Isolated precocious pubarche: an approach.

Precocious pubarche (PP) is most often a benign condition secondary to the early appearance of adrenarche. However, PP may be a manifestation of nonclassical adrenal hyperplasia. The incidence of nonclassical adrenal hyperplasia in patients with PP ranges from about 0-40% of cases. Controversy exists as to whether all children with PP should undergo an ACTH stimulation test. The aim of this study was 1) to determine the frequency of mild adrenal enzyme defects in a very large and ethnically homogeneous group of children with isolated PP (typical pubarche); 2) to determine whether clinical data, in particular bone age, and basal hormonal values can help to distinguish patients who are at risk for having adrenal enzymatic defects and thus should have an ACTH test; and 3) to determine which patients diagnosed as having a mild adrenal enzyme defect might require treatment. We studied 171 subjects (135 girls and 36 boys), aged 7 +/- 1.2 (SD) yr, with isolated PP. Thirty-eight normal subjects (18 age-matched and 20 pubertal) were studied as controls. An ACTH stimulation test (Synacthen, 0.25-mg iv bolus) was performed. Blood samples were drawn at baseline and 1 h postinjection. 17 alpha-Hydroxyprogesterone (17OHP), 17 alpha-hydroxypregnenolone (17PGN), dehydroepiandrosterone, androstenedione, testosterone, 11-deoxycortisol, and cortisol were evaluated. Haplotype (HLA) typing was performed in the patients who were diagnosed with nonclassical 21-hydroxylase deficiency (NC21OHD). Using published nomogram standards for the serum 17OHP response to ACTH, 10 patients (5.8%) were diagnosed as having NC21OHD. Seven of 112 patients (6.2%) were diagnosed as having nonclassical 3 beta-hydroxysteroid dehydrogenase deficiency (NC3HSD) on the basis of the following three criteria: stimulated 17PGN levels and stimulated 17PGN/17OHP and 17PGN/cortisol ratios higher than 2 SD above the mean for pubertal controls. None of the patients had stimulated 11-deoxycortisol values greater than 2 SD above the mean of pubertal controls. Nineteen patients (11%) had a stimulated 17OHP response characteristic of the heterozygotes for 21-hydroxylase deficiency. One hundred and thirty-five of 171 patients with no biochemical evidence of an adrenal biosynthetic defect were diagnosed as having precocious adrenarche. Bone age was advanced (> 2 SD for chronological age) in 80% of the patients with NC21OHD, in 71.4% of the patients with NC3HSD, in 58% of the patients classified as heterozygotes, and in 32.6% of the patients with precocious adrenarche. Basal hormone levels were helpful in detecting NC21OHD, but not NC3HSD. All patients with NC21OHD and only 1 with NC3HSD underwent glucocorticoid suppression treatment.(ABSTRACT TRUNCATED AT 400 WORDS)

HLA and complement factors alleles sharing in Italian couples with recurrent spontaneous abortions.

Recurrent Spontaneous Abortion (RSA) is postulated to be due to several factors including immunogenetic mechanisms. Many studies have been conducted on the effect of the MHC region in the reproductive phenomena suggesting an immunological or genetic involvement in RSA. We studied couples with 3 or more abortions among a larger group of couples in which female partners were anti-cardiolipin antibodies negative, resulting in a population of 43 couples typed for HLA-A, B, C, DR, DQ. In 16 of these 43 couples, complement factors C4A, C4B, and Bf were typed. The data shows a statistically significant increase of C4B*Q0 in RSA patients (N = 32) compared with the control population (N = 44) (pc = .00147) and also a statistically significant increase of C4B*Q0 sharing in aborting couples (43.75%) against the expected sharing rate in the control population (1.86%) (p < .001). Frequency increase of C4B*Q0 allele in aborting population leads to the hypothesis that an imbalance of complement factors expression and activity can have detrimental effects on implantation and embryo survival. Additionally, the significant sharing rate of C4B*Q0 in couples with RSA could indicate the existence of a gene in linked to this allele predisposing to RSA and acting in a recessive manner if present in double copies in the fetus.

