Clinical complexity of Leishmania (Viannia) braziliensis infections amongst travelers.

The protozoan parasite Leishmania (Viannia) braziliensis is one of the main causes of cutaneous and mucocutaneous leishmaniasis in South America. Here, we describe three cases of L. (V.) braziliensis infection which were acquired during travelling in Bolivia, Peru or Paraguay and illustrate the phenotypic heterogeneity and therapeutic complexity of the disease. Two patients presented with unusual clinical manifestations, i.e. with prominent regional lymphadenopathy ("bubonic leishmaniasis") and with simultaneously emerged skin and mucosal lesions, respectively. Both patients insufficiently responded to oral treatment with miltefosine; resolution of the lesions was only achieved after a course of intravenous liposomal amphotericin B.

Demonstration of epitope-spreading phenomena in bullous pemphigoid: results of a prospective multicenter study.

Bullous pemphigoid (BP), the most common autoimmune subepidermal bullous disease, is associated with an autoantibody response to BP180 and BP230, two components of junctional adhesion complexes in human skin promoting dermo-epidermal cohesion. Retrospective analyses demonstrated that these autoantigens harbor several epitopes targeted by autoaggressive B and T cells. The aim of this prospective multicenter study was to assess the evolution of IgG autoantibodies in 35 BP patients over a 12-month observation period. Epitope-spreading (ES) events were detected in 17 of 35 BP patients (49%). They preferentially occurred in an early stage of the disease and were significantly related to disease severity at diagnosis. Moreover, in three patients, spreading of IgG reactivity to intracellular epitopes of BP180 and BP230 was preceded by recognition of the BP180 ectodomain. Finally, IgG reactivity with extracellular epitopes of BP180 and intracellular epitopes of BP230 correlated with the severity of BP in disease course. These findings support the idea that IgG recognition of the BP180 ectodomain is an early and crucial event in BP disease, followed by variable intra- and intermolecular ES events, which likely shape the individual course of BP.

Histopathology of anti-laminin 5 mucous membrane pemphigoid.

BACKGROUND: Anti-laminin 5 mucous membrane pemphigoid (MMP) is an autoimmune blistering disease characterized by autoantibodies against the major basement membrane component laminin 5 (laminin 332, epiligrin). OBJECTIVE AND METHODS: We reviewed 17 biopsy specimens from 9 patients with anti-laminin 5 MMP in an attempt to define typical histopathologic features of the disease. RESULTS: Fifteen specimens showed subepidermal blister formation, while two biopsy specimens revealed an epithelial ulcer. In 11 biopsies a sparse to moderate inflammatory infiltrate composed of lymphocytes and neutrophils with some eosinophils was observed. Four biopsies showed a dense infiltrate dominated by neutrophils in two cases and by eosinophils in one case. The remaining biopsy revealed a dense lymphoplasmacellular infiltrate without granulocytes. Scarring of the upper dermis was present only in 5 specimens. Immunohistochemical analysis localized type IV collagen to the dermal side of the blister, suggesting that split formation occurred within the lamina lucida of the cutaneous basement membrane. LIMITATIONS: The number of patients studied was relatively small. CONCLUSIONS: Histopathology of anti-laminin 5 MMP is characterized by subepidermal blistering and a sparse to moderate superficial lymphohistiocytic infiltrate with neutrophils and/or eosinophils. Both infiltrate density and composition may vary, making anti-laminin 5 MMP indistinguishable from other autoimmune subepidermal blistering diseases by histopathology alone. Scarring is present only in a minority of cases and is not a sensitive clue to the diagnosis of anti-laminin 5 MMP.

Multicenter prospective study of the humoral autoimmune response in bullous pemphigoid.

Bullous pemphigoid (BP) is an autoimmune bullous disease, associated with autoantibodies directed against the hemidesmosomal components BP180 and BP230. In this study for the first time different laboratories have analyzed the autoantibody profile in the same group of 49 prospectively recruited BP patients. The results show that: 1) disease severity and activity correlated with levels of IgG against the BP180-NC16A domain, but also against a COOH-terminal epitope of BP180, 2) distinct epitopes of the BP180 ectodomain other than BP180-NC16A were recognized by 96% of the BP sera; and 3) the combined use of BP180 and BP230 ELISA led to the detection of IgG autoantibodies in all the BP sera. These results demonstrate the usefulness of the combined ELISAs based on various BP180 and BP230 fragments in establishing the diagnosis of BP and support the concept that BP180 is the major autoantigen of BP.

