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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.

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.

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.

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.

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.

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.

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

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).

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.

Ninety children and adolescents with autoimmune thyroid disease were screened for celiac disease. All 90 patients were typed for HLA antigen class I and II and for HLA-DQA1 and DQB1 heterodimers. Celiac disease and DQA1*0501, DQB1*02 were found in 7 (7.8%) patients. The prevalence of celiac disease was 1 of 13. Screening for celiac disease is recommended in children with autoimmune thyroid disease. (J Pediatr 2001;139:738–40)

OBJECTIVE The aim of our study was to determine whether serum TNF-alpha levels in individuals at risk of developing type 1 diabetes, such as first-degree relatives of diabetic patients and children with incidental hyperglycemia, underwent alterations, and also to establish whether these levels might be used to identify individuals prior to insulin dependence. RESEARCH DESIGN AND METHOD We studied 71 healthy first-degree relatives (FDR) of type 1 diabetic patients and 11 children with incidental hyperglycemia. We looked for immunogenetic (HLA class II serologic alleles and HLA-DQ alpha/beta genomic polymorphisms), immunologic (islet-cell and insulin autoantibodies) and metabolic (FPIR to IVGTT) markers of type 1 diabetic risk. Serum concentrations of TNF-alpha were quantified using IRMA. RESULTS We found significantly lower serum TNF-alpha levels in FDR of type 1 diabetic patients (median: 54.3 pg/ml) (p=0.01) and in children with incidental hyperglycemia (median: 10.83 pg/ml) (p

It has been suggested that women carrying the HLA-DQ3 antigen are at increased risk of developing cervical. squamous cell carcinoma (SCC)1. Since the association between cervical. SCC and human papillomavirus (HPV) types 16 and 18 has been proved by molecular studies2 and in animal. models the tumorigenic effect of HPV may differ according to the immunogenetic background,3 the presence of a given HLA type might help linking environmental. risk factors with individual. susceptibility to cervical. SCC. Subsequent studies however have reported different findings4,5 that could be in part explained by differences in HLA phenotype among populations.

Organ-specific cardiac antibodies are serological markers of autoimmunity in dilated cardiomyopathy (DCM). HLA-DR4 and possibly DR5 are immunogenetic markers of susceptibility in DCM, but it is not known whether they are associated with autoantibody production. We studied the frequency of HLA-DR antigens and the presence of organ-specific cardiac antibodies in 80 DCM Caucasian patients from Northern Italy. HLA-DR typing was performed by serology; 289 healthy blood donors from the same region were tested as controls. HLA-DR frequencies in DCM were also compared with VIII International Workshop control data for Italy. Cardiac antibodies were detected by indirect immunofluorescence on human heart. Skeletal muscle was used to identify cross-reacting antibodies. The prevalence of cardiac antibodies in DCM was: organ-specific 34% and skeletal muscle cross-reactive 30%. The previously reported positive association between DCM and HLA-DR4 was confirmed using either the controls from the same region (21.25% vs 10.73% p = 0.02, relative risk = 2.30) or from all of Italy (21.25% vs 12.3%, p = 0.03). HLA-DR5 frequency was slightly but not significantly higher in DCM than in controls from the same region (46.25% vs 31.49% p = 0.02, relative risk of 1.87, p corrected = NS) or from all of Italy (46.25% vs 35.8% p = NS). HLA-DR3 frequency was lower in DCM than in controls from the same region (12.50% vs 29.41% p = 0.003, relative risk of 0.36, p corrected = 0.03). This negative association was not confirmed using the control data from the whole of Italy (12.50% vs 16.5% p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

HLA class I (A, B, C), class II (DR, DQ) histoglobulins and HLA class III (C4A, C4B and Bf) complement factors were analysed in 87 patients with vitiligo and in controls. Two HLA supratypes seem to mark different age of onset of vitiligo: HLA-BfS, C4A3, C4B1, DR5 (W11), DQW3 is characteristic of the pediatric form; while HLA-BfS, C4A3, C4B1, DR7, DQW2 marks the adult form of disease. The importance of defining HLA supratype, not single alleles, is discussed.

