The late phase of the immediate wheal and flare skin reaction. Its dependence upon IgE antibodies.

IgE antibodies are usually thought to induce only immediate skin reactions. We have shown that the intradermal injection of a number of different allergens can produce a prolonged inflammatory reaction after the immediate wheal and flare in most sensitive subjects. This late inflammatory response occurs 6-12 h after challenge and is characterized by diffuse edema, erythema, pruritus, and heat. Both immediate and late responses can also be seen after passive sensitization of skin sites in nonatopic subjects. That IgE is involved in inducing the reaction was shown by the abolition of both immediate and late responses by passive transfer tests in the following experiments: (a) heating atopic serum at 56degreesC for 4 h, (b) removing IgE from the atopic serum by a solid phase anti-IgE immunoabsorbent, and (c) competitively inhibiting the binding of IgE antibodies to cells by an IgE myeloma protein. In addition, both responses were induced by affinity chromatography-purified IgE antibody, followed by antigenic challenge. Very similar lesions could also be induced by intradermal injection of Compound 48/80, thus suggesting a central role in the reaction for the mast cell or basophil. Histologically, the late phase is characterized by edema and a mixed cellular infiltration, predominantly lymphocytic but also containing eosinophils, neutrophils and basophils. Direct immunofluorescent staining did not show deposition of immunoglobulins or complement components, except IgM in 2 of 15 and C3 in 1 of 15 patients. This finding indicates that the late phase does not depend on the deposition of immune complexes. The results of the study suggest that IgE-allergen interaction on the surfaces of mast cells or on infiltrating basophils causes both immediate and late cutaneous responses.

Tests for treponemal antibody in CSF.

We studied the potential usefulness of CSF treponemal tests in the diagnosis of neurosyphillis. The CSF was tested with the microhemagglutination test for Treponema pallidum (CSF-MHA-TP test) and with the CSF-FTA test by using undiluted CSF and CSF diluted in saline and in sorbent. In a prospective evaluation, of 177 nonsyphilitics, none had reactive CSF-MHA-TP tests and only one had a reactive CSF-FTA test. However, five of 15 syphilitics with no other evidence of neurosyphilis had reactive CSF-FTA tests. The CSF-FTA test reactivity appeared most likely when the titer of the serum FTA test was high. In a retrospective evaluation of syphilitics with reactive CSF-FTA tests, similar patterns of reactivity occurred in patients with and without other evidence of neurosyphilis. Without other supporting clinical or laboratory data, the diagnostic value of a reactive CSF-FTA test is unknown.

C3b receptor in normal human skin.

Receptors for C3b in normal skin were studied. C3b was produced by treating normal human serum with cobra venom factor and by partial digestion of purified C3 with trypsin. Cryostat sections of normal human skin were incubated with C3b, followed by a direct immunofluorescent technique using monospecific goat antihuman C3. The histologic localization of C3b fluorescence was ascertained by fixing cryostat sections with glutaraldehyde and staining with hematoxylin and eosin. The following structures showed staining with anti-C3: (1) endothelial cells in capillaries, larger vessels, and arteries, (2) smooth muscle in arrector pilori muscles and artery walls, and (3) myoepithelial cells in the secretory portion of sweat glands. C3b did not bind to the intercellular substance nor to the basement membrane zone in normal human skin. Normal human sera treated with EDTA, EGTA, and heat (56 degrees C for 30 min) were negative, as was purified C3 by itself, thus indicating that native C3 did not bind to these receptors. Specificity for C3/C3b was shown by blocking with both unconjugated rabbit antihuman C3 and purified C3. The endothelial C3b receptor may have an important role in the localization of immune complexes in cutaneous vasculitis.

Localization of eosinophil granule major basic protein in chronic urticaria.

The role of the eosinophil in the pathogenesis of cutaneous diseases is not known. The eosinophil granule major basic protein (MBP), constituting the core and accounting for greater than 50% of the eosinophil granule, is toxic to helminths and mammalian cells. To determine whether eosinophil degranulation occurs in lesions of chronic urticaria, we performed an indirect immunofluorescence assay on sections of formalin-fixed, paraffin-embedded tissue, utilizing affinity chromatography-purified antibody to MBP. Twelve of 28 biopsies showed evidence of degranulation as judged by the deposition of MBP outside the eosinophil. The positive staining was of 3 types: (1) small blood vessel walls (5 patients), (2) dispersion of granular material (9 patients), and (3) focal or diffuse immunofluorescence of connective tissue fibers (11 patients). These results suggest a possible role for the cytotoxic molecule MBP in the evolution of lesions of chronic urticaria.

