Takayasu arteritis and cutaneous necrotizing vasculitis.

Takayasu arteritis (TA) is an inflammatory arteriopathy involving predominantly the aorta and its main branches. The disease evolves in two phases: a first, nonspecific inflammatory stage and a late 'pulseless' stage, in which complications related to arterial stenosis and aneurysm formation predominate. In both phases, skin manifestations, such as inflammatory nodules, erythema-nodosum- and pyoderma-gangrenosum-like ulcers, have been described.

IgG autoantibodies from bullous pemphigoid patients recognize multiple antigenic reactive sites located predominantly within the B and C subdomains of the COOH-terminus of BP230.

Bullous pemphigoid is a subepidermal bullous disorder characterized by an autoantibody response against the bullous pemphigoid antigen 230 (BP230) and the bullous pemphigoid antigen 180 (BP180), a cytoplasmic component and a transmembrane component, respectively, of hemidesmosomes. Although immunodominant sequences within the extracellular domain of BP180 have been identified, characterization of the antigenic sites on BP230 is still incomplete. To identify autoantibody-reactive sites on BP230 and to examine whether the targeted regions are contained within functionally important domains, recombinant fragments encompassing almost the entire BP230 were used to assess the reactivity of 25 bullous pemphigoid sera by immunoblotting.

IgG autoantibodies from a lichen planus pemphigoides patient recognize the NC16A domain of the bullous pemphigoid antigen 180.

Lichen planus pemphigoides (LPP) most likely encompasses a heterogeneous group of subepidermal autoimmune blistering disorders occurring in association with lichen planus. We describe the case of a 49-year-old patient with features characteristic of LPP. Direct immunofluorescence microscopy studies demonstrated linear deposits of C3 along the cutaneous basement membrane, while circulating IgG autoantibodies directed against the epidermal side of skin separated by 1 M NaCl were detected.

Adult-onset Still's disease with persistent plaques.

Adult-onset Still's disease (AOSD) is a systemic disorder characterized by intermittent fever, evanescent rash, arthralgias or arthritis and predominantly neutrophilic leucocytosis. We report on a 16-year-old woman with Still's disease who developed, in addition to the typical rash, persistent papular lesions on her face, neck and upper and lower back. Although the presence of fixed skin lesions is not a characteristic feature of AOSD, their appearance at the onset of the disease and their evolution suggest that they represent a specific manifestation of the disease.

Childhood bullous pemphigoid associated with IgA antibodies against BP180 or BP230 antigens.

Linear IgA bullous dermatosis (LABD) comprises a heterogeneous group of subepidermal blistering disorders characterized by in situ bound IgA antibodies in epidermal basement membrane. We report three children presenting clinical and immunopathological features characteristic of LABD. By immunoblotting, the three patients' sera contained IgA antibodies that reacted against the bullous pemphigoid (BP) antigen 180 and or BP230, molecular markers for BP.

Structure and function of hemidesmosomes: more than simple adhesion complexes.

The attachment of cells to the extracellular matrix is of crucial importance in the maintenance of tissue structure and integrity. In stratified epithelia such as in skin as well as in other complex epithelia multiprotein complexes called hemidesmosomes are involved in promoting the adhesion of epithelial cells to the underlying basement membrane. In the past few years our understanding of the role of hemidesmosomes has improved considerably.

Childhood bullous pemphigoid: report of a case with characterization of the targeted antigens.

The clinical and immunopathologic features of children with acquired subepidermal blistering disorders show considerable overlap, and their classification frequently requires characterization of the targeted antigens. A 8-month-old boy developed a generalized subepidermal blistering disorder with striking palmoplantar involvement. The patient's serum contained antibodies reacting against the epidermal side of 1 M sodium chloride separated normal human skin.

IgG autoantibodies from bullous pemphigoid (BP) patients bind antigenic sites on both the extracellular and the intracellular domains of the BP antigen 180.

