Papers by Wolfgang Weninger
The Journal of investigative dermatology, Jan 19, 2015
Deposition of immune complexes (ICs) in tissues triggers acute inflammatory pathology characteriz... more Deposition of immune complexes (ICs) in tissues triggers acute inflammatory pathology characterized by massive neutrophil influx leading to edema and hemorrhage, and is especially associated with vasculitis of the skin, but the mechanisms that regulate this Type III hypersensitivity process remain poorly understood. Here, using a combination of multiphoton intravital microscopy and genomic approaches, we re-examined the cutaneous reverse passive Arthus (RPA) reaction and observed that IC-activated neutrophils underwent transmigration, triggered further IC formation and transported these ICs into the interstitium, whereas neutrophil depletion drastically reduced IC formation and ameliorated vascular leakage in vivo. Thereafter, we show that these neutrophils expressed high levels of CXCL2, which further amplified neutrophil recruitment and activation in an autocrine/paracrine manner. Notably, CXCL1 expression was restricted to tissue-resident cell types, but IC-activated neutrophils ...
Immunity, 2000
Noninflamed skin venules support constitutive leukocyte rolling. P-selectin controls the rolling ... more Noninflamed skin venules support constitutive leukocyte rolling. P-selectin controls the rolling frequency, whereas E-selectin dictates rolling velocity (Vroll). Fucosylated selectin ligands are essential for all interactions, as rolling was absent in mice doubly deficient in alpha1,3-fucosyltransferase (FucT)-IV and FucT-VII. The rolling fraction was reduced in FucT-VII-/- animals but normal in FucT-IV-/- mice. However, Vroll was markedly increased in both strains. P-selectin ligands generated by FucT-VII are crucial for initial leukocyte tethering, whereas E-selectin ligands that permit maximum slowing of Vroll require simultaneous expression of FucT-IV and FucT-VII. These results demonstrate a role for FucT-IV in selectin-dependent adhesion and suggest that the endothelial selectins and FucTs have distinct but overlapping functions in the immunosurveillance of the skin.
Laboratory investigation; a journal of technical methods and pathology, 1999
The pleiotropic growth factor hepatocyte growth factor/scatter factor (HGF/SF) has been implicate... more The pleiotropic growth factor hepatocyte growth factor/scatter factor (HGF/SF) has been implicated by clinical and experimental studies in repair mechanisms in different organs and tissues. However, no data on the impact of HGF/SF in wound healing in the skin are yet available. Proliferating and migrating keratinocytes play a major role in repair processes in the skin by closing the wound. Recent evidence gathered from studies that used gene-deficient mice has implicated the plasminogen activator (PA)/plasmin system in wound healing, which depends on controlled matrix degradation and deposition during cell migration and proliferation. Furthermore, keratinocytes are an important source of vascular endothelial growth factor (VEGF), which is a potent inducer of angiogenesis. In this study, we show that in human keratinocytes HGF/SF but not the related cytokine macrophage stimulating protein (MSP) significantly increases expression of VEGF and plasminogen activator inhibitor-1 (PAI-1) o...
Laboratory investigation; a journal of technical methods and pathology, 1998
Kaposi's sarcoma (KS) is a tumor of presumed vascular origin frequently found in patients wit... more Kaposi's sarcoma (KS) is a tumor of presumed vascular origin frequently found in patients with AIDS. Recent data suggest that the development of KS is linked with the presence of a newly recognized herpesvirus, human herpesvirus type 8. Nitric oxide (NO), a messenger molecule with vasoactive, antitumor, and antimicrobial effects, is produced by three isoforms of nitric oxide synthases (NOS). In the present report, we investigated the expression of NOS isoforms in KS. By NADPH-diaphorase histochemistry, NOS activity was detectable in endothelia and CD45+ cells within KS lesions. Reactivity for endothelial NOS (eNOS) was found in blood vessel endothelia; however, eNOS reactivity was negative in KS spindle cells in 12 of 17 tumors, and moderately positive in the other 5 lesions. In contrast to KS, tumor cells in three hemangiomas and one angiosarcoma were strongly positive for eNOS. Inducible NOS (iNOS) was absent from KS tumor cells but was found regularly in CD45+, HLA-DR+ cells ...
