Efficacy and safety of medical termination of pregnancy in a regional primary care setting.

BACKGROUND: Australia has demonstrated high efficacy and safety of medical termination of pregnancy (MToP) using a mifepristone-buccal misoprostol regime. The provision of medical termination services in primary care has the potential to alleviate access barriers, particularly in rural and regional populations. Large-scale data are needed to support the expansion of this model. AIM: The aim was to determine the efficacy and safety of nurse-led MToP within a regional general practice clinic. METHODS: A retrospective cohort study of patients prescribed MToP from October 2014 to April 2020. Clinic nurses assessed patient eligibility and provided information, non-directive counselling and instructions. The general practitioner then confirmed eligibility, obtained informed consent and prescribed. Patients were administered 200 mg of mifepristone orally in a pharmacy and then self-administered 800-µg buccal misoprostol 36-48 h later at home. RESULTS: A total of 998 patients were included in this study, with the median patient age being 27.3 years and 30.3% of patients travelling over 100 km to access the service. MToP was successful in 965 (96.7%) patients. There were 36 (3.6%) complications, of which 33 were incomplete MToP. Haemorrhage requiring transfusion, pain requiring hospital treatment and suspected infection were rare, each having a frequency of one (0.1%). Our follow-up rate was 74.8%, with a strong correlation identified between increased gestational age and decreased follow-up (P < 0.001). CONCLUSION: This study is a large Australian example demonstrating high efficacy and safety of nurse-led MToP within regional general practice. The establishment of similar services in rural and regional Australia may address geographical and financial barriers to termination access.

A review of the main genetic factors influencing the course of COVID-19 in Sardinia: the role of human leukocyte antigen-G.

Introduction: A large number of risk and protective factors have been identified during the SARS-CoV-2 pandemic which may influence the outcome of COVID-19. Among these, recent studies have explored the role of HLA-G molecules and their immunomodulatory effects in COVID-19, but there are very few reports exploring the genetic basis of these manifestations. The present study aims to investigate how host genetic factors, including HLA-G gene polymorphisms and sHLA-G, can affect SARS-CoV-2 infection. Materials and Methods: We compared the immune-genetic and phenotypic characteristics between COVID-19 patients (n = 381) with varying degrees of severity of the disease and 420 healthy controls from Sardinia (Italy). Results: HLA-G locus analysis showed that the extended haplotype HLA-G*01:01:01:01/UTR-1 was more prevalent in both COVID-19 patients and controls. In particular, this extended haplotype was more common among patients with mild symptoms than those with severe symptoms [22.7% vs 15.7%, OR = 0.634 (95% CI 0.440 - 0.913); P = 0.016]. Furthermore, the most significant HLA-G 3'UTR polymorphism (rs371194629) shows that the HLA-G 3'UTR Del/Del genotype frequency decreases gradually from 27.6% in paucisymptomatic patients to 15.9% in patients with severe symptoms (X2 = 7.095, P = 0.029), reaching the lowest frequency (7.0%) in ICU patients (X2 = 11.257, P = 0.004). However, no significant differences were observed for the soluble HLA-G levels in patients and controls. Finally, we showed that SARS-CoV-2 infection in the Sardinian population is also influenced by other genetic factors such as ß-thalassemia trait (rs11549407C>T in the HBB gene), KIR2DS2/HLA-C C1+ group combination and the HLA-B*58:01, C*07:01, DRB1*03:01 haplotype which exert a protective effect [P = 0.005, P = 0.001 and P = 0.026 respectively]. Conversely, the Neanderthal LZTFL1 gene variant (rs35044562A>G) shows a detrimental consequence on the disease course [P = 0.001]. However, by using a logistic regression model, HLA-G 3'UTR Del/Del genotype was independent from the other significant variables [ORM = 0.4 (95% CI 0.2 - 0.7), PM = 6.5 x 10-4]. Conclusion: Our results reveal novel genetic variants which could potentially serve as biomarkers for disease prognosis and treatment, highlighting the importance of considering genetic factors in the management of COVID-19 patients.

The double-sided of human leukocyte antigen-G molecules in type 1 autoimmune hepatitis.