Whole organisms and purified cell walls compared as immunosorbents for the detection of IgE antibodies to Staphylococcus aureus.

We have developed an immunoradiometric assay for IgE antibodies to Staphylococcus aureus (Staph IgE-Ab) which uses purified cell walls (PCW) from the Wood 46 strain of S. aureus as an immunosorbent. We compared Wood 46 PCW and whole organisms (WO) as immunosorbents for Staph IgE-Ab by performing tests on sera from patients with atopic dermatitis (AD) or the hyperimmunoglobulin E syndrome (hyper IgE syndrome). Sera with Staph IgE-Ab demonstrated dose-dependent binding to PCW and WO, but the ratio of specific to non-specific binding was much greater with PCW. Mean non-specific binding to WO was greater than to PCW, 5% versus 2%; and non-specific binding to WO varied directly with the serum concentration of IgE. Results of tests on patients' sera indicated that PCW are required in screening assays for Staph IgE-Ab to avoid false positive results caused by high levels of non-specific binding to WO.

Acquired immunodeficiency syndrome-related Kaposi's sarcoma.

OBJECTIVE: To describe Kaposi's sarcoma (KS) associated with the acquired immunodeficiency syndrome (AIDS). DESIGN: A review of AIDS-related KS (AIDS-KS), with its associated epidemiologic and etiologic characteristics, pathogenesis, clinical manifestations, histopathologic features, prognosis, and treatment, is presented. RESULTS: KS is the most frequent malignant lesion in patients with AIDS. The incidence of AIDS-KS is high in homosexual and bisexual men who have multiple sexual partners and in children and women with the human immunodeficiency virus (HIV) infection. Anal-oral contact is one of the main routes of the sexually transmitted agents of AIDS-KS. The major pathogenic factors that may possibly induce AIDS-KS are HIV itself or other sexually transmitted agents, HIV tat gene, some oncogenes and cytokines such as interleukin 6, basic fibroblast growth factor, transforming growth factor-beta, oncostatin M, and platelet-derived growth factor. Treatment includes local therapy, radiotherapy, systemic chemotherapy, zidovudine, interferon, granulocyte-macrophage colony-stimulating factor, and other agents. CONCLUSION: KS may be an early manifestation of AIDS and the most frequent neoplastic complication of AIDS. Growth factors, cytokines, immunosuppression, and interaction with infectious agents seem to have a role in the development of this enigmatic disorder. Treatment of KS should be individualized. Further investigation of the agents and factors of AIDS-KS may help facilitate the treatment and prevention of this neoplasm.

Hypocomplementemic urticarial vasculitis: association with chronic obstructive pulmonary disease.

Since 1973, we have identified and collected follow-up data on 16 patients with hypocomplementemic urticarial vasculitis. Preliminary diagnostic criteria are the presence of typical urticarial skin lesions and low levels of serum complement (all components), plus two of the following: dermal venulitis, arthritis, glomerulo-nephritis, episcleritis or uveitis, recurrent abdominal pain, and C1q precipitin in plasma. Exclusions are systemic lupus erythematosus, mixed cryoglobulinemia, elevated antinuclear antibody titer, hereditary deficiency of a complement component or of C1 esterase inhibitor, and presence of anti-native DNA or hepatitis B antigen. The renal involvement is relatively benign, and generally the patients do well and respond to specific treatment when this is indicated. Eight of 10 smokers studied had evidence of chronic obstructive pulmonary disease, 1 of whom died of this complication. In three patients, severe chronic obstructive pulmonary disease developed at a young age after relatively low pack-year cigarette smoking histories. Lung disease probably results from the interaction of two major risk factors-smoking and an immunologically mediated process that has not been identified.

Skin fibrinolytic activity in cutaneous and systemic vasculitis.

Study of involved and uninvolved skin from patients with necrotizing vasculitis revealed diminished tissue fibrinolytic activity deposition of immunoreactants in involved skin. In these patients, the depletion of tissue fibrinolytic activity is probably the result of vessel injury secondary to the local deposit of immunoreactants. In addition, there was diminished tissue fibrinolytic activity in uninvolved skin from patients with and without clinical skin involvement, unassociated with the deposition of immunoreactants. The precise mechanism for diminished tissue lytic activity in these latter patients is not known, but it may be associated with generalized activation of the coagulation and fibrinolytic mechanisms that result in local depletion of tissue fibrinolytic activity. These local changes may aggravate the clinical course of the disease as well as inhibit the healing of the lesions.

