Aspirin and the risk of colorectal and other digestive tract cancers: an updated meta-analysis through 2019.

BACKGROUND: Aspirin has been associated with a reduced risk of colorectal cancer, and possibly of a few other digestive tract cancers. The quantification of risk reduction and the optimal dose and duration of aspirin use for the prevention of colorectal and other digestive tract cancers remains unclear. METHODS: To provide an up-to-date quantification of this association, we conducted a systematic review and meta-analysis of all observational studies on aspirin and cancers of the digestive tract sites published through March 2019. We estimated the pooled relative risk (RR) of cancer for regular aspirin use versus non-use using random-effects models, and, whenever data were available, we investigated the dose- and duration-risk relations. RESULTS: Regular aspirin use is associated with a reduced risk of colorectal cancer [RR = 0.73, 95% confidence interval (CI) = 0.69-0.78, 45 studies], squamous-cell esophageal cancer (RR = 0.67, 95% CI = 0.57-0.79, 13 studies), adenocarcinoma of the esophagus and gastric cardia (RR = 0.61, 95% CI = 0.49-0.77, 10 studies), stomach cancer (RR = 0.64, 95% CI = 0.51-0.82, 14 studies), hepato-biliary tract cancer (RR = 0.62, 95% CI = 0.44-0.86, five studies), and pancreatic cancer (RR = 0.78, 95% CI = 0.68-0.89, 15 studies), but not of head and neck cancer (RR = 0.94, 95% CI = 0.76-1.16, 10 studies). The associations are somewhat stronger in case-control than in cohort and nested case-control studies and are characterized by some between-study heterogeneity. Risk estimates are consistent across sex, geographical areas, and other selected covariates. For colorectal cancer, an aspirin dose between 75 and 100 mg/day conveys a risk reduction of 10%, and a dose of 325 mg/day of 35%. For all neoplasms, except head and neck cancer, inverse duration-risk relations with aspirin use are found. CONCLUSION: The present comprehensive meta-analysis supports and further quantifies the inverse association between regular aspirin use and the risk of colorectal and other digestive tract cancers, including some rare ones. The favorable effect of aspirin increases with longer duration of use, and, for colorectal cancer, with increasing dose.

Correlation of serum sHLA-G levels with cyst stage in patients with cystic echinococcosis: is it an immune evasion strategy?

Patients with cystic echinococcosis (CE) can harbour cysts for years or even decades, apparently without effect of the immune system on the metacestode. Although several immune evasion mechanisms by echinococcal cysts have been described, it is unclear whether the human leucocyte antigen (HLA) system plays a role in the susceptibility or resistance to CE in humans. HLA-G molecules are known to exert a suppressive action on dendritic cells maturation and on natural killer (NK) cells functions, therefore hampering T-cell responses and NK cytolysis. HLA-G plays an important role in immune tolerance, is involved in foetus and in allotransplant tolerance, and may be involved in tumoral and viral immune evasion. In this study, we assessed the presence and levels of soluble HLA-G (sHLA-G) in patients with CE using a commercial ELISA kit to determine whether host's HLA-G may have a role in the course of human CE.

Mycosis fungoides: association of KIR ligands and HLA-DQB1*05 with bad prognosis of the disease.

BACKGROUND: Mycosis fungoides (MF) is the most common cutaneous T-cell lymphoma. We previously reported that the prognosis of MF patients is not only related on clinical variables but it is also associated with peculiar HLA alleles. Until today, the association of HLA ligands for KIR with the prognosis of the disease has not yet been analysed. OBJECTIVE: We investigated the frequency of HLA ligands for killer cell Immunoglobulin-like receptors (KIRs) in MF patients, evaluating if the presence of particular HLA alleles that are ligands for KIR may have prognostic value. METHODS: The study includes 46 Caucasian MF patients that, between 1993 and 1997, underwent HLA genomic typing. All patients were diagnosed and followed up from 1977 to 2012 (mean follow-up of 11 years). RESULTS: MF patients have been divided into two groups (long survivors and dead patients). We noticed that the HLA-Bw6/Bw6 specificity increased among the group of seven dead patients compared to the group of 39 long survivors (71.4% vs. 41.0%, P = ns, OR = 3.59), while in the long survivors group the HLA- Bw4/Bw4 specificity increased when compared to dead patients (23.0% vs. 0%, P = ns). Moreover, we observed that six of the seven dead patients had HLA-DQB1*05; the phenotypic frequency of this HLA allele, in dead and long survivors patients, was 85.7% and 23.0% respectively (P = 0.004; OR = 20). CONCLUSION: Our observations suggest that the presence of the HLA-DQB1*05 alleles characterizes the patients with the poorest prognosis in MF. In addition, absence of the KIR-ligand epitope HLA-B Bw4 showed a trend of being more prominent in MF patients with the poorest prognosis.

