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J A Fairley

Publications and source records attributed to J A Fairley.

At least 19 recordsLinked to original sources
PubMed2000

A critical role for neutrophil elastase in experimental bullous pemphigoid.

Bullous pemphigoid (BP) is an autoimmune skin disease characterized by subepidermal blisters and autoantibodies against 2 hemidesmosome-associated proteins, BP180 and BP230. The immunopathologic features of BP can be reproduced in mice by passive transfer of anti-BP180 antibodies. Lesion formation in this animal model depends upon complement activation and neutrophil recruitment. In the present study, we investigated the role of neutrophil elastase (NE) in antibody-induced blister formation in experimental BP. Abnormally high levels of caseinolytic activity, consistent with NE, were detected in extracts of lesional skin and blister fluid of mice injected with anti-BP180 IgG. The pathogenic anti-BP180 IgG failed to induce subepidermal blistering in NE-null (NE(-/-)) mutant mice. NE(-/-) mice reconstituted with neutrophils from wild-type mice became susceptible to experimental BP. Wild-type mice given NE inhibitors (alpha1-proteinase inhibitor and Me-O-Suc-Ala-Ala-Pro-Val-CH(2)Cl), but not mice given cathepsin G/chymase inhibitors (alpha1-antichymotrypsin or Z-Gly-Leu-Phe-CH(2)Cl), were resistant to the pathogenic activity of anti-BP180 antibodies. Incubation of murine skin with NE induced BP-like epidermal-dermal detachment. Finally, NE cleaved BP180 in vitro and in vivo. These results implicate NE directly in the dermal-epidermal cleavage induced by anti-BP180 antibodies in the experimental BP model.

Animals↗
PubMed1999

Hedgehog hives.

BACKGROUND: Hedgehogs are increasingly popular pets in the United States and Europe. A number of infections may be acquired from these animals, and hedgehogs are possible hosts of parasites. However, to our knowledge there arc no previous reports of urticarial reactions to hedgehogs. OBSERVATIONS: We describe 3 patients who developed an acute, transient, urticarial reaction after contact with the extended spines of pet hedgehogs. One patient also developed a more prolonged reaction at the site of contact. Interestingly, all 3 patients had documented allergies to cats and/or dogs. The results of prick testing in 1 patient to an extract of hedgehog dander produced an immediate wheal-and-flare reaction. CONCLUSIONS: A variety of dermatologic disorders may be seen in handlers of hedgehogs. Due to the increasing popularity of these animals as pets, it is likely that these reactions will be noted more frequently by dermatologists. The presence of allergies to other pets may be predictive of hedgehog hives and further investigation of the cross reaction of various animal antigens may clarify this relationship.

Animals↗
PubMed1999

The anti-desmoglein 1 autoantibodies in pemphigus vulgaris sera are pathogenic.

Pemphigus vulgaris and pemphigus foliaceus are two closely related, but clinically and histologically distinct, autoimmune skin diseases. The autoantigens for pemphigus vulgaris and pemphigus foliaceus are desmoglein 3 and desmoglein 1, respectively. The anti-desmoglein 1 antibodies in pemphigus foliaceus and anti-desmoglein 3 antibodies in pemphigus vulgaris are pathogenic as determined by immunoglobulin G passive transfer animal models. More than 50% of pemphigus vulgaris sera also contain anti-desmoglein 1 autoantibodies; however, the pathogenicity of the anti-desmoglein 1 autoantibodies in pemphigus vulgaris remains unknown. In this study, we used soluble recombinant extracellular domains of desmoglein 1 and desmoglein 3 to obtain affinity-purified anti-desmoglein 1 and anti-desmoglein 3 autoantibodies from pemphigus vulgaris sera and examined the pathogenicity of each fraction separately using the passive transfer mouse model. By immunoprecipitation, the purified anti-desmoglein 1 and anti-desmoglein 3 showed no cross-reactivity. The anti-desmoglein 1 autoantibodies in pemphigus vulgaris induced typical pemphigus foliaceus lesions in neonatal mice, whereas the anti-desmoglein 3 fraction induced pemphigus vulgaris-like lesions. In addition, the pathogenic anti-desmoglein 1 and anti-desmoglein 3 autoantibodies in pemphigus vulgaris had predominant IgG4 subclass specificity. These findings suggest that the anti-desmoglein 1 antibodies in pemphigus vulgaris are pathogenic.

Acantholysis↗
PubMed1998

The systematic evaluation of the skin in children.

A large proportion of children seen by primary care pediatricians involve problems related to the skin. In this chapter, the importance of history and, particularly, physical examination in the diagnosis of various skin disorders is discussed. The ability to describe a rash using proper terminology will help narrow the differential and enable one to communicate what is seen to other physicians. The various primary and secondary lesions that may be present will be described along with various dermatoses as examples. Four common skin disorders that often fool the primary care physician are also discussed.

