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Biomedical subjects

W R Gammon

Publications and source records attributed to W R Gammon.

At least 37 records · Page 2Linked to original sources
PubMed1991

Childhood epidermolysis bullosa acquisita. Report of three cases and review of literature.

Epidermolysis bullosa acquisita is an acquired subepidermal blistering disease with variable clinical, pathologic, and immunologic features. The disease has been reported infrequently in adults and only rarely in children. We describe three new cases of childhood epidermolysis bullosa acquisita, review three previously reported cases, and contrast the features of the disease in children with those in adults. The results suggest that both children and adults with epidermolysis bullosa acquisita have variable clinical and pathologic features that may mimic other bullous diseases. Epidermolysis bullosa acquisita is characterized by a chronic course, poor response to therapy, and occasional clinical remissions.

Adolescent↗
PubMed1990

Epidermolysis bullosa acquisita preceding the development of systemic lupus erythematosus.

In most cases of epidermolysis bullosa acquisita that occur in patients with systemic lupus erythematosus, the diagnosis of systemic lupus erythematosus is made before the development of blistering. We observed three patients with well-documented epidermolysis bullosa acquisita that developed several years before the onset of systemic lupus erythematosus. One patient was producing anti-U1RNP autoantibodies at the time epidermolysis bullosa acquisita was diagnosed, and all five produced this antibody during the systemic lupus erythematosus phase of their illness. In addition, in all five cases of epidermolysis bullosa acquisita with systemic lupus erythematosus antibodies to double-stranded DNA ultimately developed, and severe systemic lupus erythematosus and lupus nephritis developed in four patients. Sera from 15 other patients with epidermolysis bullosa acquisita without overt systemic lupus erythematosus were analyzed for systemic lupus erythematosus-related autoantibodies. Four patients were found to have at least one such autoantibody. These findings further document an association between epidermolysis bullosa acquisita and systemic lupus erythematosus and suggest that patients with systemic lupus erythematosus who present with epidermolysis bullosa acquisita may represent a subset of lupus erythematosus that puts the patient at increased risk for the development of more severe systemic illness. Patients presenting with epidermolysis bullosa acquisita, especially those who are black or Hispanic, should be monitored for the development of potentially life-threatening systemic lupus erythematosus.

Adult↗
PubMed1990

Direct immunofluorescence studies of sodium chloride-separated skin in the differential diagnosis of bullous pemphigoid and epidermolysis bullosa acquisita.

Bullous pemphigoid and epidermolysis bullosa acquisita may have indistinguishable clinical, histologic, and routine immunohistologic features. In those cases these two diseases can be reliably distinguished in routine diagnostic studies only in seropositive cases by tests on lamina lucida-split skin and in research studies by direct immunoelectron microscopy or, in patients with circulating autoantibodies, by immunoblotting studies. The use of these methods is limited by the expense and unavailability of the methods, the requirement for circulating autoantibodies, or both. We describe a method to distinguish between the two diseases on the basis of findings of direct immunofluorescence of a biopsy specimen after separation through the lamina lucida with 1.0 mol/L sodium chloride. The IgG appeared in the dermal side of the split specimens in epidermolysis bullosa acquisita and predominantly or exclusively in the epidermal side in pemphigoid. The method was found to be relatively simple, inexpensive, applicable to specimens preserved in transport media, and 100% reliable in our group of 22 patients.

Basement Membrane↗
PubMed1990

Placental glutathione-S-transferase-pi mRNA is abundantly expressed in human skin.

Four overlapping cDNA clones were isolated from a lambda gt11 human placenta cDNA library using purified human IgG antibody, from a patient with bullous pemphigoid. The sequence was homologous to human placenta glutathione-S-transferase-pi (GST-pi). Using the placenta clone, epidermal cDNA clones were isolated from a human keratinocyte library. Expression of GST-pi mRNA in human skin, cultured keratinocytes and fibroblasts, and disorders of squamous hyperplasia was demonstrated by Northern blotting and in situ hybridization. Human epidermal and placental cDNA clones hybridized to the same genomic DNA fragments. Hybridization of placental cDNA to interspecific somatic cell hybrids showed retention of chromosome 11, confirming the assignment of GST 3 to the long arm of chromosome 11 by molecular means. Anti-GST-pi antibody did not give a basement membrane zone pattern, although some normal and BP sera contained antibodies to GST-pi. Human skin expresses glutathione-S-transferase-pi, which belongs to an enzyme family important for detoxification and carcinogenesis.

