Herpes gestationis (Pemphigoid gestationis)

J Invest Dermatol. 1997 Nov;109(5):679-83. Abstract quote

The BP180 antigen, a component of the epidermal anchoring complex, has been identified as one of the major antigenic targets of autoantibodies associated with the blistering skin disease, bullous pemphigoid.

Our research group has recently demonstrated that reactivity of bullous pemphigoid autoantibodies to the BP180 ectodomain is almost entirely restricted to a set of four antigenic sites clustered within the membrane-proximal noncollagenous stretch (NC16A). Using a passive transfer mouse model, antibodies to the corresponding noncollagenous region of murine BP180 were shown to trigger an inflammatory subepidermal blistering disease that closely mimics bullous pemphigoid.

We now report the development of an enzyme-linked immunoabsorbent assay system that is extremely sensitive in detecting disease-specific autoantibodies in the sera of bullous pemphigoid patients. The target antigen in this assay is a recombinant form of the BP180 NC16A domain that contains all four of the well-defined bullous pemphigoid-associated antigenic sites. Of 50 randomly selected bullous pemphigoid sera tested, 47 (94%) were positive in this assay, whereas no specific reactivity was detected in any of the 107 controls. Interestingly, all three of the bullous pemphigoid sera that were negative in this assay had been obtained from patients who were already undergoing treatment.

The NC16A enzyme-linked immunosorbent assay is more sensitive than any of the standard techniques for detecting circulating bullous pemphigoid autoantibodies, including other enzyme-linked immunosorbent assays, immunoblotting, and indirect immunofluorescence.

Finally, the NC16A enzyme-linked immunosorbent assay provides immunologic information that cannot be obtained from direct immunofluorescence studies of skin biopsies, and that may well be relevant in the diagnosis and treatment of bullous pemphigoid.

Epidemiology
Disease Associations
Pathogenesis
Laboratory/Radiologic/ Other Diagnostic Testing
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Special Stains/ Immunohistochemistry/ Electron Microscopy
Differential Diagnosis
Prognosis
Treatment
Commonly Used Terms
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DISEASE ASSOCIATIONS	CHARACTERIZATION
VERTICAL TRANSMISSION
Herpes Gestationis in a Mother and Newborn: Immunoclinical Perspectives Based on a Weekly Follow-up of the Enzyme-Linked Immunosorbent Assay Index of a Bullous Pemphigoid Antigen Noncollagenous Domain. Aoyama Y, Asai K, Hioki K, Funato M, Kondo N, Kitajima Y. Department of Dermatology, Gifu University School of Medicine, Yanagido 1-1, Gifu City 501-1194, Japan.	Arch Dermatol. 2007 Sep;143(9):1168-72. Abstract quote BACKGROUND: Herpes gestationis (HG) is a rare, autoimmune, bullous disease that occurs during the second or third trimester and usually resolves over weeks or months after delivery. Neonates with HG are rare (estimated at 1 per 100 000 cases). Although anti-180-kDa bullous pemphigoid (BP180) autoantibody and transfer of this autoantibody are known as the cause, to our knowledge, no coordinated analysis of clinical symptoms and anti-BP180 antibody enzyme-linked immunosorbent assay titers has been reported in a mother and neonate with HG. OBSERVATIONS: We describe a 33-year-old woman with HG and her neonate with vesicular erythematous lesions and the weekly follow-up results of the BP180 noncollagenous domain (NC16a) enzyme-linked immunosorbent assay. CONCLUSIONS: Almost the same titer of pathogenic antibody as that in the mother is transferred to the neonate. The plasma elimination half-life of anti-BP180 antibody is approximately 15 days in mother and neonate. An abrupt twin peak increase in the BP180 enzyme-linked immunosorbent assay index from maternal serum was observed just before and after delivery, possibly explaining why HG usually occurs in the last trimester of pregnancy and exacerbates postpartum. Lesions in the neonate resolve without treatment far before pathogenic antibody disappears, suggesting that factors other than anti-BP180 antibodies may be involved in the generation of eruptions. Frequent testing of the BP180 enzyme-linked immunosorbent assay greatly facilitates therapeutic planning.
Herpes gestationis with transient bullous lesions in the newborn. Bonifazi E, Meneghini CL.	Pediatr Dermatol 1984 Jan;1(3):215-8 Abstract quote A case of severe bullous dermatosis in the newborn son of a mother with herpes gestationis is reported. Bullous lesions appeared in the child about 2 hours after delivery and regressed completely without specific treatment by the end of the first month, leaving numerous epidermal cysts. The immunologic phenomena were both qualitatively and quantitatively comparable to those obtained in the mother, i.e., deposition of complement (C3) and smaller amounts of IgG at the dermo-epidermal junction of the affected skin. A transient increase of the total serum IgE was demonstrated in the mother, while the serum IgE level in the newborn was less than 5 U/ml. The pathogenetic role of IgG autoantibodies in herpes gestationis and, more generally, in autoimmune diseases is discussed.
Herpes gestationis in a mother and child. Chen SH, Chopra K, Evans TY, Raimer SS, Levy ML, Tyring SK. Department of Dermatology, UTMB, Galveston, Texas 77555-1070, USA.	J Am Acad Dermatol 1999 May;40(5 Pt 2):847-9 Abstract quote Herpes gestationis (pemphigoid gestationis) is a rare autoimmune disease that appears during pregnancy or in the immediate postpartum period. We report the cases of a mother and neonate with immunofluorescence confirmed herpes gestationis both of whom had extensive cutaneous involvement.