Bullous pemphigoid (BP) and gestational pemphigoid (PG) are subepidermal blistering disorders associated with autoantibodies directed against two components of hemidesmosomes: the BP antigen 180 (BP180) and the BP antigen 230 (BP230). Autoantibodies against the extracellular domain (ECD) of BP180 are thought to play an initiatory role in subepidermal blister formation. To characterize the targeted antigenic sites on BP180, we have assessed the reactivity of sera from BP and PG patients against eukaryotic recombinant proteins encompassing various portions of the ECD and the intracellular domain (ICD) of BP180.

Identification and characterization of autoreactive T cell responses to bullous pemphigoid antigen 2 in patients and healthy controls.

Antibodies against the extracellular domain of bullous pemphigoid antigen 2 (BPAG2) are thought to play a key role in the pathogenesis of bullous pemphigoid (BP), the most frequent autoimmune bullous disease of the skin. Autoreactive T cell responses to BPAG2 were investigated in 16 BP patients and 24 healthy controls by coculture of PBMC with two recombinant BPAG2 proteins (extracellular domain of BPAG2). Primary in vitro T cell responses to BPAG2 were observed in 10/12 BP patients expressing the BP-associated HLA-DQB1*0301 allele and 8/10 DQB1*0301 positive healthy individuals.

Hemidesmosome formation is initiated by the beta4 integrin subunit, requires complex formation of beta4 and HD1/plectin, and involves a direct interaction between beta4 and the bullous pemphigoid antigen 180.

Hemidesmosomes (HDs) are stable anchoring structures that mediate the link between the intermediate filament cytoskeleton and the cell substratum. We investigated the contribution of various segments of the beta4 integrin cytoplasmic domain in the formation of HDs in transient transfection studies using immortalized keratinocytes derived from an epidermolysis bullosa patient deficient in beta4 expression. We found that the expression of wild-type beta4 restored the ability of the beta4-deficient cells to form HDs and that distinct domains in the NH2- and COOH-terminal regions of the beta4 cytoplasmic domain are required for the localization of HD1/plectin and the bullous pemphigoid antigens 180 (BP180) and 230 (BP230) in these HDs.

Role of the bullous pemphigoid antigen 180 (BP180) in the assembly of hemidesmosomes and cell adhesion--reexpression of BP180 in generalized atrophic benign epidermolysis bullosa keratinocytes.

Bullous pemphigoid antigen 180 (BP180) is a transmembrane component of hemidesmosomes (HD), cell-substrate attachment complexes in stratified and complex epithelia. To determine the role of BP180 in the assembly of HD and cell adhesion, using SV40 virions we have immortalized BP180-deficient keratinocytes derived from a patient with the inherited skin blistering disorder generalized atrophic benign epidermolysis bullosa (GABEB). The GABEB keratinocytes form HD-like structures, which contain alpha 6 beta 4 integrin and HD1/plectin, but not the bullous pemphigoid antigen 230 (BP230).

Detection of IgG autoantibodies in the sera of patients with bullous and gestational pemphigoid: ELISA studies utilizing a baculovirus-encoded form of bullous pemphigoid antigen 2.

Autoantibodies against the extracellular domain of bullous pemphigoid antigen 2 (BPAG2) are thought to play a key role in the pathogenesis of bullous pemphigoid and their detection may thus be of diagnostic and prognostic value. The aim of this study was to develop a standardized enzyme-linked immunosorbent assay utilizing the baculovirus-derived protein BV13 (extracellular domain of BPAG2 devoid of 68 amino acids at the C terminus linked to glutathione-S-transferase and 6x His tag) to detect BPAG2-specific autoantibodies. For the enzyme-linked immunosorbent assay, nickel agarose affinity-purified BV13 protein was incubated with sera from patients with bullous pemphigoid (n = 39), gestational pemphigoid (n = 10), and pemphigus vulgaris/pemphigus foliaceus (PV/PF; n = 15), or normal human sera (NHS; n = 18).

The extracellular domain of BPAG2 localizes to anchoring filaments and its carboxyl terminus extends to the lamina densa of normal human epidermal basement membrane.