Objectives. Taking into account that genetic predisposition, marked by human leukocyte antigen (HLA) class I and II genes, augments the probability of developing an autoimmune disorder after a triggering vaccination, as largely debated, we investigated the frequency of autoantibody production after recombinant hepatitis B vaccine (rHBv) in 6-year-old children immunized at birth to evaluate an association between autoimmune disorders and hepatitis B virus vaccination. Methods. We investigated the presence of autoantibodies in 210 6-year-old children who were immunized at birth with rHBv: 200 showed anti-hepatitis B surface antigen concentrations ≥10 mUI/mL at seroconversion (responders), and 10 were nonresponders. Data were compared with those obtained in 109 unvaccinated children. All participants were screened for the presence of antinuclear antibodies (ANAs), anti-DNA, antimitochondrial, anti-liver/kidney microsomal, antireticulin, anti-smooth muscle (SMA), and antiribosomal antibodies. All participants were also screened for the presence of antithyroid antibodies, such as antithyroglobulin and antiperoxidase, and for antibodies found in type 1 diabetes, such as tyrosine phosphatase (IA-2A) and glutamic acid decarboxylase (GADA). HLA typing was extended to all 10 nonresponders. Results. Autoantibodies were found in 16 of the 200 responders: ANAs were found in 12 (6%), smooth muscle antibodies were found in 4 (2.0%), and antireticulin antibodies and endomysial antibodies were found in 1 girl with ANAs. Antithyroid antibodies, IA-2A, and GADA were not present in any of the participants. No significant difference was found in the frequency of autoantibodies between vaccinated and control children. Three of the 10 nonresponder children were SMA-positive (30% vs 2% of responders); they also carried the supratype HLA-C4AQ0,DRB1*0301,DQB1*02. A family history for autoimmune disorders was present in 3 (18%; 95% confidence interval [CI]: 4.0%–45.6%) of the 16 responder infants with autoantibodies, in 15 (8.4%; 95% CI: 4.6%–13.1%) of responder children without autoantibodies, and in 1 (10%) of the 10 nonsreponder children. Conclusions. From our data, vaccination with rHBv given during the neonatal period does not seem to increase autoantibody production in a 6-year-old children. Autoantibodies, referred to as natural autoantibodies, can be found in healthy participants, but their significance is unclear. These autoantibodies often cross-react with bacteria or tumor antigens, suggesting their importance in innate immunity. It has been demonstrated in an animal model that self-antigen can promote B-cell accumulation, and that a significant proportion of natural autoantibodies is the product of this self-antigen- dependent process. Consequently, it has been speculated that self-antigens play a positive role in recruiting B cells as a part of innate immunity, but this process carries a potential risk for unregulated growth. Spreading of the immune response is a common theme in organ-specific and systemis autoimmune diseases, and this could be initiated by exogenous agents, in genetically susceptible hosts, owing to molecular mimicry of natural antigen. Moreover, 3 (18%) of the 16 children who had autoantibodies had a family history of autoimmume diseases. Thus, it is apparent that susceptibility to autoimmunity is determined by genetic factors rather than by vaccine challenge. Among all the children considered, only 1 girl (0.5%) developed celiac disease, reflecting the prevalence described in the literature. GADA and IA-2A were not found in our children; this observation is in agreement with data showing that type 1 diabetes risk may not be altered by vaccinations administered during childhood. On the contrary, a high frequency (30%) of autoantibodies, in particular SMA, was observed in the nonresponder children. The 3 SMA-positive children carried the HLA-C4Q0,DRB1*0301,DQB1*02 haplotype, a well-known predisposing factor for autoimmune disorders. On the other hand, the presence of autoantibodies to smooth muscle is known to be common in hepatitis B infection, and, it has been shown that cross-reactive immunity targeting homologous self-protein may partly account for autoantibody production. Although hepatitis B vaccination given during the neonatal period does not increase autoantibody production in 6-year-old immunized children, we deem useful a more prolonged follow-up for these nonresponder children carrying certain HLA haplotypes (such as C4AQ0,DRB1*0301,DQB1*02), particularly because most autoimmune diseases do not develop until later in life.

The transplantation of two cord blood (CB) units obtained from unrelated donors (double CBT) is an effective strategy for adult patients with hematologic malignancies. Sustained hematopoiesis after double CBT is usually derived from a single donor, and only a few transplantation recipients displaying a stable mixed donor-donor chimerism have been reported. We investigated the mechanisms underlying single-donor predominance in double CBT by studying in vitro the role of the graft-versus-graft cell-mediated immune effect in two-way mixed-lymphocyte culture, along with the contribution of differential hematopoietic progenitor (HP) potency in HP mixed cultures. Results for the two-way mixed-lymphocyte culture showed that despite the weak and variable alloantigen-specific cytotoxic potential displayed by CB mononuclear cells, an immune-mediated dominance for one of the two CB units was detected in the majority of experiments. Alloantigen-induced cytotoxic activity was directed toward both CB-HP and phytohemagglutinin (PHA)-activated T lymphoblastoid cells. The CB unit with the higher fold expansion of CD34(+) cells in single-expansion culture was prevalent in the HP mixed-expansion culture, as shown by DNA chimerism evaluation. Based on these data, we hypothesize that the dominant CB unit is able to develop prevalent cytotoxic activity toward activated lymphocytes of the other CB unit, thereby preventing them from exerting alloantigen-specific cytotoxic potential against both activated lymphocytes and HPs of the dominant unit. In accordance with this hypothesis, we propose the evaluation of alloantigen-induced cytotoxic activity generated in two-way mixed-lymphocyte culture and directed toward PHA-activated T lymphoblastoid cells as a tool to identify the potentially predominant CB unit before double CBT.

