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Behcet syndrome (BS) is a multisystemic perivasculitis whose genetic susceptibility is linked to HLA region. We first meta-analysed all HLA class I and II genes involved in BS susceptibility in all ethnic groups worldwide. We identified 1141 articles and finally included 31 case-control studies after multiple rounds of selection. We analysed frequencies for 24 HLA-A alleles (3 alleles for HLA-A ∗ 26 at four digits), 50 HLA-B alleles (11 alleles for HLA-B ∗ 51 at four digits), 15 HLA-C alleles, 16 HLA-DRB1 alleles, 6 HLA-DQB1 alleles, and 15 HLA-DPB1 alleles. We meta-analysed only HLA allelic frequencies from at least three studies; therefore, we investigated 21 alleles out of 140. Going from 7.00 to 1.6 OR, we found 11 class I alleles conferring risk for BS: B ∗ 51 : 08 , B ∗ 51 , B ∗ 51 : 01 , B ∗ 51 : 02 , DQB 1 ∗ 03 , A ∗ 26 : 01 , Cw ∗ 14 , Cw ∗ 15 , Cw ∗ 16 , B ∗ 15 , and A ∗ 26 . Overall, the studies included populations from Europe (Greece, Spain, Italy, Germany, and Ireland), Asia (Korea, China, China Han, and Thailand), Middle East (Israel, Saudi Arabia, and Iran), and Morocco (as no other North-African population was included). We collected a number of ethnical groups sufficient to conduct an ethnic-specific meta-analysis where Europeans showed 11.25 OR for B ∗ 51:08 and Japan 3.50 OR for A ∗ 26 : 01 . A remarkable result was that the most frequent HLA − B ∗ 51 two-digit alleles associated with BS were different among populations: HLA − B ∗ 51 : 08 in Europe, HLA − B ∗ 51 : 01 in Turkey, and HLA − B ∗ 51 : 02 in Japan. Overall, we discussed our real-world results with other imputation studies.

Multiple Sclerosis (MS) displays a heterogeneous clinical onset and progression, which are mostly unpredictable, but demyelination of the central nervous system (CNS) leads to substantial deficits of sensory, motor, autonomic, and neurocognitive functions. Considering all genetic studies on MS, including the advanced genome-wide association studies, the risk linked to HLA alleles remains the highest among other susceptibility genetic variants. However, given the genetic variability of HLA alleles in different ethnic groups, we conducted a systematic review of reviews and meta-analyses aiming at summarizing all the results on the association between MS and HLA class II genes. We systematically searched meta-analyses and systematic reviews dealing with MS and HLA in all ethnicities. From 154 records, we included 5 articles collecting HLA data from 15,232 MS patients and 24,194 ethnically matched controls. DRB1∗15 (OR ranging from 1.39 in Chinese Han to 2.59 in Caucasians) and DQB1∗06:02 (OR ranging from 1.91 in Caucasians to 2.49 in Colombian) alleles confer an increased risk for MS transethnically (Caucasians, Chinese, South Americans, Carribeans, Middle Easterners, Japanese, and North Africans). DRB1∗01, DRB1∗09, DRB1∗11, DRB1∗12, and DRB1∗16 alleles were protective, in agreement with the type of amino-acidic (aa) residues (ranging from position 9 to 90) included in pockets 1, 4, 6, 7, and 9, which are most involved in peptide presentation. Changes in aa residues affect the capability of HLA molecules in binding myelin peptides. DQB1∗06:02 risk allele seems to be the most interesting target as humanized mice expressing only DQB1∗06:02 develop MS-like disease mediated by autoimmune reactions against myelin oligodendrocytic basic protein that stabilizes the myelin. Our summary of results from a high number of patients and controls suggests that allelic variants from both DQB1 and DRB1 genes are equally involved in MS susceptibility/protection transethnically.

BackgroundSpecific HLA-DQ genes have been recognized as necessary - but not sufficient - factors for the occurrence of Celiac Disease (CD). Through a meta-analysis, evaluating the distribution of CD-related HLA genotypes in children, we aimed at providing insights for a potential widened screening strategy.MethodsAfter a systematic search on the association between class II HLA genes and CD in children, 46 publications were obtained and assessed for eligibility. A total of 13 eligible studies were submitted to data extraction and analysis (10 case-control studies and 3 cohort studies). Case-control studies collectively enrolled 740 CD patients and 943 controls.ResultsIn the population-stratified analysis, the following alleles conferred a significantly increased risk for CD: HLA-DQB1*02 (odds ratio [OR]=10.28) and HLA-DQB1*03:02 (OR=2.24). By drafting a risk gradient to develop CD according to HLA genetic background, the highest risk is confirmed to exist for DQ2/DQ2 homozygous subjects, regardless of the ethnicities (OR=5.4). Actually, the genotype DQ2/β2 showed basically the same risk (OR=5.3). Indeed, no differences have been found in CD risk between DQ2/β2 and DQ2/DQ2, as well as between DQ8/β2 and DQ2/DQ8, and between β2/DQX and DQ2/X.ConclusionThe HLA-DQB1*02:01 allele is present in more than 90% CD children. In the perspective of a widened pediatric population screening for CD, a double-step process might be suggested: HLA-DQB1*02:01 might be investigated first and, only if this result is positive, children might be candidate for a prospective serologic screening, as a second step.

Juvenile Idiopathic Arthritis (JIA) is characterized with a variable pattern of articular involvement and systemic symptoms and, thus, it has been classified in several subtypes. Genetic predisposition to JIA is mainly due to HLA class II molecules (HLA-DRB1, HLA-DPB1), although HLA class I molecules and non-HLA genes have been implicated, too. Here, we carried out a meta-analysis including selected studies designed to assess HLA genetic background of JIA patients, compared to healthy controls; particularly, we focused our attention on HLA-DRB1. In summary, our meta-analysis showed four main findings regarding HLA-DRB1 locus as a genetic factor of JIA: i) HLA-DRB1*08 is a strong factor predisposing to JIA, both for oligo-articular and poly-articular forms (oJIA > pJIA); ii) HLA-DRB1*01 and HLA-DRB1*04 may be involved in the genetic predisposition of Rheumatoid Factor (RF) positive forms of JIA; iii) HLA-DRB1*11 was confirmed to be predisposing to oligo-articular JIA; iv) HLA-DRB1*04 was confirmed to have a role in systemic JIA. Importantly, RF positivity seems to select the JIA clinical subset with the strongest immunogenetic similarities with adult rheumatoid arthritis.

