S. Rendine

Increased frequency of HLA-DR6 allele in Italian patients with hepatitis C virus-associated oral lichen planus

Background Recent controlled studies have confirmed that hepatitis C virus (HCV) is the main correlate of liver disease in patients with lichen planus (LP), mainly in southern Europe and Japan. However, a low prevalence of HCV infection has been found in LP patients in England and northern France, and significant differences in serum HCV RNA levels or HCV genotypes have not been found between LP patients and controls. Thus host rather than viral factors may be prevalent in the pathogenesis of HCV‐related LP. The HLA‐DR allele may influence both the outcome of HCV infection and the appearance of symptoms outside the liver.

HLA‐DQB1 alleles in Italian patients with mucous membrane pemphigoid predominantly affecting the oral cavity

Background Mucous membrane pemphigoid (MMP) used to be considered as a single entity but it is now evident that a range of variants exists. Among them, pure ocular cicatricial pemphigoid (OCP) and pure oral pemphigoid (OP) appear to be very different subsets. Previous immunogenetics studies have found increased occurrence of the DQB1*0301 allele mainly in patients with OCP whereas in patients with OP the data are more open to doubt.

Role of non-HLA genetic polymorphisms in graft-versus-host disease after haematopoietic stem cell transplantation

Graft‐versus‐host disease (GvHD) is the main complication after haematopoietic stem cells transplantation (HSCT) and acute forms (aGvHD) occur in 20–40% of cases even after donor (D) and recipient (R) HLA matching, apparently because of D/R minor histocompatibility antigen (mHA) mismatches and cytokine polymorphisms. The genotype of cytokines and mHA of 77 haematological R following HSCT from HLA identical siblings were determined to detect genetic polymorphisms correlated with GvHD. We analysed TNFA (−863 C/A, −857 C/T and G/A at positions −574, −376, −308, −244, −238), IL‐10 (−1082 G/A, −819 C/A, −592 C/T), IL‐1B (T/C +3953), IL‐1RA (VNTR), HA‐1 (H/R allele) and CD‐31 (C/G at codon 125, A/G at codon 563). Allele frequencies were in Hardy–Weinberg equilibrium and similar to those of 77 healthy controls. We observed positive correlations between a lower risk of clinically significant aGvHD and both the presence of −1082G −819C −592C IL‐10 haplotype when both R and D are considered together and the absence of R IL‐1RA allele 2. Furthermore, we observed an association between the absence of TNF‐A −238 A allele and the risk of extensive chronic GvHD. mHA and cytokines genotyping would thus seem a valid source of information for the prior identification of recipients with a higher risk of aGvHD.

Cytokines and chronic rejection: a study in kidney transplant long-term survivors.

Background. In part, the long-term survival of kidney transplants depends on the efforts to perform grafts with good human leukocyte antigen (HLA) compatibility, but there are other mechanisms that must induce some sort of tolerance and impair the anti-graft immune reaction. Because cytokines are one of the main components of immune response, we evaluated single nucleotide polymorphisms (SNPs) of several cytokine genes that may influence the production of a given cytokine and therefore the features of immune reactions. Methods. A total of 416 first cadaveric kidney transplants were monitored for HLA matching. After 10 years, the graft was still functional in 171 of 416 patients; 102 of 171 patients were also typed for cytokine polymorphisms. Results. The mismatch distributions in patients who underwent transplantation were not statistically different from the entire group of patients who underwent transplantation during the same time period. Moreover, it seems that almost all of the HLA class I incompatible long-term survivors are homozygous for GG at the −1082 interleukin (IL)-10 or CC at the −33IL4. Conclusions. We observed that a match for class I and class II HLA antigens apparently does not favor the long-term survival of transplanted kidneys. In fact, matched grafts are lost before 10 years in the same proportion as the mismatched grafts. We also demonstrated (1) that patients who are homozygous for GG at the SNP −1082IL10 (high IL-10 producers) and HLA class I mismatched (but matched for class II) are protected from chronic rejection, and (2) that patients who are homozygous for CC at the SNP −33IL4 (low IL-4 producers) and HLA class I mismatched (regardless of matching for class II) are protected from chronic rejection.

Estimation of human leukocyte antigen class I and class II high-resolution allele and haplotype frequencies in the Italian population and comparison with other European populations

The high-resolution (HR) allele and haplotype frequencies of class I and II human leukocyte antigen (HLA) system were determined in the Italian population from a sample of donors recruited in the Italian Bone Marrow Donor Registry (IBMDR). This study analyzed the HLA-A, -B, -C, -DRB1, and -DQB1 loci. Two different samples were used: donors HR typed at least for one allele, usually when selected for donor-recipient matching (respectively: 3596, 7591, 4715, 57345, and 8196), to make a list of the observed alleles and determine the relative frequencies of the alleles in each class of the corresponding antigen; donors HR randomly typed for both the alleles (respectively: 975, 1643, 1569, 22114, and 2087) to estimate the allele and haplotype frequencies, and two loci linkage disequilibrium. The number of alleles showing a frequency >1% on the total number of observed alleles are 18/75 HLA-A, 28/142 -B, 17/57 -C, 23/154 -DRB1, and 13/31 -DQB1. In each locus they account for more than 88% of the total cumulative frequencies. The most frequent alleles are A*02: 01, B*35: 01, C*04:01, DRB1*07:01, DQB1*03:01. The most frequent five-locus haplotype in the 338 donors randomly typed is A*01: 01-C*07:01-B*08: 01-DRB1*03:01-DQB1*02:01. The genetic comparison of the Italian population with 16 European populations shows a south-north gradient.