-295 T-to-C promoter region IL-16 gene polymorphism is associated with Whipple's disease.

Whipple's disease (WD) is a rare systemic condition caused, in genetically predisposed subjects, by Tropheryma whipplei, a common bacterium widespread in the environment. The relevance of genetic predisposition in WD is shown by the association with HLA alleles DRB1*13 and DQB1*06 and by the demonstration that, in patients with WD, the cytokine genetic profile is skewed toward a Th2 and Treg response. Since IL-16 is involved in hampering the development of a protective macrophagic response against Tropheryma whipplei, we investigated whether the genetic background of IL-16 is different between patients with WD and controls. The -295 T-to-C polymorphism of the promoter region of the IL-16 gene was studied in 90 patients with WD and 152 healthy controls. Levels of serum IL-16 protein were also tested. The frequency of the wild type T allele was significantly higher in patients with WD compared to the controls (155/180 vs. 235/304; p = 0.02 for the Chi(2) test), odds ratio 1.82 [95 % confidence interval (CI) 1.07-3.10]. The TT genotype was found in 65/90 patients with WD and 88/152 controls (p = 0.026). No relationship was found between serum levels of IL-16 and genotypes. Although the functional consequences of this genetic background on levels of IL-16 and on the course of the disease are still unknown, we found, for the first time, that the wild type T allele and the TT genotype of the -295 polymorphism are associated with WD.

Immunogenetic factors in mycosis fungoides: can the HLA system influence the susceptibility and prognosis of the disease? Long-term follow-up study of 46 patients.

BACKGROUND: Mycosis fungoides (MF) is the most common and one of the least aggressive forms of cutaneous T-cell lymphoma. Several studies have demonstrated the influence of human leucocyte antigen (HLA) genes on the susceptibility of MF, highlighting the importance of certain alleles but, until today, no studies have evaluated the relationship between HLA alleles and the prognosis of patients with MF. OBJECTIVE: The aim of this retrospective cohort study was to evaluate the polymorphism of HLA class I and class II alleles in a group of 46 MF Caucasian patients, looking for their influence in susceptibility and prognosis of the disease. METHODS: Study population included a case-cohort sample of 46 Caucasian patients with MF that, between 1993 and 1997, underwent HLA class I and II genomic typing. All patients were diagnosed and followed up from 1977 to 2012 (mean follow-up of 11 years) and they were divided into three groups according to the evolution of the disease. RESULTS: Molecular typing at low-resolution level revealed that HLA-A*24, A*68, A*69, B*35 and DQB1*05:02 alleles were involved in susceptibility to MF. Correspondence analysis underlined that long-lasting remission was characterized by HLA-A*24 and HLA-A*25 alleles, frequent relapse by HLA-DRB1*01, DQA1*01:01, DQB1*05:01 alleles and death by HLA-A*68, HLA-B*08, HLA-B*35, HLA-C*03 alleles. CONCLUSION: This study suggests that the prognosis of MF patients is not only correlated with clinical/pathological/serological/immunological variables but it also relies on specific HLA alleles.

The conundrum of HLA-DRB1*14:01/*14:54 and HLA-DRB3*02:01/*02:02 mismatches in unrelated hematopoietic SCT.

