Bet v 1-independent sensitization to major allergens in Fagales pollen: Evidence at the T-cell level.

BACKGROUND: In birch-dominated areas, allergies to pollen from trees of the order Fagales are considered to be initiated by the major birch pollen allergen Bet v 1. However, the sensitizing activity of Bet v 1-homologs in Fagales pollen might be underestimated. Allergen-specific T-cells are crucial in the sensitization process. The T-cell response to major allergens from alder, hazel, oak, hornbeam, chestnut, beech, and chestnut pollen has not yet been analyzed. Here, we characterized the cellular cross-reactivity of major allergens in Fagales pollen with Bet v 1. METHODS: T-cell-lines (TCL) were established from allergic individuals with Aln g 1, Car b 1, Ost c 1, Cor a 1, Fag s 1, Cas s 1, and Que a 1, and tested for reactivity with Bet v 1 and synthetic overlapping 12-mer peptides representing its primary sequence. Aln g 1-specific TCL was additionally tested with Aln g 1-derived peptides and all allergens. IgE-competition experiments with Aln g 1 and Bet v 1 were performed. RESULTS: T-cell-lines initiated with Fagales pollen allergens varied strongly in their reactivity with Bet v 1 and by the majority responded stronger to the original stimulus. Cross-reactivity was mostly restricted to the epitope Bet v 1142-153 . No distinct cross-reactivity of Aln g 1-specific T-cells with Bet v 1 was detected. Among 22 T-cell epitopes, Aln g 1 contained two immunodominant epitopes. Bet v 1 inhibited IgE-binding to Aln g 1 less potently than Aln g 1 itself. CONCLUSION: The cellular cross-reactivity of major Fagales pollen allergens with Bet v 1 was unincisive, particularly for Aln g 1, most akin to Bet v 1. Our results indicate that humoral and cellular responses to these allergens are not predominantly based on cross-reactivity with the major birch pollen allergen but suggest a Bet v 1-independent sensitization in individuals from birch tree-dominated areas.

Neutrophils-typical atypical antigen presenting cells?

Neutrophils are the most abundant cells of the immune system and key in combating infections through phagocytosis, reactive oxygen species, neutrophil extracellular traps, and secretion of cytokines and antimicrobial peptides. Beyond this, they may influence the adaptive immune response by modulating CD4+ T cell responses. In response to cytokines, mainly GM-CSF, but also IFN-γ and TNF-α, neutrophils express major histocompatibility complex class II molecules on their surface. However, to function as antigen-presenting cells for CD4+ T cells, more requirements need to be fulfilled, like antigen internalization, processing into fragments containing T cell epitopes, and their presentation on the cell surface together with costimulatory molecules. Here, studies investigating the key features of antigen-presentation by neutrophils are summarized and discussed. Together, they provide evidence for a potential of neutrophils to specifically activate antigen-experienced CD4+ T cells.

Inflammatory immune response in recipients of transcatheter aortic valves.

Objective: Transcatheter aortic valve implantation (TAVI) is rapidly replacing cardiac surgery due to its minimal invasiveness and practicality. Midterm immunological studies on the biocompatibility of galactose-alpha-1,3-galactose (α-Gal)-carrying bioprosthetic heart valves for TAVI are not available. In this study we investigated whether bioprosthetic heart valves employed for TAVI augment an α-Gal-specific antibody-dependent and antibody-independent immune response 3 months after TAVI implantation. Methods: This prospective observational study included 27 patients with severe aortic valve stenosis undergoing TAVI and 10 patients with severe mitral valve regurgitation treated with a transcatheter MitraClip (Abbott Laboratories, Abbott Park, Ill) procedure. Blood samples were drawn before and 90 days after treatment at a routine checkup. Serum samples were analyzed using enzyme-linked immunosorbent assay. Serum concentrations of α-Gal-specific immunoglobulin (Ig) G, IgG subclasses and IgE, complement factor 3a, NETosis-specific citrullinated H3, and the systemic inflammation markers soluble suppression of tumorigenicity and interleukin 33 were evaluated. Results: Three months after TAVI, we found significantly increased serum concentrations of α-Gal-specific IgG3, complement factor complement factor 3a, citrullinated H3 levels, and soluble suppression of tumorigenicity (P = .002, P = .001, P = .025, and P = .039, respectively). Sensitization of α-Gal-specific IgE antibodies occurred in 55% of all patients after TAVI. Conclusions: Our results indicate that TAVI elicits a midterm, specific humoral immune response against α-Gal and causes an unspecific humoral inflammation compared with patients undergoing MitraClip implantation. This observation will lead to a better understanding of postintervention morbidity and the long-term durability of bioprostheses and indicates that caution is appropriate when designing implantation strategies for younger patients.

