PubMed Health⌕ Search

Biomedical subjects

M Martinetti

Publications and source records attributed to M Martinetti.

At least 19 recordsLinked to original sources
PubMed2006

Distribution of killer cell immunoglobulin-like receptors genes in the Italian Caucasian population.

BACKGROUND: Killer cell immunoglobulin-like receptors (KIRs) are a family of inhibitory and activatory receptors that are expressed by most natural killer (NK) cells. The KIR gene family is polymorphic: genomic diversity is achieved through differences in gene content and allelic polymorphism. The number of KIR loci has been reported to vary among individuals, resulting in different KIR haplotypes. In this study we report the genotypic structure of KIRs in 217 unrelated healthy Italian individuals from 22 immunogenetics laboratories, located in the northern, central and southern regions of Italy. METHODS: Two hundred and seventeen DNA samples were studied by a low resolution PCR-SSP kit designed to identify all KIR genes. RESULTS: All 17 KIR genes were observed in the population with different frequencies than other Caucasian and non-Caucasian populations; framework genes KIR3DL3, KIR3DP1, KIR2DL4 and KIR3DL2 were present in all individuals. Sixty-five different profiles were found in this Italian population study. Haplotype A remains the most prevalent and genotype 1, with a frequency of 28.5%, is the most commonly observed in the Italian population. CONCLUSION: The Italian Caucasian population shows polymorphism of the KIR gene family like other Caucasian and non-Caucasian populations. Although 64 genotypes have been observed, genotype 1 remains the most frequent as already observed in other populations. Such knowledge of the KIR gene distribution in populations is very useful in the study of associations with diseases and in selection of donors for haploidentical bone marrow transplantation.

Journal Article↗
PubMed2006

Unacylated as well as acylated ghrelin promotes cell survival and inhibit apoptosis in HIT-T15 pancreatic beta-cells.

Ghrelin is mainly produced by the stomach, although it is expressed in other tissues, including the pancreas. Among its pleiotropic actions, ghrelin prevents the development of diabetes in rats and exerts mitogenic and antiapoptotic effects in different cell types. In addition, a ghrelin-producing epsilon-cell population has been demonstrated in rodent islets, suggesting a direct role in the control of islet cell survival. In this study, we investigated the effect of acylated ghrelin (AG) and unacylated ghrelin (UAG) on cell survival of HIT-T15 pancreatic beta cells. We show that both AG and UAG equally prevented beta cell death induced by serum withdrawal. In addition, both peptides inhibited serum starvation-induced apoptosis. These findings indicate that UAG and AG prevent cell death and apoptosis of pancreatic beta cells. Since only AG, but not UAG, binds the GRLN receptor, a different and as yet unknown receptor is likely involved in these survival mechanisms.

Acetylation↗
PubMed2006

Non classical HLA genes and non-HLA genes in a population of infants at familial risk of atopy.

AIM: We investigated on parental history and IgE serum level in 2588 consecutive newborns to individuate babies "at risk" of atopy at birth and we analysed the polymorphisms of class III region to evaluate the association with immunogenetic markers of HLA: C4A, C4B, LTA, RAGE and TNFA genes; we performed TNF and IgE receptor (FCERB1) physiologically related gene polymorphisms. RESULT: 791 babies/2588 (30.6%) were considered "at risk" for atopy and followed-up: 400 had familial history of atopy (at least one parent or sibling), 256 had IgE >0.35 kUA/l at birth and during the follow-up and 135 were positive for both conditions. The allele C4B2 was significantly more frequent in the sample of babies at risk (22.1% vs 10%, p< 0.001). Furthermore, the mean value of IgE at birth in babies carrying the allele C4B2 was 2.26 KUA/l versus 0.74 KUA/l in those not carrying this allele (p=0.01). No significant association emerged for RAGE at the centromeric end of class III region and for LTA, TNFA at the telomeric one. TNFRI, TNFRII and FCERB1 gene polymorphisms also seemed not implicated. CONCLUSION: Our study confirms that HLA class III region seems involved in familial predisposition to atopy, and C4B gene probably acts as a marker of a more restricted subregion.

