Pemphigus vulgaris (PV) is a life-threatening autoimmune blistering skin disease characterized by detachment of keratinocytes (acantholysis). It has been proposed that PV IgG might trigger signaling and that this process may lead to acantholysis. Indeed, we recently identified a rapid and dose-dependent phosphorylation of p38 mitogen-activated protein kinase (p38MAPK) and heat shock protein (HSP) 27 after binding of PV antibodies to cultured keratinocytes. In human keratinocyte cultures, inhibitors of p38MAPK prevented PV IgG-induced phosphorylation of HSP27 and, more importantly, prevented the early cytoskeletal changes associated with loss of cell-cell adhesion. This study was undertaken to (i) determine whether p38MAPK and HSP25, the murine HSP27 homolog, were similarly phosphorylated in an in vivo model of PV and (ii) investigate the potential therapeutic use of p38MAPK inhibition to block blister formation in an animal model of PV. We now report that p38MAPK inhibitors prevented PV blistering disease in vivo. Targeting the end-organ by inhibiting keratinocyte desmosome signaling may be effective for treating desmosome autoimmune blistering disorders.autoimmune ͉ signaling P emphigus vulgaris (PV) is a life-threatening autoimmune blistering disease where the autoimmune response targets the epidermis and mucosal epithelia, resulting in f laccid blisters and erosions. The loss of epithelial integrity disrupts the skin barrier function, putting patients at risk for infection as well as f luid and electrolyte imbalance. Before the introduction of systemic corticosteroids, the disease was highly lethal. Although the mortality has been reduced through the use of steroids and potent immunosuppressive drugs, the disease remains lethal, and patients often suffer from and may succumb to the secondary effects of the medications used to treat the disease.In PV, IgG autoantibodies that bind to the surface of epithelial cells are pathogenic. IgG purified from PV patient sera causes blistering in mouse models (1, 2). In the PV IgG passive transfer model, autoantibodies purified from patient sera bind to keratinocyte desmoglein 3 (dsg3) (3-5) and induce loss of cell-cell adhesion, reproducing the clinical and histological features of the human disease (1, 2). In both the human disease and the PV mouse model, gentle friction of perilesional skin causes sloughing of epidermal sheets (Nikolsky's sign). Although the model mimics aspects of the disease, the molecular mechanisms of blister formation remain unresolved. In the passive transfer model, the epidermal cell-cell detachment induced by PV autoantibodies is neither Fc-(6), complement-(7), nor plasminogen activator-dependent (8). Thus, the PV passive transfer mouse model represents an end-organ damage model triggered by anti-dsg3 autoantibodies.It has been proposed that PV IgG might trigger signaling and that this process may lead to acantholysis (9 -16). Indeed, we recently identified a rapid and dose-dependent phosphorylation of p38 mitogen-activated protein kinase (p38MA...
Numerous mechanisms of action have been proposed for intravenous Ig (IVIG). In this study, we used IgG passive transfer murine models of bullous pemphigoid (BP), pemphigus foliaceus (PF), and pemphigus vulgaris (PV) to test the hypothesis that the effect of IVIG in autoantibody-mediated cutaneous bullous diseases is to accelerate the degradation of pathogenic IgG by saturation of the MHC-like Fc receptor neonatal Fc receptor (FcRn). BP, PF, and PV are organ-specific antibody-mediated diseases in which autoantibodies target the hemidesmosomal antigen BP180 and desmosomal antigens Dsg1 and Dsg3, respectively. Antibodies against BP180, Dsg1, and Dsg3, when injected into neonatal mice, induce the BP, PF, and PV disease phenotypes, respectively. We found that FcRn-deficient mice were resistant to experimental BP, PF, and PV. Circulating levels of pathogenic IgG in FcRndeficient mice were significantly reduced compared with those in WT mice. Administration of high-dose human IgG (HDIG) to WT mice also drastically reduced circulating pathogenic IgG levels and prevented blistering. In FcRn-deficient mice, no additional protective effect with HDIG was realized. These data demonstrate that the therapeutic efficacy of HDIG treatment in the pemphigus and pemphigoid models is dependent on FcRn. Thus, FcRn is a promising therapeutic target for treating such IgG-mediated autoimmune diseases.
