Protein aggregation of SERCA2 mutants associated with Darier disease elicits ER stress and apoptosis in keratinocytes.

Mutations in sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2) underlie Darier disease (DD), a dominantly inherited skin disorder characterized by loss of keratinocyte adhesion (acantholysis) and abnormal keratinization (dyskeratosis) resulting in characteristic mucocutaneous abnormalities. However, the molecular pathogenic mechanism by which these changes influence keratinocyte adhesion and viability remains unknown. We show here that SERCA2 protein is extremely sensitive to endoplasmic reticulum (ER) stress, which typically results in aggregation and insolubility of the protein.

Netting neutrophils induce endothelial damage, infiltrate tissues, and expose immunostimulatory molecules in systemic lupus erythematosus.

An abnormal neutrophil subset has been identified in the PBMC fractions from lupus patients. We have proposed that these low-density granulocytes (LDGs) play an important role in lupus pathogenesis by damaging endothelial cells and synthesizing increased levels of proinflammatory cytokines and type I IFNs. To directly establish LDGs as a distinct neutrophil subset, their gene array profiles were compared with those of autologous normal-density neutrophils and control neutrophils.

Mast cells and neutrophils release IL-17 through extracellular trap formation in psoriasis.

IL-17 and IL-23 are known to be absolutely central to psoriasis pathogenesis because drugs targeting either cytokine are highly effective treatments for this disease. The efficacy of these drugs has been attributed to blocking the function of IL-17-producing T cells and their IL-23-induced expansion. However, we demonstrate that mast cells and neutrophils, not T cells, are the predominant cell types that contain IL-17 in human skin.

Molecular dissection of psoriasis: integrating genetics and biology.

Psoriasis is a common and debilitating disease of the skin, nails, and joints, with an acknowledged but complex genetic basis. Early genome-wide linkage studies of psoriasis focused on segregation of microsatellite markers in families; however, the only locus consistently identified resided in the major histocompatibility complex. Subsequently, several groups mapped this locus to the vicinity of HLA-C, and two groups have reported HLA-Cw6 itself to be the major susceptibility allele.

Induction of IL-17+ T cell trafficking and development by IFN-gamma: mechanism and pathological relevance in psoriasis.

Th1 and Th17 T cells are often colocalized in pathological environments, yet Th1-derived IFN-gamma inhibits Th17 cell development in vitro. We explored the physiologic basis of this paradox in humans. In this study, we demonstrate increased the number of CD4(+) and CD8(+) IL-17(+) T cells in skin lesions of psoriasis.

Blocking monoclonal antibodies specific for mouse IFN-alpha/beta receptor subunit 1 (IFNAR-1) from mice immunized by in vivo hydrodynamic transfection.

Herein we report the generation of mouse monoclonal antibodies (mAbs) specific for the IFNAR-1 subunit of the mouse interferon-alpha/beta (IFN-alpha/beta) receptor (MAR1 mAbs) that block type I IFN receptor signaling and biologic response induction in vitro and in vivo. These mAbs were generated from Ifnar1 (/) mice immunized by in vivo hydrodynamic transfection with a plasmid encoding the extracellular domain (ECD) of murine IFNAR-1. All MAR1 mAbs bound native receptor expressed on cell surfaces and immunoprecipitated IFNAR-1 from solubilized cells, and two mAbs also detected IFNAR-1 by Western blot analysis.

Interferon-gamma and cancer immunoediting.

Over the last 12 yr, we have shown that interferon-gamma and lymphocytes collaborate to regulate tumor development in mice. Specifically, we found that the immune system not only prevents the growth of primary (carcinogen-induced and spontaneous) and transplanted tumors but also sculpts the immunogenicity of tumors that form. These observations led us to refine the old and controversial "cancer immunosurveillance" hypothesis of Burnet and Thomas into one that we termed cancer immunoediting that better emphasizes the paradoxical host-protective and tumor-sculpting roles of immunity on developing tumors.

A critical function for type I interferons in cancer immunoediting.

'Cancer immunoediting' is a process wherein the immune system protects hosts against tumor development and facilitates outgrowth of tumors with reduced immunogenicity. Although interferon-gamma (IFN-gamma) is known to be involved in this process, the involvement of type I interferons (IFN-alpha/beta) has not been elucidated. We now show that, like IFN-gamma, endogenously produced IFN-alpha/beta was required for the prevention of the growth of primary carcinogen-induced and transplantable tumors.

Cancer immunoediting: from immunosurveillance to tumor escape.

The concept that the immune system can recognize and destroy nascent transformed cells was originally embodied in the cancer immunosurveillance hypothesis of Burnet and Thomas. This hypothesis was abandoned shortly afterwards because of the absence of strong experimental evidence supporting the concept. New data, however, clearly show the existence of cancer immunosurveillance and also indicate that it may function as a component of a more general process of cancer immunoediting.