Female↗
PubMed2004

Lack of a strong association between HLA class II, tumour necrosis factor and transporter associated with antigen processing gene polymorphisms and virological response to alpha-interferon treatment in patients with chronic hepatitis C.

The aim of the study was to investigate whether polymorphisms of the HLA class II, tumour necrosis factor (TNF) and transporter associated with antigen processing (TAP) genes influence the response to alpha-interferon in patients with chronic hepatitis C. Twenty-seven sustained responders and 55 non-responders to alpha-interferon monotherapy were investigated. HLA-DRB1, DQA1, DQB1, TNFA, TNFB, TAP1 and TAP2 alleles were determined by PCR-based molecular techniques. Sustained virological response was defined as undetectable serum hepatitis C virus (HCV) RNA for at least 3 years after the end of treatment. Probability (P) values were corrected for the number of alleles tested (Pc). Viral genotype 1b was more frequent in responders than in non-responders (56% vs. 26%, P = 0.009). HLA-DQB1*02 occurred less frequently in responders than in non-responders (14.8% vs. 29%, Pc not significant). HLA-DRB1*11 and DQB1*0602 were found in 22.2% and 9.3% of responders and in 10.9% and 1.8% of non-responders, respectively (Pc not significant). There was no difference in the distribution of TNF alleles in the two groups. Twenty-four (88.8%) responder patients as compared with 34 (61.8%) non-responders were TAP1*0101 homozygous (Pc not significant). Thus, in European Caucasoids with chronic hepatitis C, we could not demonstrate a strong association between HLA class II, TNF, and TAP gene polymorphisms and response to interferon treatment.

ATP-Binding Cassette Transporters↗
PubMed2003

Antigen-specific T cell response in infants after recombinant hepatitis B virus vaccination at birth: evaluation of T helper lymphocyte diversity.

Recombinant hepatitis B virus antigen (rHBsAg)-specific CD4+ T cell clones (TCC) were isolated and expanded from the peripheral blood of nine children vaccinated at birth against the hepatitis B (HB) virus. Four of them responded with protective antibody production (responders), three subjects were unable to produce detectable antibody levels even after revaccination (nonresponders), and two infants produced antibodies only after revaccination (slow responders). TCC were then characterized for their ability to produce cytokines known to be important for T cell expansion (interleukin-2, IL-2) and/or effector functions (IL-4, IFN-gamma, IL-10). Results demonstrated that the frequency of rHBsAg-specific TCC in the samples of nonresponders was comparable to or higher than that in the samples of responders. Nevertheless, the majority of TCC obtained from responders or from slow responders before revaccination displayed the T helper 1 (T(H1))-dominant phenotype, while the majority of TCC obtained from nonresponders were nonpolarized T lymphocytes. After revaccination, the distribution of the different T(H) subsets in slow responders was heterogeneous. Overall, our present data suggest that an absence or delay in developing an rHBsAg-specific antibody response to vaccination is not associated with the capacity to generate an Ag-specific T cell response. However, compared to responders, nonresponding infants react to the rHBsAg vaccination with a reduced capacity to expand and differentiate toward polarized T(H) cells.

Cytokines↗
PubMed2003

Low incidence of severe acute graft-versus-host disease in children given haematopoietic stem cell transplantation from unrelated donors prospectively matched for HLA class I and II alleles with high-resolution molecular typing.