Amino Acid Sequence↗
PubMed1990

Recombinant human cytokines stimulate neutrophil adherence to IgG autoantibody-treated epithelial basement membranes.

We investigated the ability of the purified recombinant human cytokines: tumor necrosis factor-alpha (rTNF), granulocyte-macrophage colony-stimulating factor (rGM-CSF), interleukin-1 beta (rIL-1), interleukin-3, and tumor necrosis factor-beta (rTNF-beta) to stimulate neutrophil adherence (NA) to basement membranes (BMs) of stratified squamous epithelia pretreated with autoantibodies (ABM) specific for the BM matrix protein, type-VII collagen. rTNF, rGM-CSF, rIL-1, and rTNF-beta, but not IL-3, stimulated NA and stimulation was ABM- and cytokine-concentration-dependent. Stimulation was cytokine-specific and not due to endotoxin since it was significantly inhibited by cytokine-specific antibodies but not by polymyxin B (PB). rTNF and rGM-CSF were the most potent stimulators, were effective at concentrations less than 0.067 ng/ml, and stimulated NA greater than 600%. Relative potency was: rTNF = rGM-CSF greater than rTNF-beta greater than rIL-1. Stimulation by rTNF was due to a rapid, time-dependent effect on the neutrophil, and NA appeared to be dependent, in part, on the low-affinity neutrophil receptor for IgG, Fc(gamma)RIII, because it could be specifically inhibited by monoclonal antibody (3G8) to Fc(gamma)RIII. These results suggest that rTNF, rGM-CSF, rIL-1, and rTNF-beta may contribute individually or in combination to immune-mediated inflammation and tissue injury by stimulating immune adherence of neutrophils to tissue-bound autoantibodies and immune complexes.

Antibodies, Monoclonal↗
PubMed1990

Heavy and light chain isotypes of immunoglobulin in epidermolysis bullosa acquisita.

Epidermolysis bullosa acquisita (EBA) is a chronic acquired blistering disease with characteristic clinical, pathologic, and immunopathologic features. The disease is characterized immunopathologically by circulating and tissue-bound IgG class autoantibodies (EBA antibodies) to the basement membrane zone of stratified squamous epithelium. Previous studies have shown that circulating and tissue-bound EBA antibodies are heterogenous in their ability to activate complement and have raised the possibility that functional heterogeneity might be related to IgG subclass restriction. In this study, we have characterized the IgG subclasses of the circulating and tissue-bound EBA antibodies by immunofluorescence and have examined the relationship between IgG subclass and complement binding. The results show that EBA antibodies belonging to all IgG subclasses are present in the skin of EBA patients. The results also show that EBA antibodies belonging to all IgG subclasses are present in the sera of most patients, including sera with and without complement binding EBA antibodies.

Basement Membrane↗
PubMed1990

Cutaneous IgA deposits in bullous diseases function as ligands to mediate adherence of activated neutrophils.

Linear IgA bullous dermatosis and dermatitis herpetiformis are inflammatory subepidermal blistering diseases characterized by IgA deposits at the cutaneous epithelial basement membrane and in dermal papillae, respectively. Inflammation in both disorders localizes to sites of IgA deposition and is characterized by a predominance of neutrophils. From these observations we postulate that IgA deposits in both diseases may contribute to the recruitment and/or localization of neutrophils. In this study we examined the ability of in vitro and in vivo bound IgA anti-basement membrane autoantibodies from patients with linear IgA bullous dermatosis and in vivo bound IgA deposits in dermal papillae from patients with dermatitis herpetiformis to mediate adherence of neutrophils stimulated by granulocyte macrophage colony-stimulating factor. The study showed that stimulated neutrophils adhered to basement membranes and dermal papillae containing IgA deposits. Adherence was IgA anti-basement membrane antibody concentration dependent and correlated with the immunofluorescence staining intensity of IgA deposits in dermal papillae. Adherence to IgA deposits but not IgG deposits could be inhibited by purified exogenous secretory IgA but not IgG and adherence to IgG deposits could be inhibited by purified exogenous IgG but not secretory IgA. These results provide direct experimental evidence that cutaneous IgA deposits in linear IgA bullous dermatosis and dermatitis herpetiformis can function as ligands for neutrophil adherence and have a role in the localization of inflammation in these disorders.

