Bärbel Reininger

Glucocorticosteroids Modify Langerhans Cells To Produce TGF-β and Expand Regulatory T Cells

Although glucocorticosteroids (GCSs) have been used for many decades in transplantation and (auto)inflammatory diseases, the exact mechanisms responsible for their immunosuppressive properties are not fully understood. The purpose of this study was to characterize the effects of oral GCSs on the cutaneous immune response. We analyzed, by immunofluorescence staining and quantitative RT-PCR, residual skin biopsy material from a clinical study in which we had used oral GCS as positive control for determining the effects of candidate anti-inflammatory compounds on epicutaneous patch tests of Ni-allergic patients. Expectedly, oral GCS treatment led to a reduction of clinical symptoms and infiltrating leukocytes. Notably, we observed increased numbers of dermal FOXP3+CD25+ T cells and epidermal Langerhans cells (LCs) that were associated with upregulated mRNA expression of TGF-β in lesions of GCS-treated Ni-allergic patients. To investigate this phenomenon further, we exposed purified LCs to GCS. They exhibited, in contrast to GCS-nonexposed LCs, 1) a more immature phenotype, 2) higher intracellular amounts of TGF-β, and 3) increased receptor activator for NF-κB expression, conditions that reportedly favor the expansion of regulatory T cells (Tregs). Indeed, we observed an enhancement of functionally suppressive FOXP3+ T cells when CD3+ cells were incubated with GCS-pretreated LCs. The expansion of Tregs was inhibited by TGF-β blockage alone, and their suppressive activity was neutralized by a combination of anti–TGF-β and anti–IL-10 Abs. Our data show that systemically applied GCSs endow LCs with Treg-promoting properties and thus shed new light on the mechanisms of GCS-mediated immunosuppression.

High-Affinity IgE Receptors on Dendritic Cells Exacerbate Th2-Dependent Inflammation

The IgE-mediated and Th2-dependent late-phase reaction remains a mechanistically enigmatic and daunting element of human allergic inflammation. In this study, we uncover the FcεRI on dendritic cells (DCs) as a key in vivo component of this form of allergy. Because rodent, unlike human, DCs lack FcεRI, this mechanism could be revealed only by using a new transgenic mouse model with human-like FcεRI expression on DCs. In the presence of IgE and allergen, FcεRI+ DCs instructed naive T cells to differentiate into Th2 cells in vitro and boosted allergen-specific Th2 responses and Th2-dependent eosinophilia at the site of allergen exposure in vivo. Thus, FcεRI on DCs drives the cascade of pathogenic reactions linking the initial allergen capture by IgE with subsequent Th2-dominated T cell responses and the development of late-phase allergic tissue inflammation.

A quadrivalent HPV vaccine induces humoral and cellular immune responses in WHIM immunodeficiency syndrome.

WHIM-syndrome is an inherited immunodeficiency disorder with abnormal susceptibility to human papillomavirus (HPV) infection and diseases. We determined safety and immunogenicity to a quadrivalent HPV vaccine in WHIM-syndrome by detection of HPV-specific antibodies and lymphoproliferation. In virus-like-particle (VLP)-ELISA, a WHIM patient showed antibody titers up to 400 for HPV-6/11/16/18, whereas immuno-competent controls developed titers of 6400-25,600. In pseudovirion assays, the patients neutralization titers ranged from 20 to 400 to the four HPV vaccine types, while titers of 1600-25,600 were detected in healthy vaccinees. Specific proliferation of PBMC of the WHIM patient to the HPV vaccine was demonstrated. This first report on response to HPV vaccination in WHIM-immunodeficiency highlights that patients with WHIM-syndrome, and probably other immunodeficiencies, may benefit from HPV immunoprophylaxis.

Mechanisms of FcεRI-IgE-Facilitated Allergen Presentation by Dendritic Cells

Dendritic cells (DC) are of key importance for the induction of antigen-specific T cell immunity. In their immature state, DC capture antigen at peripheral sites and, thereafter, migrate to secondary lymphoid organs where they, as matured cells, efficiently present antigen-derived peptides to naive T cells (1). It is obvious that the antigen recognition, capture and internalization functions of immature DC are of major biological relevance as they are the prerequisite for the occurrence, quantity and, perhaps, quality of antigen-specific T cell responses. For a long period, it was generally believed that antigen uptake by DC is mainly accomplished by micropinocytosis. In addition to this non-selective process, three other antigen uptake mechanisms of DC were recently discovered (2). The first is macropinocytosis, an actin-dependent type of fluid phase endocytosis that is mediated by membrane ruffling and characterized by the appearance of large cytoplasmic vesicles in which macrosolutes become concentrated (3). The two other uptake mechanisms are antigen/IgG complex- or glycosylation pattern-specific and rely on the presence of cell surface receptors. DC express FcγRII- and the mannose receptor that enable efficient capture of IgG complexed antigens (4, 5) and mannosylated/fucosylated antigens (3, 6), respectively. In rodents, DC express a further C-type lectin receptor, DEC-205, which recognizes specific glycosylation patterns on proteins and, thus, may be involved in the selective uptake and presentation of certain pathogens (7).

Bovine papillomavirus type 1 (BPV1) and BPV2 are closely related serotypes

Infection with bovine papillomavirus type 1 (BPV1) or BPV2 induces fibropapillomas in cows and skin sarcoids in horses. Prophylactic vaccination targeting BPV1 and BPV2 may reduce the incidence of these economically important diseases. The L1 major capsid proteins of BPV1 and BPV2 were expressed in Sf-9 insect cells and both self-assembled into virus-like particles (VLPs). Using conformation-dependent monoclonal antibodies (mAb) both type-specific and shared epitopes were detected. Antisera were raised against BPV1 or BPV2 VLP using alum adjuvant, and their (cross)neutralization capacity was tested by C127 neutralization assays using native BPV1 and BPV2 virions, or by BPV1 pseudovirion assay. Antisera induced by either VLP vaccine were able to robustly (cross-)neutralize heterologous as well as homologous types, indicating that BPV1 and BPV2 are closely related serotypes. These results suggest that a monovalent BPV1 (or BPV2) VLP vaccine may potentially protect against both BPV1 and BPV2 infections and associated diseases.

FcεRI: Structure, Cellular Distribution, and Function

Type I allergic reactions, such as allergic rhinoconjunctivitis, allergic asthma and anaphylactic urticaria, are characterized by elevated levels of serum IgE including allergen-specific IgE. In their monomeric form, these IgE molecules are capable of binding to the high affinity receptor for IgE (FceRI) on mast cells and basophils. This receptor is one of the key molecules in triggering classical type I allergic reactions (reviewed in [1]; Fig. 1). The binding of IgE to FcsRI by itself does not induce any apparent cell activation. In sensitized individuals, however, the interaction of multivalent allergens with receptor-bound IgE induces the redistribution of IgE-receptor complexes on the cell surface, which in turn triggers cellular degranulation and the release of factors responsible for the elicitation of allergic symptoms.