Immunologic mechanisms in systemic vasculitis.

Thirty-four patients with systemic vasculitis were studied to determine the possible type and frequency of associated immunologic abnormalities. The patients were divided into three clinical groups--those with systemic vasculitis without respiratory tract involvement, those with systemic vasculitis with respiratory tract involvement (particularly Churg-Strauss vasculitis and Wegener's granulomatosis), and those with limited vasculitis without visceral involvement. A diminished level of serum complement was found in half the patients with systemic vasculitis without respiratory tract involvement. These patients usually had diffuse skin disease that often was associated with the presence of rheumatoid factor and cryoglobulinemia and most likely represented an immune-complex induced disease. The serum IgE often was elevated in patients who had systemic vasculitis with respiratory tract involvement, particularly those with Churg-Strauss vasculitis and Wegener's granulomatosis, and may be a clue to the pathogenesis in this group of patients.

The anticentromere antibody: disease specificity and clinical significance.

Serum samples from 539 subjects were screened for the presence of the anticentromere antibody on a human laryngeal carcinoma (HEp-2) cell line (Antibodies, Inc.). The antibody was present in 61 patients (11%), most of whom had features of limited scleroderma or the CREST syndrome (calcinosis cutis, Raynaud's phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia), either independently or in association with primary biliary cirrhosis. The antibody was rarely found in patients with rapidly advancing or diffuse scleroderma. The anticentromere antibody is therefore a useful prognostic indicator in patients with early scleroderma, as it may help to predict what pattern of scleroderma will evolve. Screening for this antibody should be conducted in all patients with Raynaud's phenomenon, primary biliary cirrhosis, and scleroderma. Other previous studies have indicated a similar disease specificity and prognostic importance of this antibody.

Cyclosporine in the treatment of dermatologic disease: an update.

Treatment with cyclosporine is beneficial for many dermatologic diseases such as psoriasis, lichen planus, Behçet disease, atopic dermatitis, pyoderma gangrenosum, and epidermolysis bullosa acquisita. The selective action of cyclosporine on helper T cells and its rapid therapeutic action and weak myelotoxicity are the key advantages in the treatment of many dermatologic diseases. Nevertheless, drug toxicity, especially nephrotoxicity, high rates of relapse after treatment cessation, and high cost have limited its use to those diseases refractory to other therapies. Herein we discuss the use of cyclosporine for dermatologic diseases relative to efficacy, dosage, safety profile, and monitoring. In addition, we review the formulations and metabolism of cyclosporine; discuss its mechanism of action, clinical indications in dermatology, and side effects; and provide usage guidelines for this drug. Cyclosporine can be safely administered when potential toxicities, dosing, and monitoring guidelines are known.

Primary neuroendocrine carcinomas of the skin (Merkel cell tumors). A clinical, histologic, and ultrastructural study of thirteen cases.

Neuroendocrine carcinomas of the skin have recently been recognized, and clinicopathologic information on these tumors is accumulating rapidly. We studied 13 such lesions by light and electron microscopy, and eight were subjected to immunohistochemical analysis. The ages of the patients (five women and eight men) ranged from 24 to 84 years. Nine patients had neoplasms occurring in sun-exposed areas; one patient had metachronous symmetric lesions on the arms, and another had antecedent hypohidrotic ectodermal dysplasia. Eight tumors metastasized, and six spread to regional or distant lymph nodes. Three patients died with visceral metastases to the liver, bones, and brain. All patients had their primary tumor confined to the corium and subcutaneous tissue without involvement of overlying epidermis. Tumor cells were round and uniform in size, with delicate nuclear chromatin and a high mitotic rate. An organoid growth pattern was seen in all tumors, with focal trabeculation and rare rosette formation. Ultrastructurally, peripheral cytoplasmic dense-core granules were evident, and perinuclear filament whorls could be seen in all 13 tumors. The latter feature was stable, even in specimens taken from paraffin blocks for electron microscopy. Immunoperoxidase studies failed to reveal serotonin, calcitonin, or adrenocorticotrophin within tumor cells.

Acrodermatitis and acquired zinc deficiency.

A 42-year-old woman had an acquired zinc deficiency. The patient was malnourished, secondary to chronic alcohol (ethanol) abuse and cirrhosis, with associated low serum and urinary levels of zinc. Her acrodermatitis was unresponsive to topically applied triamcinolone acetonide but cleared after oral zinc sulfate therapy.

Bullous pemphigoid and associated malignant neoplasms.

