Faculty Bibliography

The term vasculitis describes a variety of inflammatory changes in vessels. The most common type to affect the skin is a necrotizing venulitis associated with a neutrophilic polymorphonuclear leukocyte infiltrate. The most frequent presentation is palpable purpura on the lower extremities, but the lesions may include urticaria and ulcers. A diagnosis of cutaneous necrotizing venulitis obliges the physician to search for the cause, associated diseases, and the extent of the vascular involvement. Antigens, either in circulating immune complexes or as haptens bound to vessel proteins, are presumed to trigger immmune responses. The differentiation of large from small vessel disease and the prediction of systemic involvement may be difficult in a specific patient. Treatment, other than removal of the antigen, is theoretic or anecdotal

Deactivation is a phenomenon in which leucocytes exposed in vitro to a chemotactic factor in the absence of a concentration gradient are rendered relatively unresponsive to stimulation by a subsequent chemotactic gradient. In patients with idiopathic cold-induced urticaria, the elicitation of a local experimental angioedematous lesion causes the release of two chemotactic principles previously shown to deactivate leucocytes in vitro, high molecular weight neutrophil chemotactic factor (HMW-NCF) and eosinophil chemotactic factor of anaphylaxis (ECF-A), into the venous circulation draining the challenged extremity. However, biopsy specimens of lesional skin sites obtained for up to 24 hr show no infiltration of cells. For this reason, the in vitro chemotactic responsiveness of neutrophils to the chemotactic factor HMW-NCF and C5 fragments were assessed in three patients at various times after experimental challenge. Leucocytes from venous effluent draining an experimentally-induced angioedematous lesion were markedly impaired in their chemotactic responsiveness to both chemotactic factors 5 min after challenge, while cells taken from an unchallenged extremity at the same time responded normally. Cells from both arms were equally impaired in their responsiveness 1 hr later, thereby demonstrating that the chemotactic defect becomes systemic. The acquired defect was dissipated 4 hr after challenge. These data suggest that deactivation may occur in vivo and may alter host responsiveness in states where chemotactic factors are released into the circulation

An unusual patient, with dermal nodules, flexion contractures of the fingers and toes, cold-induced urticaria, dermographism and serum hypocomplementaemia, had necrotizing cutaneous venulitis underlying the spontaneous lesions. Since necrotizing cutaneous venulitis could be experimentally induced by the physical stimuli of cold or trauma, the time-course of histopathological events was documented in the skin of this patient. The histopathological alterations were studied in 1 micron thick, Epon-embedded skin biopsy specimens over an interval of 6 days. The early massive degranulation of the mast cells was followed by the sequential infiltration of neutrophilic, eosinophilic and basophilic polymorphonuclear leucocytes, by the development of venular endothelial cell necrosis and by the deposition of fibrin. The persistent serum hypocomplementaemia involved the classic activating and amplification pathways. It seems possible that the unusual combination of pathobiological processes involving the mast cells and the complement system in this patient has created a unique syndrome, in which venules are damaged and the sheaths of the extensor tendons of the hands and feet become affected in time

The effects of H2-blocking agents and the H2 receptor agonist, 4-methylhistamine, on the severity of anaphylactic reactions were studied in the guinea pig in vivo. The increase in gas volume of the lungs 90 sec after intravenous infusion of ovalbumin in animals immunized previously by intraperitoneal ovalbumin injection was used as an index of the severity of the reaction in vivo. The H2 receptor antagonists burimamide (1.0 and 3.0 mg per kg) and metiamide (3 mg per kg) significantly increased the severity of the reaction but did not significantly alter the effects of subcutaneous histamine. Neither 3 nor 30 mg of cimetidine per kg increased the severity of the reaction, and the higher dose significantly blunted the response to subcutaneous histamine. The H2 receptor agonist, 4-methylhistamine, significantly diminished the severity of the reation. These experiments demonstrate that H2 receptor stimulation may act to limit the severity of the anaphylactic reactions in vivo