Chromosome 6p-encoded HLA-DR2 determination discriminates migraine without aura from migraine with aura.

Segregation analysis indicates that migraine without aura (MWoA) and migraine with aura (MWA) have multifactorial inheritance, but involved genetic and environmental factors are largely unknown. A controlled study was performed to assess the HLA-driven liability to migraine and to verify if the heterogeneity between MWoA and MWA is HLA-linked. Forty-five migraine patients (31 MWoA, 14 MWA) and 53 healthy blood donors as controls, coming from the same geographic area, were studied. Tissue typing was performed using the standard complement-dependent microlymphocytotoxicity technique for HLA Class I and by PCR-SSP (Sequences Specific Primers) typing for HLA Class II. Data emerging from the present study showed no altered distribution for HLA Class I A, B, C antigen frequency in migraine (MWoA, MWA) if compared to the control group. HLA Class II DR2 antigen showed a decreased frequency in MWA group if compared with both MWoA (p = 0.01) and control group (p = 0.039, RR = 0.21). These results seem to support the hypothesis of a protective role of DR2 antigen in MWA and provide additional basis for the proposed difference within MWoA and MWA.

HLA antigens and antigliadin antibodies in coeliac disease.

Thirty-six coeliac children on gluten-containing diet were studied for AGA IgA and IgG levels. Patients were typed for HLA-A, -B, -C, -DR, -DQ antigens and data were analysed for any correlation between HLA-DR phenotype and AGA levels. AGA IgA and/or IgG were present in all these children. Subjects negative for DR3 or DR7 showed lower AGA levels than those DR3 + and/or DR7 positive. The data suggest that these patients could escape diagnosis if screening for those requiring intestinal biopsy is based only on AGA assay. The observation that coeliac children negative for DR3 and DR7 showed lower AGA levels is consistent with clinical and genetic heterogeneity of coeliac disease.

A study of HLA class II antigens in an Italian paediatric population with coeliac disease.

One hundred and twenty-one Italian children with coeliac disease (CD) have been compared with a control population from the same geographical area for the distribution of HLA-DR and DQ antigens. The pattern of an increase in DR3, DR7, and of heterozygotes DR5/7 was associated with an excess of heterozygotes DQw2/DQw3 in the CD population. These findings suggest that epitopes determined by specific combinations of DQ alpha and beta chains (combinatorial determinants) predispose to the disease.

HLA antigens and adult rheumatoid arthritis: a study with a monoclonal antibody.

Adult rheumatoid arthritis (RA) is a very heterogeneous disease that is associated with HLA-antigens, although no absolute association has been found with any particular HLA type. Forty-one seropositive RA patients have been studied with a local monoclonal antibody named X1 21.4 (9w940), strongly associated with HLA-DRI, DR4, Drw10 antigens, to verify a possible correlation with the disease. The results obtained have also been compared with the data reported on MC1, a serologically defined determinant correlated with RA. X1 21.4 monoclonal antibody appears to be associated with the disease and it could identify one epitope involved in the susceptibility to RA.

HLA antigens in Italian patients with systemic lupus erythematosus: evidence for the association of DQw2 with the autoantibody response to extractable nuclear antigens.

In order to verify the hypothesis that Italian patients with systemic lupus erythematosus (SLE) may be immunogenetically distinct from SLE patients born in other regions, we investigated the HLA class I and II antigens and their relation with the various autoantibodies characteristic of the disease in an Italian SLE population. Forty-four SLE patients were typed for HLA-A, -B, -C, -DR and -DQ antigens; sera from the same patients were tested for the presence of antibodies to the nuclear or cytoplasmic antigens Ro/SSA, La/SSB, Sm and RNP (ENA). Results of HLA typing showed that the frequencies of DR3 and DQw2 were increased in patients compared with controls. Analysis of the correlations between HLA antigens and anti-ENA antibodies showed that both DQw2 and DR3 were increased in patients with anti-Ro and/or antiLa antibodies, while in patients with anti-Sm and/or antiRNP antibodies the DQw2 and DR4 were found to be increased. Only DQw2 was found to be significantly increased in anti-ENA positive patients. These results might suggest that Italian patients with SLE are, at least in part, different from lupus patients living in other geographical areas and suggest the association of DQw2 with the autoantibody response to ENA in SLE.

