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BackgroundIdiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease characterized by aberrant wound healing, immune dysregulation, heterogeneous trajectories, and poor prognosis. Only two antifibrotic agents, nintedanib and pirfenidone, are currently approved to slow disease progression, yet inter-individual variability in treatment benefit remains largely unexplained. In IPF, impaired NK-cell activity within the altered lung microenvironment may hinder removal of stressed or senescent cells, promoting fibrosis. The MHC-class I chain-related gene A (MICA) encodes a stress-induced ligand of the NKG2D receptor on NK and CD8+ T cells, crucial for immune surveillance.MethodsWe analyzed clinical and genetic data from 129 Sardinian IPF patients genotyped for MICA and stratified by antifibrotic therapy (nintedanib, pirfenidone, no therapy, and switchers). Genotypes were assessed in relation to longitudinal lung function, overall survival (OS), and treatment-specific outcomes using multivariate Cox models adjusted for demographic and immunogenetic variables.ResultsMICA-129 genotype frequencies were comparable across treatment groups. In nintedanib-treated patients, the Val/Val genotype was associated with significantly reduced 48-month OS versus Met/Met and Met/Val (p = 0.005). No statistically significant association was observed among pirfenidone-treated patients. After adjustment, Val/Val remained an independent predictor of mortality in the nintedanib group (p = 0.01), irrespective of HLA background.ConclusionsThe MICA-129 Val/Val genotype may represent a candidate immunogenetic marker associated with poorer outcome in nintedanib-treated patients with IPF, underscoring the influence of immune-genetic context on antifibrotic response. Although subgroup sizes limit precision, the consistency and mechanistic plausibility of the association support integrating MICA genotyping into future randomized trials to refine personalized therapeutic strategies in IPF.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease characterized by the disruption of the alveolar and interstitial architecture due to extracellular matrix deposition. Emerging evidence suggests that genetic susceptibility plays a crucial role in IPF development. This study explores the role of human leukocyte antigen (HLA) alleles and haplotypes in IPF susceptibility and progression within the genetically distinct Sardinian population. Genotypic data were analyzed for associations with disease onset and progression, focusing on allele and haplotype frequencies in patients exhibiting slow (S) or rapid (R) progression. While no significant differences in HLA allele frequencies were observed between IPF patients and controls, the HLA-DRB1*04:05 allele and the extended haplotype (HLA-A*30:02, B*18:01, C*05:01, DQA1*05:01, DQB1*02:01, DRB1*03:01) were associated with a slower disease progression and improved survival (log-rank = 0.032 and 0.01, respectively). At 36 months, carriers of these variants demonstrated significantly better pulmonary function, measured with single-breath carbon monoxide diffusing capacity (DLCO%p) (p = 0.005 and 0.02, respectively). Multivariate analysis confirmed these findings as being independent of confounding factors. These results highlight the impact of HLA alleles and haplotypes on IPF outcomes and underscore the potential of the Sardinian genetic landscape to illuminate immunological mechanisms, paving the way for predictive biomarkers and personalized therapies.

Hepatocellular carcinoma (HCC) is the sixth most common cancer globally and the third leading cause of cancer-related mortality, primarily driven by viral infections (HCV, HBV) and steatotic liver diseases (SLD). Despite advances in treatment, early detection and accurate prognosis remain challenging. The Human leukocyte antigen G (HLA-G) molecule is dysregulated in various conditions, including cancers and viral infections. This study aimed to investigate HLA-G’s role in viral-related and SLD-driven HCC. We analyzed a cohort of 116 HCC patients and 140 healthy controls to assess HLA-G genetic variants and soluble levels. Results showed significantly higher levels of soluble HLA-G in HCC patients compared to controls (Pc = 0.003). Moreover, overall survival (OS) was significantly lower in patients with the extended HLA-G*01:01:01/UTR-1 haplotype (Log-rank test, p = 0.002), a trend consistent in both HCV and/or HBV-related HCC (p = 0.025) and SLD-related HCC (p = 0.018). Elevated sHLA-G levels were associated with shorter OS across both subgroups (p = 0.034 (HBV/HCV) and p = 0.010 (SLD), respectively). The findings suggest that elevated levels of soluble HLA-G and specific genetic variants are associated with poor prognosis in HCC patients, highlighting the potential of HLA-G as a prognostic biomarker in both viral-related and steatotic liver disease-related HCC.