The prevalence of antibodies against desmoglein 1 is high among normal subjects living in an area among where fogo selvagem is endemic, and the onset of the disease is preceded by a sustained antibody response. These findings support the concept that the production of antibodies against desmoglein 1 is initiated by exposure to an unknown environmental agent.
Bullous pemphigoid (BP) is an autoimmune skin disease characterized by autoantibodies against the hemidesmosomal protein BP180. In addition to IgG autoantibodies, IgE class autoantibodies have been reported in BP patients. Because animal models utilizing only IgG antibodies do not totally replicate human BP, we examined the specificity and potential relevance of IgE autoantibodies in this disease. Thirty BP patients participated in these studies. Serum IgE was measured and the IgE specificity was determined by immunoblotting. Double labeling Immunofluorescence was performed using combinations of specific antibodies to human mast cell tryptase, IgE and BP180. BP180-stimulated histamine release was measured from basophils of untreated BP patients (n=9), BP patients undergoing immunosuppressive therapy (n=9) and controls (n=16). Elevated IgE levels were found In 70% of untreated BP patients. IgE autoantibodies directed against BP180 were detected in 86% of untreated patients and in all but one of these patients the IgE reacted with the NC16A domain of BP180. IgE-coated mast cells were detected in perilesional skin of the BP patients. Moreover, BP180 peptides were detected on these mast cells. BP180-stimulated histamine release was significantly higher in basophils obtained from untreated BP patients compared with control basophils (p=0.006) or from treated BP patients (p=0.01). These findings support the hypothesis that IgE autoantibodies are involved in the pathogenesis of BP. IgE and IgG BP autoantibodies share the same antigenic specificity. Antigen-specific degranulation of basophils and/or mast cells from BP patients suggests a mechanism by which IgE may contribute to lesion development.
Endemic pemphigus foliaceus, like the sporadic form seen in the developed world, is mediated by IgG antibodies to desmoglein-1. We studied an endemic focus in Limao Verde, Brazil, where disease prevalence is 3.4%. We previously detected IgG antibodies to desmoglein-1 in 97% of patients, but also in 55% of normal subjects in the endemic focus, with progressively lower levels in normal subjects in surrounding areas. An environmental trigger is hypothesized to explain these and other findings. In this study we sought to determine if patients and enzyme-linked-immunosorbent-assay-positive normal subjects in Limao Verde differ in IgG subclass response to desmoglein-1. We developed a sensitive and specific subclass enzyme-linked immunosorbent assay using recombinant desmoglein-1 and standardized the assay to enable comparability between the four subclasses. We found that normal subjects have an IgG1 and IgG4 response, whereas patients have similar levels of IgG1 but a mean 19.3-fold higher IgG4 response. Patients in remission have a weak IgG4 response, and a 74.3-fold higher IgG4 response is associated with active disease. Finally, in five patients in whom we had blood samples from both before and after the onset of clinical disease, a mean 103.08-fold rise in IgG4 was associated with onset of clinical disease, but only a mean 3.45-fold rise in IgG1. These results suggest that the early antibody response in normal subjects living in the endemic area and in patients before the onset of clinical disease is mainly IgG1. Acquisition of an IgG4 response is a key step in the development of clinical disease.