Heart surgery and quality of life: a prospective study on ischemic patients.

OBJECTIVE: Recently, an interest has developed in the use of quality of life instruments to provide a more comprehensive assessment of the impact of disease and treatments on patients' everyday lives over time, particularly in the cardiovascular field. To evaluate changes in quality of life of patients with a coronary heart disease and undergoing heart surgery and to identify patients on which to concentrate stronger rehabilitative intervention, an observational prospective study with repeated measurements has been designed. METHODS: A total of 259 consecutive coronary heart disease patients (211 males, 48 females, aged 63 (S.D., 9 years) are included into the study. Quality of life has been assessed by means of Karnofsky Performance Status Scale and Nottingham Health Profile (6 dimensions of quality of life) preoperatively, at 2 and 6 months. Changes in quality of life scores at short and mid term and the influence of possible predictors have been investigated. Separate scores have been considered for each dimension of quality of life as well as a global statistics accounting for the multidimensionality of quality of life. RESULTS: Quality of life increased by 57, 64, 72, 52, 23, 44 and 56% for Karnofsky Performance Status Scale, energy, pain, emotion, sleep, social and mobility respectively at 2 months; at 6 months a further increase of 18% in sleep only occurred. Global scores appeared to be significantly influenced by sex, age class, preoperative NYHA, type of angina, associated procedure and complication at surgery. CONCLUSIONS: The increase of quality of life concentrates mainly at an early stage of post-operative period. The preoperative factors tested, allow to stratify patients based on quality of life and to identify those on which to concentrate stronger rehabilitative intervention.

HLA antigens, epilepsy and cytomegalovirus infection.

Thirty-one epileptic patients, selected from among 900 children with previous febrile convulsions and subsequent epilepsy, were typed for HLA antigens. In 16 of the 31 patients CMV was isolated from the urine shortly after the appearance of spontaneous fits; in the remaining 15 patients the virus was never detected. All the examined children were typed for 14 HLA-A, 23 HLA-B, 7 HLA-C and 9 HLA-DR specificities, and compared with a group of healthy subjects. The HLA-A11 antigen was present in 25% of the children with chronic CMV infection and epilepsy, and absent in patients with epilepsy but without CMV infection (p less than 0.02). The possibility that the A11 antigen is a marker of the predisposing genes for CMV infection in children with epilepsy following FC is proposed.

[HLA and hypo-responsivity to anti-HBV vaccination (genetic study of non-responder subjects to anti-hepatitis B viral vaccine)]. / HLA e iporesponsività alla vaccinazione anti-HBV (studio genetico di soggetti non-responders al vaccino anti-epatite virale B).

The control of the immunization due to hepatitis B vaccines (HB-VAX and HEVAC B) showed that a low percentage of healthy adults vaccinated develop a non protective title of HBsAb or do not produce antibodies. The correlation between immunity and HLA has already been demonstrated: HLA is at the base of individual immunological response; this correlation directed our genetic study of low-responders or non-responders patients to anti-HBV vaccine. In our study 11 out of 97 subjects vaccinated (11.34%) with HB VAX or HEVAC B resulted hyporesponsive and underwent complete HLA typing to verify the relation between immune deficiency response and genetic system. There was an increase in phenotype HLA-DR7 incidence, with respect to a non-selective population and a decrease of HLA-DR1, as it has already been mentioned in the literature, the variations were not statistically significant taking into account the exiguity of the samples considered.

TCR Vß repertoire in an Italian longeval population including centenarians.

During the last years, the hypothesis that aging and diseases are two distinct phenomena, and that successful aging is possible for most humans, has been put forward. We studied the TCR Vß repertoire of T lymphocytes of healthy longevals and centenarians as crossing point of genetic predisposition and environmental effects to longevity, using the Spectra-typing method. TCR Vß1, Vß8, and Vß20 were found to be expanded in the longeval population, compared with the younger control population. This repertoire can have been shaped by the selective action of particular HLA alleles, or by the clonal expansion of specific T cell clones, able to modulate the immune response to endogenous and exogenous antigens. Moreover, the skewed Vß usage and the clonal expansion seem to be the effects of physiological changes occurring with aging and not pathological signs of malignity.