To evaluate the significance of the association of systemic malignant disease with bullous pemphigoid, we reviewed the records of patients with bullous pemphigold seen at the Mayo Clinic between 1960 and 1972. Data from 73 patients with bullous pemphigoid were compared with data from 146 controls (73 with contact dermatitis and 73 with psoriasis) matched for age, sex, and calendar year of diagnosis. In the three groups, eight patients with bullous pemphigoid, 11 with contact dermatitis, and ten with psoriasis were found to have malignant disease within the period covering the five years before and five years after the diagnosis of the skin disease. These data indicate that pemphigoid does not seem to be significantly associated with malignant disease.

Cutaneous periarteritis nodosa: immunofluorescence studies.

The study of ten cases of cutaneous periarteritis nodosa by direct immunofluorescence microscopy of excision biopsy specimens revealed positive findings in nine. Deposition of IgM was found in the vessel walls in six cases, and C3 was observed in four; however, only in two cases was C3 found with IgM in the vessel walls. Deposits of IgM in the superficial vessels were found in five cases, although only the deep muscular vessels showed evidence of the vasculitis in cutaneous periarteritis nodosa. Serum hepatitis B antigen was absent in the nine cases that were tested. Positive immunofluorescence findings in superficial as well as in deep vessels suggest that although periarteritis nodosa is characterized by an inflammatory panarteritis, occasional vasculitis of small vessels might be expected.

IgE antibodies to Staphylococcus aureus. Prevalence in patients with atopic dermatitis.

We determined the prevalence of IgE antibodies to Staphylococcus aureus by optimized immunoradiometric assay methods in serum specimens from 69 patients with atopic dermatitis. All patients had positive aerobic cultures for S aureus from skin. Significant binding attributable to IgE antibodies was noted in three of 25 patients with atopic dermatitis and superimposed impetiginization or pustules, but antibodies were not detected in the remaining 44 patients whose lesions were colonized with S aureus. By comparison, IgE antibodies to S aureus were uniformly present in high titer in serum samples from patients with the hyperimmunoglobulin E syndrome. We conclude that most patients with atopic dermatitis do not have detectable levels of IgE antibodies to S aureus.

Beaded fluorescence pattern of FTA-ABS test associated with malignancy.

A beaded pattern of immunofluorescence (IF) occasionally occurs in routine FTA-ABS testing. This phenomenon strongly correlates with false-positive reactions in patients with SLE. We report on this IF finding in association with carcinoma of the colon.

Chronic urticaria-like lesions in systemic lupus erythematosus. A review of 12 cases.

Twelve of 54 patients with systemic lupus erythematosus (SLE) had nonpuric, chronic urticaria-like lessions. Skin biopsy of the lesions was performed in 11 cases, and nine showed necrotizing vasculitis. The 54 patients, in general, had severe disease, and laboratory and clinical data suggested a postivite relationship between the urticaria-like lesions and disease severity. There was no consistent relationship between the course of the urticaria-like lesions and the serologic findings and clinical activity of the SLE. The frequency and importance of urticaria-like lesions in SLE deserve further study.

Papulonecrotic tuberculid secondary to Mycobacterium bovis.

A patient with papulonecrotic tuberculid had a pruritic papular eruption associated with constitutional symptoms. The eruption flared whenever the patient received low doses of prednisone to control symptoms of temporal arteritis. A cervical lymph node biopsy specimen demonstrated acid-fast bacilli, and Mycobacterium bovis grew on the cultures. The eruption cleared completely with antituberculous therapy. This case demonstrated the clinicopathologic findings compatible with a diagnosis of papulonecrotic tuberculid. Skepticism regarding the existence of papulonecrotic tuberculid is probably a result of the current decreased prevalence of untreated tuberculosis, and the subsequently increased rarity of this entity.

The cutaneous immunopathology of necrobiosis lipoidica diabeticorum.

Twelve female patients with necrobiosis lipoidica diabeticorum (six with diabetes and six without) had a 5-mm punch biopsy of the skin lesion performed. The tissue was processed for dermatopathologic examination in 12 cases and for direct immunofluorescence in 11. Vasculopathy with inflammation and thickening of vessel walls, at times leading to occlusion, was found in lesional skin in all 12 cases. Vessels contained deposits of immunoreactants in the involved skin in 11 cases. This included IgM in six, C3 in nine, fibrin in ten, IgG in one, and IgA in two. Vessels contained deposits of immunoreactants in uninvolved skin in seven patients (C3 in four, IgM in three, fibrin in three, C4 in one, and IgA in one), three of whom had type I diabetes.