Child↗
PubMed1998

A bullous pemphigoid-like skin eruption after a chemical burn.

Bullous pemphigoid is a blistering disorder characterized by antibody deposition in the lamina lucida of the basement membrane zone. In addition to the idiopathic form, there are many agents that have been implicated in inducing bullous pemphigoid or bullous pemphigoid-like lesions. We describe a patient who developed a bullous pemphigoid-like eruption after a chemical burn.

Accidents, Occupational↗
PubMed1998

Epitope spreading: lessons from autoimmune skin diseases.

Autoimmune diseases are initiated when patients develop aberrant T and/or B cell responses against self proteins. These responses presumably are directed to single immunogenic epitopes on these proteins. Recent data in animal models of autoimmune diseases suggest that the targets of immune responses in autoimmunity do not remain fixed, but can be extended to include other epitopes on the same protein or other proteins in the same tissue, a phenomenon termed "epitope spreading." The "epitope spreading" phenomenon also applies to situations in which tissue damage from a primary inflammatory process causes the release and exposure of a previously "sequestered" antigen, leading to a secondary autoimmune response against the newly released antigen. In experimental autoimmune animal diseases, "epitope spreading" seems to have significant physiologic importance in determining the course and duration of disease. In this paper, we review the current concepts in animal models of autoimmune diseases in order to define the "epitope spreading" phenomenon, and we then propose how this phenomenon might play a significant role in the development and the course of autoimmune skin diseases. Hopefully, an understanding of "epitope spreading" will help the dermatology community to better understand the pathogenesis of autoimmune skin diseases and to rationally fashion disease-specific immune therapy in the future.

Animals↗
PubMed1997

A major role for neutrophils in experimental bullous pemphigoid.

Bullous pemphigoid (BP) is an inflammatory subepidermal blistering disease associated with an IgG autoimmune response to the hemidesmosomal protein, BP180. Using a passive transfer mouse model, our group has shown previously that antibodies to the murine BP180 (mBP180) ectodomain are capable of triggering a blistering skin disease that closely mimics human BP. In this study, we investigated the role of neutrophils in the immunopathogenesis of this disease model. BALB/c mice depleted of circulating neutrophils by treatment with neutrophil-specific antibodies were no longer susceptible to the pathogenic effects of anti-mBP180 IgG. IgG and complement were deposited at the dermal-epidermal junction of these animals, but there was no evidence of inflammatory infiltration or blistering. C5-deficient mice, which are resistant to the pathogenic activity of anti-mBP180 IgG, could be made susceptible to this IgG-mediated blistering disease by intradermal administration of a neutrophil chemoattractant, IL-8 or C5a. Intraperitoneal injection of IL-8, which sequesters neutrophils in the peritoneal cavity, interferes with anti-mBP180-induced neutrophilic infiltration of the skin and prevented the development of BP disease in BALB/c mice. These findings provide the first direct evidence that neutrophils recruited to the skin via a C5-dependent pathway play an essential role in subepidermal blister formation in experimental BP, and suggest new directions for disease intervention.

Animals↗
PubMed1997

Development and characterization of desmoglein-3 specific T cells from patients with pemphigus vulgaris.

Pemphigus vulgaris (PV) is a cutaneous autoimmune disease characterized by blister formation in the suprabasilar layers of skin and mucosae and anti-desmoglein-3 (Dsg3) autoantibodies bound to the surface of lesional keratinocytes and circulating in the serum of patients. This disease can be reproduced in neonatal mice by passive transfer of patients' IgG, indicating that humoral immunity plays an important role in the pathogenesis of PV. Currently, the role of T lymphocytes in the development of PV is not clear. Here, we report that three immunoreactive segments of the ectodomain of Dsg3 specifically induced proliferation of T cells from PV patients. We found that T lymphocytes from 13 out of 14 patients responded to at least one of three Dsg3 peptides. T cells from controls and other patient groups did not respond to these Dsg3 peptides. The major T cell population stimulated by these Dsg3 peptides was CD4 positive. Dsg3-specific T cell lines and clones were developed and were shown to express a CD4 positive memory T cell phenotype. Upon stimulation, these cell lines and clones secreted a Th2-like cytokine profile. The Dsg3 responses of these T cells were restricted to HLA-DR, and not -DQ and -DP, of the major histocompatibility complex. This information will help to elucidate the cellular immune abnormalities leading to production of pathogenic IgG autoantibodies in patients with PV.

Autoantibodies↗
PubMed1997

Mechanisms of acantholysis in pemphigus foliaceus.