Incomplete auriculotemporal nerve syndrome--mimicry of oral allergy syndrome.

Pollen allergies are commonly symptomatic as seasonal rhinoconjunctivitis. The majority of patients with pollen allergies develop an oral allergy syndrome due to cross-reactive homologous allergens in plant foods. Symptoms may vary from minor local oropharyngeal sensations and swelling to life threatening angioedema and glottis edema. We present the case of a 6-year-old male with suspected oral allergy syndrome who was referred for allergological work up. However, an incomplete auriculotemporal nerve syndrome was diagnosed, mimicking oral allergy syndrome.

Autoreactive T and B cells from bullous pemphigoid (BP) patients recognize epitopes clustered in distinct regions of BP180 and BP230.

Bullous pemphigoid (BP) is a well-characterized model of autoantibody-mediated autoimmunity, which presumably depends on autoreactive Th cells that promote the activation of autoreactive B cells. The two major autoantigens of BP are BP180 and BP230, two components of dermoepidermal adhesion complexes. Both, autoreactive Th cell responses and autoantibody profiles were characterized in 35 patients with acute onset BP using BP180 and BP230 proteins. Our findings indicate the following: 1) autoreactive Th cells recognized epitopes within the NH2-terminal (77.1%), COOH-terminal (65.7%), and central portion (57.1%) of the BP180 ectodomain; 2) IgG autoantibodies were found to exhibit similar or identical reactivity against the NH2-terminal (82.8%), COOH-terminal (77.1%), and central portion (37.1%) of the BP180 ectodomain; 3) T and B cell reactivity with the NH2-terminal portion of the BP180 ectodomain was associated with extensive BP, whereas the central portion was more frequently recognized in limited BP; 4) only 7 of 16 (43.7%) and 6 of 16 (37.5%) BP patients showed a Th cellular response against the COOH- and NH2-terminal regions of BP230, respectively, whereas 5) IgG reactivity against the COOH- and NH2-termini of BP230 was detected in 5 of 16 (31.3%) and 6 of 16 (37.5%) patients, respectively. These results demonstrate that Th and B cell reactivities against BP180, are, in contrast to BP230 reactivity, almost constantly detectable in BP patients, and differential epitope recognition of BP180 seems to be associated with distinct clinical severity. These observations support the concept that BP180, but not BP230, is the primary autoantigen of BP critical for disease development.

Detection of laminin 5-specific auto-antibodies in mucous membrane and bullous pemphigoid sera by ELISA.

Mucous membrane pemphigoid (MMP) is an autoimmune bullous disease that primarily affects mucous membranes leading to a scarring phenotype. MMP patients produce auto-antibodies (auto-ab) that preferentially recognize two components of the dermoepidermal basement membrane zone (BMZ): bullous pemphigoid (BP)180 and laminin 5 (LN5). Since detection of disease-specific auto-ab may be critical for diagnosis of MMP, we developed an ELISA with affinity-purified native human LN5. A total of 24 MMP, 72 BP, and 51 control sera were analyzed for LN5-specific auto-ab: 18/24 (75.0%) MMP and 29/72 (40.3%) BP sera were LN5 reactive. Sensitivity and specificity of the LN5 ELISA for MMP were 75% and 84.3%, respectively, and 40.3% and 88.2% for BP, respectively. The LN5 ELISA was more sensitive than a dot blot assay with native LN5, which detected LN5-reactive IgG in 14/24 (58.3%) MMP and 16/72 (22.2%) BP sera. In MMP, but not BP, levels of LN5-reactive IgG correlated with disease severity. Furthermore, IgG reactivity to LN5 of the MMP and BP sera was not significantly associated with IgG reactivity against other autoantigens of the BMZ, such as BP180 or BP230. Thus, the established LN5 ELISA holds great promise as a novel diagnostic and prognostic parameter for MMP.

BP230- and BP180-specific auto-antibodies in bullous pemphigoid.