PATHOGENESIS	CHARACTERIZATION
EOSINOPHILS
Out Evidence for eosinophil degranulation in the pathogenesis of herpes gestationis. Scheman AJ, Hordinsky MD, Groth DW, Vercellotti GM, Leiferman KM. Department of Dermatology, University of Minnesota, Minneapolis.	Arch Dermatol 1989 Aug;125(8):1079-83 Abstract quote Herpes gestationis is a pregnancy-related bullous dermatosis of unknown origin with associated tissue and peripheral blood eosinophilia. In this report, eosinophil degranulation in herpes gestationis was studied, and the role that the eosinophil may have as an effector cell that induces tissue damage through deposition of toxic cationic proteins is discussed. Using indirect immunofluorescence with antibody to human eosinophil granule major basic protein, major basic protein was observed both within tissue eosinophils and deposited extracellularly outside eosinophils in the dermis of eight patients with herpes gestationis. Possible mechanisms whereby eosinophils might be activated to degranulate in herpes gestationis are reviewed.
HLA
Clues to the aetiology and pathogenesis of herpes gestationis. Holmes RC, Black MM, Jurecka W, Dann J, James DC, Timlin D, Bhogal B.	Br J Dermatol 1983 Aug;109(2):131-9 Abstract quote In a study of twenty-five patients with herpes gestationis we found that 80% possessed the HLA antigen DR3, which confers increased immune responsiveness and a predisposition to 'auto-immune disease'. In five patients the development of herpes gestationis coincided with a change in sexual partner, suggesting that the development of herpes gestationis may depend on exposure to an antigen derived from the father. This might share determinants with a component of the basement membrane zone of skin. Although anti-basement membrane zone antibodies are present in HG it is not clear whether they play a pathogenic role. The infrequency of neonatal involvement and the lack of correlation between immunofluorescence findings and clinical activity in our patients suggested that the antibodies might be a result of tissue damage rather than its cause. Two patients in our study were exceptional in that episodes of herpes gestationis were followed by normal pregnancies. In these patients the relationship of their DR antigens to those of the fetus may have been important in determining whether or not the pregnancy would be affected by herpes gestationis.
Herpes gestationis. Shornick JK. Department of Dermatology, Group Health Cooperative of Puget Sound, Seattle, Washington.	Dermatol Clin 1993 Jul;11(3):527-33 Abstract quote HG expresses a broader clinical range than previously thought. Disease may be mild and nonvesicular during one pregnancy, followed by explosive vesiculobullous disease during another. On the other hand, patients with extensive HG during one pregnancy may experience mild or even subclinical disease during a subsequent gestation. The broad range of clinical signs and the lack of demonstrable fetal or maternal risk associated with HG have important ramifications for patients desirous of further children. There is a genetic predisposition to HG. DRB10301 (HLA-DR3) is increased and 90% of patients express either DRB10301 (HLA-DR3) or DRB10401/040X (HLA-DR4). Ninety percent of patients also carry a C4 null allele, which may be due to linkage dysequilibrium with DRB10301 or DRB1*0401/040X. The disease appears to be mediated by an IgG1 specific for a 180-kD component of hemidesmosomes. This protein is distinct from the 240-kD hemidesmosomal antigen seen in BP and is coded for by a different cDNA on a different chromosome. Abnormal expression of class II MHC occurs in the placental villi of those with HG, suggesting ongoing immunologic stimulation. This has led some investigators to believe that the primary immunologic event is taking place within the placenta and that the skin is an immunologic bystander.