We enrolled 151 healthy mother/newborn couples and 26 with gestational diabetes mellitus (GDM). HLA-G and PAPP-A plasma levels were measured by ELISA at first and second trimesters, at delivery, and in cord blood. HLA-G 14 bp ins/del and PAPP-A A/C polymorphisms were genotyped. HLA-G del/del and PAPP-A C/C genotypes were more frequent among GDM mothers than controls. We observed a genetic epistasis between the two polymorphisms: the HLA-G del/del and PAPP-A C/C combination was carried by 8% of GDM mothers and 1.3% of controls (OR = 9.5, 95% CI = 0.8–109, p=0.07). GDM mothers showed increased sHLA-G levels compared to controls (p=0.004), and those carrying the HLA-G del/del genotype produced more sHLA-G at the second trimester and at delivery (p=0.014). A genetic pressure by fetal genotype on maternal sHLA-G production was observed in GDM mothers with heterozygous HLA-G del/ins newborns (p=0.02). Babies born to GDM mothers showed higher sHLA-G concentrations compared to those born to healthy mothers, and those carrying HLA-G del/del showed the highest sHLA-G levels (p=0.013). PAPP-A amounts significantly increased along pregnancy (p<0.001), but the median levels at the first and second trimesters were significantly lower in GDM (p=0.03). Our findings first suggest an involvement of HLA-G and PAPP-A gene-protein interaction in GDM and highlight a possible contribution of the fetus in balancing maternal inflammation.

The competitive binding between CpG-ODN (single-stranded DNA from pathogens) and HLA-B and HLA-A ligands for the inhibitory Killer Immunoglobulin-like Receptors (KIR)3DL1/2 may lead to possible hypo-sensing of pathogens and ineffective clearance. We observed an overabundance of HLA ligands for inhibitory KIR with three domains in KD subjects.

HLA typing requests for association studies of immune-mediated diseases are often redundant and inadequate. We designed a series of meta-analyses to evaluate the accuracy of typing and distribution of HLA alleles predisposing to diseases, aiming at developing an app that can help doctors in choosing the most suitable molecular analysis. The first study was on celiac disease (CD) and HLA-DQ in children. We searched all english articles published in the main bibliographic databases up to May 2016. The search strategy has been developed using controlled terms (e.g. MeSH) and free terms. We identified 1885 articles. 1334 abstracts were examined. 46 manuscripts were evaluated, and 13 studies were included in the meta-analysis (740 CD and 943 controls). The risk of developing CD in children with allelic variants encoding the HLA-DQ2.5 and/or HLA-DQ8 molecules has been confirmed. The greatest CD risk resides in carriers of two DQ2.5 molecules, i.e. subjects homozygous for the DQB1*02:01 and DQA1*05 alleles (OR=5.4, 95 % CI=4.1-6.8) compared to any other DQ genotype. Carriers of two DQB1*02:01 (chain β2) alleles and one DQA1*05 (chain α5) allele have the same risk (p=0.8089) of DQ2.5 homozygotes (OR=5.3%, 95 CI=4,1 to 6.5). We found no differences between DQ8/β2 and DQ2.5/DQ8, nor between β2/DQX and DQ2.5/X. We suggest a two-step process: first typing the DQB1*02:01 allele and, in case of a negative result, full typing of HLA-DQ.

Autoimmune rheumatic diseases in pregnancies are associated with increased adverse obstetric outcomes. We compared maternal soluble human leucocyte antigen-G (sHLA-G) blood levels in subjects with a rheumatic disease preexisting pregnancy and unaffected controls. Third-trimester blood maternal sHLA-G concentrations were significantly higher in subjects with rheumatic diseases than in controls (mean 93.1ng/ml [SD 42.1] vs 58.1ng/ml [SD 96.3], p=0.003). Cord blood sHLA-G concentrations were significantly higher in rheumatic disease than in those born to control mothers (median 41.2ng/ml [IQR: 3.3-44.0] vs 17.9ng/ml [IQR: 17.2-88.1], p=0.007). A strict positive correlation (r=0.88, p

Problem To target gestational diabetes mellitus (GDM) by means of temporal variation in pregnancy-associated plasma protein A (PAPP-A) and soluble human leukocyte antigen-G (sHLA-G). Method of study Retrospective analysis of PAPP-A and sHLA-G blood levels in historical samples of 112 GDM and 112 controls, drawn at first trimester, and prospective study in 18 GDM and 105 controls collected in triplicate along the pregnancy. Six hundred and sixty-five samples were analyzed. Results Gestational diabetes mellitus had significantly lower first-trimester PAPP-A concentrations than controls (2343 ± 1519 versus 2996 ± 1955 mU/mL, in retrospective brunch and 2490.57 ± 1828.52 versus 3240.84 ± 1930.69 mU/L in prospective one, P

Background: Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) may develop in susceptible patients after administration of different drugs. Only mild cutaneous reactions have been related to lomefloxacin. A correlation between human leucocyte antigen (HLA) and cutaneous adverse reaction has been identified. Case Report: Twenty-four hours after intake of lomefloxacin, a 30-year-old Caucasian woman developed a severe skin reaction with symptoms suggesting SJS/TEN. The fast onset reaction worsened with skin blisters and 20% body surface area skin detachment within 48 h. Burn unit admittance was required; corticosteroids and human immunoglobulins were administered. Complete recovery occurred within 3 months, except for epidermal discoloration. Molecular studies showed a peculiar profile characterized by HLA class I genotype rich of ligands for natural killer cell immunoglobulin-like receptors (KIR) and HLA class II haplotype, HLA-DRB1*03:01,DQB1*02:01, prone to autoimmunity. Conclusion: While the HLA profile approaches our case to other well-documented drug-induced SJS/TEN, KIR involvement still remains puzzling.

Little is known about soluble HLA-G (sHLA-G) concentrations in obese pregnant women with uncomplicated pregnancies.To investigate the role of sHLA-G in obese pregnancies.Case-control study, from 2013 to 2015.A tertiary care centre.168 healthy normal weight women and 59 overweight/obese women; to avoid the effect of preeclampsia on sHLA-G concentrations, cases were further divided in two groups: 42 with normotensive pregnancy and 17 who developed preeclampsia.all the women enrolled received standard antenatal care and plasma sample collections were performed.sHLA-G concentrations during pregnancy, before delivery and in cord blood.Maternal sHLA-G concentrations in overweight/obese with normotensive pregnancies increased by 14.7% (IQR=-26.4 to +89.6) in the 2nd trimester and by 19.6% (IQR=-33 to +104) before delivery and were significantly higher than in controls (p=0.024). Median cord blood sHLA-G concentrations were 53.5ng/ml (IQR=36-62.7) in the overweight/obese women with uncomplicated pregnancies (p0.001 compared to controls) and 19.7ng/ml (IQR=7.5-36.3) in controls. Maternal concentrations of sHLA-G in the two trimesters and before delivery were significantly lower among subjects who developed preeclampsia than in controls (p0.001) or in obese subjects with normotensive pregnancies (p0.001).sHLA-G concentratons are higher in normotensive overweight/obese women and their babies while lower in preeclamptic overweight/obese women and their cords. Obesity influences maternal and fetal sHLA-G concentrations during pregnancy, to optimize the reproductive success, while preeclampsia impairs the mother-offspring antinflammatory response.