We studied nine patients with bullous pemphigoid, a generalized cutaneous eruption- for evidence of mast-cell involvement during development of lesions. As in other reports, six of nine patients demonstrated a serum antibody directed against the epidermal basement-membrane zone. Direct immunofluorescence studies of lesions revealed depostion of immunoglobulin and complement proteins at the basement-membrane zone in six of nine and nine of nine patients, respectively. Participation of mast cells was suggested by a sequence of pathologic alterations in which there was progressive mast-cell degranulation and late eosinophil infiltration. In addition, a factor chemotactic for human eosinophils with the size and charge characteristics of the eosinophil chemotactic factor of anaphylaxis was identified in blullous fluid. The data indicate that, in addition to activation of the complement system, involvement of mast cells is an early and continuing event in the development of the cutanenous lesions of bullous pemphigoid

The distinctive cutaneous changes that occur in both the acute and chronic forms of the graft-vs-host reaction (GVHR) are described in two living patients in whom the GVHR developed after bone marrow transplantation for aplastic anemia. In the skin, the mild form of the acute GVHR is recognized as a subtle macular erythema, and the severe form appears as erythematous papules and violaceous macules with scale. Skin biopsy specimens in both of the acute forms show vacuolar alterations of the epidermal basal-cell layer with a perivenular infiltrate of lymphocytes. The chronic GVHR evolves from generalized scaling to diffuse areas of aclerotic and atrophic skin with a curious reticulated hyperpigmentation, ulcerations, and alopecia. Histopathologic study shows collagenization of the dermis that can be correlated with the clinical sclerodermoid changes. Owing to its visibility, the skin offers a unique opportunity for the early recognition of the GVHR

In a group of patients with a syndrome consisting of recurrent episodes of urticaria, arthralgia, abdominal pain, and (rarely) glomerulonephritis, examination of skin biopsy specimens showed necrotizing venulitis. An elevated erythrocyte sedimentation rate was the most common laboratory abnormality. Analyses of serum immunoglobulins revealed random abnormalities of immunoglobulin levels, and assessment of the complement system showed two groups of patients--some with hypocomplementemia and others with a normal complement system. In those with hypocomplementemia, there were low levels of C1q, C4 and, occasionally, C3, compatible with activation of the classic complement pathway. Although the cause of this syndrome is unknown, the complement profiles suggest that more than one mechanism of vascular damage may be operative

Lymphocytotoxic antibodies (LCTAB) were sought in sera of patients with rheumatic diseases and in family members. Patients with SLE and cutaneous necrotizing venulitis and family members of JRA patients had an increased frequency of LCTAB; JRA patients and family members of SLE patients did not. The only association between LCTAB and the HLA phenotype of persons with LCTAB was a decreased frequency of LCTAB in individuals with HLA-B27

The activation of mast cells by immunologic or physical stimuli leads to the generation of unstored intermediates (mediators) such as slow reacting substance of anaphylaxis (SRS-A) and platelet activating factor (PAF), and to their release along with performed mediators, histamine, eosinophil chemotactic factor of anaphylaxis (ECF-A), and neutrophil chemotactic factor (NCE), and macromolecular heparin. The internal regulation of mast cell-dependent phenomenons occurs at at least four levels: 1) the intensity and nature of the activating stimulus, 2) the regulation of mediator generation and release of cellular levels of the cyclic nucleotides, 3) the capacity of target cells to bind and respond to primary mediators, and 4) the rate at which mediators undergo biodegradation. Inasmuch as the mast cell is present at cutaneous and mucosal surfaces about venules, it seems likely that the initial or humoral phase of its response achieves an influx of plasms proteins, such as immunoglobulins and complement components, whereas the subsequent cellular phase augments local host defense through the entrance of neutrophils and eosinophils that terminate the humoral phase. The activation of mast cells is considered herein in terms of defined physical stimuli that are characterized by urticaria and angioedema