by early detection and appropriate management. Of the two available surveillance strategies, thyroid ultrasound and neck palpation, neither was shown to be superior. Consequently, a decision aid was formulated to guide the health care provider in counseling the survivor. The recommendations highlight the need for shared decision making regarding whether to undergo surveillance for DTC and in the choice of surveillance modality.
NADPH oxidase‐mediated production of ROS within phagosomes is an electrogenic process critical for microbial killing and antigen processing. However, mechanisms regulating oxidase targeting and ...activation at phagosomes are not well understood and differ according to cell type. This review summarizes recent advances revealing prominent roles for PI(3)P, p40phox, and trafficking of membrane organelles for regulating phagosomal oxidase activity. Additional recent studies have highlighted the importance of intraphagosomal ionic balance including pH, chloride and calcium fluxes for sustaining optimal phagosomal oxidase function.
The production of reactive oxygen species (ROS) within immune cell phagosomes is critical for antimicrobial activity and for correct antigen processing, and influences signaling pathways that direct host responses to infection and inflammation. Because excess oxidants can cause tissue damage and oxidative stress, phagocytes must precisely control both the location and timing of NADPH oxidase activity. How differential regulation is achieved at phagosomes is not well understood. Recent studies have revealed that the PI(3)P phosphoinositide plays an important role in locally boosting phagosomal NADPH oxidase activity through its binding to the p40phox NADPH oxidase subunit. Furthermore, phox subunit dynamics at phagosomes may regulate the timing of the oxidative burst. Novel elements regulating catalytic core trafficking include Rab27 and SNAP‐23. In addition to trafficking events, the activity of the electrogenic oxidase is also governed by ionic fluxes, which are constrained at phagosomes owing to low intraphagosomal volume and dynamic display of channels, transporters, and pumps. New insights on the interdependence of phagosomal pH and ROS have been recently elucidated, and chloride channels important for microbicidal functions, including CFTR, and CLIC family channels, have been identified. Finally, periphagosomal calcium microdomains and calcium‐dependent S100A8/9 protein recruitment may help fine‐tune spatiotemporal regulation of NADPH oxidase activation for an effective immune response.
Chronic granulomatous disease (CGD) is a recessive disorder characterized by a defective phagocyte respiratory burst oxidase, life-threatening pyogenic infections and inflammatory granulomas. Gene ...targeting was used to generate mice with a null allele of the gene involved in X-linked CGD, which encodes the 91 kD subunit of the oxidase cytochrome b. Affected hemizygous male mice lacked phagocyte superoxide production, manifested an increased susceptibility to infection with Staphylococcus aureus and Aspergillus fumigatus and had an altered inflammatory response in thioglycollate peritonitis. This animal model should aid in developing new treatments for CGD and in evaluating the role of phagocyte-derived oxidants in inflammation.
Immune deficiencies resulting from inherited defects in neutrophil function have revealed important features of the innate immune response. Although sharing an increased susceptibility to bacterial ...and fungal infections, these disorders each have distinctive features in their clinical manifestations and characteristic microbial pathogens. This review provides an update on several genetic disorders with impaired neutrophil function, their pathogenesis, and treatment strategies. These include chronic granulomatous disease, which results from inactivating mutations in the superoxide-generating nicotinamide dinucleotide phosphate oxidase. Superoxide-derived oxidants play an important role in the control of certain bacterial and fungal species, and also contribute to the regulation of inflammation. Also briefly summarized are updates on leukocyte adhesion deficiency, including the severe periodontal disease characteristic of this disorder, and a new immune deficiency associated with defects in caspase recruitment domain-containing protein 9, an adaptor protein that regulates signaling in neutrophils and other myeloid cells, leading to invasive fungal disease.