Type 1 diabetes mellitus (T1DM), celiac disease (CD) and autoimmune thyroid disease (ATD) are autoimmune conditions relatively common in paediatric age and frequently occur in association in the same subject. This event is not by chance and requires an explanation. Here, we studied the distribution of HLA-DQ αβ heterodimers in 334 Italian children with T1DM, ATD and CD alone or in association and in 224 Italian healthy controls. In particular, 164 patients had T1DM (133 alone, 20+ATD, 7+CD and 4+CD+ATD), 118 had ATD (110 alone, 8+CD) and 52 had CD (40 alone, 11+ATD and 1+T1DM). 51 patients suffered from multiple autoimmune diseases. The risk for multiple autoimmune diseases was significantly associated with the increased number of HLA-DQ markers of susceptibility for both T1DM (p = 0.003) and CD (p = 0.006). The presence of one or more diabetogenic DQ molecules significantly increased the probability of developing not only T1DM (p0.001) but also CD (p0.001) and ATD (p = 0.001). Similarly, the presence of one or more celiac HLA-DQ heterodimers significantly increased the likelihood of developing not only CD (p0.001), but also T1DM (p0.001) and ATD (p0.001). We confirm that the sharing of the immunogenetic background is responsible for the development of multiple autoimmune diseases although with a different risk according to the number and type of susceptible HLA-DQ heterodimers as reported in the algorithm proposed here. It is likely that combinations of DQA1 and DQB1 alleles are the real culprits of the progression towards multiple autoimmune diseases and HLA-DQ genomic typing will improve the capability to predict associated autoimmune diseases in infancy.

Background HLA-DQB1*02 homozygosity was shown to be more common in patients with complicated rather than uncomplicated celiac disease (CD). Goals To study HLA-DQA1 and DQB1 profile in adult patients with different forms of CD, including patients with complicated and potential CD, the most affected and the most preserved histologic end of the pathologic celiac spectrum. Study HLA-DQA1 and DQB1 molecular typing was performed in 218 adult CD patients (169 with uncomplicated CD, 27 with complicated CD, and 22 with potential CD) and 224 healthy stem cell donors. HLA-DQA1 and DQB1 gene polymorphism was analyzed using polymerase chain reaction sequence-specific primers and/or reverse polymerase chain reaction sequence-specific oligonucleotides techniques. Results As expected, the frequency of HLA-DQB1*02 allele, DQB1*02 homozygosity, and DQB1*0302 gene were statistically different in the 4 groups. However, multivariate analysis demonstrated that patients with potential CD have a higher frequency of both HLA-DQB1*0302 and HLA-DQB1*0603 alleles and a reduced frequency of DQB1*02 homozygosity compared with patients with uncomplicated and complicated CD. Conclusions The increased frequency of DQB1*0302 and the reduced frequency of DQB1*02 homozygosity in potential CD is consistent with the idea that different clinical/pathologic evolutions might be related to different immunogeneses. This could be clinically relevant in the future.

Even though autoantibodies to pancreatic islet cells are normally found in type 1 diabetes and insulin-resistance due to overweight is more reminiscent of type 2 diabetes, some studies have described β-cell antibodies also in maturity-onset diabetes of the young (MODY) and in type 2 diabetes. A 7-year-old girl was referred to our Unit for incidental hyperglycemia and family history of MODY2 and type 2 diabetes. Genetic evaluation confirmed mutation L134P in exon 4 of the glucokinase gene and a high HLA-risk of type 1 diabetes. During follow-up, she developed type 1 diabetes and overweight-induced metabolic syndrome. The coexistence of MODY, type 1 diabetes and overweight-induced metabolic syndrome confirms that diabetes subtype probably represents a continuum of immune and metabolic dysfunction modified by genetic factors.

An increased frequency of autoimmune diseases as well as an elevated incidence of autoantibodies has been observed in patients with Turner syndrome; the most common autoimmune diseases appear to be thyroid autoimmune disease and inflammatory bowel diseases. Turner patients evolve towards autoimmunity much more frequently than people with normal karyotype without any relevant excess of the putative immunogenetic risk markers. That underscores the great influence of X-chromosome abnormalities in the development of autoimmune disorders and suggests an epistatic interaction of X genes with immune response genes. Interestingly, one of the human MHC-paralogues is located in the long arm of the X chromosome, so that who is defective in this region might be less efficient to control the pathogenic repertoire during the lifespan. Medical care for patients with TS should routinely include screening for the autoimmune disorders in order to assure early detection and appropriate treatment.

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.

Type 1 diabetes (T1D) is an autoimmune disease triggered by environmental factors. Among those of infectious origin, viruses mostly associated to T1D are rubella virus, enteroviruses (Rotavirus, Coxackie B), Cytomegalovirus and mumps virus. The role of bacterial infections is still controversial, acting either as modulators or precipitating factors of an already started autoimmune process. Polymorphic genes of innate immunity, such as Toll-like receptors, nucleotide-binding oligomerization domain (NOD) 1 and NOD2 and mannose-binding lectin (MBL) genes, did not show a strict association with T1D onset, while protein tyrosine phosphatase (PTPN22), cytotoxic T-lymphocyte antigen (CTLA)4 and natural killer cells immunoglobulin-like receptor (KIR) genes appear to play an important role. However, the adaptive immune response genes (HLA) still provide the major contribution to T1D susceptibility. Here, we review the mechanism by which microorganisms might induce autoimmunity.

In utero selection processes are probably related to mother-father compatibility as has been reported in abortion-prone couples and in Down syndrome studies. In order to analyse this phenomenon, we investigated families with chromosomal imbalance (Turner syndrome). We chose this model because previous data indicated a high frequency of HLA-A31 and B38 in Turner patients and in their mothers. We report high HLA antigen sharing in Turner families and great histocompatibility between mother and affected daughter, not related to abortion histories. The proportion of HLA-A homozygous cases among Turner children was higher than expected. The level of lymphocytotoxic antibodies against fetus in mothers of Turner patients was comparable to that of mothers of families with normal fertility and probably favoured these pregnancies.

OBJECTIVE—Perforin plays a key role in cell-mediated cytotoxicity. Mutations of its gene, PRF1, cause familial hemophagocytic lymphohistiocytosis but have also been associated with lymphomas and the autoimmune/lymphoproliferative syndrome. The aim of this work was to investigate the role of PRF1 variations in type 1 diabetes. RESEARCH DESIGN AND METHODS—We typed for the N252S and A91V variations in an initial population of 352 type 1 diabetic patients and 816 control subjects and a second population of 365 patients and 964 control subjects. Moreover, we sequenced the coding sequence and intron-exons boundaries in 200 patients and 300 control subjects. RESULTS—In both cohorts, allelic frequency of N252S was significantly higher in patients than in control subjects (combined cohorts: 1.5 vs. 0.4%; odds ratio 6.68 [95% CI 1.83–7.48]). Sequencing of the entire coding region detected one novel mutation in one patient, causing a P477A amino acid change not detected in 199 patients and 300 control subjects. Typing for HLA-DQA1 and DQB1 alleles showed that type 1 diabetes–predisposing DQα/DQβ heterodimers were less frequent in patients carrying N252S or P477A than in those carrying wild-type PRF1. We previously found that natural killer (NK) activity is not decreased in most N252S heterozygotes, but we detected one whose NK activity was normal at the age of 12 but strikingly low in early childhood. Here, we discovered that NK function was low in three heterozygotes in early childhood, one homozygous adult, and in the subject carrying P477A. CONCLUSIONS—These data suggest that N252S and possibly other PRF1 variations are susceptibility factors for type 1 diabetes development.

