Rationale: Children are an at-risk population for developing complications following influenza infection, but immunologic correlates of disease severity are not understood. We hypothesized that innate cellular immune responses at the site of infection would correlate with disease outcome.Objectives: To test the immunologic basis of severe illness during natural influenza virus infection of children and adults at the site of infection.Methods: An observational cohort study with longitudinal sampling of peripheral and mucosal sites in 84 naturally influenza-infected individuals, including infants. Cellular responses, viral loads, and cytokines were quantified from nasal lavages and blood, and correlated to clinical severity. Measurements and Main Results:We show for the first time that although viral loads in children and adults were similar, innate responses in the airways were stronger in children and varied considerably between plasma and site of infection. Adjusting for age and viral load, an innate immune profile characterized by increased nasal lavage monocyte chemotactic protein-3, IFN-a2, and plasma IL-10 levels at enrollment predicted progression to severe disease. Increased plasma IL-10, monocyte chemotactic protein-3, and IL-6 levels predicted hospitalization. This inflammatory cytokine production correlated significantly with monocyte localization from the blood to the site of infection, with conventional monocytes positively correlating with inflammation. Increased frequencies of CD14 lo monocytes were in the airways of participants with lower inflammatory cytokine levels.Conclusions: An innate profile was identified that correlated with disease progression independent of viral dynamics and age. The airways and blood displayed dramatically different immune profiles emphasizing the importance of cellular migration and localized immune phenotypes.

Glutathione S -transferases (GSTs) detoxify potentially mutagenic and toxic DNA-reactive electrophiles, including metabolites of several chemotherapeutic agents, some of which are suspected human carcinogens. Functional polymorphisms exist in at least three genes that encode GSTs, including GSTM1, GSTT1, and GSTP1. We hypothesize, therefore, that polymorphisms in genes that encode GSTs alter susceptibility to chemotherapy-induced carcinogenesis, specifically to therapy-related acute myeloid leukemia (t-AML), a devastating complication of long-term cancer survival. Elucidation of genetic determinants may help to identify individuals at increased risk of developing t-AML. To this end, we have examined 89 cases of t-AML, 420 cases of de novo AML, and 1,022 controls for polymorphisms in GSTM1, GSTT1, and GSTP1 . Gene deletion of GSTM1 or GSTT1 was not specifically associated with susceptibility to t-AML. Individuals with at least one GSTP1 codon 105 Val allele were significantly over-represented in t-AML cases compared with de novo AML cases [odds ratio (OR), 1.81; 95% confidence interval (CI), 1.11–2.94]. Moreover, relative to de novo AML, the GSTP1 codon 105 Val allele occurred more often among t-AML patients with prior exposure to chemotherapy (OR, 2.66; 95% CI, 1.39–5.09), particularly among those with prior exposure to known GSTP1 substrates (OR, 4.34; 95% CI, 1.43–13.20), and not among those t-AML patients with prior exposure to radiotherapy alone (OR,1.01; 95% CI, 0.50–2.07). These data suggest that inheritance of at least one Val allele at GSTP1 codon 105 confers a significantly increased risk of developing t-AML after cytotoxic chemotherapy, but not after radiotherapy.

NAD(P)H:quinone oxidoreductase 1 (NQO1)is an enzyme that detoxifies quinones and reduces oxidative stress. A cysteineto-threonine (C 3 T) substitution polymorphism at nucleotide 609 of the NQO1 complementary DNA (NQO1 C609T ) results in a lowering of NQO1 activity. Individuals homozygous for this mutation have no NQO1 activity, and heterozygotes have low to intermediate activity compared with people with wild type. DNA samples from 493 adult de novo acute leukemia patients and 838 matched controls were genotyped for NQO1 C609T. The majority of cases were diagnosed as acute myeloid leukemia (AML) (n ‫؍‬ 420); 67 as acute lymphoblastic leukemia (ALL); and 6 as other forms of acute leukemia. The frequency of cases with low or null NQO1 activity (heterozygote ؉ homozygous mutant) was significantly higher among total acute leukemia case subjects compared with their matched controls (odds ratio [ IntroductionClues to the etiology of leukemia may be gained through the study of genetic susceptibility in candidate genes. NAD(P)H:quinone oxidoreductase 1 (NQO1; EC 1.6.99.2), originally called DTdiaphorase, 1 is an enzyme that is able to detoxify a number of natural and synthetic compounds, including quinones and their derivatives. 2,3 It is induced by synthetic antioxidants and cruciferous vegetables 4,5 and protects cells against oxidative stress.A single nucleotide polymorphism (cysteine-to-threonine, [C 3 T]) at position 609 in the NQO1 gene has been identified in a human colon cancer cell line with very low NQO1 activity. 6 This variant produces a proline-to-serine substitution that inactivates the enzyme. People who are homozygous for the variant allele completely lack NQO1 activity, and heterozygotes have low to intermediate activity compared with people with the wild type. 7 The incidence of the polymorphism varies widely by race, 8 and associations have been made between the presence of variant alleles and lung and urological cancers. [9][10][11] Evidence that the NQO1 variant allele may be significantly overrepresented in therapy-related myeloid leukemias and in those with specific chromosome aberrations has been recently presented. 12 In addition, it has been reported that infant leukemias with MLL gene rearrangements have a significantly increased frequency of the NQO1 C609T allele. 13 The NQO1 C609T polymorphism has also been shown to be associated with a greater risk of leukopenia (low white blood cell counts) in benzene-exposed individuals. 14 Lack of, or low, NQO1 activity may therefore predispose individuals exposed to chemotherapy drugs and benzene to a greater risk of leukemia. These studies led us to ask whether low NQO1 activity may play a role in the etiology of adult acute leukemia in the general population. In the present study, we have applied a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay to survey the distribution of mutant NQO1 alleles in white patients with de novo acute leukemia and more than 800 control subjects. Patients and methods Case-control study p...