Laboratory investigation; a journal of technical methods and pathology, 1996
Vascular endothellal growth factor (VEGF) increases vascular permeability and acts as a mitogen f... more Vascular endothellal growth factor (VEGF) increases vascular permeability and acts as a mitogen for endothelial cells in vivo and in vitro. We and others recently demonstrated that cultured human keratinocytes constitutively secrete VEGF. In the present study, we examined the expression of this growth factor in various epithelial skin tumors and in normal skin. Using in situ hybridization, we detected strong VEGF mRNA expression in all of 10 squamous cell carcinomas, 13 common warts, 11 seborrheic keratoses, and in 7 of 8 keratoacanthomas studied. By contrast, we found no VEGF mRNA in 9 of 14 basal cell carcinomas. VEGF mRNA was readily detectable within the epidermis adjacent to the tumors as well as in tumor cells and in the epidermis of normal human skin. Northern hybridization of RNA derived from normal human epidermis identified VEGF transcripts of 3.7 and 1.8 kb, and reverse transcriptase polymerase chain reaction confirmed that epidermal cells, like keratinocytes in vitro, ex...
The American journal of pathology, 1996
The CD40 antigen is a member of the tumor necrosis factor receptor/nerve growth factor receptor s... more The CD40 antigen is a member of the tumor necrosis factor receptor/nerve growth factor receptor superfamily and is involved in cell proliferation, differentiation, and survival. Using different monoclonal antibodies, we found CD40 expression by immunohistochemistry on CD31- and CD34-positive Kaposi's sarcoma spindle cells in all tumors of 18 HIV-1 seropositive and 4 HIV-1 seronegative patients. Western blot analysis of tumor lysates detected a 48- to 50-kd glycoprotein corresponding to the CD40 antigen expressed by B lymphocytes. CD40 expression was also detectable in one of four cultures of spindle cells derived from Kaposi sarcoma tissue. Treatment of the CD40-positive spindle cells but not of the CD40-negative ones with interferon-gamma up-regulated CD40 surface expression. Besides on Kaposi sarcoma tumor cells, CD40 was distinctly present on vascular endothelial cells in areas within and adjacent to the tumors and in benign inflammatory lesions such as granulation tissue of ...
The American journal of pathology, 1995
The Bcl-2 proto-oncogene regulates cell survival by antagonizing events that lead to apoptotic ce... more The Bcl-2 proto-oncogene regulates cell survival by antagonizing events that lead to apoptotic cell death and has been reported to be expressed in situ in lymphoid tissues, glandular epithelium, neurons, and basal epidermal cells. When we performed immunostaining on cryostat sections of normal skin, anti-Bcl-2 reactivity was confined to scattered dendritic cells in the basal epidermal layer. Double-staining experiments showed that the Bcl-2+ cells were positive for vimentin but negative for cytokeratins, CD1a, and CD45 antigens, excluding keratinocytes and Langerhans cells as possible candidates for constitutive Bcl-2 expression. Bcl-2+ epidermal cells also reacted with the monoclonal anti-melanocyte antibody NKI/beteb, and were absent from lesional skin in vitiligo, confirming that they represented epidermal melanocytes. Western blot analysis of cultured melanocytes and melanoma cell lines revealed a 26-kd protein specifically reacting with the anti-Bcl-2 monoclonal antibody. Immun...
Immunology and Cell Biology, 2015
The skin serves as a critical barrier against pathogen entry. This protection is afforded by an a... more The skin serves as a critical barrier against pathogen entry. This protection is afforded by an array of skin-resident immune cells, which act as first-line responders against barrier breach and infection. The recruitment and positioning of these cells is controlled at multiple levels by endothelial cells, pericytes, perivascular macrophages and mast cells, and by the fibroblasts in the dermis and keratinocytes in the epidermis. Chemokine signalling through chemokine receptors expressed by the various leukocyte subsets is critical for their trafficking into and within the skin. The role of chemokines in the skin is complex, and remains incompletely understood despite three decades of investigation. Here, we review the roles that different chemokine pathways play in the skin, and highlight the recent developments in the field.Immunology and Cell Biology advance online publication, 17 March 2015; doi:10.1038/icb.2015.16.