Pemphigus foliaceus (PF) is a dermatosis characterized by subcorneal vesicles and pathogenic IgG autoantibodies against desmoglein 1. PF IgG passively transferred into neonatal mice induces a blistering disease that duplicates the key findings of PF. In this study we have used this animal model to investigate the role of complement and IgG valence in triggering blister formation. In the passive transfer experiments, we found that PF IgG, as well as the F(ab')2 and Fab fragments, was capable of inducing the typical subcorneal blistering disease in both complement-deficient and complement-sufficient mice. Moreover, the disease activity in these mice correlated well with the dose of IgG or its proteolytic fragments injected in the animals. We conclude that neither complement activation nor IgG-mediated cell surface antigen crosslinking is required for the induction of acantholysis in the experimental PF model.

Acantholysis↗
PubMed1997

Mechanisms of acantholysis in pemphigus vulgaris: role of IgG valence.

Pemphigus vulgaris (PV) is a dermatosis mediated by autoantibodies against desmoglein 3 (Dsg3). It was known that intraperitoneal (i.p.) injections of PV IgG and PV F(ab')2, but not of PV Fab, into neonatal mice reproduced the key features of the disease in these animals. It was proposed that crosslinking of antigen by bivalent PV autoantibodies may trigger acantholysis in PV. In the present study, we have used subcutaneous (s.c.) injections of PV IgG and its proteolytic fragments into neonatal mice to test equimolar amounts of these autoantibody fractions. Mice developed clinical and histological features of PV in a dose-dependent manner following a similar time course. PV IgG and Fab fractions induced acantholysis as early as 2 hr after the injection. It was also demonstrated that sc injections of PV Fab were more effective in inducing disease than ip injections. PV autoantibodies may bind an "adhesive site" of Dsg3 and impair its function, thus triggering acantholysis.

Acantholysis↗
PubMed1997

Mucosal and mucocutaneous (generalized) pemphigus vulgaris show distinct autoantibody profiles.

Pemphigus vulgaris is an autoimmune bullous disorder characterized by autoantibodies directed against desmoglein 3. A group of 19 pemphigus vulgaris sera were characterized by immunoblotting, immunofluorescence, immunoprecipitation, and the passive transfer mouse model. The aim of these studies was to determine the specificity of the autoantibody response in these patients. All patients had clinical and histologic evidence of pemphigus vulgaris. Fogo selvagem sera (n = 8), bullous pemphigoid sera (n = 8), antinuclear antibodies positive sera from patients with lupus erythematosus (n = 2), and normal human sera (n = 8) were used as controls. All pemphigus vulgaris patients showed titers of IgG autoantibodies by indirect immunofluorescence > or = 1:60, predominantly of the IgG4 subclass and immunoprecipitated recombinant desmoglein 3 expressed in the baculovirus system. Patients with disease localized to the mucous membranes showed no reactivity with desmoglein 1 and only one had weak reactivity with mouse skin by indirect immunofluorescence (titer = 1:20). Sera of four of these mucosal patients were tested in the mouse model and three of four did not elicit skin or mucosal disease in the animals. In contrast, sera from all seven patients with disease involving the skin and mucous membranes (generalized disease) produced disease in neonatal mice. In one patient the disease evolved from pure mucosal involvement associated with anti-desmoglein 3 antibodies to a disorder involving mucosas and skin. This transition was associated with the appearance of anti-desmoglein 1 antibodies in the patient's serum. These studies indicate that the autoantibody response in pemphigus vulgaris is heterogeneous. Epitopes recognized by some pemphigus vulgaris sera are species specific and others may be mucosal specific.

Animals↗
PubMed1997

T lymphocytes from a subset of patients with pemphigus vulgaris respond to both desmoglein-3 and desmoglein-1.

Pemphigus vulgaris and pemphigus foliaceus are cutaneous autoimmune diseases characterized by intraepithelial blisters and autoantibodies to desmosomal glycoproteins. The antigens recognized by pemphigus vulgaris and pemphigus foliaceus autoantibodies are desmoglein-3 (Dsg3) and desmoglein-1 (Dsg1), respectively. Dsg3 and Dsg1 are members of the desmoglein subfamily of the cadherin supergene family of cell adhesion molecules. It has been well documented that a subset of pemphigus vulgaris sera have IgG reactivity to both Dsg1 and Dsg3, suggesting that Dsg1 may also participate in the autoimmune response of these patients. The cellular mechanisms of T cell autoimmunity in these patients, however, are completely unknown. In this study, we tested the proliferative responses of T lymphocytes from eight pemphigus vulgaris patients after incubation with Dsg3 and Dsg1 fusion proteins. The sera of four of these PV patients showed reactivity with both Dsg1 and Dsg3, whereas the remaining four reacted only with Dsg3. We found that T cells obtained from those patients that exhibited the combined Dsg1/Dsg3 autoantibody reactivity showed a proliferative response after exposure to either Dsg1 or Dsg3 fusion proteins. The cellular responses to both of these recombinant proteins were highly specific and restricted to the CD4-positive T cell population. T cells from pemphigus vulgaris patients with no anti-Dsg1 serum reactivity showed a proliferative response to Dsg3, but not to Dsg1. The Dsg1 fusion protein used in this study has minimal sequence homology with Dsg3. Thus, this study provides the first evidence that T cells from a subset of pemphigus vulgaris patients respond to both Dsg1 and Dsg3.