Primary cutaneous T-cell lymphomas are exceedingly rare in children and adolescents. However, mycosis fungoides (MF) is the most frequent primary cutaneous lymphoma diagnosed in childhood. Two cases of MF in siblings (a 14-year-old boy and his 10-year-old sister) are reported. On the basis of clinical features (histopathological and immunophenotypical findings) a diagnosis of MF patch lesions was made in both siblings. Since recent data in the literature have underlined a high frequency of the HLA-DQB1*03 allele in patients with familial MF (including child patients), the HLA profile of the patients was analysed, indicating the presence of a haplotype (HLA-DQB1*03,*03 in the girl, HLA-DQB1*02,*03 in the boy) corresponding with that described in recent literature. Two rare and exceptional cases of MF in siblings are reported, highlighting the presence of a peculiar haplotype.

Introduction Crohn’s disease (CD) is a disabling chronic enteropathy sustained by a harmful T-cell response toward antigens of the gut microbiota in genetically susceptible subjects. Growing evidence highlights the safety and possible efficacy of mesenchymal stem cells (MSCs) as a new therapeutic tool for this condition. Therefore, we aimed to investigate the effects of bone marrow-derived MSCs on pathogenic T cells with a view to clinical application. Methods T-cell lines from both inflamed and non-inflamed colonic mucosal specimens of CD patients and from healthy mucosa of control subjects were grown with the antigen muramyl-dipeptide in the absence or presence of donors’ MSCs. The MSC effects were evaluated in terms of T-cell viability, apoptotic rate, proliferative response, immunophenotype, and cytokine profile. The role of the indoleamine 2,3-dioxygenase (IDO) was established by adding a specific inhibitor, the 1-methyl-DL-tryptophan, and by using MSCs transfected with the small interfering RNA (siRNA) targeting IDO. The relevance of cell-cell contact was evaluated by applying transwell membranes. Results A significant reduction in both cell viability and proliferative response to muramyl-dipeptide, with simultaneous increase in the apoptotic rate, was found in T cells from both inflamed and non-inflamed CD mucosa when co-cultured with MSCs and was reverted by inhibiting IDO activity and expression. A reduction of the activated CD4+CD25+ subset and increase of the CD3+CD69+ population were also observed when T-cell lines from CD mucosa were co-cultured with MSCs. In parallel, an inhibitory effect was evident on the expression of the pro-inflammatory cytokines tumor necrosis factor-α, interferon-γ, interleukin-17A and -21, whereas that of the transforming growth factor-β and interleukin-6 were increased, and production of the tolerogenic molecule soluble HLA-G was high. These latter effects were almost completely eliminated by blocking the IDO, whose activity was upregulated in MSCs co-cultured with CD T cells. The use of a semipermeable membrane partially inhibited the MSC immunosuppressive effects. Finally, hardly any effects of MSCs were observed when T cells obtained from control subjects were used. Conclusion MSCs exert potent immunomodulant effects on antigen-specific T cells in CD through a complex paracrine and cell-cell contact-mediated action, which may be exploited for widespread therapeutic use.

Mother-to-infant transmission of Hepatitis C Virus (HCV) represents the major cause of pediatric HCV infection today. Immunogenetic influence has been poorly investigated and mainly confined to HLA-class II serological polymorphisms. Among 290 parities, 135 from Pavia and 155 from Bergamo, of HCV-RNA-infected Italian women, 21 babies (7.24%) were HCV-RNA positive at birth and steadily positive over 20 months of life. All the 21 infected babies and 44 randomly selected uninfected ones, born to HCV-RNA+ mothers but steadily negative for HCV-RNA during a follow-up of 2 years, and their mothers were investigated for HLA-G, -C, -DRB1, -DQA1 and -DQB1 genomic polymorphisms. Among the different covariates, HLA-Cw*07, -G*010401, -DRB1*0701, -DRB1*1401 and homozigosity for HLA-G 14bp deletion can be considered as risk factors for HCV vertical transmission. On the contrary, protection was conferred by the HLA-DQB1*06, -G*0105N, -Cw*0602, DRB1*1104 and -DRB1*1302 alleles. Our initial question was: has the immunogenetic profile any role in the protection of the fetus growing in an infected milieu and, if so, is it independent from the other non-immunogenetic parameters? The answer to both questions should be yes.

To assess the occurrence of growth hormone deficiency (GHD) in patients with coeliac disease (CD).A total of 1066 children diagnosed elsewhere with short stature were referred to our centre for second-line evaluation in a 6-year period. All patients were screened for CD by antiendomysial antibodies (EMA) and those with positive sera underwent intestinal biopsy.Among the 1066 short children, 210 (19.7%) had GHD and 12 (1.12%; chronological age from 3.6 to 12.3 years, bone age from 1.5 to 10.5 years, SDS height from -3.05 to -0.48), having positive EMA, showed histologically confirmed CD. Nine of these latter 12 CD children had a beneficial effect on growth rate after the first year of gluten-free diet, while the remaining three showed no catch-up growth. A careful endocrinological investigation in these three CD boys showed an isolated GHD in two cases and a multiple GHD in one case. The congenital origin of GHD is supported by the congenital abnormalities documented by magnetic resonance imaging. GH therapy associated with gluten-free diet led to an increased growth rate.GH secretion should be evaluated in coeliac patients showing no catch-up growth after a period on a gluten-free diet in spite of reversion to seronegativity for EMA. In the case of GHD and CD, replacement GH therapy should be started during a gluten-free diet.

Primary atrophic rhinitis is a chronic inflammation of the nasal mucosa characterized by atrophy of the mucous and bony tissue of the turbinates and by a thick, dense secretion, which quickly forms a characteristically fetid-smelling, greenish crust. We report the results of the clinical, genetic and immunologic investigations performed on eight subjects (three with ozena and five asymptomatic), members of the same familial group. The presence of the disease in the family fits well with dominant inheritance. All the culture specimens from the patients affected by ozena were positive for Klebsiella ozaenae, and one of them was also positive for Pseudomonas aeruginosa. All the three patients with ozena and two of the five apparently unaffected family members were positive for antinuclear antibodies. Immunoblotting showed a reactivity to a 50-kD protein, which was not identified by the common, recognized nuclear autoantigens. This was present in one of the three patients and three of the five other family members. Positivity for IgG-class anticardiolipins was correlated with disease manifestation in that it was found in two of the three patients and only in one of the five asymptomatic family members. The hypothesis of a genetic factor that could drive the chronicity of the inflammatory pattern of a pre-existing infectious nasal disease is suggested.

