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.

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.

Class II major histocompatibility complex typing across the ethnic barrier in pemphigoid gestationis. A study in Mexicans.

BACKGROUND: Pemphigoid gestationis (PG), also called herpes gestationis, is a rare autoimmune disease of pregnancy or puerperium (estimated 1 out of 50,000 pregnancies among Caucasians). A previous series has demonstrated an association of PG with human leukocyte antigen (HLA)-DR3 or HLA-DR4 haplotypes. While these haplotypes are most commonly found in individuals of European ancestry, they have also been found in African-American patients affected with PG. PG has rarely been reported in other ethnic groups, and the HLA association in non-Europeans has not been examined. METHODS: We have characterized eight patients of Mexican ancestry who have PG by clinical, histologic, and immunofluorescence criteria. Class I and class II major histocompatibility complex (MHC) antigens were studied by standard microlymphocytotoxicity assays. Class II MHC antigens were further studied by polymerase chain reaction (PCR) amplification of HLA-DRB1, DQA, and DQB genes and allele-specific oligonucleotide hybridization. For comparison purposes, we used results obtained from a group of 100 ethnically matched healthy individuals. RESULTS: We found that all eight patients had the HLA-DR3/DR4 phenotype; all HLA-DR3 haplotypes were HLA-DRB1*0301, DQA1*0501, and DQB1*0201, whereas half of the HLA-DR4 haplotypes were from the DRB1*0401 subtype and the other half were DRB1 *0407. CONCLUSIONS: These results suggest that, in Mexicans, the genetic susceptibility for the development of PG is strongly influenced by the genetic admixture of Caucasian origin, and the role of class II MHC antigens in the pathophysiology of this disease is confirmed.

Class II MHC typing in pemphigoid gestationis.

Pemphigoid gestationis (PG) is a rare, autoimmune skin disease associated with pregnancy or the immediate post-partum period, previously shown to be associated with the HLA class II antigens DR3 and DR4. Advances in molecular analytical techniques now allow the identification of HLA alleles previously difficult to define by serological assays. Unsuspected polymorphism within the HLA-DR3 and DR4 classes can, therefore, be identified. The aim of our study was to apply these newer techniques to the question of genetic predisposition in PG by re-evaluating the association with DR3 and by studying a possible link with DQ. We have investigated by restriction fragment length polymorphism, the DQA, and by sequence specified oligonucleotide probing the DQB and DRB1 (HLA DR) specificities of 41 women with immunofluorescence-confirmed PG. The principal finding of this study is that there is an association between PG and DRB1*0301 (DR3) and DRB1*0401/040X (DR4). Although there is also an increase (P = 0.06) in the concurrent presence of both antigens, this appears to be due to the association with either antigen alone. We also found an increase in the frequency of DQA1*2 (P = 0.016 vs. control) and a decrease in frequency of DQB1*0201 (P = 0.022 vs. controls) and DQB1*0602 (P = 0.026 vs. controls).

[Herpes gestationis: immunologic and immunogenetic aspects]. / Herpes gestationis: immunologische und immungenetische Aspekte.

Herpes gestationis or pemphigoid gestationis (PG) is a bullous disease developing in association with pregnancy. It is believed to be an immunologically mediated disorder. Antibody binding by specific autoantibodies was detected in placental tissue and in the area of the hemidesmosomes and the basal membrane zone of the skin. These autoantibodies react with antigens of 180 kDa and 230 kDa relative molecular mass, which are presumably identical to the bullous pemphigoid antigen BPAG1 and BPAG2. The herpes gestationis factor (HG factor) preferentially binds to the 180-kDa antigen (BPAG2). The involvement of specific autoantibodies against adhesion molecules suggests the involvement of an aberrant immune response. Several groups have reported an association of pemphigoid gestationis to alleles of the human leukocyte antigens; HLA-B8 (class I) and HLA-DR3 and HLA-DR4 (class II), encoded on the short arm of chromosome 6. The unique feature of pemphigoid gestations is compared with other bullous dermatoses the association with the hormonal regulation during pregnancy and the presence of allogenic tissue. The hormonal regulation at the level of gene expression, possibly including gene expression of non-classic HLA class I molecules such as HLA-G, may be a cofactor in the pathogenesis of pemphigoid gestationis. This account, together with a case report, discusses the association of pemphigoid gestationis with HLA and a putative pathophysiological role of the newly described non-classical HLA molecules encoded in the MHC.

[Immunogenetic findings in herpes gestationis]. / Immungenetische Befunde bei Herpes gestationis.

A 27-year-old woman suffered from herpes gestationis in her second pregnancy. The pruricy urticarial and bullous skin lesions were exacerbated immediately after birth, and premenstrually after the onset of menstruation. The diagnosis was confirmed by the determination of anti-basement membrane antibodies of the IgG class both in the serum (herpes gestationis factor) and in lesional skin by immunofluorescence techniques. The newborn had no skin lesions and no basement membrane zone antibodies were detected. The HLA (human leucocyte antigen) typing revealed the HLA-A11/1, B18/w63, C-/-, DR4/w13, DQw3/w1 haplotype in the mother and the HLA-A3/31, B7/35, Cw7/w4, DR2/3, DQw1/w2 haplotype in the father. Comparison with the first child (HLA-A11/31, B18/35, -/Cw4, DR4/3, DQw3/w2) showed that the second child (HLA-A11/3, B18/7, -/Cw7, DR4/2, DQw3/w1) had a different HLA haplotype. The pattern of the HLA haplotype of the mother and the father seems to be important in the immunopathogenesis of herpes gestationis.