We evaluated the outcome of 63 children given haematopoietic stem cell transplantation from unrelated donors (URD-HSCT) prospectively selected using DNA high-resolution typing of both HLA class I and class II loci. Thirty patient/donor pairs (48%) were fully matched. Among the others, HSCT was performed in the presence of one (n=22), two (n=9), or three (n=2) HLA disparities. Patients had either malignant (n=46) or non-malignant (n=17) disease. In all cases, graft-versus-host disease (GVHD) prophylaxis consisted of cyclospor-in A, short-term methotrexate and pretransplant anti-thymocyte globulin. The probability of haematopoietic recovery at day 100 was 97%. Two patients experienced primary graft failure. The cumulative probability of grades III-IV acute GVHD and of extensive chronic GVHD equalled 8 and 14%, respectively. A total of 12 patients died of transplant-related complications. The probability of transplant-related mortality (TRM) at 100 and 180 days was 10 and 15%, respectively, whereas the cumulative incidence of TRM was 22%. The probability of GVHD-related mortality equalled 6% at 2.5 years. The overall and disease-free survival rates were 67 and 65%, respectively. URD-HSCT with donor selection based on high-resolution HLA typing is associated with low incidence of both severe acute GVHD and graft failure. The observed outcome is comparable to that of children transplanted from HLA-identical siblings.

Adolescent↗
PubMed2002

Permanent diabetes mellitus in the first year of life.

AIMS/HYPOTHESIS: The pathogenesis of permanent diabetes mellitus diagnosed early in life is heterogeneous and, in most cases, not known. We aimed at identifying markers differentiating between non-autoimmune and autoimmune diabetes. METHODS: The clinical, genetic and epidemiological features of 111 diabetic patients (62 males) who received insulin within 12 months of life were studied. RESULTS: The epidemic curve by age of diabetes onset revealed two subsets of patients at a cutoff of 180 days. In the group with diabetes onset before 180 days ("early onset" permanent diabetes) the analysis of HLA susceptibility heterodimers (available for 21 individuals) showed that 76% had a "protective" HLA genotype for Type I (insulin-dependent) diabetes mellitus as compared to 11.9% (5/42) of the later onset group. Accordingly, "early onset" children were less likely to have autoimmunity markers (4 out of 26 tested) than children with onset after 180 days (13 out 20 tested) (15.4% vs. 65.0%, p<0.01). Of note, 19 out of 20 (or the 95%) patients who were born on the island of Sardinia, an Italian region where the incidence of Type I diabetes is six times higher than continental Italy (33/100,000/year vs 5/100,000/year), were included in the later onset group (>180 days). Small-for-date birthweight, a possible sign of reduced foetal insulin secretion, was more common in the "early onset" group (OR=9.9, 95%-CI 2.6-38.6). CONCLUSION/INTERPRETATION: These results, obtained in the largest population-based cohort of diabetic infants hitherto reported, suggest that "early onset" permanent diabetes cases differ from later onset cases and that most of them do not have an autoimmune pathogenesis.

Age of Onset↗
PubMed2002

An immunogenetic map of Lombardy (Northern Italy).

For this study we consulted the Bone Marrow Donors' Registry of Lombardy (Italy) and analyzed 43937 HLA-A,B phenotypes and 13922 HLA-A,B,DR phenotypes. We estimated the HLA-A,B and HLA-A,B,DR haplotype frequencies via the maximum-likelihood method. We analyzed the genetic structure of the 11 provinces of Lombardy by means of Principal Component Analysis and Correspondence Analysis, and estimated the variety of the different haplotypes at provincial level and the percentage of unique phenotypes at village level. We found 11189 different HLA-A,B phenotypes, 661 different HLA-A,B haplotypes and more than 4000 different HLA-A,B,DR haplotypes. We identified 20 villages, in Western Lombardy, very rich in unique/rare phenotypes. Here we report a formula which allows the identification of a putative donor matched for two haplotypes with a recipient. This result may be of great importance for the genetic study of the population of Lombardy and, even more, for bone marrow transplantation programs.

Alleles↗
PubMed2001

Hypersomnia in the Prader Willi syndrome: clinical-electrophysiological features and underlying factors.