A letter in response to: Sanchez-Giron F, Villegas-Torres B, Jaramillo-Villafuerte K et al. Association of the genetic marker for abacavir hypersensitivity HLA-B*5701 with HCP5 rs2395029 in Mexican Mestizos. Pharmacogenomics 12(6), 809–814 (2011).

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.

Hepatitis C outcome is likely related both to viral factors and host's immune responses. We correlated the severity of liver disease with human leukocyte antigen (HLA) genes (C4A, C4B, TNFA, TNFB, DRB1, DRB3, DRB4, DRB5, DQA1, DQB1, TAP1, and TAP2) in three groups of subjects: 99 patients with chronic hepatitis, 41 asymptomatic carriers, and 179 uninfected controls. Patients with grade/stage 3 to 4 hepatitis significantly differentiated for their low frequency of alleles TNFB*1, DRB1*1104, and DRB3*03, which had a protective role, and high frequency of allele DRB1*1001, which was associated with disease severity. HLA-DRB*11 subtypes were differentially distributed: DRB1*1104 was most frequent in carriers, whereas DRB1*1101 was more frequent in patients. The TAP1C,2A haplotype was also underrepresented in patients with respect to controls. Finally, a decrease of heterozygous subjects was observed in patients with respect to carriers at the DQB1 locus. Multivariate analysis by correspondence analysis and multiple logistic regression indicated that age, sex, and hepatitis C virus (HCV) type were the strongest risk factors; however, some immunogenetic variables (TNFB*1, DRB1*1104, and DRB3*03) showed an independent contribution, especially in comparing patients with extreme manifestations of disease. The involvement of different genes in various HLA subregions suggests that anti-HCV responses are modulated by a complex gene interplay rather than by single alleles.

OBJECTIVE Following the observation of two patients affected by true precocious puberty who went on to develop polycystic ovary syndrome (PCOS) and who were found to be heterozygotes (carriers) for 21-hydroxylase deficiency (21-OHD), we decided to evaluate the frequency of heterozygosity for adrenal 21-OHD in patients with true precocious puberty. STUDY DESIGN We investigated 32 girls affected by true precocious puberty, by the single-dose ACTH stimulation test, HLA typing and the molecular analysis of the CYP21B gene encoding for the 21-OH enzyme, in order to detect gene deletions or point mutations. Twenty-eight cases were on LHRH analogue treatment and the remaining four, untreated owing to parental refusal, were investigated 0.5–1.5 years after spontaneous menarche. RESULTS After ACTH testing, 13 out of the 32 (41%) cases displayed higher 17-hydroxyprogesterone (17-OHP) levels than normal but less than those found in patients affected by nonclassical adrenal hyperplasia (CAH); these levels were similar to those observed in obligate heterozygotes for CAH due to 21-hydroxylase deficiency (21-OHD). HLA typing showed a significantly increased frequency of the HLA alleles A28 and B14 which are peculiar to the HLA haplotypes of nonclassical CAH due to 21-OHD. Molecular analysis of the CYP21B gene showed that in four out of the 10 tested patients with an exaggerated 17-OHP response there were heterozygous point mutations of the CYP21B gene. In contrast, no CYP21B gene abnormalities were detected in the eight tested patients with normal 17-OHP. No differences were found between carriers and non-carriers of the 21-OHD with regard to age at onset of precocious puberty, clinical features, bone age acceleration and gonadal suppression induced by LH-RH analogue treatment. Two out of the four untreated patients who were investigated after menarche were found to be carriers of the 21-OHD; these girls showed signs of androgen excess, irregular menses and polycystic ovaries. CONCLUSIONS A high frequency of heterozygosity for adrenal steroid 21-OHD was found in our patients with true precocious puberty. This adrenal defect does not seem to influence the pattern of central precocious puberty, but these patients require long-term follow-up as they might go on to develop polycystic ovary syndrome (PCOS). Whether or not heterozygosity of the 21-OHD may be related to the premature activation of the hypothalamo-pituitary-gonodal axis remains to be defined.

Background/Aims: Recent studies have suggested that the course of chronic hepatitis C may be influenced by the immunogenetic background of the host. Specifically, HLA-DR11 (5) has been associated with less advanced hepatitis C virus (HCV)-related liver disease. The aim of the present study was to investigate whether HLA-DRB1*11 subtypes of HLA-DQA1 and DQB1 genes might be associated with protection from or susceptibility to chronic HCV infection, histological severity of HCV-induced liver disease and infecting HCV genotype. Methods: Ninety-nine unrelated outpatients with histologically documented chronic hepatitis C were studied and their allele frequencies were compared with those of 179 ethnically matched controls and with those of 41 HCV RNA-positive patients with persistently normal aminotransferase levels (HCV carriers). HLA-DQ types and HLA-DRB1*11 subtypes were determined by polymerase chain reaction gene amplification with sequence specific primers. Results: None of 10 DQA1 or 12 DQB1 alleles was significantly associated with susceptibility to or protection from chronic HCV infection or with histological staging or with HCV genotype. However, analysis of DQA1-DQB1 combinations showed that DQA1*0201-DQB1*0201 combination was significantly more frequent in patients compared to controls, both in cis (26.3% vs 16.2%, p =0.04, odds ratio=1.8, 95% confidence interval, 0.96–3.5) and in trans (12.2% vs. 1.1%, p =0.0001, OR=12.2, 95% CI, 2.6–113.7). HCV carriers did not differ from controls or from patients in the frequency of DQA1-DQB1 combinations. The extended haplotype DRB1*1104, DQA1*0501, DQB1*0301 was seen signficantly less frequently in patients than in controls (8% vs 22.3%, p =0.0025, OR=0.31, 95% CI, 0.12-0.7) or HCV-RNA carriers (8% vs 26.8%, p =0.003, OR=0.24, 95% CI, 0.08–0.73). Conclusions: Immunogenetic factors may play a role in determining both protection from and susceptibility to chronic hepatitis C, the trans -dimer DQA1*0201-DQB1*0201 predisposing to and the DRB1*1104, DQA1*0501, DQB1*0301 haplotype protecting from chronic hepatitis C.

