Expression of PD-1 and Tim-3 is increased in skin of patients with bullous pemphigoid and pemphigus vulgaris.

BACKGROUND: Bullous pemphigoid (BP) and pemphigus vulgaris (PV) are common autoimmune bullous dermatoses (AIBD) characterized by blisters and erosions. Treatment options are limited and often insufficient. Immune checkpoint receptors play critical roles in immune homoeostasis and self- tolerance. Targeting checkpoint receptors is highly efficient in treatment of various cancers, but often also associated with autoimmune side effects. OBJECTIVES: We therefore aimed to investigate the expression of immune checkpoint receptors in patients with BP and PV. METHODS: We analysed expression of the checkpoint receptors programmed cell death protein 1 (PD-1), T-cell immunoglobulin and mucin domain 3 (Tim-3) and lymphocyte activation gene 3 (Lag-3) in lesional skin of patients with BP and PV compared to healthy control skin as well as the expression patterns of PD-1 and Tim-3 on various infiltrating immune cells in skin sections of AIBD by immunohistochemistry and immunofluorescence. We also measured serum levels of soluble PD-1, Tim-3 and Lag-3 in AIBD patients by ELISA. RESULTS: We report on increased expression of PD-1 and Tim-3, but not Lag-3, in lesional skin of patients with BP and PV. Investigating the expression pattern of PD-1 and Tim-3 on different cutaneous immune cells, we observed significant upregulation of PD-1 predominantly on infiltrating CD8 T cells and upregulation of Tim-3 on CD8 T cells as well as macrophages. CONCLUSIONS: Our results suggest exploring immune checkpoint receptors as novel therapeutic targets using an agonistic approach in autoimmune bullous diseases.

[Anti-laminin 332 mucous membrane pemphigoid with irreversible ocular and tracheobronchial involvement : Delayed diagnosis of a severe autoimmune bullous disease]. / Anti-Laminin-332-Schleimhautpemphigoid mit irreversiblem okulärem und tracheobronchialem Befall : Verspätete Diagnosestellung einer schweren bullösen Autoimmunerkrankung.

A 53-year-old man presented with a 37-year history of erosive and scarring mucosal lesions of several organs. An initial diagnosis of Stevens-Johnson syndrome was maintained for many years. Due to late correct diagnosis of an anti-laminin 332 mucous membrane pemphigoid and the fact that early, targeted, intensified immunosuppressive therapy was not initiated, the disease led to almost complete loss of vision and obstruction of airways.

Influence of cigarette smoking on pemphigus - a systematic review and pooled analysis of the literature.

Epidemiological evidence suggests that smoking cigarettes may be beneficial in pemphigus, but no systematic evaluation exists to corroborate this assumption. Therefore, a systematic literature review with pooled data analysis of the smoking status in patients with pemphigus was conducted. Electronic searches using PubMed from inception to November 2017 identified 13 reports meeting predetermined inclusion and exclusion criteria. Most were case-control studies partly reporting that pemphigus vulgaris and foliaceus occurred less frequently in current and former smokers. Studies also indicated that duration of smoking and number of cigarettes smoked were lower in patients with pemphigus than controls and that remission may be achieved sooner in those who smoke. However, although a generally low prevalence of smoking was demonstrated in patients with pemphigus, which was lower than in controls by pooled analysis, some investigations found no difference regarding the smoking status compared with non-pemphigus subjects. One study demonstrated more severe mucosal involvement in non-smoking patients with pemphigus, whereas another observed no difference in the rate of cutaneous or mucosal lesions between smokers and non-smokers with pemphigus. This review indicates that smoking may be a possible protective factor in pemphigus, although some compromised study methodologies yet hinder any firm conclusion. Further investigations with a refined quality design are required to resolve the so far partly conflicting results in this area.

Calcitriol exerts anti-inflammatory effects in keratinocytes treated with autoantibodies from a patient with bullous pemphigoid.

BACKGROUND: The hormonally active vitamin D metabolite calcitriol and its analogues exert potent effects on cellular differentiation and regulation of immune responses. Although topical vitamin D analogues are widely used for treatment of psoriasis and vitamin D has been increasingly implicated in prevention and protection from several autoimmune diseases, experimental and clinical data in autoimmune bullous diseases are generally lacking. OBJECTIVE: Here, we investigated the effects of calcitriol on keratinocytes treated by bullous pemphigoid (BP) autoantibodies. METHODS: Human keratinocyte (HaCaT) cells were treated with purified human BP or normal IgG from one BP patient and healthy subject, respectively, in the absence or presence of calcitriol and effects on (i) cell viability, (ii) IL-6 and IL-8 secretion, (iii) STAT3 and NFκB activation, (iv) heat shock protein 70 (Hsp70) level, and (v) vitamin D receptor (VDR) expression were studied. RESULTS: We found that BP IgG-induced IL-6 and IL-8 release from HaCaT cells was reduced in the presence of non-toxic doses of calcitriol. Additionally, calcitriol blunted BP IgG-mediated STAT3 phosphorylation and NFκB activity, whereas Hsp70 and VDR expression were not affected. CONCLUSION: Although the results of this study are based on autoantibodies prepared from a single patient, they show that calcitriol protects from BP IgG-induced inflammatory processes in vitro, thus favouring its potential inclusion into the therapeutic repertoire of BP.