An ongoing sero-epidemiological study of the Terena reservation of Limao Verde, known to have a high prevalence and incidence of FS, has revealed important information about this autoimmune disease. During surveillance of this population of approximately 1,200, which began in 1994, we documented 43 FS cases and studied the transition from the normal state to the disease state in several of these individuals. Furthermore, we established that FS patients as well as a large number of normal individuals on the reservation possess anti-dsg1 autoantibodies. The following interesting observations were made: (1) the ectodomain of dsg1 contains epitopes recognized by both autoantibodies and T cells from FS patients; (2) pathogenic anti-dsg1 autoantibodies in FS belong to the IgG4 subclass; (3) nonpathogenic anti-dsg1 autoantibodies of the IgG1 subclass were detected in normal individuals from Limao Verde and in patients in the preclinical stage of the disease; (4) anti-dsg1 autoantibodies from normal individuals and patients in the preclinical stage of FS recognize the EC5 domain of dsg1, whereas pathogenic anti-dsg1 autoantibodies bind the EC1/EC2 domains; (5) houses of FS patients are rustic, with thatched roofs and walls and dirt floors; (6) there was a high frequency of hematophagous insects (bedbugs and kissing bugs) in the houses of FS patients; (7) previous studies revealed that the predominant black fly on this reservation belongs to the species Simunlium nigrimanum. These findings suggest that the environmental antigen(s) triggering the autoimmune response in FS may be linked to exposure to hematophagous insects.
Pemphigus foliaceus (PF) and the endemic form Fogo Selvagem (FS) are mediated by pathogenic antibodies to the EC1-2 domains of desmoglein-1. There is a preclinical phase with antibodies to only EC5. Based on geographic clustering of cases, FS is thought to have an, as yet unidentified, environmental trigger. In this study we have searched for anti-desmoglein-1 antibodies in sera from parasitic (leishmaniasis, Chagas, and onchocerciasis), and infectious diseases (leprosy and South American (SA) blastomycosis), which are prevalent in the same geographic regions of Brazil as FS. A specific and sensitive desmoglein-1 ELISA detected antibodies in 34 of 41 onchocerciasis (83%), 38 of 88 leishmaniasis (43%), 18 of 31 Chagas disease (58%), 7 of 28 SA blastomycosis (25%), and 14 of 83 leprosy sera (17%). These sera recognized epitopes restricted to the EC5 domain. These findings identify several etiological factors for FS. It is hypothesized that a component of insect vector saliva, rather than the parasite itself may trigger an antibody response to EC-5. In persons with the known HLA susceptibility alleles and living in endemic areas, a response to the EC1-2 domains may subsequently develop by epitope spreading with associated clinical signs of FS.
In pemphigus vulgaris the major pathogenic antibody binds desmoglein-3, and mediates mucosal disease. Development of cutaneous disease is associated with acquisition of antibodies to desmoglein-1. In pemphigus foliaceus, and its endemic form, fogo selvagem by contrast, the major pathogenic antibody recognizes desmoglein-1 and mediates cutaneous disease only. In this study, we sought to determine the prevalence of antibodies to desmoglein-3 in patients with pemphigus foliaceus and fogo selvagem. We produced recombinant desmoglein-1 and desmoglein-3, and used them in highly sensitive and specific enzyme-linked immunosorbent assays, as well as immunoprecipitation assays. We detected antibodies to desmoglein-3 in 19 of 276 patients with pemphigus foliaceus and fogo selvagem, who had cutaneous disease only. We showed that these antibodies to desmoglein-3 could be absorbed in a concentration-dependent manner by desmoglein-3 but not by desmoglein-1. Also antibodies to desmoglein-1 could be absorbed in a concentration-dependent manner by desmoglein-1 but not desmoglein-3. This suggests that two separate species of antibody are present rather than one antibody capable of cross-reacting with both desmoglein-1 and desmoglein-3. Finally, it was shown that affinity-purified antibodies to desmoglein-3 from patients with pemphigus foliaceus and fogo selvagem induced a pemphigus vulgaris-like skin disease in mice by passive transfer. These results suggest that a subset of patients with pemphigus foliaceus and fogo selvagem have antibodies to desmoglein-3 that may be involved in the pathogenesis of their cutaneous disease.
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