The effect of minor H antigen mismatching on the occurrence of graft-versus-host disease (GvHD) and graft-versus-leukemia (GvL) after HLA-matched hematopoietic stem cell transplantation (HSCT) has mainly been demonstrated in single-center studies. Yet, the International Histocompatibility and Immunogenetics Workshops (IHIW) provide a collaborative platform to execute crucial large studies. In collaboration with 20 laboratories of the IHIW, the roles of 10 autosomal and 10 Y chromosome-encoded minor H antigens were investigated on GvHD and relapse incidence in 639 HLA-identical related donor (IRD) and 210 HLA-matched unrelated donor (MUD) HSCT recipients. Donor and recipient DNA samples were genotyped for the minor H antigens HA-1, HA-2, HA-3, HA-8, HB-1, ACC-1, ACC-2, SP110, PANE1, UGT2B17, and HY. The correlations with the primary outcomes GvHD (acute or chronic GvHD), survival, and relapse were statistically analyzed. The results of these multicenter analyses show that none of the HLA class I-restricted HY antigens were found to be associated with any of the primary outcomes. Interestingly, of the HLA class II-restricted HY antigens analyzed, HLA-DQ5 positive recipients showed a significantly increased GvHD-free survival in female-to-male HSCT compared with male-to-female HSCT (P= .013). Yet, analysis of the overall gender effect, thus independent of the known HY antigens, between the gender groups demonstrated an increased GvHD incidence in the female-to-male transplantations (P < .005) and a decreased GvHD-free survival in the female-to-male transplantations (P < .001). Of all autosomally encoded minor H antigens, only mismatching for the broadly expressed minor H antigen HA-8 increased the GvHD incidence in IRD HSCT (Hazard ratio [HR]= 5.28, P < .005), but not in MUD HSCT. Most striking was the influence of hematopoietic restricted minor H antigens on GvL as mismatching for hematopoietic minor H antigens correlated with lower relapse rates (P= .078), higher relapse-free survival (P= .029), and higher overall survival (P= .032) in recipients with GvHD, but not in those without GvHD. In conclusion, the significant GvHD effect of the broadly expressed minor H antigen HA-8 favors matching for HA-8 in IRD, but not in MUD, patient/donor pairs. The GvHD-GvL association demonstrating a significant lower relapse in hematopoietic minor H antigen mismatched patient/donor pairs underlines their clinical applicability for adoptive immunotherapy, enhancing the GvL effect in a GvHD controllable manner. © 2013 American Society for Blood and Marrow Transplantation.

We pooled immunogenetic data obtained in independent studies in two European populations (Italian and Czech) of patients affected by sarcoidosis. Correspondence analysis was used to investigate the associations between clinical and immunogenetic data. Two hundred and thirty-three patients were enrolled in the study, of which 126 were from the Czech Republic and 107 from Italy. Using a common protocol, we examined each patient for sex, age of disease onset, roentgenologic stage, extrapulmonary spread, and clinical course. One thousand and ten healthy individuals, HLA typed for class I and II serologic polymorphisms, served as controls. Findings that were essentially in agreement in both populations were: (1) a positive association of sarcoidosis with HLA-A1, B8, and DR3 markers, and a negative association with HLA-B12 and DR4; (2) a prevalence of HLA-DR3 and DR4 among females and of DR5 among males; (3) a relationship of B13 and B35 with early onset and of A30, B8, DR3, and DR4 with late onset of disease; (4) an association of B27 with sarcoidosis restricted to the lungs; (5) a relationship of A1, B8, B27, and DR3 to roentgenologic stage I and of B12 and DR4 to stage III; and (6) an association of HLA-DR3 with a good outcome. Population-restricted findings essentially concerned the alleles HLA-B13 and B22, the former being associated with the disease, male sex, early onset, extrapulmonary localization and relapse only in Czechs, and the latter to disease spread only in Italians. Our results seem to support the concept that immunogenetic background may at least partly account for the clinical heterogeneity of sarcoidosis.

Chronic fatigue syndrome (CFS) is an inflammatory disease of unknown aetiology. Researchers have proposed infectious, neurological and immunological causes of this syndrome. Recently, the xenotropic murine leukemia virus-related virus was detected in 67% of patients with CFS in a US study. This observation is in agreement with one ascertained aspect of the disease: a decreased efficiency in NK cell lytic activity in CFS patients. Here, we analyzed the genomic polymorphism of killer cell immunoglobulin-like receptors (KIRs) and their HLA class I cognate ligands in patients with certified CFS. An excess of KIR3DS1 was found in CFS patients with respect to controls, as well as an increased frequency of the genotype missing KIR2DS5. Forty-four CFS patients and 50 controls also underwent genomic typing for the HLA-ligands. In the patients, a great proportion of KIR3DL1 and KIR3DS1 receptors were found to be missing their HLA-Bw4Ile80 binding motif. We hypothesize that an excess of KIR3DS1, combined with an excess of ligand-free KIR3DL1 and KIR3DS1 receptors, may hamper the clearance of a pathogen via NK cells, thus favouring the chronicity of the infection.

We studied the HLA polymorphisms (class I, II, and III) in 107 Italian patients with biopsy specimen-proven sarcoidosis in order to investigate the immunogenetic background of this disease. The mean age of onset of the disease was 36.08±12.4 years. Four patients (3.73 percent) were in radiologic stage 0, 38 patients (35.51 percent) were in radiologic stage I, 40 patients (37.38 percent) were in stage II, and 25 (23.36 percent) were in stage III. Thirty-eight patients (35.51 percent) had one or more extrapulmonary localization(s) of the disease. Positive association between sarcoidosis and HLA-B8 (χ 2 = 6.07, p =0.0127, RR=1.91) was confirmed. Regarding the age of onset of the disease, HLA-B35 was more frequent (χ 2 = 7.34, p =0.0056, pc 2 = 7.22, p =0.0061, pc

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.

Dilated cardiomyopathy (DCM) is an idiopathic heart muscle disorder. The presence of circulating cardiac antibodies and the association with HLA-DR4 are consistent with autoimmune pathogenesis in a subset of patients. Sixty-eight DCM patients and 277 controls were typed for IgG heavy-chain constant region (Gm) and kappa light-chain (Km) allotypes. All patients and 210 of the 277 controls were HLA-DR typed. The Gm (1, 3, 17; 23; 5*, 21, 28) phenotype was overrepresented in DCM compared with controls (25% vs 13%, p = 0.0139, pc = NS, RR = 2.23). The frequency of this phenotype was higher in patients with younger age at onset, shorter symptom duration, and among those who were positive for cardiac as well as for non-organ-specific autoantibodies than in controls. A higher frequency of the Gm (1, +/- 2, 3, 17; +/- 23; 5*, 21, 28) heterozygous phenotypes was also found in DCM compared to controls (40.91% vs 26.89%; p = 0.02, pc = 0.04, RR = 1.88). The finding of Gm heterozygosity in DCM was associated with serum positivity for cardiac antibodies. A higher proportion of DCM patients were positive for both the Gm (1, 3, 17; 23; 5*, 21, 28) phenotype and HLA-DR4 compared to normals (3/68 vs 0/210; p = 0.04, RR = 22.50).(ABSTRACT TRUNCATED AT 250 WORDS)

Eighty-six patients affected by vitiligo were investigated for Gm, and Km polymorphisms, HLA markers and the presence of organ and non organ-specific autoantibodies. Vitiligo patients had an increased frequency of autoantibodies (71%), in particular anti-parietal cells (26.6%), antithyroglobulin (24.4%) and antithyroid microsomal antibodies (43%). One patient was also affected by Hashimoto's thyroiditis, 4 by Graves' disease and two others by nontoxic, multinodular goiter. No correlation was found between chronologic age and sex and the presence of autoantibodies, while an increased frequency of organ-specific autoantibodies was found with longer duration of vitiligo. HLA-A3 and Gm (3; 23; 5, 10, 11, 13, 14) phenotype frequencies were significantly increased in patients without autoantibodies (P less than 0.05). Patients negative for these two phenotypes were significantly more prone to develop autoantibodies than those positive (P = 0.0032). C4AQO allele showed a significantly decreased frequency in the whole group of patients when compared to the controls (P less than 0.05).

