HLA-C dysregulation as a possible mechanism of immune evasion in SARS-CoV-2 and other RNA-virus infections

One of the mechanisms by which viruses can evade the host's immune system is to modify the host's DNA methylation pattern. This work aims to investigate the DNA methylation and gene expression profile of COVID-19 patients, divided into symptomatic and asymptomatic, and healthy controls, focusing on genes involved in the immune response. In this study, changes in the methylome of COVID-19 patients' upper airways cells, the first barrier against respiratory infections and the first cells presenting viral antigens, are shown for the first time. Our results showed alterations in the methylation pattern of genes encoding proteins implicated in the response against pathogens, in particular the HLA-C gene, also important for the T-cell mediated memory response. HLA-C expression significantly decreases in COVID-19 patients, especially in those with a more severe prognosis and without other possibly confounding co-morbidities. Moreover, our bionformatic analysis revealed that the identified methylation alteration overlaps with enhancers regulating HLA-C expression, suggesting an additional mechanism exploited by SARS-CoV-2 to inhibit this fundamental player in the host's immune response. HLA-C could therefore represent both a prognostic marker and an excellent therapeutic target, also suggesting a preventive intervention that conjugate a virus-specific antigenic stimulation with an adjuvant increasing the T-cell mediated memory response

The HLA Variant rs6903608 Is Associated with Disease Onset and Relapse of Immune-Mediated Thrombotic Thrombocytopenic Purpura in Caucasians

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening thrombotic microangiopathy caused by severe ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin motifs 13) deficiency, recurring in 30-50% of patients. The common human leukocyte antigen (HLA) variant rs6903608 was found to be associated with prevalent iTTP, but whether this variant is associated with disease relapse is unknown. To estimate the impact of rs6903608 on iTTP onset and relapse, we performed a case-control and cohort study in 161 Italian patients with a first iTTP episode between 2002 and 2018, and in 456 Italian controls. Variation in rs6903608 was strongly associated with iTTP onset (homozygotes odds ratio (OR) 4.68 (95% confidence interval (CI) 2.67 to 8.23); heterozygotes OR 1.64 (95%CI 0.95 to 2.83)), which occurred over three years earlier for each extra risk allele (β -3.34, 95%CI -6.69 to 0.02). Of 153 survivors (median follow-up 4.9 years (95%CI 3.7 to 6.1)), 44 (29%) relapsed. The risk allele homozygotes had a 46% (95%CI 36 to 57%) absolute risk of relapse by year 6, which was significantly higher than both heterozygotes (22% (95%CI 16 to 29%)) and reference allele homozygotes (30% (95%CI 23 to 39%)). In conclusion, HLA variant rs6903608 is a risk factor for both iTTP onset and relapse. This newly identified biomarker may help with recognizing patients at high risk of relapse, who would benefit from close monitoring or intensified immunosuppressive therapy

The features of acquired thrombotic thrombocytopenic purpura occurring at advanced age

Introduction: Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare life-threatening thrombotic microangiopathy (TMA) affecting more frequently women of 30–50 years of age. There is scarce information on the clinical features of aTTP occurring in the elderly. Our goal was to evaluate the impact of an elderly-onset disease on the expression, severity and management of aTTP. Materials and methods: We performed a cross-sectional study of patients enrolled in the Milan TTP Registry (www.ttpdatabase.org) after a first acute episode of aTTP from January 2002 to March 2018. The aTTP diagnosis was suspected on the basis of the presence of thrombocytopenia and microangiopathic hemolytic anemia with no alternative causes, and was confirmed centrally by a severe plasma deficiency of ADAMTS13 activity (<10%). Triggers, clinical manifestations, laboratory parameters, management and outcome of the first acute events of elderly-onset aTTP patients (≥65 years) were compared with those of younger patients. Results: Among 143 eligible patients, 16 (11%) were elderly at onset. In comparison with younger cases they showed a lower rate of bleeding symptoms and severe anemia (30% and 18%), with a trend towards a higher rate of neurological and renal signs and symptoms. These patients were less frequently treated with plasma exchange and corticosteroids and more often with plasma infusion. No difference for gender, triggers and episode outcomes was observed. Conclusions: Older patients with aTTP differed from younger patients mainly for being treated less frequently with plasma exchange and corticosteroids, perhaps for the perceived risks associated with these treatments in the elderly