Uncertainty still exists on the role of polymorphisms outside the HLA-DRB1 binding site or inside the HLA-DRB3 binding groove in unrelated hematopoietic SCT (HSCT). The ideal model to solve the conundrum consists of the transplants mismatched for HLA-DRB1*14:01/*14:54 and/or for HLA-DRB3*02:01/*02:02. A task force was set up in Italy to recruit transplanted pairs defined as HLA-DRB1*14:01 before 2006, the year crucial for the proper definition of the HLA-DRB1*14:54 allele in molecular biology. Out of 2723 unrelated pairs, 189 transplanted in Italy from 1995 to 2006 were HLA-DRB1*14:01 positive; 103/189 pairs with good historical DNA were retyped for HLA-DRB1*14 and HLA-DRB3 at-high resolution level; 31/103 pairs had HLA-DRB1*14 and/or HLA-DRB3 mismatched; 99/103, having complete clinical data, underwent statistical analysis for OS, TRM, disease-free survival and acute and chronic GvHD. No significant involvement of HLA-DRB1*14:01/*14:54 or HLA-DRB3*02:01/*02:02 mismatches was found, either alone or combined. Our findings suggest that disparities at exon 3 of the HLA-DRB1 gene seem unlikely to influence the outcome after HSCT. The same may be envisaged for HLA-DRB3(*)02:01 and (*)02:02 alleles which, although differing in the Ag binding site, seem unable to modulate an appreciable immune response in an HSCT setting.

The osteopontin gene +1239A/C single nucleotide polymorphism is associated with type 1 diabetes mellitus in the Italian population.

Secreted phosphoprotein 1, also known as Osteopontin (Opn), is a proinflammatory cytokine involved in the TH1 response and is highly expressed in the islets and pancreatic lymph nodes of non-obese diabetic mice before the onset of diabetes. In humans, typing of the +1239A/C single nucleotide polymorphism (SNP) in the 3UTR of the Opn gene (SPP1) showed that +1239C carriers displayed higher Opn serum levels than +1239A homozygotes and a higher risk of developing autoimmune/lymphoproliferative syndrome, multiple sclerosis, and systemic lupus erythematosus. The aim of this work is to evaluate whether +1239A/C is also associated with type 1 diabetes mellitus (T1DM). We typed +1239A/C in an initial cohort of 184 T1DM patients and 361 controls, and confirmed our data in a second cohort of 513 patients and 857 controls. In both cohorts, +1239C carriers displayed a significantly higher risk of T1DM than +1239A homozygotes (combined cohorts: OR=1.63, 95 percent CI: 1.34-1.97). Clinical analysis did not detect any differences between patients carrying or not +1239C in terms of gender distribution and age at T1DM diagnosis. These data suggest that SPP1 variants marked by +1239C are associated with T1DM development in the Italian population. The predisposing effect may depend on its effect on Opn levels.

Molecular study of receptor for advanced glycation endproduct gene promoter and identification of specific HLA haplotypes possibly involved in chronic fatigue syndrome.

The receptor for advanced glycation end product (RAGE) is thought to play an important role in inflammation. Chronic fatigue syndrome (CFS) is a long-lasting fatigue that compromises at least 50% of a subject's daily activities without other known cause. Immune dysfunction has been implicated and an association with a peculiar genetic cytokine profile, predisposing to an immunomodulatory response of inflammatory nature, was found. The aim of this study is to analyse RAGE polymorphisms and HLA-DRB1 alleles in seventy-five Italian CFS patients and 141 controls matched for age, sex and ethnicity. These two groups underwent genomic study for RAGE 374T/A and 429C/T promoter polymorphisms; moreover, 46 patients and 186 controls were typed for HLA-DRB1 at low resolution molecular level. Of these, 31 patients and 99 controls also underwent high resolution analysis to define the HLA-DRB1*11 and DRB1*13 alleles. The haplotypes RAGE-374T, DRB1*04; RAGE-374T, DRB1*09; RAGE-374T, DRB1*11; RAGE-374A, DRB1*13; RAGE-429T, DRB1*04 and RAGE-429C, DRB1*11 were significantly more frequent in CFS patients, whereas RAGE-429C, DRB1*07 would seem protective. A significantly lower frequency of DRB1*1104 (5.4% vs 12.9% p=0.04, OR=0.39) and a significantly higher frequency of HLA-DRB1*1301 (13.0% vs 5.1% p=0.006, OR= 2.79) were found in CFS patients. A synergic effect was observed with RAGE polymorphism. The OR values strengthened in the following cis combinations: RAGE-374A, HLA-DRB1*1104 (OR=0.27) and RAGE-374A, HLADRB1*1301 (OR=6.23). HLA haplotypes rather than single alleles of RAGE or of DRB1 genes seem to be involved in CFS, probably including a subregion of major interest.