The Major Histocompatibility Complex (MHC) is considered a system completely defined and only connected with the immune response. However, in addition to the well-known correlation between MHC and the non-self recognition, the MHC region controls a lot of other functions: the recognition of genetic individuality in social relationships, the mate choice and the feto-maternal interplay. Starting from protocordates, the first MHC function was the individual self-identification inside a group, but then it turned into an inter-individual recognition system, which could transmit information about the MHC genotypes. In mammals, the MHC system is functionally and physically linked to the olfactory receptors: when smelling each other, we are able to make a direct genetic analysis through the nose. The MHC individual genetic recognition system plays a fundamental role, both in mate choice and in foeto-maternal selection, from the very start of implantation. All these data suggest that the MHC polymorphism is driven not only by pathogen selection, but also by sexual reproductive-mechanisms. Questions remain about the relative involvement of these two selective forces in MHC evolution.

A project of the 15th International Histocompatibility Workshop examined the rarity of human leukocyte antigen (HLA) alleles. A section was constructed in the website, www.allelefrequencies.net to contain this data from different sources. A mechanism to search the data was implemented for use by any individual.

Background & Aims Whipple's disease is a systemic, chronic, relapsing disorder caused by a combination of environmental ( Tropheryma whipplei ) and unknown host factors. Because it is a rare disease, the association between HLA type and Whipple's disease has been studied in only small numbers of patients; these studies have led to conflicting results. We aimed to investigate whether disease phenotype and outcome are associated with HLA type in 122 patients with Whipple's disease. Methods Genomic DNA was collected from 103 German, 11 Italian, and 8 Austrian patients with Whipple's disease, along with 62 healthy Austrian workers exposed to T whipplei (14 stool samples contained the bacterium). HLA class I and II alleles were identified by polymerase chain reaction analysis. Patient genotypes were compared with those of healthy German and Austrian populations; data for Italian controls were obtained from the Pavia HLA bone marrow donors' bank. Results HLA-DRB1*13 and DQB1*06 alleles occurred significantly more frequently in patients with Whipple's disease but not in healthy individuals who had been exposed to T Whipplei . The cumulative odds ratios for disease were 2.23 for the DRB1*13 allele ( P ) and 2.25 for the DQB1*06 allele ( P ). Conclusions DRB1*13 and DQB1*06 alleles were found to be risk factors in the largest HLA study ever performed in patients with Whipple's disease.

We analyzed 21 children with leukemia receiving haploidentical hematopoietic stem cell transplantation (haplo-HSCT) from killer immunoglobulin (Ig)–like receptors (KIR) ligand-mismatched donors. We showed that, in most transplantation patients, variable proportions of donor-derived alloreactive natural killer (NK) cells displaying anti-leukemia activity were generated and maintained even late after transplantation. This was assessed through analysis of donor KIR genotype, as well as through phenotypic and functional analyses of NK cells, both at the polyclonal and clonal level. Donor-derived KIR2DL1+ NK cells isolated from the recipient displayed the expected capability of selectively killing C1/C1 target cells, including patient leukemia blasts. Differently, KIR2DL2/3+ NK cells displayed poor alloreactivity against leukemia cells carrying human leukocyte antigen (HLA) alleles belonging to C2 group. Unexpectedly, this was due to recognition of C2 by KIR2DL2/3, as revealed by receptor blocking experiments and by binding assays of soluble KIR to HLA-C transfectants. Remarkably, however, C2/C2 leukemia blasts were killed by KIR2DL2/3+ (or by NKG2A+) NK cells that coexpressed KIR2DS1. This could be explained by the ability of KIR2DS1 to directly recognize C2 on leukemia cells. A role of the KIR2DS2 activating receptor in leukemia cell lysis could not be demonstrated. Altogether, these results may have important clinical implications for the selection of optimal donors for haplo-HSCT.

Functional polymorphisms of two MHC genes (DRB1 and RAGE) were analysed in Italian pediatric patients with Type 1 diabetes and in a control group. The diabetic condition is related positively to the positive electric charge of the pocket 4 of pro-inflammatory DRB1 alleles (R = 0.5072, P = 0.0001) and negatively to at least one anti-inflammatory RAGE allele (R = -0.2200, P = 0.0106). The association DRB1-disease decreases from high risk positively charged alleles to low risk negatively ones. A multiple regression model including the effect of electric charges at positions 70 and 74 of the DRB1 explains more than 31% of the variability of our data. The addition of the RAGE dependent variables does not increase the significance of the model. Our results confirm that the interaction between a negatively charged amino acid of insulin autoantigenic peptides and a positively charged DRB1 is the key event triggering the autoimmune process. The linkage disequilibrium between RAGE and DRB1 is the main cause of the association between the variants of RAGE and the initial outcome of the disease. However, since RAGE ligands increase during the disease progression, the observed association suggests that the proinflammatory RAGE and DRB1 polymorphisms synergize to activate the immune response which leads to the complications of diabetes. These evidences support a new hypothesis that considers the largely unexplored role of the MHC genes in genetic adaptation to a variable environment and in the maintenance of the metabolic biodiversity. A mechanism based on the maternal immunization against the negatively charged autoantigens, such as the insulin peptide B9-23, and on the fetal-maternal interaction might transform the physiological adaptation into adaptive changes of the genetic population structure. According to the "thrifty-genotype" hypothesis, "thrifty DRB alleles" with a positive charge are responsible for the susceptibility to diabetes and for an efficient storage of caloric intake in arctic climates with scarce food availability while "non-thrifty DRB alleles" with a negative or neutral charge are advantaged in tropical climates with constant food supply.