The immunomodulatory effects of HLA-G expression and its role in cancers, human liver infections and liver transplantation are well documented, but so far, there are only a few reports addressing autoimmune liver diseases, particularly autoimmune hepatitis (AIH). Method and materials: We analyzed the genetic and phenotypic characteristics of HLA-G in 205 type 1 AIH patients (AIH-1) and a population of 210 healthy controls from Sardinia (Italy). Results: Analysis of the HLA-G locus showed no substantial differences in allele frequencies between patients and the healthy control population. The HLA-G UTR-1 haplotype was the most prevalent in both AIH-1 patients and controls (40.24% and 34.29%). Strong linkage was found between the HLA-G UTR-1 haplotype and HLA-DRB1*03:01 in AIH-1 patients but not controls (D' = 0.92 vs D' = 0.50 respectively; P = 1.3x10-8). Soluble HLA-G (sHLA-G) levels were significantly lower in AIH-1 patients compared to controls [13.9 (11.6 - 17.4) U/mL vs 21.3 (16.5 - 27.8) U/mL; P = 0.011]. Twenty-four patients with mild or moderate inflammatory involvement, as assessed from liver biopsy, showed much higher sHLA-G levels compared to the 28 patients with severe liver inflammation [33.5 (23.6 - 44.8) U/mL vs 8.8 (6.1 - 14.5) U/mL; P = 0.003]. Finally, immunohistochemistry analysis of 52 liver biopsies from AIH-1 patients did not show expression of HLA-G molecules in the liver parenchyma. However, a percentage of 69.2% (36/52) revealed widespread expression of HLA-G both in the cytoplasm and the membrane of plasma cells labeled with anti-HLA-G monoclonal antibodies. Conclusion: This study highlights the positive immunomodulatory effect of HLA-G molecules on the clinical course of AIH-1 and how this improvement closely correlates with plasma levels of sHLA-G. However, our results open the debate on the ambiguous role of HLA-G molecules expressed by plasma cells, which are pathognomonic features of AIH-1.

A Protective HLA Extended Haplotype Outweighs the Major COVID-19 Risk Factor Inherited From Neanderthals in the Sardinian Population.

Sardinia has one of the lowest incidences of hospitalization and related mortality in Europe and yet a very high frequency of the Neanderthal risk locus variant on chromosome 3 (rs35044562), considered to be a major risk factor for a severe SARS-CoV-2 disease course. We evaluated 358 SARS-CoV-2 patients and 314 healthy Sardinian controls. One hundred and twenty patients were asymptomatic, 90 were pauci-symptomatic, 108 presented a moderate disease course and 40 were severely ill. All patients were analyzed for the Neanderthal-derived genetic variants reported as being protective (rs1156361) or causative (rs35044562) for severe illness. The ß°39 C>T Thalassemia variant (rs11549407), HLA haplotypes, KIR genes, KIRs and their HLA class I ligand combinations were also investigated. Our findings revealed an increased risk for severe disease in Sardinian patients carrying the rs35044562 high risk variant [OR 5.32 (95% CI 2.53 - 12.01), p = 0.000]. Conversely, the protective effect of the HLA-A*02:01, B*18:01, DRB*03:01 three-loci extended haplotype in the Sardinian population was shown to efficiently contrast the high risk of a severe and devastating outcome of the infection predicted for carriers of the Neanderthal locus [OR 15.47 (95% CI 5.8 - 41.0), p < 0.0001]. This result suggests that the balance between risk and protective immunogenetic factors plays an important role in the evolution of COVID-19. A better understanding of these mechanisms may well turn out to be the biggest advantage in the race for the development of more efficient drugs and vaccines.

Natural killer-cell immunoglobulin-like receptors trigger differences in immune response to SARS-CoV-2 infection.