Amino Acid Sequence↗
PubMed1997

Vulvar basal cell carcinoma.

BACKGROUND: Vulvar basal cell carcinoma is a rare neoplasm that often displays aggressive biologic behavior. Recurrence after simple excision is common, and metastases have been reported. Early diagnosis is essential and rests upon histopathologic examination of biopsy specimens, since the clinical appearance of these neoplasms may be deceptively innocent. CASE: A 65-year-old woman was seen with a nonhealing skin lesion on the right vulva. Physical examination revealed a 0.3 X 0.3 cm crusted papule on the right labium majus. A saucerization biopsy was performed. Histopathologic examination of the biopsy specimen revealed basal cell carcinoma. The patient underwent Mohs micrographic excision of the tumor, the total extent of which measured 0.9 X 1.8 cm. CONCLUSION: Vulvar basal cell carcinoma is a rare but important consideration in the differential diagnosis of cutaneous vulvar lesions. Accurate diagnosis depends upon a high index of suspicion, biopsy, and histopathologic examination. Mohs micrographic excision is the treatment of choice.

Aged↗
PubMed1997

Nonsecretory IgA1 autoantibodies targeting desmosomal component desmoglein 3 in intraepidermal neutrophilic IgA dermatosis.

Intraepidermal neutrophilic IgA dermatosis, a rare skin disease entity manifested with blisters and pustules clinically and lower epidermal blister, acantholysis, and neutrophilic infiltration pathologically, was first reported in 1985. Although the disease is characterized by IgA autoantibodies targeting the epithelial cell surface component, the target antigen has not been determined. We investigated a patient with this disease by histopathology, direct and indirect immunofluorescence, immunoblotting, and immunoadsorption studies. The pustular lesion was characterized by blister at the lower epidermis, acantholysis, and neutrophilic infiltration. Nonsecretory IgA1 subclass autoantibodies targeting the lower epithelial cell surfaces were detected in the patient's skin and serum. The patient's IgA autoantibodies labeled a recombinant desmosomal protein desmoglein 3 on immunoblotting and the immunolabeling of epithelial cell surfaces was eliminated by preadsorption with desmoglein 3. Thus, desmoglein 3 is identified as a target antigen in intraepidermal neutrophilic IgA dermatosis. The ability of IgA1 autoantibodies to bind neutrophils may be responsible for the prominent neutrophilic infiltration observed histopathologically and for the pustular lesions observed clinically.

Aged↗
PubMed1996

Calciphylaxis.

Explore the source record for details and available documents.

Adult↗
PubMed1996

An active focus of high prevalence of fogo selvagem on an Amerindian reservation in Brazil. Cooperative Group on Fogo Selvagem Research.

Fogo Selvagem (FS) is an autoimmune disease characterized by subcorneal vesicles and antidesmoglein-1 autoantibodies. Previous epidemiologic data have linked the onset of FS to exposure to an environmental antigen(s). This investigation describes a unique human settlement with an extraordinarily high prevalence of FS. This community is made up of Amerindians belonging to the Terena tribe, which has settled on the Limao Verde reservation in the state of Mato Grosso do Sul in Brazil. Twenty-six well-characterized FS cases have been identified within a total population of 998, yielding a prevalence of 2.6%. Seventeen of the patients (65 %) were males, and over 50% were older than 30 y of age. The incidence of the disease shows temporal periodicity, i.e., years with several cases of FS alternating with years with no cases. Over one-half of the cases occurred in genetically related family members. Another Terena reservation, the Ipegue/Taunay, located 90 km west of the Limao Verde reservation, was also evaluated as a control group. This reservation, with a population of 2203, had no recorded cases of FS. Thus, the Limao Verde reservation represents a new focus of FS in which the disease exhibits temporal, geographic, and familial clustering. These results suggest that the environmental antigen or antigens precipitating FS are endemic to the Limao Verde reservation. This reservation appears to be an ideal population for carrying out sero-epidemiologic, genetic, and environmental studies aimed at disclosing the etiology of FS.

Adolescent↗