Transmissibility of characteristic lesions to experimental animals may help us understand the pathomechanism of human autoimmune disease. Here we show that human autoimmune disease can be reproduced using genetically engineered model mice. Bullous pemphigoid (BP) is the most common serious autoimmune blistering skin disease, with a considerable body of indirect evidence indicating that the underlying autoantigen is collagen XVII (COL17). Passive transfer of human BP autoantibodies into mice does not induce skin lesions, probably because of differences between humans and mice in the amino acid sequence of the COL17 pathogenic epitope. We injected human BP autoantibody into Col17-knockout mice rescued by the human ortholog. This resulted in BP-like skin lesions and a human disease phenotype. Humanization of autoantigens is a new approach to the study of human autoimmune diseases.

IMPORTANCESkin cancer is the most common malignancy occurring after organ transplantation. Although previous research has reported an increased risk of skin cancer in solid organ transplant recipients (OTRs), no study has estimated the posttransplant population-based incidence in the United States. OBJECTIVE To determine the incidence and evaluate the risk factors for posttransplant skin cancer, including squamous cell carcinoma (SCC), melanoma (MM), and Merkel cell carcinoma (MCC) in a cohort of US OTRs receiving a primary organ transplant in 2003 or 2008. DESIGN, SETTING, AND PARTICIPANTS This multicenter retrospective cohort study examined 10 649 adult recipients of a primary transplant performed at 26 centers across the United States in the Transplant Skin Cancer Network during 1 of 2 calendar years (either 2003 or 2008) identified through the Organ Procurement and Transplantation Network (OPTN) database. Recipients of all organs except intestine were included, and the follow-up periods were 5 and 10 years.MAIN OUTCOMES AND MEASURES Incident skin cancer was determined through detailed medical record review. Data on predictors were obtained from the OPTN database. The incidence rates for posttransplant skin cancer overall and for SCC, MM, and MCC were calculated per 100 000 person-years. Potential risk factors for posttransplant skin cancer were tested using multivariate Cox regression analysis to yield adjusted hazard ratios (HR).RESULTS Overall, 10 649 organ transplant recipients (mean [SD] age, 51 [12] years; 3873 women [36%] and 6776 men [64%]) contributed 59 923 years of follow-up. The incidence rates for posttransplant skin cancer was 1437 per 100 000 person-years. Specific subtype rates for SCC, MM, and MCC were 812, 75, and 2 per 100 000 person-years, respectively. Statistically significant risk factors for posttransplant skin cancer included pretransplant skin cancer (

CD200 (OX-2) is a transmembrane glycoprotein that transmits an immunoregulatory signal through the CD200 receptor (CD200R) to attenuate inflammatory reactions and promote immune tolerance. CD200 expression in the skin has not been described previously. We now report that freshly isolated cells of the murine epidermis contain a subpopulation of major histocompatibility complex (MHC) class II-negative, CD3-negative keratinocytes that are CD200-positive. CD200 expression was accentuated in keratinocytes comprising the outer root sheath of the murine hair follicle (HF). When syngeneic skin grafts were exchanged between gender-matched wild-type (WT) and CD200-deficient C57BL/6 mice, significant perifollicular and intrafollicular inflammation was observed, eventually leading to the destruction of virtually all HF (alopecia) without significant loss of the CD200-negative grafts. Minimal and transient inflammation was observed in WT grafts, which persisted long term with hair. There was a 2-fold increase in graft-infiltrating T cells in CD200-deficient skin at 14 d. Alopecia and skin lesions were induced in CD200-deficient hosts by adoptive transfer of splenocytes from WT mice previously grafted with CD200-negative skin, but not from mice grafted with WT skin. Collectively, these results suggest that the expression of CD200 in follicular epithelium attenuates inflammatory reactions and may play a role in maintaining immune tolerance to HF-associated autoantigens.

