Deficiency of Tfh Cells and Germinal Center in Deceased COVID-19 Patients

Summary:The COVID-19 pandemic caused by SARS-CoV2 is characterized by a remarkable variation in clinical severity ranging from a mild illness to a fatal multi-organ disease.Understanding the dysregulated human immune responses in the fatal subjects is critical for management of COVID-19 patients and the pandemic.In this study,we examined the immune cell compositions in the lung tissues and hilar lymph nodes using immunohistochemistry on 6 deceased COVID-19 patients and 4 focal organizing pneumonia(FOP)patients who underwent lung surgery and served as controls.We found a dominant presence of macrophages and a general deficiency of T cells and B cells in the lung tissues from deceased COVID-19 patients.In contrast to the FOP patients,Tfh cells and germinal center formation were largely absent in the draining hilar lymph nodes in the deceased COVID-19 patients.This was correlated with reduced IgM and IgG levels compared to convalescent COVID-19 patients.In summary,our data highlight a defect of germinal center structure in deceased COVID-19 patients leading to an impaired humoral immunity.Understanding the mechanisms of this deficiency will be one of the key points for the management of this epidemic.

The relationship between loss expression of DPC4/Smad4 gene and carcinogenesis of pancreatobiliary carcinoma

Objective: To clarify the relationship between loss of DPCA gene expression and pathogenesis of pancreato- biliary carcinoma. Methods: 75 slides of normal duct (20), hyperplasia (15), dysplasia (15), invasive carcinoma (25) from patients with pancreatic diseases including pancreatic carcinoma (25 patients), chronic pancreatitis (6), pancreas injury (2) and 71 slides of common bile duct (CBD) carcinoma (38), gallbladder carcinoma (18), hilar bile duct (HBD) carcinoma (15) from patients with primary biliary tract carcinoma were analyzed for the expression of DPC4 protein by im- munohistochemical staining. Results: All specimens from 20 cases of normal duct and 15 cases of hyperplasia showed marked expres- sion of DPC4 protein. The frequency of loss expres- sion of the DPC4 gene was 33 % in dysplasia, and 48% in invasive carcinoma. There was a significant statistical difference between byperplasia and dyspla- sia (P<0.01) and in dysplasia vs invasive carcinoma (P<0.05). The frequency of loss expression of the DPC4 gene was 47.3% in CBD carcinoma, 11% in gallbladder carcinoma, and 13% in HBD carcinoma. The frequency of loss expression of the DPCA gene was significantly different in CBD carcinoma vs gall- bladder carcinoma and HBD carcinoma (P<0.01). Conclusions: Inactivation of the DPC4 gene occurs late in the neoplastic progression of pancreatic carci- noma. The frequency of DPC4 gene alternation was different in various locations of biliary tract carcino- ma. In CBD carcinoma, this frequency is similar to that in pancreatic carcinoma, indicating their similar molecular alternations.

Clinical characteristics and risk factors of COVID-19 patients with chronic hepatitis B:a multi-center retrospective cohort study

The coronavirus disease 2019(COVID-19)has spread globally.Although mixed liver impairment has been reported in COVID-19 patients,the association of liver injury caused by specific subtype especially chronic hepatitis B(CHB)with COVID-19 has not been elucidated.In this multi-center,retrospective,and observational cohort study,109 CHB and 327 non-CHB patients with COVID-19 were propensity score matched at an approximate ratio of 3:1 on the basis of age,sex,and comorbidities.Demographic characteristics,laboratory examinations,disease severity,and clinical outcomes were compared.Furthermore,univariable and multivariable logistic and Cox regression models were used to explore the risk factors for disease severity and mortality,respectively.A higher proportion of CHB patients(30 of 109(27.52%))developed into severe status than non-CHB patients(17 of 327(5.20%)).In addition to previously reported liver impairment markers,such as alanine aminotransferase,aspartate aminotransferase,alkaline phosphatase,and total bilirubin,we identified several novel risk factors including elevated lactate dehydrogenase(≥245 U/L,hazard ratio(HR)=8.639,95%confidence interval(CI)=2.528–29.523;P<0.001)and coagulation-related biomarker D-dimer(≥0.5μg/mL,HR=4.321,95%CI=1.443–12.939;P=0.009)and decreased albumin(<35 g/L,HR=0.131,95%CI=0.048–0.361;P<0.001)and albumin/globulin ratio(<1.5,HR=0.123,95%CI=0.017–0.918;P=0.041).In conclusion,COVID-19 patients with CHB were more likely to develop into severe illness and die.The risk factors that we identified may be helpful for early clinical surveillance of critical progression.

ATP6V0d2 mediates leucine-induced mTORCI activation and polarization of macrophages

Dear Editor, mTORCI, as a center regulatory hub of metabolism, senses the cellular energy status, nutrition and extracellular stimuli and regulates cell growth, differentiation and functions of immune cells (Powell et al., 2012). Lysosomal localization of key signal comp orients is critical for mTORCI activati on: mTORCI activation requires co-localization of activated Rheb and mTORCI to the lysosome membrane (Buerger et al., 2006). Signals in eluding growth factors, cellular stresses and energy levels act on the disruption the formation of tuberous sclerosis complex (TSC) complex, comprised of TSC1, TSC2 and TBC1D7, which leads to the translocation and activation of Rheb on the lysosome membrane (Dibble et al., 2012). In response to nutrient levels, specifically the availability of amino acids and glucose (Efeyan et al., 2013), mTORCI is recruited to the lysosomal surface by Rag GTPases that are heterodimers of RagA or RagC bound to RagB or RagD. Multiple protein complexes have been implicated in regulation of mTORCI upon nutrient sensing including Ragulator, GATOR1, GATOR2, KICSTOR and vacuolar ATPases (Wolfson et al., 2017). Vacuolar ATPases are large multiple-protein complexes that acidify the lysosome and may mediate additional functions independent of their proton pump activity (Nishi and Forgac, 2002).

DAPK1(death associated protein kinase 1)mediates mTORC1 activation and antiviral activities in CD8^(+)T cells

Mechanistic target of rapamycin complex 1(mTORCt)regulates CD8^(+)T-cell differentiation and function.Despite the links between PI3K-AKT and mTORCI activation in CD8^(+)T cells,the molecular mechanism underlying mTORCI activation remains undear.Here,we show that both the kinase activity and the death domain of DAPK1 are required for maximal mTOR activation and CD8^(+)T-cell function.We found that TCR-induced activation of calcineurin activates DAPK1,which subsequently interacts with TSC2 via its death domain and phosphorylates TSC2 to mediate mTORCI activation.Furthermore,both the kinase domain and death domain of DAPK1 are required for CD8^(+)T-cell antiviral responses in an LCMV infection model.Together,our data reveal a novel mechanism of mTORCI activation that mediates optimal CD8^(+)T-cell function and antiviral activity.