HLA haplotypes and birth weight variation: is your future going to be light or heavy?

Birth weight is known to be a direct indicator of perinatal mortality and a clear predictor of adult pathologies too. It has been correlated with several causes of mortality in adulthood: low birth weight with diabetes, nephropathy and cardiovascular diseases and high birth weight with autoimmune diseases and cancer. In genome-wide studies, an extended human leucocyte antigen (HLA) region has been linked to birth weight variation. We focused our attention on the HLA haplotypes marked by HLA-A, HLA-B and HLA-DRB1 polymorphisms in 1206 healthy Caucasian newborns belonging to the Cord Blood Bank of Pavia (Italy) and their mothers, aiming to investigate the association between this restricted HLA region and birth weight variation. In our study, the HLA-B*38;DRB1*13 haplotype showed an ascending trend among centiles addressing to the high foetal weight. The HLA-A*02;B*15 haplotype showed a descending trend among centiles addressing to the low foetal weight. Besides the acknowledged correlation between the HLA-A*02 and HLA-B*15 alleles (as well as low birth weight) and type I diabetes and between the HLA-B*38 and HLA-DRB1*13 alleles (as well as high birth weight) and several autoimmune diseases, we cannot predict if our babies, healthy at birth, will suffer from these pathologies during life. Nevertheless, our data point to the HLA telomeric end for markers linked to the low birth weight and to the HLA centromeric end for markers linked to the high birth weight, thus limiting the region involved in birth weight variation, which still represents a useful predictor of disease risk in adulthood.

Myocardial adenomatoid tumor in eight cattle: evidence for mesothelial origin of bovine myocardial epithelial inclusions.

The adenomatoid tumor is an uncommon benign lesion, thus far described only in humans. Adenomatoid tumors typically arise in the genital tract, exceptionally in the heart, and usually represent an incidental finding. Microscopically, they are constituted by epithelioid cells that form tubular structures and anastomosing channels within a fibrous stroma. Mesothelial origin of these lesions is suggested by their immunohistochemical characteristics. In cattle, previously reported myocardial epithelial inclusions are morphologically similar in that the cells are immunoreactive for both cytokeratins and vimentin, and bear surface microvilli. Myocardial lesions found incidentally at slaughter in 8 cattle histologically resembled the so-called bovine myocardial epithelial inclusions and had morphologic and immunohistochemical features consistent with human adenomatoid tumor. All lesions were in the left ventricular myocardium, adjacent to the epicardium, and composed of epithelioid cells that formed cords and tubules, and were immunoreactive for pan-cytokeratins, cytokeratin 5/6, vimentin, calretinin, Wilms' tumor 1 suppressor gene, and CD30 antigen. By electron microscopy, numerous long slender microvilli were associated with desmosomes and tonofibrils. The immunohistochemical and ultrastructural features were considered consistent with mesothelial origin. These lesions, corresponding to the previously described myocardial epithelial inclusions in cattle, might be considered embryologic rests and could represent the bovine counterpart of the human adenomatoid tumor.

Case mix at the European Institute of Oncology: first report of the Tumour Registry, 2000-2002.