Alum triggers infiltration of human neutrophils ex vivo and causes lysosomal destabilization and mitochondrial membrane potential-dependent NET-formation.

Aluminium salts have been used in vaccines for decades. However, the mechanisms underlying their adjuvant effect are still unclear. Neutrophils, the first immune cells at the injection site, can release cellular DNA together with granular material, so-called neutrophil extracellular traps (NETs). In mice, NETs apparently play a role in aluminium hydroxide (alum)-adjuvant immune response to vaccines. Although no experimental data exist, this effect is assumed to be operative also in humans. As a first step to verify this knowledge in humans, we demonstrate that the injection of alum particles into human skin biopsies ex vivo leads to similar tissue infiltration of neutrophils and NET-formation. Moreover, we characterized the mechanism leading to alum-induced NET-release in human neutrophils as rapid, NADPH oxidase-independent process involving charge, phagocytosis, phagolysosomal rupture, Ca2+ -flux, hyperpolarization of the mitochondrial membrane, and mitochondrial ROS. Extracellular flow and inhibition experiments suggested that no additional energy from oxidative phosphorylation or glycolysis is required for NET-release. This study suggests a so far unappreciated role for neutrophils in the initial phase of immune responses to alum-containing vaccines in humans and provides novel insights into bioenergetic requirements of NET-formation.

Types of Inner Dialogues and Functions of Self-Talk: Comparisons and Implications.

Intrapersonal communication occurs in several modes including inner dialogue and self-talk. The Dialogical Self Theory (Hermans, 1996) postulates a polyphonic self that is comprised of a multiplicity of inner voices. Internal dialogical activity implies an exchange of thoughts or ideas between at least two so-called "I-positions" representing specific points of view. Among the functions served by self-talk are self-criticism, self-reinforcement, self-management, and social assessment (Brinthaupt et al., 2009). This paper explores the relationships among different types of internal dialogues and self-talk functions. Participants included college students from Poland (n = 181) and the United States (n = 119) who completed two multidimensional measures of inner dialogue and self-talk. Results indicated moderately strong relationships between inner dialogue types and self-talk functions, suggesting that there is a significant overlap between the two modes of communication. We discuss several implications of these findings for exploring similarities and differences among varieties of intrapersonal communication.

T-cell-derived cytokines enhance the antigen-presenting capacity of human neutrophils.

Activated allergen-specific Th2 and Th1 cells release cytokines that transform neutrophils into functional APCs characterized by the expression of HLA-DR and CD58 as well as enhanced survival and antigen uptake, irrespectively of the presence of IL-10, which reduces allergen uptake by neutrophils.

A novel role for neutrophils in IgE-mediated allergy: Evidence for antigen presentation in late-phase reactions.

BACKGROUND: Neutrophils and allergen-specific T cells accumulate in patients with allergic late-phase reactions (LPRs). Their presence is associated with severe inflammation. Cytokines, such as GM-CSF, IFN-γ, and IL-3, which are typically found in patients with allergic LPRs, have been proposed to convert neutrophils into antigen-presenting cells (APCs). OBJECTIVE: We sought to assess the antigen-processing and antigen-presenting capacities of neutrophils from allergic patients. METHODS: Neutrophils were isolated from peripheral blood of donors with birch pollen allergy and stimulated with GM-CSF, IFN-γ, and IL-3. The viability and expression of HLA-DR, CD80, and CD86 were assessed by using flow cytometry. HLA-DM expression was analyzed by means of immunoblotting. Allergen uptake was studied after fluorescence labeling of the major birch pollen allergen Bet v 1. Bet v 1 was digested with neutrophilic endolysosomal extracts, and the resulting fragments were sequenced by using mass spectrometry. Neutrophils were used as APCs in coculture experiments with autologous HLA-DR-restricted and Bet v 1-specific T-cell clones reactive with epitopes in different regions of the allergen. In all experiments monocytes were used for comparison. Fluids from suction blisters formed on top of LPRs induced by using intradermal allergen injection were assessed for HLA-DR+ neutrophils by using flow cytometry. RESULTS: The cytokines significantly enhanced the survival, allergen uptake, and expression of HLA-DM and HLA-DR on neutrophils. Neutrophils rapidly degraded Bet v 1 into fragments containing all relevant T-cell epitopes. Cytokine-activated, allergen-pulsed neutrophils induced proliferative and cytokine responses of Bet v 1-specific T cells irrespective of epitope specificity, confirming that they fully processed and presented the allergen. HLA-DR+ neutrophils were detected in patients with cutaneous allergic LPRs. CONCLUSION: Neutrophils can serve as APCs for local allergen-specific effector T cells in patients with allergic LPRs.