OBJECTIVE: Excessive daytime sleepiness is a common symptom in Prader Willi syndrome (PWs). Sleep disordered breathing (SDB) and narcoleptic traits such as REM sleep onsets (SOREMPs) have been reported in these subjects. We evaluated nighttime and daytime sleep patterns in patients with PWs in order to clarify the nature of their hypersomnia. DESIGN AND METHODS: We performed overnight continuous EEG-polysomnographic studies (with breathing monitoring included) in 14 subjects (6 M,8 F; mean age 17 years, range 8-37) affected by PWs unselected for sleep disturbances. Ten patients underwent a Multiple Sleep Latency Test (MSLT) the day following the nocturnal sleep studies. Patients assessment was completed by means of immunogenetic characterization. RESULTS: Nocturnal polysomnographic investigation documented sleep related breathing abnormalities such as central apneas, hypopneas or hypoventilation which mainly occurred during REM sleep in 8 subjects and did not cause sleep disruption. Only 4 subjects presented an increase in the Respiratory Disorder Index (RDI) slightly above the normal limits. In 8 subjects out of 10, with and without SDB, the mean daytime sleep latency could be considered abnormal according to the Tanner staging of pubertal development. Five patients showed at least two SOREMPs at MSLT. Subjects with and without SOREMPs had, respectively, a mean age of 18.6 SD 7.9 (4 M, 1 F) and 14.5 SD 2.9 (4 F, 1 M). The paternal deletion:uniparental dysomy ratio at genotypic characterization was 4:1 and 3.5:1 in subjects with and without SOREMPs, respectively. No patient presented DR-15 nor Dq-6. CONCLUSIONS: Excessive sleepiness is a frequent disturbance in PWs. Subgroups of PW patients show hypersomnolence and SOREMPs. Sleep disordered breathing appears to have a limited role in the genesis of hypersomnia which not seems on the other hand attributable to the coexistence of narcolepsy phenotype. Hypersomnia in PW syndrome is likely to mainly be attributable to a primary hypothalamic dysfunction. The potential interacting role of other factors such as subjects age, sex and genetic pattern is suggested and deserve further investigation.

Adolescent↗
PubMed2001

Family study of non-responsiveness to hepatitis B vaccine confirms the importance of HLA class III C4A locus.

Non-responsiveness to hepatitis B virus (HBV) vaccine in adults is strongly associated with HLA-C4AQ0,DRB1*0301,DQB1*02 haplotype. This association was also demonstrated in neonates who failed to mount a humoral response to challenge with HBV vaccine. About 4% of vaccinated newborns do not reach a protective antibody level (> or =10 mIU/ml) at seroconversion and 0.4% is a non-responder even after receiving a fourth dose of vaccine (true non-responders (TNR)); while 3.6% achieved an antibody level > or =10 mIU/ml (slow responders (SR)) only when reboostered with the fourth dose. In the present study we extend the vaccination and HLA typing to 91 family members of probands to understand better the possible parent-to-child transmission of this trait. A transmission disequilibrium test (TDT), performed in 27 families, showed that the C4AQ0 allele was almost always transmitted to probands, both TNRs and SRs. Although not statistically significant, the highest LOD score was obtained with C4A locus: 1.58. These results suggest the presence of a region regulating immune response against HBV vaccination near to or coincident with the C4A locus.

Alleles↗
PubMed2001

Specific cytotoxic T lymphocyte responses against Melan-A/MART1, tyrosinase and gp100 in vitiligo by the use of major histocompatibility complex/peptide tetramers: the role of cellular immunity in the etiopathogenesis of vitiligo.

Vitiligo is a common skin disease characterized by the presence of well circumscribed, depigmented, milky white macules devoid of identifiable melanocytes. Although the detection of circulating anti-melanocytic antibodies and of infiltrating lymphocytes at the margin of lesions supports the view that vitiligo is an autoimmune disorder, its etiology remains unknown. In particular, it is still a matter of debate whether the primary pathogenic role is exerted by humoral or cellular abnormal immune responses. In this study, the presence of specific cytotoxic T lymphocyte responses against the melanocyte differentiation antigens Melan-A/MART1, tyrosinase, and gp100 in vitiligo patients have been investigated by the use of major histocompatibility complex/peptide tetramers. High frequencies of circulating melanocyte-specific CD8+ T cells were found in all vitiligo patients analyzed. These cells exerted anti-melanocytic cytotoxic activity in vitro and expressed skin-homing capacity. In one patient melanocyte-specific cells were characterized by an exceptionally high avidity for their peptide/major histocompatibility complex ligand. These findings strongly suggest a role for cellular immunity in the pathogenesis of vitiligo and impact on the common mechanisms of self tolerance.