Minor histocompatibility (H) antigens are allogeneic target molecules having significant roles in alloimmune responses after human leukocyte antigen–matched solid organ and stem cell transplantation (SCT). Minor H antigens are instrumental in the processes of transplant rejection, graft-versus-host disease, and in the curative graft-versus-tumor effect of SCT. The latter characteristic enabled the current application of selected minor H antigens in clinical immunotherapeutic SCT protocols. No information exists on the global phenotypic distribution of the currently identified minor H antigens. Therefore, an estimation of their overall impact in human leukocyte antigen–matched solid organ and SCT in the major ethnic populations is still lacking. For the first time, a worldwide phenotype frequency analysis of ten autosomal minor H antigens was executed by 31 laboratories and comprised 2,685 randomly selected individuals from six major ethnic populations. Significant differences in minor H antigen frequencies were observed between the ethnic populations, some of which appeared to be geographically correlated., Author Summary Peptides from cellular proteins evoking alloimmune responses in human leukocyte antigen–identical transplantation are called minor histocompatibility (H) antigens. Upon hematopoietic stem cell transplantation (HSCT) for hematological malignancies or for solid tumors, responses to minor H antigens may have detrimental effects, e.g., graft-versus-host-disease and graft rejection, but can also significantly contribute to the eradication of the tumor cells. We designated the latter antigens as “tumor” minor H antigens. Current clinical trials aim at using these tumor minor H antigens to boost the graft-versus-tumor response. So far, it is unclear how frequently the HSCT recipient and donor differ in their minor H antigens and thus how many cancer patients are eligible for minor H antigen-based treatment. Therefore, worldwide 31 laboratories joined forces to determine the genotype and phenotype frequencies of ten autosomally encoded minor H antigens in six ethnic populations. The frequencies vary depending upon ethnic background and geographic location of the population, implying that the potential applicability of the tumor minor H antigens differs from one population to another. Depending on the population, the current theoretical percentages of clinical application of the eight tumor minor H antigens in HLA-matched combinations is estimated at 12% to 34%.

This report describes a case of retinal vasculitis which occurred in hairy cell leukaemia and was localized only in the right eye. An immunogenetic study investigates the possible genetic association between vascular uveitis and hairy cell leukaemia.

Summary Cytokines and chemokines determine mobilisation of Langerhans cells and their dysregulation is implicated in the pathogenesis of Langerhans cell histiocytosis (LCH). Twenty point mutations of 12 different cytokine genes were studied in 41 Italian children, 15 with single-system (SS) and 26 with multi-system disease. The allele and genotype distributions of interleukin-4 (IL-4) and interferon-γ (IFNγ) were significantly different in patients vs. 140 controls (P = 0.007, and P = 0.018). Older children with single-system disease shared the ‘anti-inflammatory profile’ determined by the intermediate producer genotype IFNγ +874A/T (P = 0.029) and the high-producer genotypes IL-4 –590C/T and T/T (P = 0.029). Our findings suggest that specific cytokine gene variants affect susceptibility to LCH and its clinical heterogeneity.

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.

Pathogenesis of autoimmune thyroid disease (ATD) is multifactorial. Helicobacter pylori (Hp) infection has been proposed to be involved in nongastrointestinal conditions and reported more frequently in ATD adult patients. We evaluated the prevalence of Hp antibodies in young ATD patients and investigated the possibility that a susceptible immunogenetic profile could influence the development of ATD in subjects with Hp infection.We retrospectively studied 90 children with ATD (median age 11.2 yr), 70 age- and sex-matched healthy subjects as controls, and 65 patients with Turner syndrome (median age 18.8 yr). Antibodies to Hp were determined at diagnosis in ATD patients and, in Turner patients, at the last control in cases without ATD and before the appearance of thyroid autoantibodies in the others. Serological and molecular human leukocyte antigen (HLA) typing for classes I and II polymorphisms was performed.Prevalence of positive Hp serology resulted significantly higher in ATD patients than controls (P = 0.032). No association was found between individual HLA alleles and Hp serology. HLA-A1, B8, and DRB1*0301 were found significantly associated with ATD. A significant interaction between HLA-DRB1*0301 and Hp infection was present in ATD patients and not controls (P = 0.007), suggesting that the copresence of these two factors might favor ATD development. A similar phenomenon was observed in Turner syndrome patients (P = 0.02; cumulative Mantel test, P = 0.0001).Another target of Hp-elicited immune inflammatory response might be the thyroid gland in subjects with a peculiar immunogenetic profile so that ATD may be a consequence. Our findings suggest the opportunity of eradicating Hp infection in children with ATD and/or susceptible HLA alleles.

The importance of HLA-DPB1 matching for the outcome of allogeneic hematologic stem cell (HSC) transplantation is controversial. We have previously identified HLA-DPB1*0901 as a target of cytotoxic T cells mediating in vivo rejection of an HSC allograft. Here we show that HLA-DPB1*0901 encodes a T-cell epitope shared by a subset of DPB1 alleles that determines nonpermissive mismatches for HSC transplantation. Several T-cell clones obtained from the patient at the time of rejection showed HLA-DP restricted recognition of allogeneic targets expressing HLA-DPB1*0901, *1001, *1701, *0301, *1401, and *4501, but not other alleles. Based on these findings, we developed an algorithm for prediction of nonpermissive HLA-DPB1 mismatches. Retrospective evaluation of 118 transplantations showed that the presence of nonpermissive HLA-DPB1 mismatches was correlated with significantly increased hazards of acute grade II to IV graft-versus-host disease (HR = 1.87, P =.046) and transplantation-related mortality (HR = 2.69, P = .027) but not relapse (HR = 0.98, P = .939), as compared with the permissive group. There was also a marked but statistically not significant increase in the hazards of overall mortality (HR = 1.64, P = .1). These data suggest that biologic characterization of in vivo alloreactivity can be a tool for definition of clinically relevant nonpermissive HLA mismatches for unrelated HSC transplantation. RI apperley, jane/B-4367-2009

Idiopathic pulmonary fibrosis (IPF) is a chronic, fibrotic disorder underlain by aberrant wound healing of repeated lung injury. Environmental triggers and genetic background are likely to act as modifiers of the fibrotic response. Erythrocyte complement receptor 1 is a membrane protein mediating the transport of immune complexes to phagocytes. Three gene polymorphisms are related to the erythrocyte surface density of complement receptor 1 molecules, which in turn are related to the rate of immune complexes' clearance. There is evidence of association between sarcoidosis and the complement receptor 1 gene. We wondered whether IPF is associated with the complement receptor 1 gene alleles coding for a reduced molecule/erythrocyte ratio. We studied 74 patients and 166 control subjects. Three polymorphic sites of the gene, A3650G exon 22, HindIII RFLP intron 27, and C5507G exon 33, were analyzed and found to be in linkage disequilibrium. The GG genotype for the C5507G exon 33 polymorphism was significantly more common in patients with IPF than in control subjects (odds ratio = 6.232, 95% confidence interval = 2.198-18.419, p = 0.00023). The significant difference was found in both sexes. These findings agree with speculations on the role of the complement receptor 1 gene in idiopathic pulmonary fibrosis.