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The genealogic origin of steroid 21-hydroxylase gene (CYP21) mutations and associated haplotypes was determined in 74 unrelated Finnish families with CYP21 deficiency (congenital adrenal hyperplasia, CAH). These families account for two thirds (85/119) of all diagnosed patients of Finnish descent found in this country. We recently demonstrated that multiple founder mutations each associated with a particular haplotype can be found in Finland. Interestingly, some of the haplotypes were identical to those observed in various European populations, whereas others have not been described elsewhere, indicating a local and perhaps a more recent origin. In the present report we show that each of the major founder haplotypes originates from a particular geographic region of Finland. Thus many local genetic isolates are to be expected in Finland. Our finding is in a clear contrast to the genetic diseases known as the 'Finnish disease heritage', in which only one mutation usually predominates. Some of the CYP21 haplotypes proved very informative for analysis of the history of the Finnish population. For example, the origin of one frequent haplotype was shown to cluster in a region assumed by archaeological data to be a major site of immigration by settlers of either Scandinavian or Baltic origin during the first centuries AD. As this haplotype is frequent in many European patient populations, we provide independent genetic evidence of this Iron Age immigration. On the other hand, another frequent haplotype found solely in Finland reflects a more recent (post 15th century) settlement expansion. Consequently, well characterised and sufficiently frequent autosomal gene markers can provide useful information on migrations both between and within populations.

In congenital heart block (CHB), abnormal maternal immunisation leads to autoantibody production against SS-A/Ro and SS-B/La antigens. These maternal antibodies are transferred across the placenta to the unborn child and are believed to transmit irreversible immunological injury in developing foetal heart tissue, thus causing 3rd-degree atrioventricular block. The mothers may suffer from systemic lupus erythematosus (SLE) or primary Sjögren's syndrome (SS), but they may be asymptomatic. Women with primary SS show a typical autoimmune HLA antigen pattern, namely higher frequency of HLA B8 and DR3 than in the normal population. The HLA pattern may affect individual ability to resist infecting bacteria and viruses and to response in various ways to autoantigens. It is probable that other factors such as genetic regulation of immune response are involved in CHB. We compared the HLA class I and class II alleles of mothers having CHB children with those of women suffering from primary SS and having healthy children, and with those of healthy Finns. Antibodies against 52-kD and 60-kD SS-A/Ro and 48-kD SS-B/La antigens were compared between the two groups of mothers. Our results show that anti-SS-A/Ro antibody-positive mothers all show a strong association with known autoimmune-predisposing HLA alleles, however, the mothers of CHB children differ in some HLA class I alleles, and especially in HLA haplotypes, from mothers of healthy children. Mothers with HLA A1, Cw7, B8 and without B15 are at particularly high-risk of having CHB children.

Congenital heart block (CHB) is a syndrome of uncertain pathogenesis leading to cardiac conduction disturbances in the foetus and newborns. It has been proposed that maternal antibodies transmit immunological injury in the developing foetal heart, thus causing irreversible damage of the atrioventricular node, leading to third-degree atrioventricular block. However, some genetic or environmental factors may also be involved. We have searched for genetic markers that play a role in immune response and that would be pathognomonic for the disease, either in mothers by regulating their immune response or in children by affecting antigen presentation and target for the maternal immune response. We have compared HLA class I and II alleles of the children with their mother and with healthy individuals and searched for HLA markers that would be emphasized in children. We have shown that particular DQ alleles in the child predispose to CHB, perhaps serving as antigen-presenting molecules on site. In addition, the HLA-Cw3 allele is involved, although its function remains to be clarified. In our results, children with CHB were often identical to their mothers in alleles of DRB, DQA and DQB loci, thus affecting foetomaternal recognition and suggesting that cell-mediated mechanisms could be involved in the pathogenesis.

We describe an alloimmunized female patient who developed serious adverse reactions when receiving HPA-incompatible platelet transfusions. She had received 13 transfusions with random platelets before the first allergic reactions. Antibodies against both the human leucocyte antigens (HLA) and several human platelet antigens (HPA) were detected at the time of transfusions. When the patient received HLA- and HPA-compatible platelets, no reactions followed the transfusions and platelet count increments were good. When she was transfused with platelets from donors with one foreign HLA antigen, her reactions were fever, chills and headache and the response to platelet transfusions was poor. When the platelets were HLA compatible but HPA incompatible, the reactions were repeatedly rapid pulse, shortness of breath, tightness of chest and wheezing interpretable as anaphylactoid reactions. Platelet count increments were satisfactory. When rare side-effects occur after transfusion, detailed immunohaematological studies are indicated.

Congenital heart block without intracardiac anatomic malformations is a potentially lethal disease affecting children and newborns. The mother often has an autoimmune disorder with autoantibodies against SS-A/Ro and/or SS-B/La antigens. However, only a minority of the children of these mothers develop complete heart block. It is believed that the maternal antibodies are pathogenic, but other immunological mechanisms such as cell-mediated injury cannot be excluded. Maternal cells may recognize fetal antigens adjacent to fetal HLA, and thus some children may be more susceptible to heart block than others, depending on their HLA genetics. The purpose of this study was to evaluate whether there are HLA differences between children with heart block and their healthy siblings. Six affected children in four families and their siblings were studied. MHC class I were typed serologically and class II and some non-HLA alleles were typed by DNA techniques. DQB1*03/04 were seen more often in the affected children than in the siblings. Some other differences were also seen in the other antigens of the MHC area.

The Finnish Bone Marrow Donor Registry was established 1992 to serve Finnish patients in urgent need of bone marrow transplantation. This study details the HLA antigen frequencies, including those of the A 19 subtypes, in the Finnish population. Large regional variations were found in antigen frequencies between the different geographical areas of Finland. In particular, antigens A9, B12, B35, Cw4 and DR3 display regional frequency deviations, but B7, B8 and B15 also exhibit regional variations. The present population is the largest (n = 10,000) ever HLA-typed in Finland. 97% of the donors were HLA-A-B-DR typed. Confirmation of the serological HLA type was performed by DNA typing on 3% of the donors in the registry. A potential donor was found for 52% of Finnish patients in need of a matched unrelated donor for a bone marrow transplantation. Due to the ethnic origin of the Finns, it is not easy to find suitable bone marrow donors for Finnish patients in worldwide registries. It is thus important to maintain a national bone marrow donor registry which recruits donors from all over the country.

We describe a volunteer unrelated peripheral blood progenitor cell donor with previously diagnosed dermatitis herpetiformis in whom the administration of G-CSF for the mobilization of precursor cells induced acute iritis. G-CSF has been administered to healthy people with minimal side-effects but when used in patients with autoimmune disorders worsening of symptoms or new manifestations may be a potential concern.