Antigens, Neoplasm↗
PubMed2001

Celiac disease in children with autoimmune thyroid disease.

Ninety children and adolescents with autoimmune thyroid disease were screened for celiac disease. All 90 patients were typed for HLA antigen class I and II and for HLA-DQA1 and DQB1 heterodimers. Celiac disease and DQA1*0501, DQB1*02 were found in 7 (7.8%) patients. The prevalence of celiac disease was 1 of 13. Screening for celiac disease is recommended in children with autoimmune thyroid disease.

Adolescent↗
PubMed2001

Paternal HLA genotype and offspring sex ratio.

For twenty years, W.H. James has been proposing that the sex hormone level of both parents could control at least a quota of the secondary sex ratio variation at the time of conception. Observations supporting this hypothesis have come from investigations on some diseases related to the human leukocyte antigen (HLA). In the present study on 1102 healthy Italian families, we investigated the potential effect on the offspring sex ratio of HLA-B alleles on the basis of a genetic model. We defined three subsets of HLA-B alleles and hypothesized a locus (L) with three alleles, L(H), L(N), L(B15), on the basis of the positive, neutral, or negative effect on the testosterone level. According to the genetic model and the dominance relation L(H) > L(B15) > L(N), six genotypic and three phenotypic classes (H, N, B15) can be expected. We found a significantly high number of daughters (66%) born to fathers carrying the B15 phenotype. This result suggests an effect of the HLA-B15 allele on the secondary sex ratio, mediated by a low testosterone level.

Female↗
PubMed2001

Risk of type 1 diabetes development in children with incidental hyperglycemia: A multicenter Italian study.

OBJECTIVE: The aim of our study was to determine whether children with incidental hyperglycemia are at an increased risk of developing type 1 diabetes. RESEARCH DESIGN AND METHODS: A total of 748 subjects, 1-18 years of age (9.04 +/- 3.62, mean +/- SD), without family history of type 1 diabetes, without obesity, and not receiving drugs were studied and found to have incidental elevated glycemia defined as fasting plasma glucose >5.6 mmol/l confirmed on two occasions. Subjects were tested for immunological, metabolic, and immunogenetic markers. RESULTS: Islet cell antibodies >5 Juvenile Diabetes Foundation units were found in 10% of subjects, elevated insulin autoantibody levels in 4.6%, GAD antibody in 4.9%, and anti-tyrosine phosphatase-like protein autoantibodies in 3.9%. First-phase insulin response (FPIR) was <1st centile in 25.6% of subjects. The HLA-DR3/DR3 and HLA-DR4/other alleles were more frequent in hyperglycemic children than in normal control subjects (P = 0.012 and P = 0.005, respectively), and the HLA-DR other/other allele was less frequent than in normal control subjects (P = 0.000027). After a median follow-up of 42 months (range 1 month to 7 years), 16 (2.1%) subjects (11 males and 5 females), 4.1-13.9 years of age, became insulin dependent. All had one or more islet autoantibodies, and the majority had impaired insulin response and genetic susceptibility to type 1 diabetes. Diabetes symptoms were recorded in 11 patients and ketonuria only in 4 patients. The cumulative risk of type 1 diabetes was similar in males and females, and it was also similar in subjects under or over 10 years, whereas the cumulative risk of type 1 diabetes was increased in subjects with one or more autoantibodies and in those with FPIR <1st centile. CONCLUSIONS: Children with incidental hyperglycemia have a higher-than-normal frequency of immunological, metabolic, or genetic markers for type 1 diabetes and have an increased risk of developing type 1 diabetes.