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During apoptotic cell death, biochemical processes modify self-proteins and create potential autoantigens. To maintain self-tolerance in the face of natural cell turnover, the immune system must prevent or control responses to apoptosisassociated autoantigens or risk autoimmunity. The molecular mechanisms governing this process remain largely unknown. Here, we show that expression of the immunoregulatory protein CD200 increases as murine dendritic cells (DCs) undergo apoptosis. We define CD200 as a p53-target gene and identify both p53-and caspase-dependent pathways that control CD200 expression during apoptosis. CD200 expression on apoptotic DCs diminishes proinflammatory cytokine production in response to self-antigens in vitro and is required for UVB-mediated tolerance to haptenated self-proteins in vivo. Up-regulation of CD200 may represent a novel mechanism, whereby immune reactivity to apoptosis-associated self-antigens is suppressed under steady state conditions. IntroductionAs a result of natural cell turnover, cells in peripheral tissues continually undergo apoptosis. These apoptotic cells are associated with a distinct lack of inflammation, leading to the initial perception that the process of apoptosis is immunologically silent and passive. 1 However, it is now clear that apoptotic cells do not just quietly disappear. Instead, they actively inhibit immune responses by providing immunoregulatory signals directly to cells of the immune system. For example, when added to human lymphocyte cultures stimulated with lipopolysaccharide, apoptotic cells inhibit production of proinflammatory cytokines such as tumor necrosis factor ␣ (TNF-␣), interleukin 1 (IL-1), and IL-12 and promote the production of the anti-inflammatory cytokine IL-10. 2 T-cell activation is inhibited when apoptotic cells are added to splenocytes in the presence of Con A. 3 Macrophages that have ingested apoptotic cells increase production of anti-inflammatory cytokines and inhibit production of proinflammatory cytokines. 4 Furthermore, immature dendritic cells (DCs) that have taken up apoptotic cells have a compromised ability to mature into immunostimulatory antigen-presenting cells (APCs). 5 Given their immunosuppressive capacity, it has been suggested that apoptotic cells generated during natural cell turnover play a central role in the establishment and maintenance of peripheral self-tolerance. 6 Immature DCs and monocytes traffic through tissues, phagocytose apoptotic cells, and migrate to lymphoid tissue 7 ; DCs that have ingested apoptotic cells process and present apoptotic cell-derived peptides on major histocompatibility complex (MHC) class I and class II molecules 8 ; and DCs that have taken up apoptotic cells fail to initiate productive T-cell responses, possibly through the induction of regulatory T cells. 9,10 Patients with autoimmune diseases have abnormal immune responses to self-peptides generated during apoptosis, suggesting that mechanisms exist in healthy individuals that suppress immunoreactivity to apoptosis-associat...

Bullous pemphigoid antigen 2 (BPAG2) is targeted by autoantibodies in patients with bullous pemphigoid (BP) and absent in patients with one type of epidermolysis bullosa (OMIM #226650). A keratin 14 promoter construct was used to produce transgenic (Tg) mice appropriately expressing human BPAG2 (hBPAG2) in murine epidermal basement membrane (BM). Grafts of Tg skin placed on gender-matched, syngeneic wild type (Wt) or MHC I-/-mice elicited IgG that bound human epidermal BM and BPAG2. Production of such IgG in grafted mice was prompt (detectable within 16±2 days), robust (titer ≥ 1280), durable (present ≥ 380 days), and correlated with the involution and loss of Tg skin grafts. MHC II-/-mice grafted with Tg skin did not develop anti-hBPAG2 IgG or graft loss indicating that MHC II:CD4+ T cell interactions were crucial for these responses. Tg skin grafts on Wt mice developed neutrophil-rich infiltrates, dermal edema, subepidermal blisters, and deposits of immunoreactants in epidermal BM. This model shows fidelity to alterations seen in patients with BP, has relevance to immune responses that may arise in patients with epidermolysis bullosa following BPAG2 gene replacement, and can be used to identify interventions that may block production of IgG against proteins in epidermal BM.

Chemokine receptors on dendritic cells (DC) and chemokines within lymph nodes (LN) contribute to trafficking of DC to appropriate sites within the LN. Here we show that DC that have migrated out of skin ex vivo (migratory DC, migDC) express 50‐fold more CXCR5 mRNA than fresh Langerhans cells and migrate in response to B lymphocyte chemoattractant (BLC) in vitro. When injected into the footpad of mice, migDC emigrate to regional LN where up to 40 % are found in B cell zones. By contrast, murine bone marrow‐derived DC display 14‐fold less CXCR5, do not migrate to BLC in vitro, and migrate strictly to T cell zones in LN. We propose that activated skin DC utilize CXCR5 and BLC as a possible mechanism to home to B cell zones of LN, where they may have direct effects on B cells.

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