Cytokine gene polymorphisms in hepatitis C virus‐related oral lichen planus

Abstract:  Cytokine polymorphisms may influence both the risk of developing oral lichen planus (OLP) and the outcome of hepatitis C virus (HCV)‐infected patients and OLP has been frequently associated with HCV infection. The aim of the present study was to analyse whether cytokine polymorphisms may influence the susceptibility to HCV‐related OLP. Thirty‐five patients with OLP and chronic HCV infection (OLP–HCV+ve) took part in the study. As controls, 44 patients with OLP but without HCV (OLP–HCV−ve) infection and 140 healthy donors were studied. Thirteen cytokine genes with 22 single nucleotide polymorphisms (SNP) were studied. IFN‐γ UTR 5644 genotype frequencies showed an increase in number of A/T heterozygote in OLP–HCV+ve patients compared with OLP–HCV−ve that approached the statistical significance [P = 0.03, P‐corrected (PC) = 0.66]. Contrarily, in OLP–HCV+ve patients, the frequency of genotype −308 G/A of the TNF‐α was decreased, whereas the genotype −308 G/G was increased compared with OLP–HCV−ve (P = 0.0005, PC = 0.011 and P = 0.0016, PC = 0.0352, respectively). OLP patients with and without HCV infection showed a different genetic cytokine background suggesting distinct pathogenetic mechanisms.

The distribution of KIR-HLA functional blocks is different from North to South of Italy

The killer cell immunoglobulin-like receptor (KIR)-human leukocyte antigen (HLA) interaction represents an example of genetic epistasis, where the concomitant presence of specific genes or alleles encoding receptor-ligand units is necessary for the activity of natural killer (NK) cells. Although KIR and HLA genes segregate independently, they co-evolved under environmental pressures to maintain particular KIR-HLA functional blocks for species survival. We investigated, in 270 Italian healthy individuals, the distribution of KIR and HLA polymorphisms in three climatic areas (from cold north to warm south), to verify their possible geographical stratification. We analyzed the presence of 13 KIR genes and genotyped KIR ligands belonging to HLA class I: HLA-C, HLA-B and HLA-A. We did not observe any genetic stratification for KIR genes and HLA-C ligands in Italy. By contrast, in a north-to-south direction, we found a decreasing trend for the HLA-A3 and HLA-A11 ligands (P = 0.012) and an increasing trend for the HLA-B ligands carrying the Bw4 epitope (P = 0.0003) and the Bw4 Ile80 epitope (P = 0.0005). The HLA-A and HLA-B KIR ligands were in negative linkage disequilibrium (correlation coefficient -0.1211), possibly as a consequence of their similar function in inhibiting NK cells. The distribution of the KIR-HLA functional blocks was different along Italy, as we observed a north-to-south ascending trend for KIR3DL1, when coupled with HLA-B Bw4 ligands (P = 0.0067) and with HLA-B Bw4 Ile80 (P = 0.0027), and a descending trend for KIR3DL2 when coupled with HLA-A3 and HLA-A11 ligands (P = 0.0044). Overall, people from South Italy preferentially use the KIR3DL1-HLA-B Bw4 functional unit, while those from the North Italy equally use both the KIR3DL2-HLA-A3/A11 and the KIR3DL1-HLA-B Bw4 functional units to fight infections. Thus, only KIR3DL receptors, which exert the unique role of microbial sensors through the specific D0 domain, and their cognate HLA-A and HLA-B ligands are selectively pressured in Italy according to geographical north-to-south distribution.

Analysis of the turin umbilical cord blood bank registry.

BACKGROUND: The polymorphic nature of the HLA system reduces a patients probability of finding an HLA‐compatible unrelated bone marrow (BM) donor, even though more than 6 million individuals are enrolled in international registries. Recently, umbilical cord blood (UCB) has been successfully employed as a source of HPCs. The use of such cells reduces the risk of GVHD and allows transplants with one or two HLA mismatches. UCB represents an expensive resource: therefore, it is necessary to carefully manage the UCB unit inventory.

HLA-C/KIR GENOTYPES IN ORAL LICHEN PLANUS PATIENTS INFECTED OR NON INFECTED WITH HEPATITIS C VIRUS

OBJECTIVES Oral Lichen Planus (OLP) is associated with hepatitis C virus (HCV) infection and resembles graft-versus-host disease (GVHD) both clinically and histologically. The killer cell immunoglobulin-like receptor (KIR) genes encode a family of receptors expressed on NK and T cells and are supposed to play a significant role in GVHD and HCV infection. The aim of this study was to analyze the association among OLP, HCV infection and variants in KIR gene expression. METHODS A total of 81 patients with OLP (36 HCV+ve and 45 HCV-ve) and 217 healthy controls (HCV-ve) were typed for the presence of eight KIR genes and of HLA-Cw* alleles by polymerase chain reaction-sequence specific primer. RESULTS There were no significant differences in the frequency of the KIR genes and HLA-C1/C2 group alleles between cases and controls. We only found a significant difference in the frequency of the gene KIR2DL2 between HCV+ve and HCV-ve OLP patients. CONCLUSIONS The present data suggest that OLP is not associated with particular KIR genes or with HLA-Cw* alleles in patients without HCV infection. Contrarily, the role of the genes in OLP-HCV+ve patients remains unclear and might warrant further researches.

Natural killer-mediated cytotoxicity in patients with laryngeal carcinoma

Natural killer (NK)-mediated cytotoxicity against the K562 cell line was evaluated in normal subjects and in patients with laryngeal cancer. Results showed reduced lymphocyte cytotoxicity in patients with neoplastic disease and further reduction in NK activity following postoperative radiation therapy. The authors discuss the possibility of using this test in the immunological monitoring of patients with laryngeal carcinoma.