Nature Communications, 2015
The precise pathways of memory T-cell differentiation are incompletely understood. Here we exploi... more The precise pathways of memory T-cell differentiation are incompletely understood. Here we exploit transgenic mice expressing fluorescent cell cycle indicators to longitudinally track the division dynamics of individual CD8 þ T cells. During influenza virus infection in vivo, naive T cells enter a CD62L intermediate state of fast proliferation, which continues for at least nine generations. At the peak of the anti-viral immune response, a subpopulation of these cells markedly reduces their cycling speed and acquires a CD62L hi central memory cell phenotype. Construction of T-cell family division trees in vitro reveals two patterns of proliferation dynamics. While cells initially divide rapidly with moderate stochastic variations of cycling times after each generation, a slow-cycling subpopulation displaying a CD62L hi memory phenotype appears after eight divisions. Phenotype and cell cycle duration are inherited by the progeny of slow cyclers. We propose that memory precursors cell-intrinsically modulate their proliferative activity to diversify differentiation pathways.
Naive T cells are usually excluded from nonlymphoid tissues. Only when such tertiary tissues are ... more Naive T cells are usually excluded from nonlymphoid tissues. Only when such tertiary tissues are subjected to chronic inflam- mation, such as in some (but not all) autoimmune diseases, are naive T cells recruited to these sites. We show that the CCR7 ligand CC chemokine ligand (CCL)21 is sufficient for attracting naive T cells into tertiary organs. We performed intravital
A central feature of the immune response is the precise spatio-temporal convergence of T cells an... more A central feature of the immune response is the precise spatio-temporal convergence of T cells and antigen presenting cells (APC) in particular microenvironments within secondary lymphoid organs (SLO). CCR7 and its ligands CCL19 and CCL21 have been identified as the gatekeepers for both naïve T lymphocytes and dendritic cells (DC) to these defined anatomical compartments. A new perception on the regulation of lymphocyte traffic in lymph nodes (LN) has come from observations that sphingosine-1-phosphate (S1P) receptor agonists affect T cell entry and exit from these organs. Recent developments in intravital microscopy (IVM) techniques reveal unexpected autonomous random motion of lymphocytes within secondary lymphoid tissues, and provoke questions about the mechanisms that guide their compartmental navigation.
Immunity, 2000
Noninflamed skin venules support constitutive leukocyte rolling. P-selectin controls the rolling ... more Noninflamed skin venules support constitutive leukocyte rolling. P-selectin controls the rolling frequency, whereas E-selectin dictates rolling velocity (Vroll). Fucosylated selectin ligands are essential for all interactions, as rolling was absent in mice doubly deficient in α1,3-fucosyltransferase (FucT)-IV and FucT-VII. The rolling fraction was reduced in FucT-VII−/− animals but normal in FucT-IV−/− mice. However, Vroll was markedly increased in both strains.
Infection and immunity, Jan 2, 2015
IFNγ drives antiparasite responses and immunopathology during infection with Plasmodium species. ... more IFNγ drives antiparasite responses and immunopathology during infection with Plasmodium species. Immunity-related GTPases (IRGs) are a class of IFNγ-dependent proteins that are essential for cell autonomous immunity to numerous intracellular pathogens. However, it is currently unknown whether IRGs modulate responses during malaria. We have used the Plasmodium berghei ANKA (PbA) model, in which mice develop experimental cerebral malaria (ECM), to study the roles of IRGM1 and IRGM3 in immunopathology. Induction of mRNA for Irgm1 and Irgm3 was found in the brains and spleens of infected mice at times of peak IFNγ production. Irgm3(-/-), but not Irgm1(-/-) mice, were completely protected from the development of ECM, and this protection was associated with decreased induction of inflammatory cytokines, as well as decreased recruitment and activation of CD8(+) T cells within the brain. Although antigen-specific proliferation of transferred CD8(+) T cells was not diminished compared to WT ...