Cell Adhesion↗
PubMed1990

Acquired epidermolysis bullosa. A bullous disease associated with autoimmunity to type VII (anchoring fibril) collagen.

Epidermolysis bullosa acquisita (EBA) is a chronic subepidermal blistering disease of the skin in which one finds tissue-bound and circulating antibodies are bound to type VII collagen. Although not definitely proven, current evidence strongly suggests that EBA is an autoimmune disease. The true etiology or initiating event that triggers EBA has not been identified.

Autoimmune Diseases↗
PubMed1989

Generation of C5-dependent bioactivity by tissue-bound anti-BMZ autoantibodies.

We previously reported that complement-binding antibasement membrane zone (BMZ) autoantibodies can mediate complement-dependent directed migration and adherence of leukocytes to the BMZ in cryostat skin sections and that there is heterogeneity in the ability of anti-BMZ autoantibodies to mediate that response. Those observations suggested that directed migration and adherence of leukocytes to the BMZ might be dependent on the amount of complement-activating autoantibody deposited at the BMZ and the extent to which those antibodies could activate complement and generate C5-derived peptides (C5a, C5a des arg). In this study, we have examined the role of autoantibody concentration and C5 in mediating the adherence response. When cryostat skin sections were pretreated with anti-BMZ autoantibodies and subsequently incubated with neutrophils suspended in fresh serum, neutrophils adhered to the BMZ. Adherence was anti-BMZ autoantibody specific and proportional to anti-BMZ autoantibody concentration. To determine the role of C5 in mediating adherence, neutrophils were suspended in increasing concentrations of: 1) fresh serum, 2) heat-inactivated serum, 3) serum pretreated with antihuman C5, 4) serum pretreated with antihuman IgG, 5) C5-depleted serum, 6) purified C5, and 7) C5-depleted serum reconstituted with increasing concentrations of purified C5. The suspensions were then incubated with autoantibody-treated skin sections. The results showed a dose-dependent requirement for fresh serum and for C5-depleted serum reconstituted with increasing doses of C5. Adherence could be detected with C5 concentrations less than 200 ng/ml, which correspond to a C5a/C5a des arg concentration of 10(-8)-10(-9) molar. These results suggest that complement-dependent neutrophil adherence is a highly sensitive method for detecting and quantitating the ability of tissue-deposited anti-BMZ autoantibodies to activate complement and generate C5-derived bioactive peptides, for estimating the amount of C-activating anti-BMZ autoantibody deposited at the BMZ in vivo, and for evaluating the potential role of C-activating anti-BMZ autoantibodies in the pathogenesis of lesions.

Antibody Specificity↗
PubMed1989

The carboxyl-terminal domain of type VII collagen is present at the basement membrane in recessive dystrophic epidermolysis bullosa.

Recent studies showing that type VII collagen is a component of anchoring fibrils suggests that the absence of anchoring fibrils in recessive dystrophic epidermolysis bullosa may be due to a defect in the synthesis, secretion, and deposition of type VII collagen. That hypothesis is further supported by recent studies suggesting that monoclonal antibodies to type VII collagen do not react with the basement membrane in most patients. To investigate further, we examined skin from 12 patients by electron microscopy and by immunohistology and immunoelectron microscopy using a concentrated and purified monoclonal antibody to the carboxy-terminal domain of Type VII collagen. Although anchoring fibrils were not detected by electron microscopy, the results of immunohistology showed definite, but reduced, binding of the monoclonal antibody to type VII collagen at the basement membrane in a linear pattern in 11 of 12 patients. By immunoelectron microscopy, reduced deposition of anti-type VII collagen antibody was detected beneath the lamina densa. The results of this study show that the carboxyl-terminal domain of type VII collagen is synthesized, secreted, and deposited at the basement membrane zone in 11 of 12 patients with recessive dystrophic epidermolysis bullosa and suggest that the absence of anchoring fibrils may be due either to deposition of abnormal type VII collagen, reduced levels of normal type VII collagen, defective assembly of type VII collagen into anchoring fibrils, or destruction of the collagenous domain of type VII collagen.