Neutrophils employ several mechanisms to restrict fungi, including the action of enzymes such as myeloperoxidase (MPO) or NADPH oxidase, and the release of neutrophil extracellular traps (NETs). ...Moreover, they cooperate, forming "swarms" to attack fungi that are larger than individual neutrophils. Here, we designed an assay for studying how these mechanisms work together and contribute to neutrophil's ability to contain clusters of live Candida. We find that neutrophil swarming over Candida clusters delays germination through the action of MPO and NADPH oxidase, and restricts fungal growth through NET release within the swarm. In comparison with neutrophils from healthy subjects, those from patients with chronic granulomatous disease produce larger swarms against Candida, but their release of NETs is delayed, resulting in impaired control of fungal growth. We also show that granulocyte colony-stimulating factors (GCSF and GM-CSF) enhance swarming and neutrophil ability to restrict fungal growth, even during treatment with chemical inhibitors that disrupt neutrophil function.
OBJECTIVE
Differentiated thyroid cancer (DTC), including papillary (PTC) and follicular (FTC) variants, is unusual in children and accounts for only 10% of all cases. For that reason, knowledge of ...the clinical features which predict recurrence is limited. We reviewed 170 cases of childhood DTC to determine if specific clinical or pathological findings were associated with increased risk of recurrence.
DESIGN
This was a retrospective study of children and adolescents with DTC registered in the Department of Defense Automated Centralized Tumor Registry.
PATIENTS
We reviewed 137 cases of PTC and 33 cases of FTC diagnosed between 1953 and 1996 at ≤ 21 years of age.
RESULTS
In the PTC group (median follow‐up 6.6 years, range 2 month — 39.5 years), only one patient died, but 21 developed local and 6 developed distant recurrence. By univariate analysis, recurrence was more common in patients with multifocal (odds ratio 7.5) or large tumours (odds ratio 4.1), and in those with palpable cervical lymphadenopathy (odds ratio 3.0) or metastasis at diagnosis (odds ratio 2.8). By multivariate analysis focality was the best predictor of recurrence (P = 0.0019). In the FTC group (median follow‐up 5 years, range 6 month — 38.1 years), no patient died of disease, but 5 developed recurrence. As with PTC, recurrence was more likely in patients with multifocal tumours (odds ratio 22.0).
CONCLUSIONS
Differentiated thyroid cancer in children and adolescents has low mortality, but a high risk of recurrence. Young patients with large, multifocal tumours that are already metastatic at diagnosis have the greatest risk of recurrence.
Primary disorders of neutrophil function result from impairment in neutrophil responses that are critical for host defense. This chapter summarizes inherited disorders of neutrophils that cause ...defects in neutrophil adhesion, migration, and oxidative killing. These include the leukocyte adhesion deficiencies, actin defects and other disorders of chemotaxis, hyperimmunoglobulin E syndrome, Chédiak-Higashi Syndrome, neutrophil specific granule deficiency, chronic granulomatous disease, and myeloperoxidase deficiency. Diagnostic tests and treatment approaches are also summarized for each neutrophil disorder.
Reactive oxygen species (ROS) are important signal transduction molecules in ligand-induced signaling, regulation of cell growth, differentiation, apoptosis and motility. Recently NADPH oxidases ...(Nox) homologous to Nox2 (gp91
phox
) of phagocyte cytochrome b
558 have been identified, which are an enzymatic source for ROS generation in epithelial cells. This study was undertaken to delineate the requirements for ROS generation by Nox4. Nox4, in contrast to other Nox proteins, produces large amounts of hydrogen peroxide constitutively. Known cytosolic oxidase proteins or the GTPase Rac are not required for this activity. Nox4 associates with the protein p22
phox
on internal membranes, where ROS generation occurs. Knockdown and gene transfection studies confirmed that Nox4 requires p22
phox
for ROS generation. Mutational analysis revealed structural requirements affecting expression of the p22
phox
protein and Nox activity. Mechanistic insight into ROS regulation is significant for understanding fundamental cell biology and pathophysiological conditions.
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