Autoimmune pre-disease.

Approximately 5% of the world-wide population is affected by autoimmune diseases. Overall, autoimmune diseases are still difficult to treat, impose a high burden on patients, and have a significant economic impact. Like other complex diseases, e.g., cancer, autoimmune diseases develop over several years. Decisive steps in the development of autoimmune diseases are (i) the development of autoantigen-specific lymphocytes and (often) autoantibodies and (ii) potentially clinical disease manifestation at a later stage. However, not all healthy individuals with autoantibodies develop disease manifestations. Identifying autoantibody-positive healthy individuals and monitoring and inhibiting their switch to inflammatory autoimmune disease conditions are currently in their infancy. The switch from harmless to inflammatory autoantigen-specific T and B-cell and autoantibody responses seems to be the hallmark for the decisive factor in inflammatory autoimmune disease conditions. Accordingly, biomarkers allowing us to predict this progression would have a significant impact. Several factors, such as genetics and the environment, especially diet, smoking, exposure to pollutants, infections, stress, and shift work, might influence the progression from harmless to inflammatory autoimmune conditions. To inspire research directed at defining and ultimately targeting autoimmune predisease, here, we review published evidence underlying the progression from health to autoimmune predisease and ultimately to clinically manifest inflammatory autoimmune disease, addressing the following 3 questions: (i) what is the current status, (ii) what is missing, (iii) and what are the future perspectives for defining and modulating autoimmune predisease.

Whole-Genome Expression Profiling in Skin Reveals SYK As a Key Regulator of Inflammation in Experimental Epidermolysis Bullosa Acquisita.

Because of the morbidity and limited therapeutic options of autoimmune diseases, there is a high, and thus far, unmet medical need for development of novel treatments. Pemphigoid diseases, such as epidermolysis bullosa acquisita (EBA), are prototypical autoimmune diseases that are caused by autoantibodies targeting structural proteins of the skin, leading to inflammation, mediated by myeloid cells. To identify novel treatment targets, we performed cutaneous genome-wide mRNA expression profiling in 190 outbred mice after EBA induction. Comparison of genome-wide mRNA expression profiles in diseased and healthy mice, and construction of a co-expression network identified Sykb (spleen tyrosine kinase, SYK) as a major hub gene. Aligned, pharmacological SYK inhibition protected mice from experimental EBA. Using lineage-specific SYK-deficient mice, we identified SYK expression on myeloid cells to be required to induce EBA. Within the predicted co-expression network, interactions of Sykb with several partners (e.g., Tlr13, Jdp2, and Nfkbid) were validated by curated databases. Additionally, novel gene interaction partners of SYK were experimentally validated. Collectively, our results identify SYK expression in myeloid cells as a requirement to promote inflammation in autoantibody-driven pathologies. This should encourage exploitation of SYK and SYK-regulated genes as potential therapeutic targets for EBA and potentially other autoantibody-mediated diseases.

Reduced skin blistering in experimental epidermolysis bullosa acquisita after anti-TNF treatment.

Epidermolysis bullosa acquisita (EBA) is a difficult-to-treat subepidermal autoimmune blistering skin disease (AIBD) with circulating and tissue-bound anti-type VII collagen antibodies. Different reports have indicated an increased concentration of tumor necrosis factor alpha (TNF) in the serum and blister fluid of patients with subepidermal AIBDs. Furthermore, successful anti-TNF treatment has been reported for individual patients with AIBDs. Here, we show that in mice, induction of experimental EBA by repeated injections of rabbit-anti mouse type VII collagen antibodies led to increased expression of TNF in skin, as determined by real-time PCR and immunohistochemistry. To investigate if the increased TNF expression is of functional relevance in experimental EBA, we inhibited TNF function using the soluble TNF receptor fusion protein etanercept (Enbrel®) or a monoclonal antibody to murine TNF. Interestingly, mice receiving either of these two treatments showed significantly milder disease progression than controls. In addition, immunohistochemical staining demonstrated reduced numbers of macrophages in lesional skin in mice treated with TNF inhibitors compared to controls. Furthermore, etanercept treatment significantly reduced the disease progression in immunization-induced EBA. In conclusion, the increased expression of TNF in experimental EBA is of functional relevance, as both the prophylactic blockade of TNF and the therapeutic use of etanercept impaired the induction and progression of experimental EBA. Thus, TNF is likely to serve as a new therapeutic target for EBA and AIBDs with a similar pathogenesis.

Revisiting the role of mast cells in autoimmunity.

Beside their well known role in allergy, mast cells (MCs) are capable to sense multiple signals and have therefore the potential to be involved in many immune responses. MCs are actively present in the target tissues of some autoimmune disorders, suggesting a possible function in the manifestation of such diseases. This idea is strengthened by the evidence that KIT-dependent MC-deficient mice are protected from disease in many mouse models of autoimmunity, including multiple sclerosis, rheumatoid arthritis and autoimmune skin blistering diseases. Thus, the essential role of MCs in autoimmunity not only significantly extends the knowledge of MCs in the immune response but also provides novel therapeutic targets for the treatment of such diseases. However, recent studies using a new generation of KIT-independent MC-deficient strains could not confirm an essential participation of MCs in autoimmune diseases. Therefore, it is necessary to clarify the observed discrepancies and to elucidate the role of MCs in autoimmune diseases. Here, we review the impact of MCs on the development of autoimmune diseases with focus on the controversial effects of MC deficiency in different mouse models of autoimmune diseases. We also try to clarify contradictory findings in mouse studies to finally elucidate the role of MCs in autoimmunity.

Conditional depletion of mast cells has no impact on the severity of experimental epidermolysis bullosa acquisita.

The role of mast cells (MCs) in autoimmunity is the matter of an intensive scientific debate. Based on observations in different MC-deficient mouse strains, MCs are considered as fundamental players in autoimmune diseases. However, most recent data suggest that the outcome of such diseases is strongly affected by the individual mouse strain used. By the use of two c-Kit mutant MC-deficient mouse strains and one c-Kit-independent strain, we here investigated the role of MCs in a systemic Ab transfer model of epidermolysis bullosa acquisita, a subepidermal autoimmune blistering skin disease characterized by autoantibodies against type VII collagen. While C57BL/6J-Kit(W-sh/W-sh) mice developed an unexpected increased blistering phenotype, no significant differences to WT controls were seen in WBB6F1 -Kit(W/W-v) or the novel Mcpt5-Cre iDTR animals. Interestingly, in a local Ab transfer model, which induces a localized disease, we showed that application of high concentrations of anti-COL7 (where COL7 is type VII collagen) Abs induced MC activation and MC-dependent edema formation that did, however, not contribute to blister induction. Our results indicate that in the autoimmune disorder epidermolysis bullosa acquisita MCs do not contribute to the immune-mediated tissue injury. Modern c-Kit mutant-independent MC-deficient mouse strains will help to further redefine the role of MCs in autoimmunity.