Bullous pemphigoid is a subepidermal blistering disease associated with auto-antibodies (auto-ab) to BP180 and BP230. We developed ELISAs utilizing baculovirus-encoded recombinant proteins of BP230 and BP180 and studied their diagnostic and prognostic values by assessing the profile of the auto-ab response in 127 patients with BP. 39 patients had focal involvement, whereas 88 had generalized disease; 51 individuals served as controls. The results indicate: (1) BP180 IgG reactivity was associated with an overall sensitivity of 0.953 and specificity of 0.940; (2) 105 of 127 BP patients also displayed BP230 auto-reactivity, the global diagnostic performance of which, however, was moderate compared to BP180-auto-reactivity (sensitivity 0.815 vs 0.953, specificity 0.648 vs 0.940); (3) 101 patients (79.5%) had concordant BP180 and BP230 reactivity; (4) the association between the presence of BP230 auto-reactivity and focal involvement was stronger than in generalized disease (odds ratio (OR) 17.7 vs 10.2), independently from BP180 auto-ab profile; (5) correlation of total IgG with IgG1 and IgG4 was variable for both BP180 and BP230. Collectively, the global diagnostic properties of the BP180-ELISA outperform those of the BP230-ELISA. Presence of BP230 auto-reactivity, however, supports the diagnosis of BP and might be indicative for the extent of the disease.

Pemphigus vulgaris localized to the nose and cheeks.

Pemphigus vulgaris is an autoimmune blistering disease characterized by disseminated bullae and erosions of the mucosal surfaces and skin. Cases of pemphigus vulgaris with localized lesions on glabrous skin have been reported, and most of them have been attributed to the Koebner phenomenon. Lesions limited to the nose have mostly been described in pemphigus foliaceus, but the nose has also been the initial site of pemphigus vulgaris in a few patients. We report 4 cases of localized pemphigus vulgaris: one case with lesions limited to the nose and cheeks and 3 cases with isolated lesions on the nose. Recurrent episodes in these patients also occurred on the nose. None of them showed mucosal involvement or dissemination during a follow-up period of 2 to 9 years. Three patients had autoantibodies against desmoglein-3 as detected by immunoblot. In the other patient, antibodies against desmoglein-3 were detected by enzyme-linked immunosorbent assay. These localized lesions may represent a subgroup of pemphigus vulgaris or a period of limited activity during this chronic disease.

Severity and phenotype of bullous pemphigoid relate to autoantibody profile against the NH2- and COOH-terminal regions of the BP180 ectodomain.

Bullous pemphigoid, the most common autoimmune subepidermal bullous disorder, is associated with autoantibodies targeting antigenic sites clustered within the extracellular domain of BP180. To investigate epitope and subclass specificity of autoantibodies in bullous pemphigoid, we developed an enzyme-linked immunosorbent assay utilizing baculovirus-expressed recombinant forms of the NH2- and COOH-terminal regions of the extracellular domain of BP180 and examined sera obtained from patients with active bullous pemphigoid (n=116) and controls (n=100). Ninety-three (80%) and 54 (47%) of the 116 bullous pemphigoid sera recognized the NH2- and COOH-terminal regions, respectively, of the extracellular domain of BP180. Detailed analysis demonstrates that (i) this novel enzyme-linked immunosorbent assay is highly specific (98%) and sensitive (93%) as 108 of 116 bullous pemphigoid sera reacted with at least one of the baculovirus-derived recombinants, (ii) in active bullous pemphigoid, autoantibodies against the NH2-terminus of the extracellular domain of BP180 were predominantly of the IgG1 class, whereas a dual IgG1 and IgG4 response to this region was related to a more severe skin involvement, (iii) autoreactivity against both the NH2- and COOH-terminal regions was more frequently detected in patients with mucosal lesions, and (iv) levels of IgG (and IgG1) against the NH2-terminal, but not against the COOH-terminal portion of the extracellular domain of BP180, reflected disease severity indicating that autoantibodies against the NH2-terminus are critical in the pathogenesis of bullous pemphigoid. In conclusion, this novel enzyme-linked immunosorbent assay represents a highly sensitive and specific assay for rapid diagnosis of bullous pemphigoid and related disorders and may provide predictive parameters for the management of bullous pemphigoid patients.