Antibodies, Monoclonal↗
PubMed1989

The presence of intra-lamina lucida blister formation in epidermolysis bullosa acquisita: possible role of leukocytes.

In evaluating patients we have noted disparity between the locations of bound immunoreactants and the level of blistering in epidermolysis bullosa acquisita (EBA). We examined 10 consecutive EBA patients by routine histology, direct (DIF) and indirect (IIF; intact and NaCl-split skin) immunofluorescence, immunofluorescence mapping (IM), and/or direct immunoelectron microscopy (DIEM). DIF was positive in each. IIF was positive in 3/8 and 6/7 patients when intact and split skin were used as substrates. DIEM revealed immunoreactants within the lamina densa (LD) in 6/10, sub-LD in 1/10, and both LD and sub-LD in 3/10 patients. In contrast, by DIEM and IM, blister formation was noted within the lamina lucida (LL) in 7/9 and 8/10, sub-LD in 1/9 and 1/10, and within both LL and sub-LD in 1/9 and 1/10, respectively. In the presence of neutrophils within the upper dermis (n = 6), cleavage occurred within the LL in 5 specimens; in one additional specimen containing predominantly neutrophils, cleavage occurred within both LL and sub-LD. In the presence of mononuclear cells (n = 2), intra-LL cleavage occurred. In the presence of eosinophils, cleavage occurred within both LL and sub-LD. In the one specimen lacking any infiltrate, the cleavage plane was exclusively sub-LD. Intra-LL cleavage planes are more common than sub-LD ones in at least early cases of EBA. These findings likely represent the intra-LL-separating effect of leukocyte-derived proteolytic enzymes, when such cells are chemoattracted to the dermoepidermal junction by bound immuno-reactants.

Adult↗
PubMed1988

Clearing of epidermolysis bullosa acquisita with cyclosporine.

Epidermolysis bullosa acquisita is a chronic, severe, subepidermal, blistering disease of the skin, characterized by marked resistance to topical and systemic therapy. This report concerns a well-documented case of a woman who had had epidermolysis bullosa acquisita for 6 years and had remained hospitalized continuously for 7 months in 1987. Her case ultimately was controlled with cyclosporine after the failure of a variety of therapeutic modalities in the hospital, including prednisone, methotrexate, azathioprine, phenytoin, vitamin E, gold sodium thiomalate (Myochrysine), isotretinoin, and plasmapheresis. In contrast to patients with pemphigus and pemphigoid treated with cyclosporine, our patient's autoantibodies did not disappear on therapy. Although its mechanism of action in epidermolysis bullosa acquisita is unknown, we propose that cyclosporine may be a helpful drug for patients whose disease is refractory to more traditional forms of therapy.

Aged↗
PubMed1988

Absence of specific histologic changes in guinea pig skin treated with bullous pemphigoid antibodies.

Previous studies have reported that intradermal injections of bullous pemphigoid antibodies into guinea pigs can reproduce the histologic and immunohistologic features of bullous pemphigoid lesions. In this study we examined this model to determine its reproducibility and suitability for testing other types of anti-BMZ antibodies. Twenty guinea pigs were injected intradermally with 0.1, 0.3, or 0.5 ml of either bullous pemphigoid serum or IgG fraction containing high-titer complement-binding anti-BMZ antibodies or an equivalent volume of normal human serum or IgG fraction as control. Sites were biopsied at intervals after injection and were examined by routine histology and direct immunofluorescence. The results showed (a) no difference in the incidence of dermal epidermal separation or type of inflammation in experimental and control sites; (b) no evidence of an eosinophil-rich inflammatory reaction typical of bullous pemphigoid; (c) an absence of linear BMZ deposits of IgG and complement in the majority of sites injected with bullous pemphigoid antibodies; and (d) no correlation between dermal-epidermal separation and deposition of immune reactants at the BMZ. These results suggest the histologic changes seen in guinea pigs that are administered intradermal injections of bullous pemphigoid antibodies are nonspecific and that the model is not suitable for testing the pathogenicity of anti-BMZ antibodies in sera or IgG fractions.

Animals↗