[Anti-p200/anti-laminin γ1 pemphigoid and BP180 NC16A/4575- positive mucous membrane pemphigoid : late diagnosis in a patient with disease-related loss of vision and multiple previous surgical interventions]. / Anti-p200/Laminin-γ1-Pemphigoid in Kombination mit einem BP180 NC16A/4575-positiven Schleimhautpemphigoid : Späte Diagnosestellung bei krankheitsbedingter Amaurosis und mehrfachen Voroperationen.

A 87-year-old woman presented with a three-year history of partially erosive, partially bullous skin and mucosal lesions, symblepharon of both eyelids as well as dysphagia. To date, multiple excisions of the skin lesions, which had been described as "skin tumors" by surgeons, had been performed. The synopsis of histology, direct and indirect immunofluorescence established the diagnosis of anti-p200/anti-laminin γ1 pemphigoid and BP180 NC16A/4575- positive mucous membrane pemphigoid with an unusual "epitope-spreading" phenomenon. Due to the late initiation of therapy, the disease-related loss of vision unfortunately was irreversible.

[Bullous pemphigoid]. / Bullöses Pemphigoid.

Pemphigoid diseases are a group of autoimmune disorders characterized by subepidermal blistering and autoantibodies against structural proteins of the dermal-epidermal junction. In bullous pemphigoid, the most common subepidermal blistering autoimmune disease, antibodies are directed against the hemidesmosomal antigens BP180 (collagen type XVII) and BP230. Bullous pemphigoid typically presents with severe pruritus and tense blisters accompanied by erosions and crusts in elderly patients. Diagnostic landmarks are the detection of linear IgG and/or C3 deposits at the dermo-epidermal junction by direct immunofluorescence microscopy of a perilesional biopsy and the detection of serum autoantibodies by indirect immunofluorescence microscopy on human salt-split skin and ELISA employing recombinant immunodominant fragments of BP180 and BP230. Treatment options include topical (class IV) and/or systemic corticosteroids, frequently combined with immunomodulatory agents like dapsone and tetracyclines or immunosuppressants such as methotrexate and azathioprine.

[Bullous autoimmune disorders in children]. / Bullöse Autoimmunkrankheiten bei Kindern.

We review the pathogenesis, clinical features, diagnosis, differential diagnosis, and therapy of autoimmune bullous skin diseases of childhood, especially of the most common linear IgA dermatosis. In autoimmune bullous diseases, autoantibodies are formed against different adhesion molecules of the skin. These are not only pathophysiologically relevant, but also serve as basis for diagnosis and follow-up of these diseases. In case an autoimmune bullous disease is suspected, histopathology and immunohistopathology (direct immunofluorescence microscopy) as well as serological tests (indirect immunofluorescence microscopy, ELISA, immunoblot) should be performed. Therapy depends on the diagnosis. In IgA-mediated pathogenesis, dapsone can be successfully used. In IgG-mediated diseases, immunosuppression with corticosteroids and steroid-sparing agents should be initiated, although only local therapy is sufficient to control a self-limiting pemphigus neonatorum. In dermatitis herpetiformis, a life-long gluten-free diet is recommended.

Treatment of severe pemphigus with a combination of immunoadsorption, rituximab, pulsed dexamethasone and azathioprine/mycophenolate mofetil: a pilot study of 23 patients.

BACKGROUND: It has been previously shown in a relatively small group of patients that a combination of immunoadsorption (IA) and rituximab with daily use of high-dose oral corticosteroids and azathioprine/mycophenolate mofetil may induce a rapid and durable remission in severe, treatment-resistant pemphigus. OBJECTIVES: To achieve a more rapid reduction of serum autoantibody levels by a more frequent use of IA in the initial phase of treatment and to reduce the number of severe adverse events of continuous oral corticosteroid therapy by switching to pulsed intravenous applications. METHODS: Twenty-three consecutive patients with severe pemphigus were included. IA was performed at initially 3- and later 4-week intervals until lesions healed by 90%; 1000mg rituximab was given at weeks 1 and 3, and intravenous dexamethasone pulses were administered at first every 3weeks and then at increasing intervals in addition to daily azathioprine/mycophenolate mofetil. RESULTS: Along with a fast and durable decline of circulating autoantibody levels, all patients showed improvement of pemphigus lesions within the first weeks of therapy and long-term complete remission was induced in 19 (83%) patients. In the remaining four patients, one (4%) minimal disease and three (13%) partial remissions were observed. Over the long-term follow-up of 11-43 (mean 29) months, six (26%) patients had a recurrence and in two (9%) patients, severe adverse events occurred. CONCLUSIONS: This novel protocol treatment induces a fast and long-term remission in severe pemphigus and seems to offer an improved side-effect profile compared with daily use of corticosteroids.

