Genetic predisposition and environmental factors associated with the development of atopic dermatitis in infancy: a prospective birth cohort study.

The influence of environmental factors on atopic dermatitis (AD) has been investigated in many cross-sectional studies. It remains however unclear if they could influence AD development early in life. This prospective birth cohort study aimed to monitor aspects of family lifestyle and child's nutrition within a Caucasian population and to assess its association with AD development over the first 2 years of life. Genetic predisposition was evaluated based on family history and profilaggrin genotyping. Of 149 included children, 36 developed AD. Infants with a family history of atopy developed AD 2.6 times more frequently (30 of 97) than infants without atopic predisposition (6 of 52). Genotyping was carried out on 50% of the children included. Profilaggrin mutations (R501X, 2282del4, R2447X, and S3247X) were infrequent in our population. Lower incidence of AD was observed in infants exposed to a damp housing environment, lower household income, and smoking mothers with a higher but not with a lower education level.Conclusion: Family history of atopy was a significant risk factor for AD regardless of the most common, currently defined, FLG mutations. Humidity at home and passive smoking seem associated with AD development in infancy. What is Known: • Atopic dermatitis (AD) is associated with mutations in various genes of the immune system and the epidermal barrier complex in particular filaggrin (FLG) mutation. • Inherited factors alone cannot explain the rising AD; environmental factors are therefore likely to play a decisive role in this rise but the exact role that these factors may play in increasing AD risk in infancy remains unclear. Moreover, the relationship between environmental factors and AD has been the focus of mostly cross-sectional studies and not prospective studies. What is New: • This prospective birth cohort study demonstrates that family history of atopy is a significant risk factor for AD regardless of the most common, currently defined, FLG mutations. • A lower incidence of AD was observed in infants exposed to a moist housing environment, lower household income, and smoking of mothers with a higher but not with a lower education level.

Skin Colonization by Staphylococcus aureus Precedes the Clinical Diagnosis of Atopic Dermatitis in Infancy.

Atopic dermatitis (AD) has a well-established association with skin colonization or infection by Staphylococcus aureus, which can exacerbate the disease. However, a causal relationship between specific changes in skin colonization during the first years of life and AD development still remains unclear. In this prospective birth cohort study, we aimed to characterize the association between skin colonization and AD development in 149 white infants with or without a family history of atopy. We assessed infants clinically and collected axillary and antecubital fossa skin swabs for culture-based analysis at birth and at seven time points over the first 2 years of life. We found that at age 3 months, S. aureus was more prevalent on the skin of infants who developed AD later on. S. aureus prevalence was increased on infants' skin at the time of AD onset and also 2 months before it, when compared with age-matched, unaffected infants. Furthermore, at AD onset, infants testing positive for S. aureus were younger than uncolonized subjects. In conclusion, our results suggest that specific changes in early-life skin colonization may actively contribute to clinical AD onset in infancy.

Definition of key variables for the induction of optimal NY-ESO-1-specific T cells in HLA transgene mice.

An attractive treatment of cancer consists in inducing tumor-eradicating CD8(+) CTL specific for tumor-associated Ags, such as NY-ESO-1 (ESO), a strongly immunogenic cancer germ line gene-encoded tumor-associated Ag, widely expressed on diverse tumors. To establish optimal priming of ESO-specific CTL and to define critical vaccine variables and mechanisms, we used HLA-A2/DR1 H-2(-/-) transgenic mice and sequential immunization with immunodominant DR1- and A2-restricted ESO peptides. Immunization of mice first with the DR1-restricted ESO(123-137) peptide and subsequently with mature dendritic cells (DCs) presenting this and the A2-restriced ESO(157-165) epitope generated abundant, circulating, high-avidity primary and memory CD8(+) T cells that efficiently killed A2/ESO(157-165)(+) tumor cells. This prime boost regimen was superior to other vaccine regimes and required strong Th1 cell responses, copresentation of MHC class I and MHC class II peptides by the same DC, and resulted in upregulation of sphingosine 1-phosphate receptor 1, and thus egress of freshly primed CD8(+) T cells from the draining lymph nodes into circulation. This well-defined system allowed detailed mechanistic analysis, which revealed that 1) the Th1 cytokines IFN-gamma and IL-2 played key roles in CTL priming, namely by upregulating on naive CD8(+) T cells the chemokine receptor CCR5; 2) the inflammatory chemokines CCL4 (MIP-1beta) and CCL3 (MIP-1alpha) chemoattracted primed CD4(+) T cells to mature DCs and activated, naive CD8(+) T cells to DC-CD4 conjugates, respectively; and 3) blockade of these chemokines or their common receptor CCR5 ablated priming of CD8(+) T cells and upregulation of sphingosine 1-phosphate receptor 1. These findings provide new opportunities for improving T cell cancer vaccines.

