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With an Italian case series of 81 Italian patients and 130 controls, we analysed associations between myasthenia gravis (MG) and genetic polymorphisms in the MHC class II/III region. Increases in the frequency of the TNF-B*1, C4A*Q0, C4B*1, DRB1*03 supratype, which is likely part of the 8.1 ancestral haplotype, were maximal in females with early onset (EO) MG vs. controls [p<0.05, relative risk (RR)=9.9]. These patients showed neither a significantly high frequency of thymic hyperplasia, nor high levels of serum anti-acethylcholine receptor antibodies. The DRB1*03 allele was absent in patients with thymoma; however, in comparison with controls, occurrence of this marker was frequent in MG patients (p<0.005; RR=6.2), more frequent in females (p<0.005; RR=7.8) and most frequent in EOMG female patients (p<0.005; RR=15.1). Analysis of the TNF-B*1, C4A*Q0, C4B*1, DRB1*03 supratype and its recombinants showed that the MHC region between C4 and TNF might contain genes that influence susceptibility to MG in females. Polymorphic markers within the supratype, e.g. TNF-B*1 and C4A*Q0, might contribute to pathogenetically significant abnormalities in immune responses in a subset of female MG patients. The combined effect of other intervening genes cannot be excluded.

Objective: Following the chance observation of congenital adrenal hyperplasia in a patient with Turner's syndrome we decided to evaluate the incidence of 21-hydroxylase deficiency (21-OHD) in patients with Turner's syndrome and in their relatives., Subjects: Fifty-two patients with Turner's syndrome (mean age +/- SD 14.7 +/- 5.6 years) and 26 relatives were studied., Measurements: 17-Hydroxyprogesterone (17-OHP) serum levels before and after i.m. administration of 0.25 mg of ACTH(1-24) were evaluated in patients with Turner's syndrome and relatives. In Turner patients basal testosterone and dehydroepiandrosterone concentrations were determined. The results of ACTH tests were analysed according to HLA class I and II alleles of subjects., Results: The baseline 17-OHP was in the range of the classical form of 21-OHD in one Turner patient, who had severe clitoral enlargement since birth. In 11 patients the stimulated 17-OHP serum level was higher than in normal controls and similar to that found in 21-OHD heterozygous subjects. Clitoral enlargement was significantly more frequent in patients with high stimulated 17-OHP levels (P < 0.001). The frequency of heterozygous-type responses was higher in Turner subjects (1:4.6) than in the Italian population (1:47 for the classic form and 1:9.5 for the non-classic form of the disease). In our patients the frequencies of HLA antigens and haplotypes, usually associated with 21-OHD, were different compared to the controls. HLA-B8, which is negatively associated to 21-OHD, was less frequent in Turner patients than in controls and absent in those with an elevated 17-OHP level. HLA-B14, B22 and B35 were more frequent, though not significantly so, in Turner patients than in controls and even more so in the group with an elevated 17-OHP level. The same investigations performed in 26 relatives of the Turner patients showed a high frequency of carriers of 21-OHD and three subjects with the cryptic form of the disease., Conclusions: Although in the literature there are only two reports of the association of Turner's syndrome and 21-OHD, on the basis of our experience this association was more frequent, in the Italian population. Since some of the typical signs of 21-OHD (short final stature, varying degrees of virilization, menstrual irregularities, amenorrhoea, infertility) in patients with Turner's syndrome could also be attributed to the chromosomal abnormality, it is therefore more difficult to diagnose 21-OHD in Turner subjects. Adrenal function should be assessed, at least in the presence of clitoral enlargement, in patients with Turner's syndrome, particularly if their karyotype does not contain a Y chromosome. The hypothesis of the presence of cryptic Y chromosome material in these patients should also be considered.

Much of the surrounding studies on the association between HLA and diseases reflects a new insight into the key role of HLA molecules in the generation and regulation of the immune response. HLA molecules, on the surface of antigen presenting cells, bind foreign peptides. This HLA-antigen complex is then recognized by T lymphocytes and triggers the alloresponse against the peptide. Since many diseases associated with peculiar HLA antigens are thought to be autoimmune, the idea that certain Major Histocompatibility Complex (MHC) molecules could form complexes with self-peptides in anomalous ways, leading to an autoimmune reaction, is particularly attractive. Recent advances in molecular technology, x-ray crystallography and DNA studies have allowed the determination of the three-dimensional structure of some HLA class I and II molecules and also the amino acid sequences involved in binding of antigen fragments. This new information has prompted a search for differences, at the amino acid level, between HLA alleles previously shown to be positively or negatively associated with a pathology. Our own experience on the immunogenetic aspect of dilated cardiomyopathy (DCM) allowed us to assess some predisposing (HLA-DR4, DR5, C4A4) and protective (HLA-DR3) factors for DCM. Clinical heterogeneity also seems to imply a peculiar genetic background. The actual research is addressed to the study of the antigen binding site sequences and to the consideration of other new loci such as those entrapped within the HLA class III subregion (HSP70) and those lying within the class II region (PSF).

HLA class III polymorphisms (BF, C4A, C4B) were studied in 55 patients of different age and sex suffering from allergic contact dermatitis, with sensitization to different substances. In the overall group of patients no significant correlation between the disease and HLA markers was found. BF F allele was present in 34% and BS S in 64% of patients suffering from allergic contact dermatitis to nickel only versus 16.45% (relative risk, RR = 2.61) and 80.76% (RR = 0.42), respectively, of the control population. The BF FB subtype frequency was 23.91% versus 7.57% in the control samples (RR = 3.88). We thus hypothesize that this polymorphic serum protein might be involved in the pathogenesis of allergic contact dermatitis to nickel.