Clearance rates of circulating and tissue-bound autoantibodies to type VII collagen in experimental epidermolysis bullosa acquisita.

BACKGROUND: Epidermolysis bullosa acquisita (EBA) is a severe autoimmune skin disease characterized by autoantibodies to type VII collagen, the major component of anchoring fibrils. In this and other autoimmune bullous dermatoses, specific autoantibody detection systems are not only of diagnostic use but also allow monitoring of circulating and skin-bound autoantibodies during the course of the disease. However, little is known about their natural clearance rates in these different compartments. OBJECTIVES: To study clearance rates of circulating and tissue-bound autoantibodies to type VII collagen in experimental EBA. METHODS: Using offspring from mice with experimentally induced EBA, we examined retention times of diaplacentally transmitted autoantibodies to type VII collagen in serum of neonatal mice by enzyme-linked immunosorbent assay and of immunoreactant deposits in skin by direct immunofluorescence microscopy. Additionally, the pathogenic potential of transmitted autoantibodies was evaluated in descendant mice. RESULTS: Immediately after birth, comparable levels of pathogenic antibody concentrations were observed in maternal and neonatal mice. The clearance time of skin-bound autoantibodies was twice as long as that of circulating autoantibodies (8 and 4 weeks, respectively). Maternofetal transfer of pathogenic autoantibodies produced specific immunopathological (IgG, IgG1, IgG2a/b and complement C3 deposits) but not histological or clinical alterations in skin of offspring mice. CONCLUSIONS: Although still to be confirmed in humans, our findings add to the knowledge on turnover rates of circulating and skin-bound autoantibodies in autoimmune bullous dermatoses, which in turn may facilitate a more specific monitoring of these antibodies during the disease course, reduce the need for repeated skin biopsies, and may also be helpful in guiding treatment decisions.

Relapse-associated autoantibodies to BP180 in a patient with anti-p200 pemphigoid.

Anti-p200 pemphigoid and bullous pemphigoid (BP) are autoimmune subepidermal blistering diseases characterized by autoantibodies to a 200-kDa dermal antigen (p200) and two hemidesmosomal proteins (BP180 and BP230), respectively. We report a 70-year-old man with haemorrhagic blisters, widespread crusted erosions, and the immunopathological characteristics of anti-p200 pemphigoid. Treatment with doxycycline, topical corticosteroids and immunoadsorption led to rapid clinical remission. However, 19 weeks later, a relapse occurred with generalized itchy urticarial erythema and tense blisters. At this time, both strong dermal and epidermal IgG staining was detected by indirect immunofluorescence microscopy on salt-split skin, and autoantibodies against both p200 and the 16th noncollagenous (NC16A) domain of BP180 were found. Interestingly, the relapse was associated not only with the detection of autoantibodies to a second autoantigen (BP180), but also with an altered clinical phenotype. This case was a unique occasion to directly monitor the emergence of intermolecular epitope spreading during the course of an autoimmune bullous disorder.

[Rituximab (anti-CD20) for the treatment of autoimmune bullous diseases]. / Rituximab (anti-CD20) zur Behandlung von bullösen Autoimmundermatosen.

Treatment of autoimmune bullous diseases can often be challenging and primarily consists of conventional systemic corticosteroids and other immunosuppressant agents. Rituximab is a chimeric monoclonal antibody against human CD20 leading to a transitory B-cell depletion with a lowering of autoantibody levels. Applications for autoimmune diseases have emerged in recent years and case reports support the use of rituximab in different autoimmune blistering disorders. Of the patients treated, 90% showed significant clinical improvement. In about a third of these patients, a clinical remission requiring further immunosuppressive medication was achieved, and in about a quarter, complete long-term remission was induced. About one third of patients suffered from serious adverse events after rituximab treatment. The combination of rituximab and intravenous immune globulin or immunoadsorption appears to be advantageous in severe cases. Randomized controlled trials are necessary to better determine the efficacy and adverse effects of rituximab in the treatment of autoimmune blistering diseases.