BACKGROUND: The diversity in the clinical course of COVID-19 has been related to differences in innate and adaptative immune response mechanisms. Natural killer (NK) lymphocytes are critical protagonists of human host defense against viral infections. It would seem that reduced circulating levels of these cells have an impact on COVID-19 progression and severity. Their activity is strongly regulated by killer-cell immuno-globulin-like receptors (KIRs) expressed on the NK cell surface. The present study's focus was to investigate the impact of KIRs and their HLA Class I ligands on SARS-CoV-2 infection. METHODS: KIR gene frequencies, KIR haplotypes, KIR ligands and combinations of KIRs and their HLA Class I ligands were investigated in 396 Sardinian patients with SARS-CoV-2 infection. Comparisons were made between 2 groups of patients divided according to disease severity: 240 patients were symptomatic or paucisymptomatic (Group A), 156 hospitalized patients had severe disease (Group S). The immunogenetic characteristics of patients were also compared to a population group of 400 individuals from the same geographical areas. RESULTS: Substantial differences were obtained for KIR genes, KIR haplotypes and KIR-HLA ligand combinations when comparing patients of Group S to those of Group A. Patients in Group S had a statistically significant higher frequency of the KIR A/A haplotype compared to patients in Group A [34.6% vs 23.8%, OR = 1.7 (95% CI 1.1-2.6); P = 0.02, Pc = 0.04]. Moreover, the KIR2DS2/HLA C1 combination was poorly represented in the group of patients with severe symptoms compared to those of the asymptomatic-paucisymptomatic group [33.3% vs 50.0%, OR = 0.5 (95% CI 0.3-0.8), P = 0.001, Pc = 0.002]. Multivariate analysis confirmed that, regardless of the sex and age of the patients, the latter genetic variable correlated with a less severe disease course [ORM = 0.4 (95% CI 0.3-0.7), PM = 0.0005, PMC = 0.005]. CONCLUSIONS: The KIR2DS2/HLA C1 functional unit resulted to have a strong protective effect against the adverse outcomes of COVID-19. Combined to other well known factors such as advanced age, male sex and concomitant autoimmune diseases, this marker could prove to be highly informative of the disease course and thus enable the timely intervention needed to reduce the mortality associated with the severe forms of SARS-CoV-2 infection. However, larger studies in other populations as well as experimental functional studies will be needed to confirm our findings and further pursue the effect of KIR receptors on NK cell immune-mediated response to SARS-Cov-2 infection.

Use of DPB1 T-cell epitope algorithm among italian transplant centers: A survey on behalf of Associazione Italiana di Immunogenetica e Biologia dei Trapianti.

The HLA-DPB1 locus has been demonstrated to have a significant role on patients' outcome after allogeneic HSCT, and the so-called T-cell epitope (TCE) algorithm has been incorporated in international guidelines for the selection of unrelated donors. The purpose of the present study is to measure, through a national survey conducted on behalf of the Associazione Italiana di Immunogenetica e Biologia dei Trapianti (AIBT), the extent of awareness and use of HLA-DPB1 TCE-based algorithms during the donor search. 89% of the HLA laboratories answered to a short questionnaire and the results showed a progressive increase of the laboratories typing DPB1 in patients and their potential donors during the search (from 44% to 79% during the 2010-2019 period) as well as the application of a TCE-based algorithm for the donor choice whenever possible (from 24% to 65% during the same period). The DP-permissiveness status is detailed in the official HLA typing report by 12%, 32% and 50% of laboratories in 2010, 2015 and 2019, respectively. The present data indicate an encouraging raise in the awareness of the HLA-DPB1 role in unrelated donor selection; noteworthy, mentioning the TCE-based permissiveness status in the HLA typing report of each potential unrelated donor represents a notable mean to raise awareness among transplant physicians and to support them in their task of choosing the best donor. Nonetheless, despite the compelling evidence of the predictive ability of TCE-based algorithms, further efforts are still needed to extend its application to all transplant centers in Italy.

Human Leukocyte Antigen Complex and Other Immunogenetic and Clinical Factors Influence Susceptibility or Protection to SARS-CoV-2 Infection and Severity of the Disease Course. The Sardinian Experience.