Antibody-mediated rejection is a significant cause of kidney transplant failure. Recent studies have shown that the MHC class I gene influences the transplantation outcome. However, the role of the primary receptor, NKG2D, has yet to be explored. We aimed to investigate the correlation between recipient/donor allele matching and genotype with the risk of antibody-mediated rejection and their potential clinical effects and implications for organ maintenance therapy. Of the 524 patients who underwent transplantation, 387 were eligible for the study. Complete allele and two functional polymorphisms of ( and ) were analyzed in 148 transplanted patients and 146 controls. Increased recipient/donor allele mismatches correlate with an elevated risk of antibody-mediated rejection (X = 6.95; Log-rank=0.031). Notably, the genotype contributes to a significantly increased risk of antibody-mediated rejection (X = 13.44; Log-rank=0.001 and = 0.34; Log-rank=0.84). The combined effect of two allele mismatches and genotype shows the highest risk (X = 23.21; Log-rank<0.001). Most importantly, patients with and AA genotypes may respond less to mTOR inhibitor immunosuppressive therapy than Calcineurin inhibitors ( P=0.035; and ; P=0.002). Recipient/donor allele mismatches and specific variants, as well as their combinations, influence kidney transplant outcomes, providing insights for personalized treatment and enhancing graft survival.

Primary biliary cholangitis (PBC) is a rare autoimmune liver disease involving bile duct damage and fibrosis. This study explores the role of HLA-G, an immunomodulatory molecule crucial for immune tolerance, in PBC pathogenesis and treatment. A cohort of 166 PBC patients from Sardinia was compared to 180 healthy controls and 205 autoimmune hepatitis type 1 (AIH-1) patients. Plasma soluble HLA-G (sHLA-G) levels, alleles, and haplotypes were analyzed alongside clinical data, including therapy response to ursodeoxycholic acid. The UTR-1 haplotype was significantly more frequent in PBC patients than in controls (48.2% vs 34.3%, Pc= 0.0018). The extended haplotype was also strongly associated with PBC (23.2% vs 12.5% in controls, Pc = 0.008; 23.2% vs 6.6% in AIH-1, Pc= 2.6×10 ). PBC patients exhibited lower sHLA-G levels compared to controls and AIH-1 (9.1 U/mL vs 24.03 U/mL and 13.9 U/mL, respectively). Among carriers, sHLA-G levels were particularly reduced in PBC patients. The haplotype correlated with the lowest sHLA-G levels and poorer therapy response (60% vs 24.1%, P = 0.0001). These findings suggest HLA-G variants, especially , as potential biomarkers for PBC prognosis and treatment outcomes.

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 gene polymorphisms and sHLA-G, can affect SARS-CoV-2 infection. 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). HLA-G locus analysis showed that the extended haplotype 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% 15.7%, OR = 0.634 (95% CI 0.440 - 0.913); P = 0.016]. Furthermore, the most significant polymorphism ( ) shows that the genotype frequency decreases gradually from 27.6% in paucisymptomatic patients to 15.9% in patients with severe symptoms (X = 7.095, P = 0.029), reaching the lowest frequency (7.0%) in ICU patients (X = 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 β-thalassemia trait ( C>T in the gene), -C C1+ group combination and the haplotype which exert a protective effect [P = 0.005, P = 0.001 and P = 0.026 respectively]. Conversely, the Neanderthal gene variant ( A>G) shows a detrimental consequence on the disease course [P = 0.001]. However, by using a logistic regression model, genotype was independent from the other significant variables [OR = 0.4 (95% CI 0.2 - 0.7), P = 6.5 x 10 ]. 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.

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 β°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.

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).