RIVALIDAD ENTRE COMPETIDORES EXISTENTES

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 aim of this section is to summarise the results of the thesis in relation to the specific aims listed on page 74.

Specific aim 1. ‘....to advance further the clinical-genetic characterisation of the condition with emphasis on the effect of parity, the patterns of affected

pregnancies following changes in paternity and the causes and principal factors responsible for the development of skip pregnancies...’

The time of onset of PG is variable, but it is much more likely to begin in the second or third trimester than in the first, confirming previous reports. There is a significant association between developing PG in the first and subsequent pregnancy. However, there is no association between change in partner and the development of PG as previously suggested in the literature. The frequency of an uninvolved pregnancy following a previously affected

pregnancy is 8%. This figure is higher than the previously reported figure of 5%. The explanation as to why such skip pregnancies occurs is uncertain but is not due to the mother and foetus being fully compatible at the DR locus nor due to a change in partner, both of which have been previously suggested. The fact that PG fails to occur in patients who have been affected previously suggests that PG is actively suppressed in the skip pregnancies. Idiotype-anti-idiotype

interactions are extremely important in the matemal-foetal relationship and, therefore, enhancement or suppression of the immune response in PG could result in either development or conversely suppression of the disease in genetically susceptible individuals.

specific aim 2 . ‘....advance further the molecular-genetic characterisation of the condition by defining the relationship between PG and newly identified MHC class n subtypes and MHC class IQ genes, especially C4 null alleles, which are located close to the class Q loci...’

In view of the significant advances in technologies for studying MHC class n antigens, this study has analysed the class Q associations in PG particularly DR3 and also reports the results of an analysis of DR4 subtypes. The primary statistical MHC association with PG is with the class Q allele DRB 1 *0301. When DRB 1 *0301 patients are removed from the analysis, D R B l*0401/040X appears to confer susceptibility. Indeed, 35 of 41 patients have DRB 1*0301 or D R B l*0401/040X (p=0.002 vs. controls).

Linkage disequilibrium between DR3 and C4 null alleles is a common characteristic in Western Europeans and, therefore, the frequency of C4 null alleles (C4QO) in PG is important to try to determine the primary genetic association in PG. This study demonstrates a significant association with a C4QO, particularly C 4A Q 0 and PG. It is possible that both DR and C 4Q 0 may play a role in the development of PG since it is known that complement-mediated pathology can be associated with genetically-determined defects of C4.

Specific aim 3. ‘....examine the role of potential downstream effector systems in the generation of the PG phenotype and, in particular, examine the relationship between anti-HLA antibodies in PG and IgG and C3. In addition, the potential role of IgE has been studied by examining both serum IgE and IgE BMZ deposition in PG. PEP has been used to provide control samples as it has clinical and histological similarities to PG...’

Since the unusually high frequency of anti-HLA antibodies in PG raises the possibility that they may be related to the pathogenesis of disease, the present study examined the frequency, immunological correlations and specificity of anti-HLA antibodies in PG.

Virtually all (97.7%) patients with a history of PG had demonstrable anti- HLA antibodies and is particularly striking in comparison to controls (10%) highlighting the immunological abnormality in PG.

One key question was the role of these anti-HLA antibodies: did they represent a universally present epi-phenomenon, or did they play some role in the development of disease? In order to try to establish whether anti-HLA antibodies develop as the primary immunological event in PG serial measurements of circulating IgG, and C3, and anti-HLA antibodies were performed in a group of patients. This study showed no correlations between anti-HLA antibody production in PG and circulating IgG, nor C3 detected by indirect IF. The development of anti-HLA antibodies and circulating IgG therefore appear to be independent immunological events in the pathogenesis of PG .

Because of the similarities of BP and PG and the findings of increased serum IgE levels and anti-BMZ IgE in BP a study was designed to explore possible associations of raised serum IgE and anti-BMZ IgE antibodies with PG. The results show that in PG, and PEP, unlike BP there is no significant

elevation in serum IgE level. In addition only 3/12 (25%) patients with PG had circulating anti-BMZ IgE contrasting with a previous study of BP patients in which 9/17 (53%) sera had IgE anti-BMZ antibodies (Soh et a l, 1993). Since IgE does not cross the placenta and the results from my study are negative it would appear that IgE does not represent an important primary pathogenic factor in PG.

Peripheral eosinophils were counted in 9/17 patients with PG and were all within the normal range. This contradicts previous studies suggesting that peripheral eosinophilia can be a feature of PG.

Specific aim 4 . ‘....characterise components of distal effector systems in the production of the clinical phenotype, using the split skin technique to detect IgG and C3 deposition along the cutaneous BMZ...’

This study demonstratejthat indirect IF split skin is a more sensitive substrate than intact skin for detecting circulating IgG and C3 in PG. In addition, detection of C3 is a more sensitive assay than IgG. Routine use of split skin as tissue substrate for indirect IF and employing the C3 amplification step, therefore, appears to be a practical and reliable method for the diagnosis of PG .