A subset of patients with pemphigoid (herpes) gestationis has serological evidence of celiac disease.

BACKGROUND: Pemphigoid (herpes) gestationis (PG) is an uncommon, self-limited disease with other autoimmune associations; however, celiac disease (CD) is not recognized as one. METHODS: From 71 patients' sera submitted for herpes gestationis factor (HGF) testing over a 5-year period, 12 were consistent with PG demonstrating HGF and increased IgG BP180 antibody levels; these sera were tested for IgA and IgG endomysial antibodies (EMA), epithelial basement membrane zone and cell surface antibodies by indirect immunofluorescence, and for IgA and IgG tissue transglutaminase (transglutaminase 2 or TG2) antibodies, IgA epidermal transglutaminase (transglutaminase 3 or TG3) antibodies, IgG BP230, and IgG desmoglein 1 and desmoglein 3 antibodies by enzyme-linked immunosorbent assays (ELISAs). RESULTS: Three of 12 patients' sera with PG (25%) had CD antibodies with positive IgA EMA and increased IgA TG2 antibody levels; two of these had positive IgG EMA, and one other had an increased IgA TG3 antibody level. CONCLUSIONS: A subset of patients with serological findings of PG also has serological evidence of CD, which may have implications in the etiopathogenesis of PG and which reveals important information about the mother's, and possibly her infant's, health.

Pemphigoid gestationis.

Pemphigoid gestationis is a rare autoimmune subepidermal bullous dermatosis that occurs during pregnancy and postpartum. Diagnosis is made on the basis of the presence of a subepidermal vesicle on routine histologic examination and of linear deposition of complement along the basement membrane zone of perilesional skin. The disorder is accompanied by severe pruritus and polymorphous bullous skin lesions. Clinical diagnosis is confirmed by histology and positive cutaneous immunofluorescence and immunoelectron microscopy tests (linear deposition of C3, with or without immunoglobulin G, along the basement membrane zone, within the lamina lucida, and localized to the proximal part of anchoring filaments of the epidermal fragment of salt-split skin). Enzyme-linked immunosorbent assay for pemphigoid gestationis antibody (BP180) is commercially available. If local treatment fails, systemic corticosteroid therapy should be administered. Oral corticosteroids are the therapeutic mainstay in pregnancy and postpartum. The prognosis is good for mother and child, except that there is a risk of preterm delivery and of moderate fetal growth restriction. Recurrence is possible during subsequent pregnancies. There is no significant maternal morbidity or mortality.

The intracellular and extracellular domains of BP180 antigen comprise novel epitopes targeted by pemphigoid gestationis autoantibodies.

Pemphigoid gestationis (PG) is an autoimmune sub-epidermal bullous dermatosis of pregnancy associated with circulating autoantibodies targeting the extracellular non-collagenous (NC) 16A domain of bullous pemphigoid (BP) 180 antigen. In order to determine whether BP180 regions other than NC16A are recognized by PG autoantibodies, we have analyzed the reactivity of 15 PG patient sera against several BP180 antigenic sites by sensitive methods such as immunological screening and ELISA. Most PG sera tested (13 of 15) reacted with an epitope (amino acid 508-541) mapped in the NC16A domain. Of note, nine of 15 PG patient sera reacted with at least one additional antigenic site other than NC16A. Specifically, two epitopes in the BP180 extracellular domain and five epitopes in the intracellular one were recognized by three and seven PG sera, respectively. In addition, a representative intracellular epitope was recognized by PG autoantibodies as a portion of BP180 antigen both in denaturating and native conditions. Finally, reactivity against epitopes additional to NC16A was also detected at an early stage of the disease. The identification and characterization of hitherto unrecognized epitopes targeted by PG patient autoantibodies provide novel insights into the pathophysiology of humoral immune response to BP180 in PG.

Immunoblotting and enzyme-linked immunosorbent assay for the diagnosis of pemphigoid gestationis.

OBJECTIVES: To investigate the sensitivity of immunoblotting and enzyme-linked immunosorbent assay (ELISA) to detect autoantibodies to bullous pemphigoid antigen 180 in patients with pemphigoid gestationis and to correlate autoantibody serum levels with disease activity. METHODS: In serum samples obtained from 44 pregnant patients before initiation of therapy and from the same number of healthy blood donors, the autoantibody reactivity was assayed by immunofluorescence microscopy on human skin sections as well as Western blot analysis and 2 different ELISAs by using recombinant forms of the immunodominant domain of BP180. In addition, ELISA reactivity with this autoantigen was assayed in 6 patients during the course of the disease, and its correlation with the clinical disease activity was estimated by applying the Spearman rank correlation test. RESULTS: By indirect immunofluorescence microscopy, complement-fixing autoantibodies to the dermal-epidermal junction were found in 93% of patients' sera. By immunoblotting and ELISA, autoantibodies to bullous pemphigoid antigen 180 were detected in 93% and 86.3% of pemphigoid gestationis patients, respectively, but in none of the healthy controls. Serum levels of autoantibodies as detected by ELISA paralleled the patients' disease activity. CONCLUSIONS: Our study shows that immunoblotting and ELISA are sensitive tools for the detection of autoantibodies to bullous pemphigoid antigen 180 in patients with pemphigoid gestationis. In addition, the ELISA is useful to monitor autoantibody serum levels. LEVEL OF EVIDENCE: II-2

Molecular mapping of the major epitopes of BP180 recognized by herpes gestationis autoantibodies.