Berger’s disease is characterized by mesangial granular deposits of IgA, with or without other immunoglobulin or complement protein deposits, and no evidence of systemic diseases. This form of glomerulonephritis has an unclear pathogenesis, but it is considered to be the consequence of immunological injuries. The diagnosis is based on the immunofluorescent examination of renal biopsy, laboratory data, and clinical findings. HLA histoglobulin frequency data, available from several studies, show that B35 (1,2) and B12 (3,4) seem to have a significant association with this disease. Fauchet (5) reported a statistical decrease of the DR3 frequency among the Berger’s patients. However, there is evidence of heterogeneity in these data: multiple reports from Japanese (6,7,8) and French (9,10) investigators show also a positive association with HLA-DR4 antigen.

Congenital hypothyroidism is commonly due to developmental abnormalities of thyroid resulting in ectopic or hypoplastic thyroid gland as well as in total thyroid agenesis. The etiology of these abnormalities has not been yet clarified. Moreover, a less common cause of congenital hypothyroidism is thyroid dyshormonogenesis,due to several hereditary defects in thyroid hormone synthesis or metabolism1. An association among the human hystocompatibility system and autoimmune thyroid diseases2 and non autoimmune endocrine diseases such as congenital adrenal hyperplasia has been reported2. The aim of the present study was to evaluate the HLA involvement and immune response modulation in congenital hypothyroidism.

Endomyocardial biopsies from 174 patients with dilated cardiomyopathy (DC) were examined. Eight patients with histologically proven myocarditis were excluded from the study. A peculiar pattern of oversized and bizarre nuclei was observed in only some of the remaining patients. Two groups were identified: those with and without this feature (groups A and B, respectively). Myocyte width, nuclear diameter and nuclear/sarcoplasmic ratio were significantly higher in group A. The mean respective values were 36 +/- 5 mu, 14 +/- 3 mu and 0.41 +/- 0.08 for group A versus 20 +/- 8 mu, 7 +/- 2 mu and 0.37 +/- 0.08 for group B. Interstitial fibrosis was similarly present in groups A and B. Endocardial thickness was significantly increased in all patients, with group A showing the highest mean value. The morphologic features showed no correlation with the clinical condition of the patients at time of presentation. HLA typing was performed in 50 consecutive patients, 38 from group A and 12 from group B. DR4 and DR5 antigens were significantly more frequent in DC patients than in a normal population control (400 blood donors), while DR3 was less frequent. Group A was more strongly associated with the DR5 antigen than group B (55.3 vs 25.0%, respectively). It was less strongly associated with the DR4 antigen compared with group B (21.5 vs 41.7%, respectively). No difference was observed between the 2 groups concerning negative association with the DR3 antigen. Endomyocardial biopsies from DC patients reveal marked morphologic changes from patient to patient.(ABSTRACT TRUNCATED AT 250 WORDS)

Stem cell transplantation from unrelated cord blood (CB) donors is nowadays a standard practice for treatment of both malignant and non-malignant haematological disorders. The degree of HLA disparities, the cell dose and the prompt availability of the CB unit strongly influence the donor choice. According to FACT Netcord standards, HLA A, B and DRB1 shall be determined on a pre-cryopreservation sample from each CB. Once a CB unit is identified for potential use, a sample is tested to verify HLA type and confirmation of maternal haplotype is provided. The recipient’s HLA typing and its matching to the donor are confirmed as well prior to CB release for transplant. Quality of the stem cell product represents a basic assumption for the final success of transplant and an essential requirement for CB Banks (CBB). Each CBB shall establish a program of quality assurance that includes identification and traceability. The protection of confidentiality of mother and infant donors and the maintenance of linkage of a particular CB to its mother/neonate pair is of the highest priority. For this purpose each CB is assigned a unique numeric identifier that accompanies the unit in all steps of management and by which it is related to its maternal/infant data and reference samples. At the Pavia CBB, all CB donations are routinely typed for both HLA class I and class II by molecular techniques (low resolution for A and B loci and high resolution for DRB1). The mother haplotype is also assessed by molecular methods at time of banking. Therefore each CB/mother pair is checked before inclusion in the inventory. We retrospectively evaluate the impact of such a strategy on ensuring both identification and linkage of our CB repository. We review the data referring to the CBs stored in our Bank, all typed by LR-DNA for class I loci and by LR/HR-DNA for class II loci. Our inventory consists of 1987 units available for donor selection. In 2 pairs (0.1%) the mother’s typing was found fully disparate as respect to the supposed corresponding CB/neonate. The identification cannot be confirmed leading to discard of the unit. We also review the data pertinent to the 45 units released for transplant by our CBB: in all cases the cord’s confirmatory typing was coherent to the previous typing thus confirming the identity of the product ready for shipment. In our hands, the practice of confirming maternal haplotype at time of banking provides the final evidence of correct assignment and identification before inclusion in the inventory, ensuring the highest quality of the product supplied. This strategy also optimizes the time for the search requests management contributing to prompt availability of the graft.