Aim: SARS-CoV-2 infection is a world-wide public health problem. Several aspects of its pathogenesis and the related clinical consequences still need elucidation. In Italy, Sardinia has had very low numbers of infections. Taking advantage of the low genetic polymorphism in the Sardinian population, we analyzed clinical, genetic and immunogenetic factors, with particular attention to HLA class I and II molecules, to evaluate their influence on susceptibility to SARS-CoV-2 infection and the clinical outcome. Method and Materials: We recruited 619 healthy Sardinian controls and 182 SARS-CoV-2 patients. Thirty-nine patients required hospital care and 143 were without symptoms, pauci-symptomatic or with mild disease. For all participants, we collected demographic and clinical data and analyzed the HLA allele and haplotype frequencies. Results: Male sex and older age were more frequent in hospitalized patients, none of whom had been vaccinated during the previous seasonal flu vaccination campaignes. Compared to the group of asymptomatic or pauci-symptomatic patients, hospitalized patients also had a higher frequency of autoimmune diseases and glucose-6-phosphate-dehydrogenase (G6PDH) deficiency. None of these patients carried the beta-thalassemia trait, a relatively common finding in the Sardinian population. The extended haplotype HLA-A*02:05, B*58:01, C*07:01, DRB1*03:01 [OR 0.1 (95% CI 0-0.6), Pc = 0.015] was absent in all 182 patients, while the HLA-C*04:01 allele and the three-loci haplotype HLA-A*30:02, B*14:02, C*08:02 [OR 3.8 (95% CI 1.8-8.1), Pc = 0.025] were more frequently represented in patients than controls. In a comparison between in-patients and home care patients, the HLA-DRB1*08:01 allele was exclusively present in the hospitalized patients [OR > 2.5 (95% CI 2.7-220.6), Pc = 0.024]. Conclusion: The data emerging from our study suggest that the extended haplotype HLA-A*02:05, B*58:01, C*07:01, DRB1*03:01 has a protective effect against SARS-CoV-2 infection in the Sardinian population. Genetic factors that resulted to have a negative influence on the disease course were presence of the HLA-DRB1*08:01 allele and G6PDH deficiency, but not the beta-thalassemic trait. Absence of influenza vaccination could be a predisposing factor for more severe disease.

Entropy of human leukocyte antigen and killer-cell immunoglobulin-like receptor systems in immune-mediated disorders: A pilot study on multiple sclerosis.

BACKGROUND: Entropy is a thermodynamic variable statistically correlated with the disorder of a system. The hypothesis that entropy can be used to identify potentially unhealthy conditions was first suggested by Schrödinger, one of the founding fathers of quantum mechanics. Shannon later defined entropy as the quantity of information stored in a system. Shannon's entropy has the advantage of being adaptable across a variety of disciplines, including genetic studies on complex immunogenetic systems such as the human leukocyte antigen (HLA) and killer-cell immunoglobulin-like receptor (KIR) systems. METHODS: In our study, entropy associated to the HLA and KIR systems was compared between a cohort of 619 Sardinian healthy controls and a group of 270 patients affected by multiple sclerosis (MS), the latter stratified into 81 patients with primary progressive multiple sclerosis (PPMS) and 189 patients with relapsing remitting multiple sclerosis (RRMS). RESULTS: The entropy associated to HLA four-loci haplotypes (A, B, C, DR) and combinations of two inhibitory KIR genes was significantly higher in patients affected by RRMS than in healthy controls. No significant differences were observed for patients with PPMS. By calculating the total HLA and KIR entropy ratio in each subject, it was possible to determine the individual risk of developing MS, particularly RRMS. CONCLUSIONS: In addition to the standard statistical methods used to evaluate immunogenetic parameters associated to immune-mediated disease, the analysis of entropy measures the global disorder status deriving from these parameters. This innovative approach may represent a useful complementary tool to the risk assessment of immune-mediated disorders. Improved risk assessment is particularly important for family members of patients with MS. However, further investigation is warranted to confirm our findings and to evaluate the validity of the entropy-based method in other types of immune-mediated disorders.

AIF-1 gene does not confer susceptibility to Behçet's disease: Analysis of extended haplotypes in Sardinian population.