Current Dermatology Reports, 2013
The skin provides an effective physical and biological barrier against environmental and pathogen... more The skin provides an effective physical and biological barrier against environmental and pathogenic insults whilst ensuring tolerance against commensal microbes. This protection is afforded by the unique anatomy and cellular composition of the skin, particularly the vast network of skin-associated immune cells. These include the longappreciated tissue-resident macrophages, dendritic cells, and mast cells, as well as the more recently described dermal γδ T cells and innate lymphoid cells. Collectively, these cells orchestrate the defense against a wide range of pathogens and environmental challenges, but also perform a number of homeostatic functions. Here, we review recent developments in our understanding of the various roles that leukocyte subsets play in cutaneous immunobiology, and introduce the newer members of the skin immune system. Implications for human disease are discussed.
The Journal of Immunology, 2014
Proceedings of the National Academy of Sciences, 2014
CD8 T-cell responses to liver-expressed antigens range from deletional tolerance to full effector... more CD8 T-cell responses to liver-expressed antigens range from deletional tolerance to full effector differentiation resulting in overt hepatotoxicity. The reasons for these heterogeneous outcomes are not well understood. To identify factors that govern the fate of CD8 T cells activated by hepatocyte-expressed antigen, we exploited recombinant adenoassociated viral vectors that enabled us to vary potential parameters determining these outcomes in vivo. Our findings reveal a threshold of antigen expression within the liver as the dominant factor determining T-cell fate, irrespective of T-cell receptor affinity or antigen cross-presentation. Thus, when a low percentage of hepatocytes expressed cognate antigen, high-affinity T cells developed and maintained effector function, whereas, at a high percentage, they became functionally exhausted and silenced. Exhaustion was not irreversibly determined by initial activation, but was maintained by high intrahepatic antigen load during the early phase of the response; cytolytic function was restored when T cells primed under high antigen load conditions were transferred into an environment of low-level antigen expression. Our study reveals a hierarchy of factors dictating the fate of CD8 T cells during hepatic immune responses, and provides an explanation for the different immune outcomes observed in a variety of immune-mediated liver pathologic conditions. rAAV | CTL | TCR | cytotoxicity T he liver is acknowledged to possess unique tolerogenic properties, which have likely evolved to maintain immunological unresponsiveness toward food-derived and microbial antigens that enter the circulation via the gut (1, 2). This tolerogenic capability of the liver is demonstrated in animal models of liver transplantation, in which liver allografts are accepted across complete MHC mismatch barriers and are able to protect other donor tissues from rejection (reviewed in ref. 3). In humans, the tolerogenic hepatic environment is likely to contribute to impaired immune clearance of the hepatitis B virus (HBV) and hepatitis C virus (HCV), which result in persistent infection in a significant proportion of exposed individuals and are associated with major morbidity and mortality. In contrast, effective immune responses to hepatotropic pathogens leading to resolution of infection are observed in most hepatitis A and E virus infections, the majority of individuals infected with HBV during adulthood, and a minority of those infected by HCV (reviewed in refs. 4, 5). The liver is also susceptible to a variety of autoimmune-mediated conditions (6). Collectively, these observations indicate that effective immune responses can be initiated and/or sustained in the liver despite its apparent predisposition toward the generation of tolerance. Unfortunately, there is no small animal model in which to study the parameters that determine the balance between intrahepatic immunity and toler-ance in viral hepatitis. Thus, the factors that shape immune outcome have not yet been identified.
Journal of Investigative Dermatology, 2014
Cellular Immunology, 2014
Monocytes are mononuclear myeloid cells that develop in the bone marrow and circulate within the ... more Monocytes are mononuclear myeloid cells that develop in the bone marrow and circulate within the bloodstream. Although they have long been argued to play a role in the repopulation of tissue-resident macrophages, this has been questioned by numerous recent studies, which has forced a reappraisal of their biology. Here we discuss monocyte development, as well as the homeostatic control of monocyte subpopulations within the blood. We also outline the known functions of monocyte subsets. Finally, we highlight the plastic nature of monocytes, which are capable of a remarkable range of phenotypic and functional changes that depend on signals from local microenvironments.
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Papers by Wolfgang Weninger