Herpes gestationis (HG) is an autoantibody-mediated subepidermal bullous dermatosis associated with pregnancy. The primary target of HG autoantibodies is BP180, a 180-kDa hemidesmosomal glycoprotein. We previously showed that autoantibodies and autoimmune T lymphocytes from HG patients recognize the MCW-1 antigenic site (AA 507-520), which is located in the membrane-proximal noncollagenous domain (NC16A) of BP180. Here, we analyzed the sera of 37 HG patients to further define the sites on BP180 that are targeted by autoantibodies. All of the HG sera, but none of the control sera, were immunoreactive with sec180e, a 120-kDa recombinant protein encompassing the entire BP180 extracellular domain. HG sera depleted of reactivity to NC16A no longer reacted with sec180e, indicating that the major HG-associated epitopes on BP180 are restricted to the NC16A domain. The vast majority of the HG sera (34 of 37) reacted with a 7 amino acid peptide corresponding to the N-terminal half of MCW-1 (MCW-1A). Eleven HG sera (including the 3 that failed to react with MCW-1A) recognized one or more of three antigenic sites located within a 15 amino acid stretch immediately downstream of MCW-1A. In summary, we have identified four major HG-associated epitopes clustered within a 22 amino acid region of the BP180 ectodomain. These findings support the hypothesis that an autoimmune response to the BP180 NC16A domain is a crucial step in the pathogenesis of HG.

Polymorphic eruption of pregnancy and herpes gestationis: comparison of granulated cell proteins in tissue and serum.

Polymorphic eruption of pregnancy (PEP) and herpes gestationis (HG) are pregnancy-related dermatoses of unknown aetiology with eosinophil infiltration which, at early stages, may show similar clinical and histopathological features. To determine the relative contributions of eosinophils, neutrophils and mast cells to the pathogenesis of PEP and HG through deposition of granule proteins, we studied tissue and serum from 15 patients with PEP and 10 with HG. Using indirect immunofluorescence with antibodies to human eosinophil granule major basic protein (MBP), eosinophil-derived neurotoxin (EDN), eosinophil cationic protein (ECP), neutrophil elastase and mast cell tryptase, we determined and compared cellular and extracellular staining patterns in lesional skin biopsy specimens and, using immunoassay, measured MBP, EDN, and ECP in patients' sera. Eosinophil infiltration and extracellular protein deposition of all three eosinophil granule proteins were present in both PEP and HG indicating a pathogenic role for eosinophils in both diseases. Staining for eosinophil granule proteins was especially prominent in urticarial lesions and around blisters in HG. EDN and ECP serum levels in PEP and ECP serum levels in HG were significantly increased compared with those in normal pregnant and normal nonpregnant serum. Neutrophils were more prominent in HG specimens than in PEP specimens; extracellular neutrophil elastase was minimally present and similar in both diseases. Mast cell numbers and extracellular tryptase deposition did not differ between the two diseases and did not differ from mast cell counts in skin of normal pregnant women. This study shows that eosinophil granule proteins are deposited extracellularly in tissue and are increased in serum in both PEP and HG. Moreover, eosinophil involvement in the two diseases is more consistent than neutrophil and mast cell involvement. Comparatively, tissue eosinophil infiltration and extracellular protein deposition is more extensive in HG than in PEP, suggesting that eosinophil involvement is greater in the pathogenesis of HG than PEP and similar to that found in bullous pemphigoid.

Serum eosinophil cationic protein (ECP) in bullous pemphigoid.

BACKGROUND: The importance of eosinophils in the pathogenesis of the major forms of pemphigoid (bullous pemphigoid, cicatricial pemphigoid, herpes gestationis) remains to be confirmed. METHODS: To evaluate the role of eosinophilic infiltrates in these diseases and to detect the presence and activity of eosinophils, we compared the serum levels of eosinophil cationic protein (ECP), an eosinophil-derived protein, in 11 healthy subjects and in 10 patients with pemphigoid diseases (8 with bullous pemphigoid, one with cicatricial pemphigoid, and one with herpes gestationis). The serum of two patients with epidermolysis bullosa acquisita (EBA) and one with linear IgA bullous dermatosis (LABD) were utilized as a further control. RESULTS: There was a significant difference between the mean of serum ECP levels in patients with pemphigoid diseases (25.1 +/- 12.3 micrograms/L, M = SD) and control subjects (2.30 +/- 2.41, micrograms/L +/- SD 2.41) (T = 4.272 P < 0.0001). The two patients with EBA (10.8 and 17.7 micrograms/L) showed contrasting results; the patient with LABD had normal ECP serum levels. The serum levels of ECP were not significantly correlated with the blood eosinophil count (R = 0.103; P = 0.777) in any of the cases. CONCLUSIONS: In pemphigoid disease, the serum levels of ECP seem to be correlated with the activated secreting and tissue-damaging eosinophils found in the dermis, supporting the concept of an active participation of eosinophils in generating cutaneous lesions.

[Immunoglobulin level in herpes gestationis]. / Immunglobulinspiegel bei Herpes gestationis

At a patient with herpes gestationis the immunoglobulins IgG, IgA and IgM as well as the proteins albumin, transferrin and coeruloplasmin were determined in the serum. The relation of this illness of pregnancy with immunological factors is in discussion.