BACKGROUND: Behçet's disease (BD) is a polygenic immune-mediated disorder characterized by a close association with the HLA-B*51 allele. The HLA region has a strong linkage disequilibrium (LD) and carries several genetic variants (e.g. MIC-A, TNF-α genes) identified as associated to BD because of their LD with HLA-B*51. In fact, the HLA-B*51 is inherited as part of extended HLA haplotypes which are well preserved in patients with BD. Sardinian population is highly differentiated from other Mediterranean populations because of a distinctive genetic structure with very highly preserved HLA haplotypes. PATIENTS AND METHODS: In order to identify other genes of susceptibility to BD within the HLA region we investigated the distribution of human Allograft Inflammatory Factor-1 (AIF-1) gene variants among BD patients and healthy controls from Sardinia. Six (rs2736182; rs2259571; rs2269475; rs2857597; rs13195276; rs4711274) AIF-1 single nucleotide polymorphisms (SNPs) and related extended haplotypes have been investigated as well as their LD within the HLA region and with HLA-B*51. Overall, 64 BD patients, 43 HLA-B*51 positive healthy controls (HC) and 70 random HC were enrolled in the study. RESULTS: HLA-B*51 was the only allele with significantly higher frequency (pc = 0.0021) in BD patients (40.6%) than in HC (9.8%). The rs2259571T AIF-1 variant had a significantly reduced phenotypic, but not allelic frequency in BD patients (72.1%; pc = 0.014) compared to healthy population (91.3%). That was likely due to the LD between HLA-B*51 and rs2259571G (pc = 9E-5), even though the rs2259571G distribution did not significantly differ between BD patients and HC. CONCLUSION: No significant difference in distribution of AIF-1 SNPs haplotypes was observed between BD patients and HC and between HLA-B*51 positive BD patients and HLA-B*51 positive HC. Taken together, these results suggest that AIF-1 gene is not associated with susceptibility to BD in Sardinia.

HLA-G molecules and clinical outcome in Chronic Myeloid Leukemia.

The human leukocyte antigen-G (HLA-G) gene encodes a tolerogenic protein known to promote tumor immune-escape. We investigated HLA-G polymorphisms and soluble molecules (sHLA-G) in 68 chronic myeloid leukemia (CML) patients. Patients with G*01:01:01 or G*01:01:02 allele had higher value of sHLA-G compared to G*01:01:03 (109.2±39.5 vs 39.9±8.8 units/ml; p=0.03), and showed lower event free survival (EFS) (62.3% vs 90.0%; p=0.02). The G*01:01:03 allele was associated with higher rates and earlier achievement of deep molecular response (MR)4.5 (100% vs 65%, median of 8 vs 58 months, p=0.001). HLA-G alleles with higher secretion of sHLA-G seem associated with lower EFS, possibly because of an inhibitory effect on the immune system. Conversely, lower levels of sHLA-G promoted achievement of MR4.5, suggesting increased cooperation with immune system.

KIR and their HLA Class I ligands: Two more pieces towards completing the puzzle of chronic rejection and graft loss in kidney transplantation.

BACKGROUND: Kidney transplantation is a life-saving treatment for patients with end-stage renal disease. However, despite progress in surgical techniques and patient management, immunological rejection continues to have a negative impact on graft function and overall survival. Incompatibility between donors and recipients for human leukocyte antigens (HLA) of the major histocompatibility complex (MHC) generates a series of complex cellular and humoral immune response mechanisms that are largely responsible for rejection and loss of graft function. Within this context, a growing amount of evidence shows that alloreactive natural killer (NK) cells play a critical role in the immune response mechanisms elicited by the allograft. Killer immunoglobulin-like receptors (KIRs) are prominent mediators of NK cell alloreactivity. METHODS AND FINDINGS: A cohort of 174 first cadaveric kidney allograft recipients and their donors were selected from a total cohort of 657 transplanted patients for retrospective immunogenetic analyses. Patients with HLA Class II mismatches were excluded. HLA Class I allele frequencies were compared among patients with chronic rejection, patients with stable graft function and a group of 2388 healthy controls. Activating and inhibitory KIR gene frequencies, KIR haplotypes, KIR-HLA ligand matches/mismatches and combinations of recipient KIRs and donor HLA Class I ligands were compared among patients with and without chronic rejection and a group of 221 healthy controls. Patients transplanted from donors homozygous for HLA-C1 antigens had a significantly higher risk for chronic rejection than patients transplanted from donors homozygous or heterozygous for HLA-C2 antigens or with epitopes belonging to the HLA-Bw4 ligand group. The Kaplan-Meier curves obtained by dividing the patients into 3 groups according to the presence or absence of one or both of the combinations of recipient KIRs and donor HLA ligands (rKIR2DL1/dHLA-C2 and rKIR3DL1/dHLA-Bw4) showed a significantly higher cumulative incidence of chronic rejection in the group of patients completely lacking these functional units. These patients showed a progressively stronger decline in modification of diet in renal disease-estimated glomerular filtration rate. CONCLUSIONS: KIR genotyping should be performed at the time of enrolment of patients on the waiting list for organ transplantation. In our study, a significantly higher risk of chronic rejection after kidney transplantation was observed when recipient (r) and donor (d) pairs completely lacked the two functional rKIR-dHLA ligand combinations rKIR2DL1/dHLA-C2 and rKIR3DL1/dHLA-Bw4. This immunogenetic profile corresponds to low levels of NK cell inhibition. Therefore, patients with this high risk profile could benefit from immunosuppressive therapy aimed at reducing NK-cell cytotoxicity.