Adolescent↗
PubMed2000

Humoral response to recombinant hepatitis B virus vaccine at birth: role of HLA and beyond.

From 1991 to 1998 we vaccinated 4835 neonates against hepatitis B virus (HBV) and monitored their humoral response to the recombinant vaccine. In a sample of 184 of these babies we studied the association between HLA class I and II genomic polymorphisms and humoral response to the vaccine and the association between the response and immune-mediated diseases. A subgroup of 96 babies also underwent HLA class III (C4A and C4B) typing. Four levels of humoral response were identified, each with a peculiar MHC restriction. Different HLA products seem to act as agonists (C4AQ0 and HLA-DQB1(*)02) or antagonists (C4AQ0, HLA-DQB1(*)02, and HLA-DRB1(*)11, DQB1(*)0301) in lowering humoral response to HBV vaccine. The group of responders was characterized more for lacking "nonresponder" alleles than for having specific "responder" ones. Tolerance to HBV peptides may have clinical implications, possibly being a marker for babies with a genetic risk of immunopathologies. In fact, many of the poor responders carried from two to four HLA-DQ alpha beta heterodimers predisposing to insulin-dependent diabetes mellitus and celiac disease. Two true nonresponders suffered from allergies and two slow responders had transient episodes of hyperglycemia.

Alleles↗
PubMed2000

New HLA-DRB1* nucleotide sequence of Italian origin: HLA-DRB1*13022.

High-resolution polymerase chain reaction using sequence-specific primer typing of the HLA-DRB1 gene of an Italian patient waiting for unrelated bone marrow transplantation revealed a new allelic variant of HLA-DRB1*13. Sequencing the exon 2 of DRB1* gene demonstrated a G-->C transition at the nucleotide 216 resulting in a silent mutation at codon 72: CGG-->CGC. The closest sequence was the HLA-DRB1*1302 and the new allele was named HLA-DRB1*13022. This variant was carried by the haplotype HLA-A*24; Cw*0702; B*39; DRB1*13022; DRB3*0301; DQA1*0102; DQB1*0604 as demonstrated by a family study.

Adult↗
PubMed2000

HLA-Gm/kappam interaction in sarcoidosis. Suggestions for a complex genetic structure.

The aetiology of sarcoidosis is still unknown. Environmental exposures are believed to interact with genetic factors in determining the pattern of sarcoidosis presentation, progression and prognosis. The frequency of serological polymorphism of immunoglobulin G heavy chain (Gm) and kappa light chain (kappam) markers in 107 patients with biopsy-proven sarcoidosis and in 227 controls, and their interactions with histocompatibility leukocyte antigen (HLA) class I, II, and III markers, were studied. A "protective" effect of the Gm(3 5*) phenotype in the sarcoid group versus controls (p-value for number of specificities tested (p(c))=0.05, odds ratio 0.15) and a reduced frequency of Gm(3 23 5*) in patients with advanced chest radiographic stage (Chi-squared (two degrees of freedom)(chi2(2df) 17.61, p(c)=0.0058) were observed. With reference to epistatic interactions, the combination Gm(3 23 5*)/BfS had a "protective" effect towards stage II (chi2(2dt) 13.86, p(c)=0.043). Finally, correspondence analysis defined two clusters: HLA-DR4, C4BQ0, Gm(1, 3, 17 23 5*, 21, 28) and BfF associated with stage II, and HLA-DR3, C4AQ0, kappam(1) and Gm(3 23 5*) associated with stage I. These data further support the hypothesis that sarcoidosis results from an interplay of environmental factors and genes, each contributing to the susceptibility/resistance to and/or the clinical heterogeneity of the disease. In addition, these data provide the first evidence of an interaction between immunoglobulin G heavy chain/kappa light chain markers and histocompatibility leukocyte antigen class III genes in a disease.

Adult↗