Diabetes-related autoantibodies do appear in children with coeliac disease.

Humoral immune factors related to type 1 diabetes have been investigated in children with coeliac disease. Anti-insulin (IAAb), immunoglobulin (alpha IgAb), islet cell (ICA) and glucagon autoantibodies were examined in 15 children with coeliac disease at diagnosis (group 1), in 15 children with coeliac disease following a gluten-free diet (group 2) and in 30 control patients (groups 3 and 4). IAAb were present in 27% of group 1 and in 20% of group 2 patients and alpha IgAb were significantly increased in group 1 and 2 patients; two patients in group 2 were positive for ICA; none of the coeliac disease patients were positive for anti-glucagon antibodies. The levels of anti-gliadin antibodies in group 1 were positively correlated with those of alpha IgAb. Coeliac disease-related HLA antigens were not correlated with antibody presence. The presence of diabetes-related humoral immune factors in coeliac disease raises the question as to whether or not they are predictive of subclinical pancreatic damage or whether they are simply indicators of a more general autoimmune diathesis.

Beta 2-microglobulin levels in celiac disease.

The serum levels of beta 2-microglobulins (beta 2-m) were studied in 65 celiac children. Significant statistical differences (p less than 0.05) were found between the values of patients on a gluten-containing diet (mean +/- SD, 1.92 +/- 0.64 mg/L) and those on a gluten-free diet for less than (mean +/- SD, 2.38 +/- 0.76 mg/L) or greater than (mean +/- SD, 1.46 +/- 0.77 mg/L) 8 months. A significant difference was also found between the first group and the 15-subject control group, who underwent intestinal biopsy for low stature or chronic diarrhea but had normal intestinal mucosa (mean +/- SD, 1.56 +/- 0.42 mg/L). Serum beta 2-m levels were above normal values (less than 2 mg/L) in 10 of 26 (38.5%) celiac patients on a gluten-containing diet and in two of 15 (13.3%) subjects of the control group. The beta 2-m values of patients on a gluten-free diet for less than or equal to 8 months were significantly different (p less than 0.001) from those of patients on a gluten-free diet for greater than 8 months, as well from those of the control group. No significant differences were found between patients on a gluten-free diet for greater than 8 months and the control group. A significant correlation between the antigliadin antibody (AGA) IgA and beta 2-m in the patients on a gluten-free diet for greater than 8 months and control-group patients was found.(ABSTRACT TRUNCATED AT 250 WORDS)

HLA-DR and DQ antigens and anticardiolipin antibodies in women with recurrent spontaneous abortions.

IgG anticardiolipin antibodies (ACL) have been shown to occur in a high proportion of women with repeated unexplained miscarriages. Forty-nine women with unexplained recurrent spontaneous abortions (RSA), previously assayed for the presence of ACL by an enzyme-linked immunoabsorbent assay, were typed for HLA-DR and DQ antigens by the classical microlymphocytotoxicity test. Twenty-five women were positive for ACL and 24 were negative. HLA-DR7 was found in 24.5% of 49 habitually aborting women vs. 28% of healthy controls; but the DR7 frequency was 40% in ACL positive patients vs. 8.3% in ACL negative patients (P = 0.011). These results show that in the Italian population an association between HLA-DR7 antigen and ACL is present in women with unexplained RSA, suggesting that HLA-DR genes might control the susceptibility to specific autoantibody production.

Humoral and cellular immunological factors as possible markers of clinical relapse in HLA-typed Graves' patients followed with time.