The favorable role of homozygosity for killer immunoglobulin-like receptor (KIR) A haplotype in patients with advanced-stage classic Hodgkin lymphoma.

BACKGROUND: Interim positron emission tomography after 2 cycles of ABVD (iPET-2) is a good predictor of outcome in advanced-stage classic Hodgkin lymphoma. So far, there are no other prognostic biomarkers capable of identifying chemotherapy refractory patients with comparable accuracy. Despite the considerable amount of evidence suggesting that antitumor immune surveillance is downregulated in classic Hodgkin lymphoma (cHL), few data exist on the impairment of natural killer cell function and the role of their killer immunoglobulin-like receptors (KIRs). METHODS: We investigated KIR gene frequencies, KIR haplotypes, and KIR-ligand combinations in a cohort of 135 patients with advanced-stage classic Hodgkin lymphoma and 221 healthy controls. We furthermore evaluated the correlation of KIR genes and KIR haplotypes with the achievement of negative iPET-2. RESULTS: In the cohort of patients, the 5-year overall survival and progression-free survival were 93.6 and 79%, respectively. Homozygosity for KIR A haplotype and the HLA-C1 KIR ligand (KIR-AA/C1C1) was significantly higher in healthy controls (15.7 vs. 4.8%, p = 0.001). The KIR-AA genotype resulted to have a significant predictive power for achieving iPET-2 negativity (p = 0.039). CONCLUSIONS: Homozygosity for KIR A haplotype offers protection against classic Hodgkin lymphoma. The association found for the KIR-AA genotype and achievement of negative iPET-2 suggests that KIR-AA could be used in clinical practice to enhance the chemosensitivity predictive power of iPET-2. Our results point to the possibility of adapting treatment strategies based on the combination of KIR biomarkers and PET scan.

Exploring the Role of Killer Cell Immunoglobulin-Like Receptors and Their HLA Class I Ligands in Autoimmune Hepatitis.

BACKGROUND: Natural killer cells are involved in the complex mechanisms underlying autoimmune diseases but few studies have investigated their role in autoimmune hepatitis. Killer immunoglobulin-like receptors are key regulators of natural killer cell-mediated immune responses. METHODS AND FINDINGS: KIR gene frequencies, KIR haplotypes, KIR ligands and combinations of KIRs and their HLA Class I ligands were investigated in 114 patients diagnosed with type 1 autoimmune hepatitis and compared with a group of 221 healthy controls. HLA Class I and Class II antigen frequencies were compared to those of 551 healthy unrelated families representative of the Sardinian population. In our cohort, type 1 autoimmune hepatitis was strongly associated with the HLA-B18, Cw5, DR3 haplotype. The KIR2DS1 activating KIR gene and the high affinity HLA-C2 ligands were significantly higher in patients compared to controls. Patients also had a reduced frequency of HLA-Bw4 ligands for KIR3DL1 and HLA-C1 ligands for KIR2DL3. Age at onset was significantly associated with the KIR2DS1 activating gene but not with HLA-C1 or HLA-C2 ligand groups. CONCLUSIONS: The activating KIR gene KIR2DS1 resulted to have an important predictive potential for early onset of type 1 autoimmune hepatitis. Additionally, the low frequency of the KIR-ligand combinations KIR3DL1/HLA-Bw4 and KIR2DL3/HLA-C1 coupled to the high frequency of the HLA-C2 high affinity ligands for KIR2DS1 could contribute to unwanted NK cell autoreactivity in AIH-1.

