Jenkins, Rachel Edwina; (1997) Immunopathogenesis and clinical presentation in pemphigoid gestationis. Doctoral thesis (M.D), UCL (University College London).

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Abstract

Pemphigoid gestationis (PG) is a rare vesiculo-bullous disorder of pregnancy characterised by linear deposition of C3, with or without IgG, along the basement membrane zone of skin and placenta. It is known to be associated with HLA antigens DR3 and DR4, with aberrant expression of MHC class II antigens on the placenta and, in some cases, with anti-HLA antibodies. The principal hypothesis of the present study is that the critical events leading to the clinical phenotype in genetically predisposed individuals with PG are immunologically mediated. The specific aims were, therefore, to advance further the clinical-genetic and the molecular-genetic characterisation of the condition, to examine the role of potential downstream mechanisms in the generation of the PG phenotype and to characterise the patterns of expression of components of possible immunological mediators in relation to the clinical phenotype. There was a significant association between the development of PG in the first pregnancy and subsequent pregnancies but no significant association between development of PG and change in partner. 8% of patients had an uninvolved pregnancy following a previously affected pregnancy. Analysis of class II MHC subtypes demonstrated an association between PG and DRB1*0301 and, to a lesser extent, DRB1*0401/040X. Analysis of complement component polymorphism identified a significant association with a C4 null allele which may contribute to impaired immune complex and autoantibody handling with subsequent disruption of the BMZ and clinical presentation of the disease. Anti-HLA antibodies are universally present in PG and are mainly against class I MHC antigens but their titre does not correlate with IgG nor C3 titres. The development of anti-HLA antibodies and IgG, therefore, appear to be two independent immunological events in the pathogenesis of PG. There was no increase in anti-HLA antibodies detected in patients with PEP. In PG there was no significant elevation of serum IgE level nor circulating IgE anti-BMZ antibodies. The use of NaCl-separated skin as a substrate for indirect IF is more sensitive than intact skin for detecting circulating IgG and C3 deposition and standardisation of this technique will allow results from different centres to be compared more readily. This study, therefore, adds to the growing body of evidence that PG is a complex disease determined by a fundamentally immunological substrate. The continued study of this rare condition is clearly indicated and may shed further light on the complex interaction between the mother and her foetus.

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