INTRODUCTION: An institutional and centralized hospital-based tumour registry (TR) is the ideal supporting tool for the organization and management of clinical data in a comprehensive cancer centre. The purpose of this paper is to describe the development of the TR at the European Institute of Oncology (IEO), Milan, Italy, from its origin to its current applications. MATERIAL AND METHODS: After a series of meetings with members of administrative, clinical, research and informatics departments, the TR was activated in March 2006 with the aim of collecting data on all the individuals referred to the institute, with or at risk of developing a tumour. It was implemented on an Oracle™-based interface. A minimum dataset of variables was defined and data collection was divided into four forms, which together gather all the relevant data on patients, tumours, treatments and subsequent events. RESULTS: After a six-month pilot period, which involved the training of the tumour registrars, adjustments to the structure of the registry, development of a data quality control procedure and finalization of the operative protocol, since September 2006 the data collection has been fully operative. Five registrars have been chronologically entering data of all individuals who visited the IEO for the first time since 1 January 2000. As of March 2009, data on 69,637 individuals and 43,567 tumours has been reviewed, recoded and registered in the TR. Twenty-two per cent of the tumours (n=9578) were first invasive primaries, diagnosed and treated in the IEO; the most common sites were breast (n=4972), lung (n=627), intestines (n=479) and prostate (n=376). CONCLUSION: The IEO TR has been proven functional and reliable in monitoring the activity of the hospital, allowing extraction of data from any subpopulation with characteristics of interest. The structured and centralized TR represents an important tool for our research-oriented institution.

The prevalence and the causes of minimal intestinal lesions in patients complaining of symptoms suggestive of enteropathy: a follow-up study.

AIMS: Although they are non-specific, minimal intestinal lesions are at the end of the coeliac histological damage spectrum. To investigate whether minimal intestinal lesions in patients without endomysial antibodies are due to coeliac disease, their prevalence, causes and risk of evolving into frank coeliac disease were studied. METHODS: From January 2000 to December 2005, 645 duodenal biopsies were performed. In 209 patients, duodenal biopsies were performed independently of endomysial antibody results. Clinical data and HLA-typing of all the patients negative to endomysial antibodies but with minimal mucosal lesions were re-evaluated. Three years later, they were offered to be seen again, and further investigations were proposed. RESULTS: 14 out of 209 patients had minimal mucosal lesions and negative endomysial antibodies. Two patients were lost to follow-up; in 7/12 patients, symptoms and histological lesions were due to a different condition, not related to coeliac disease. In 11/12 patients, HLA-typing made diagnosis of coeliac disease very unlikely. Only one patient was on a gluten-free diet because of gluten-sensitive symptoms and was DQ2(+)/DQ8(+). CONCLUSIONS: Minimal duodenal lesions in patients negative to endomysial antibodies are rare and are likely to be due to conditions unrelated to coeliac disease.

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.

A first study of cytokine genomic polymorphisms in CFS: Positive association of TNF-857 and IFNgamma 874 rare alleles.

OBJECTIVE: In the past two years we have developed a biological bank of genomic DNA, cDNA, serum and red blood cells of Italian patients with certified CFS from the two Italian referral centers for the syndrome. Recent studies have shown an imbalance in cytokine production in disease states similar to Chronic Fatigue Syndrome (CFS), such as sickness behavior, both in animals and in humans. However we notice that serum cytokine concentrations are often inconstant and degrade rapidly. With this in mind, we investigated cytokine gene polymorphisms in 80 Italian patients with CFS in order to ascertain whether in this group of patients it is possible to describe a genetic predisposition to an inflammatory response. METHODS: We analyzed the promoter polymorphisms of IL-10, IL-6 and the IFNgamma 874 T/A polymorphism in intron 1 with a PCR-SSP method (Cytogen One Lambda Inc. Canoga Park, CA, U.S.A) in 54 patients and TNF-308 G/A and -857 C/T promoter polymorphisms with a PCR-RFLP method (in 54 and 80 patients respectively). RESULTS: There is a highly significant increase of TNF -857 TT and CT genotypes (p = 0.002) among patients with respect to controls and a significant decrease of IFN gamma low producers (A/A) (p = 0.04) among patients with respect to controls. CONCLUSIONS: We hypothesize that CFS patients can have a genetic predisposition to an immunomodulatory response of an inflammatory nature probably secondary to one or more environmental insults of unknown nature.

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.

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.

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.

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.

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.

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.