Complement polymorphism in herpes gestationis: association with C4 null allele.

BACKGROUND: Herpes gestationis (HG) is a rare, pregnancy-related skin disease characterized by the production of an autoantibody to a component of the hemidesmosome. It is associated with the class II antigens HLA-DR3 and HLA-DR4, but its potential association with the "class III antigens" C2, C4, and factor B has not previously been studied. OBJECTIVE: Our purpose was to study complement polymorphism in HG. METHODS: Using electrophoresis and immunofixation techniques, we determined the allele frequencies of C4A, C4B, C3, and factor B in 42 patients with a history of HG. RESULTS: Ninety percent of patients carried a C4 null allele (C4*QO). No statistically significant association with C3 or factor B alleles was seen. CONCLUSION: HG is associated with the presence of a C4*QO. Whether the C4*QO is the primary genetic association, or whether the C4*QO is related to its linkage disequilibrium with DR3 and DR4 has yet to be determined.

Secondary autoimmune diseases in herpes gestationis (pemphigoid gestationis).

BACKGROUND: Herpes gestationis (HG) is an autoimmune disease of the skin that occurs exclusively in association with pregnancy (or trophoblastic disease). It is associated with the HLA-DR3 and -DR4 antigens that are also associated with several other autoimmune diseases. HG has previously been reported in association with Graves' disease. OBJECTIVE: Our purpose was to determine the frequency of other autoimmune disease(s) in patients with a history of HG. METHODS: Seventy-five patients with a history of HG were studied for the frequency of other autoimmune diseases. RESULTS: We found an increased frequency of Graves' disease in patients with a history of HG. Those with HG have an increased risk for the development of other autoantibodies. There is an increased frequency of autoimmune diseases in the family members of patients with HG. CONCLUSION: Secondary autoimmune disease in HG is unusual, but does occur. The most frequent is Graves' disease.

Immunity in herpes gestationis: inhibition of mixed lymphocyte culture by patients' sera.

The families of four patients with herpes gestationis (HG) (pemphigoid gestationis) and five patients with polymorphic eruption of pregnancy (PEP) were HLA typed. Anti-HLA-D antibodies in the maternal sera were sought using mixed lymphocyte culture (MLC) inhibition test. Two of the four patients with HG had Dw3, one of which was combined with Dw4. One of the fathers had Dw2. The sera of the four patients with HG strongly inhibited (48-100%) the MLC reaction of maternal cells against cells of the father or the child. This kind of inhibition could not be shown in the patients with PEP. We conclude that patients with HG often seem to have MLC inhibiting factors which obviously are antibodies directed against HLA-D region determinants. Their pathogenic role is still obscure.

Clues to the aetiology and pathogenesis of herpes gestationis.

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.

High frequency of histocompatibility antigens HLA-DR3 and DR4 in herpes gestations.

Herpes gestationis (HG) is a rare, autoimmune, vesiculobullous disease of pregnancy or the puerperium characterized by the deposition of complement (and occasionally immunoglobulin) within the lamina lucida of the cutaneous basement membrane zone. We have studied 23 patients with a history of HG, 20 of whom had typical immunofluorescence findings during the active phase of their disease. HLA typing showed HLA-DR3 in 61% of patients (controls 22%, Pc less than 0.005) and the combination of DR3, DR4 in 43% (controls 3%, Pc less than 0.00001). The most striking finding of this study was that the greatest risk of HG is associated with the concurrent presence of two specific histocompatibility leukocyte antigen (HLA)-DR antigens.

Herpes gestationis and anti-HLA immunization.

The lymphocytotoxicity technique at +15 degrees C and +37 degrees C was used to identify anti-HLA and cold lymphocytotoxic antibodies in sera from two women with herpes gestationis. The degree of severity of the illness was different in the two cases. The more serious case (widespread cutaneous involvement, repeated fetal deaths) had a very powerful anti-HLA-A9 +anti-HLA-B5 antibody (titre 1/1000); the other had less severe skin lesions; she had an anti-HLA-B13 antibody (titre was 1/256). Both cases had cold lymphocytotoxic auto-antibodies.

Herpes gestationis. A high titre of anti-HLA-B8 antibody in the mother and pemphigoid-like immunohistological findings in the mother and the child.

A mother with herpes gestationis and her child without cutaneous lesions had analogous immunohistological findings. In the skin they had deposits of IgG and C3 component of complement at the basement membrane zone. Circulating IgG antibody to the basement membrane was also demonstrated in both. The mother also had a high titre of anti-HLA antibody against a histocompatibility antigen (HLA-B8) present in the child. A possible role of this HLA antibody in the pathomechanism of herpes gestationis is discussed.