Killer immunoglobulin-like receptors can predict TKI treatment-free remission in chronic myeloid leukemia patients.

Several factors are predictive of treatment-free remission (TFR) in chronic myeloid leukemia (CML), but few data exist on the role of natural killer (NK) cells and their killer-cell immunoglobulin-like receptors (KIRs). KIR and human leukocyte antigen (HLA) genotypes were investigated in 36 CML patients who discontinued tyrosine kinase inhibitor (TKI) treatment after achieving deep molecular response (MR(4.5)). Cumulative TFR was significantly higher in patients homozygous for KIR A haplotype (85.7% vs. 45.5%; p = 0.029). Younger age, Bx haplotype, and the combination KIR3DS1/KIR3DL1 present/HLA-Bw4 present were significantly associated with relapse. KIR genotypes could prove useful in identifying patients that are likely to maintain MR(4.5) after discontinuing TKI treatment.

Role of human leukocyte antigen-G 14-base pair polymorphism in kidney transplantation outcomes.

BACKGROUND: Both the membrane-bound and soluble forms of human leukocyte antigen-G (HLA-G) molecules exhibit a multitude of immunomodulatory properties that can potentially obviate or delay graft rejection. The 14-base pair (14-bp) polymorphism in the 3'-untranslated region of the HLA-G gene is thought to have a role in soluble HLA-G (sHLA-G) expression. METHODS: In this study, we retrospectively investigated a large cohort of 418 kidney transplant recipients with the aim of establishing whether the HLA-G 14-bp insertion/deletion polymorphism could serve as an effective genetic risk marker for acute and/or chronic deterioration of transplanted kidney function. RESULTS: A statistically significant higher incidence of chronic kidney dysfunction leading to allograft loss was observed in transplant recipients homozygous for the HLA-G 14-bp deletion polymorphism. This difference increased over time and was confirmed by progressive decline in the glomerular filtration rate. CONCLUSIONS: These results suggest that alongside other factors previously consolidated in clinical practice, recipient HLA-G 14-bp genotype may serve as an adjuvant independent predictor of long-term outcome of kidney transplantation.

HLA-G gene polymorphism in human placentas: possible association of G*0106 allele with preeclampsia and miscarriage.

Definite causes for several pathologies of pregnancy remain unknown. In light of several recent studies, however, diminished or aberrant HLA-G expression may be associated with certain complication of pregnancy and be linked to HLA-G polymorphism. We analyzed DNA from 60 normal placentas (controls), 140 placentas from miscarriage, 36 placentas from preeclampsia, 76 placentas from fetal hypotrophy, and 34 placentas with hypoxia for variations in coding regions (allelic groups G*0101 to G*0107) and the 14-bp deletion/insertion into the 3'-untranslated region. No statistically significant differences were observed in the distribution of allelic group between pathological placentas and controls with the exception of G*0106 allele frequency in preeclamptic compared with control placentas (21.2% and 6.6%, respectively). A greater frequency of this allele also was observed in the two subgroups of miscarriage and hypoxia compared with that in controls. In addition, presence of the 14-bp sequence was prominent in preeclampsia compared with controls (60.8% vs. 35%, respectively), and homozygotes with deletion were not detected in the pathology. The results suggest that the G*0106 allele, which is coupled with the presence of the 14-bp sequence, contributes and/or is a relevant marker in some specific complications of pregnancy, especially preeclampsia.

The human leucocyte antigen-G 14-basepair polymorphism correlates with graft-versus-host disease in unrelated bone marrow transplantation for thalassaemia.

The presence of the 14-bp insertion polymorphism of the human leucocyte antigen (HLA)-G gene (HLA-G) promotes immune tolerance through increased synthesis of HLA-G molecules. We investigated this polymorphism in a large cohort of 53 thalassaemia patients transplanted from an unrelated donor. Sixteen patients (30.2%) homozygous for the 14-bp deletion had a higher risk of developing acute graft-versus-host disease (aGvHD) than patients homozygous for the 14-bp insertion (-14-bp/-14-bp vs +14-bp/+14-bp: Relative Risk = 15.0; 95% confidence interval 1.59-141.24; P = 0.008). Therefore, the 14-bp polymorphism could be an important predictive factor for aGvHD following bone marrow transplantation.