Dynamic CD8 T-cell responses to tumor-associated Epstein-Barr virus antigens in patients with Epstein-Barr virus-negative Hodgkin's disease.

In almost half of patients diagnosed with Hodgkin's disease (HD), the malignant Reed-Sternberg (RS) cells express Epstein-Barr virus (EBV) antigens. Multiple translational efforts are actively investigating antitumor immune strategies by stimulating cytotoxic T lymphocytes (CTL) against tumor-associated EBV antigens. It has previously been believed that this therapeutic strategy and presence of EBV-specific CTLs are limited to EBV-positive HD. In an effort to explore the EBV-specific immune response, here we characterize EBV-specific CTL responses to lytic and latent EBV antigens in 12 consecutive EBV carriers with EBV-negative HD. Compared to healthy donors, we detected weak, baseline EBV-specific responses to both lytic and latent antigens by IFN-gamma ELISPOT in patients with EBV-negative HD at diagnosis. Chemoradiotherapy was associated temporally with a decrease EBV-specific responses. At final follow-up (24 months), recovery of EBV-specific CTL responses was observed with robustness of lytic-specific response equivalent to healthy controls. We confirm evidence of EBV-specific CTLs in patients with EBV-negative HD and provide the first report of dynamic variance in this population during treatment. Our observation challenges prior belief that patients with HD remain immunodeficient following therapy and argues that the clinical significance of the EBV-specific immune response in EBV-negative HD should be further investigated.

Increased mobility of major histocompatibility complex I-peptide complexes decreases the sensitivity of antigen recognition.

CD8(+) cytotoxic T lymphocytes (CTL) can recognize and kill target cells expressing only a few cognate major histocompatibility complex (MHC) I-peptide complexes. This high sensitivity requires efficient scanning of a vast number of highly diverse MHC I-peptide complexes by the T cell receptor in the contact site of transient conjugates formed mainly by nonspecific interactions of ICAM-1 and LFA-1. Tracking of single H-2K(d) molecules loaded with fluorescent peptides on target cells and nascent conjugates with CTL showed dynamic transitions between states of free diffusion and immobility. The immobilizations were explained by association of MHC I-peptide complexes with ICAM-1 and strongly increased their local concentration in cell adhesion sites and hence their scanning by T cell receptor. In nascent immunological synapses cognate complexes became immobile, whereas noncognate ones diffused out again. Interfering with this mobility modulation-based concentration and sorting of MHC I-peptide complexes strongly impaired the sensitivity of antigen recognition by CTL, demonstrating that it constitutes a new basic aspect of antigen presentation by MHC I molecules.

Rational design of combination enzyme therapy for celiac sprue.

Celiac sprue (also known as celiac disease) is an inheritable, gluten-induced enteropathy of the upper small intestine with an estimated prevalence of 0.5%-1% in most parts of the world. The ubiquitous nature of food gluten, coupled with inadequate labeling regulations in most countries, constantly poses a threat of disease exacerbation and relapse for patients. Here, we demonstrate that a two-enzyme cocktail comprised of a glutamine-specific cysteine protease (EP-B2) that functions under gastric conditions and a PEP, which acts in concert with pancreatic proteases under duodenal conditions, is a particularly potent candidate for celiac sprue therapy. At a gluten:EP-B2:PEP weight ratio of 75:3:1, grocery store gluten is fully detoxified within 10 min of simulated duodenal conditions, as judged by chromatographic analysis, biopsy-derived T cell proliferation assays, and a commercial antigluten antibody test.