CLINICAL VARIANTS	CHARACTERIZATION
Clinical experience in pemphigoid gestationis: report of 10 cases. Castro LA, Lundell RB, Krause PK, Gibson LE. Department of Dermatology, Mayo Clinic, Rochester, Minnesota 55905, USA.	J Am Acad Dermatol. 2006 Nov;55(5):823-8. Epub 2006 Sep 14. Abstract quote BACKGROUND: Pemphigoid gestationis is a rare autoimmune blistering disease that occurs during pregnancy. OBJECTIVE: This study reviewed our clinical experience with pemphigoid gestationis. METHODS: We reviewed medical records of 10 patients with pemphigoid gestationis seen at Mayo Clinic, Rochester, Minnesota, between 1976 and 2004. RESULTS: Urticarial papules were the most frequent clinical presentation followed by blisters and rash. Pruritus was the cardinal symptom. Lesions presented initially on the legs, thighs, back, and chest. Direct immunofluorescence had the highest diagnostic test sensitivity. Systemic corticosteroids were the mainstay of treatment. Fetal and maternal outcome was good in all cases. LIMITATIONS: This was a retrospective, single-institution study. CONCLUSIONS: This condition can be easily confused with other dermatoses of pregnancy, for example, pruritic urticarial papules of pregnancy. Biopsy for direct immunofluorescence is the preferred test for confirmation of diagnosis. On the basis of good patient outcomes, conservative treatment seems warranted.
Herpes gestationis: clinical and histologic features of twenty-eight cases. Shornick JK, Bangert JL, Freeman RG, Gilliam JN.	J Am Acad Dermatol 1983 Feb;8(2):214-24 Abstract quote We have studied 28 patients with well-documented herpes gestationis (HG) to determine the frequency of complications and to review the histopathology, immunopathology, and clinical parameters of disease. T he frequency of miscarriages and other maternal complications in our series was not extraordinary. Fetal complications were similarly limited. Less than 5% of infants had cutaneous lesions, and no other untoward fetal complications were apparent. Although the clinical features of our patients largely paralleled those typically reported for patients with HG, several variants of disease were noted. We report one woman with immunofluorescence-confirmed HG who had no clinical disease during a subsequent pregnancy. We also identified cases in which the characteristic vesiculobullous lesions of HG never developed. Instead, four women had urticarial papules or plaques throughout their clinical courses. HG was verified in these four women by typical immunofluorescent findings and by recurrent, classical disease during subsequent pregnancies in two. In addition, two women were identified with recurrent HG during pregnancies by different husbands.
MUCOSAL INVOLVEMENT
Pemphigoid gestationis with predominant involvement of oral mucous membranes and IgA autoantibodies targeting the C-terminus of BP180. Shimanovich I, Skrobek C, Rose C, Nie Z, Hashimoto T, Brocker EB, Zillikens D. Department of Dermatology, University of Wurzburg, and the Department of Dermatology, Kurume University School of Medicine, Fukuoka.	J Am Acad Dermatol 2002 Nov;47(5):780-4 Abstract quote Pemphigoid gestationis (PG) is an autoimmune pregnancy-associated subepidermal blistering disease. It usually affects skin and, rarely, mucous membranes. In the vast majority of patients with PG, the autoimmune response is directed to the membrane-proximal NC16A domain of the 180-kd bullous pemphigoid (BP) antigen (BP180) and is mediated by IgG1 and IgG3 autoantibodies. We report the case of a patient with PG associated with extensive lesions on oral mucous membranes. Immunoblotting studies demonstrated the presence of circulating IgA autoantibodies in the patient's serum that were exclusively directed to a 49 amino acid stretch on the C-terminal portion of the BP180 ectodomain located 800 amino acids downstream from NC16A. This C-terminal stretch of BP180 has previously been demonstrated to localize to the lamina lucida/lamina densa interface and to be recognized by IgG and IgA antibodies in a subgroup of patients with cicatricial pemphigoid as well as by IgG autoantibodies in some BP sera. Our patient's lesions healed without scarring within 6 weeks after delivery of a healthy child. The findings in this patient extend the clinical and immunopathologic spectrum of PG.