Bullous pemphigoid antigen 2 (BPAG2) is a 180 kDa type II transmembrane protein associated with hemidesmosomes (HDs) in basal keratinocytes. To better understand how BPAG2 promotes keratinocyte adhesion to epidermal basement membrane (BM), purified IgG against a baculovirus-encoded recombinant was used to localize its carboxyl terminus in human skin by immunogold electron microscopy (IEM). A 2.

The localization of bullous pemphigoid antigen 180 (BP180) in hemidesmosomes is mediated by its cytoplasmic domain and seems to be regulated by the beta4 integrin subunit.

Bullous pemphigoid antigen 180 (BP180) is a component of hemidesmosomes, i.e., cell-substrate adhesion complexes.

The subcellular distribution of the high molecular mass protein, HD1, is determined by the cytoplasmic domain of the integrin beta 4 subunit.

The high molecular mass protein, HD1, is a structural protein present in hemidesmosomes as well as in distinct adhesion structures termed type II hemidesmosomes. We have studied the distribution and expression of HD1 in the GD25 cells, derived from murine embryonal stem cells deficient for the beta 1 integrin subunit. We report here that these cells possess HD1 but not BP230 or BP180; two other hemidesmosomal constituents, and express only traces of the alpha 6 beta 4 integrin.

Hemidesmosomes: roles in adhesion, signaling and human diseases.

Our understanding of the role of hemidesmosomes in cell-substratum adhesion has greatly improved both as a result of targeted gene mutation experiments and by means of observations of several blistering disorders of the skin in which the absence or defects of hemidesmosomal proteins have been demonstrated. Functionally important domains within the proteins that constitute hemidesmosomes have recently been identified by transfection and mutagenesis studies. These multiprotein complexes appear not only to mediate cell adhesion, but also to transduce signals from the extracellular matrix to the cell interior that may profoundly modulate cell behavior.

Genomic organization of the mouse beta 1 gene: conservation of the beta 1D but not of the beta 1B and beta 1C integrin splice variants.

We have determined the genomic organization of the 3'-region of the murine beta 1 gene and cloned the murine beta 1D integrin splice variant. Overlapping genomic clones encompassing the region of the beta 1D-specific exons were isolated from a phage lambda FIXII library, mapped and partially sequenced. All of the exon-intron junctions identified in the murine beta 1 gene fit with the consensus splice donor and acceptor sequences and occur at the same positions as in their human counterparts.

Passive transfer of autoantibodies from a patient with mutilating epidermolysis bullosa acquisita induces specific alterations in the skin of neonatal mice.

Background: Epidermolysis bullosa acquisita is a subepidermal bullous disease characterized by IgG autoantibodies directed against type VII collagen in anchoring fibrils. These autoantibodies are believed to play an important role in the pathogenesis of sub-lamina densa blister formation in this disease.

Observations: We describe a patient with epidermolysis bullosa acquisita who has developed mutilating acral involvement with early syndactyly and extensive scarring lesions of the scalp.

IgM autoantibodies to 180- and 230- to 240-kd human epidermal proteins in pregnancy.

Background And Design: A previous study has suggested that there is a novel entity among the polymorphous eruptions of pregnancy (PEP) associated with circulating anti-basement membrane zone IgM autoantibodies. To determine if the presence of anti-basement membrane zone IgM autoantibodies is a feature of PEP, serum samples from 52 patients with a PEP, 69 healthy pregnant women, and 42 nonpregnant women were prospectively evaluated by indirect immunofluorescence using salt-split human skin as substrate. Serum samples were also tested by immunoblotting using keratinocyte extracts and anti-human IgM antibodies.

Penicilliosis marneffei infection in AIDS.

Penicillium marneffei infection has emerged as a new potential indicator disease for AIDS in Southeast Asia. We report two additional cases of P. marneffei infection in patients infected with HIV who had traveled to endemic areas and review the mucocutaneous features of previously reported cases.