Humoral and cellular immune factors were studied in 33 newly diagnosed Graves' patients at diagnosis and in 12 of these patients at regular intervals thereafter. All the patients were treated with carbimazole for 15 months (initially 60 mg and then 20 mg supplemented with L-Thyroxine). The incidence of relapse after treatment was 42%. Thyrotropin receptor antibodies (TRAb), T-cell subsets, K and NK cells and mononuclear cells expressing surface antigen markers of different activation were evaluated respectively by the use of a radioimmunoassay and a panel of monoclonal antibodies. Patients in the follow-up study were HLA-A, B, C and D typed. TRAb levels (91%) and levels of 4F2-positive cells (73%) and class II-positive lymphocytes (69.6%) were significantly increased in newly diagnosed Graves' patients in comparison with normal controls, whereas CD8 cells were significantly decreased. There was a significant inverse correlation between the increase in 4F2-positive cells and TRAb values. In the follow-up study both humoral and cellular immunological parameters showed a wide variation in levels, but TRAb, 4F2 and L243 values declined on average with respect to diagnosis. After 15 months some patients still showed abnormal values of activated T cells and TRAb values. All patients who relapsed (42%) after medical treatment showed a significant increase of 4F2-positive cells, and some of TRAb, some time before the appearance of clinical symptoms. Finally, no correlation was found between HLA type and relapse of the disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Expression of class II MHC antigens in the intestinal epithelium of pediatric celiac disease.

Class II MHC antigen expression in the intestinal epithelium of 28 small bowel biopsies from 23 celiac patients were studied by means of indirect immunofluorescence and immunoperoxidase using monoclonal antibodies. Patients were divided on the basis of diet into two subgroups: 15 subjects on a gluten-containing diet (GCD) and 13 on a gluten-free diet (GFD). The control group included 10 pediatric subjects with normal intestinal mucosa who underwent intestinal biopsy for chronic diarrhea or short stature. DR antigens and invariant chain were expressed in all patients, regardless of the diet, as well as in the control subjects. DQ was found in one patient only on GCD. DP antigens were present in 12/15 patients on GCD, and in 2/13 on GFD (Fisher's exact test, p = 8.8 x 10(-4), as well as in 3/10 control subjects. In 4/5 celiac patients, DP antigens, which were undetectable on GFD, could be demonstrated after gluten challenge. The results of the study show that DR antigens are expressed by intestinal mucosa of celiac patients independently of their gluten exposure and that DQ antigens are consistently undetectable. Statistically significant differences in expression of DP antigens on enterocytes of celiac patients on GCD and their neoexpression after gluten challenge may represent a basis for further investigation.

HLA-linked spinocerebellar ataxia: a clinical and genetic study of large Italian kindreds.

Five families with late onset autosomal dominant spinocerebellar ataxia, were studied. Linkage between the disease and HLA loci on the short arm of chromosome 6 was shown in the two largest pedigrees. Clinical study of 26 patients and neuropathological study in one are reported. The disease was characterized by cerebellar and pyramidal involvement variably associated with cranial nerve and peripheral nervous system disorders. A remarkable concordance of the main clinical features was observed in patients with similar disease duration. Comparison with previous reports of HLA-linked spinocerebellar ataxia kindreds showed differences in clinical phenotypes. Although these might be due to genetic variation, the hypothesis is suggested that the phenotype might appear more homogeneous if disease duration is taken into account.

[Effect of vitamin B6 on some immune responses in chronic uremia (author's transl)]. / Vitamine ed immunità: effeto della vitamina B6 sull'immunocompetenza dell'uremico cronico.

Patients with chronic uremia undergoing periodic haemodialysis were found to have low levels of vitamin B6 (12 out of 18 patients). The same subjects also showed a reduction of the immunocompetence. The AA. report that the administration of pyridoxine (100 mg/die for 4 weeks) can induce a normalization of the vitamin levels and of some immunological parameters.

A cytotoxic anti-HLA-AB monoclonal antibody which in dilution becomes specific to HLA-A3 crossreacting group.

XI 20.4 monoclonal antibody belongs to the IgM class. It precipitates two polypeptide chains characteristic of HLA Class I antigens. At the highest dilutions it is cytotoxic against lymphocytes carrying antigens of the HLA-A3 crossreacting group. Lysostrip experiments show that, at the lowest dilutions, the antibody reacts either with HLA-A, or B antigens.