ObjectivesUncontrolled thromboinflammation plays an important role in the pathogenesis of coronavirus disease (COVID-19) caused by SARS-CoV-2 virus. Complement was implicated as key contributor to this process, therefore we hypothesized that markers of the complement profile, indicative for the activation state of the system, may be related to the severity and mortality of COVID-19.MethodsIn this prospective cohort study samples of 102 hospitalized and 26 outpatients with PCR-confirmed COVID-19 were analyzed. Primary outcome was in-hospital, COVID-19 related mortality, and secondary outcome was COVID-19 severity as assessed by the WHO ordinal scale. Complement activity of alternative and classical pathways, its factors, regulators, and activation products were measured by hemolytic titration, turbidimetry, or enzyme-immunoassays. Clinical covariates and markers of inflammation were extracted from hospital records.ResultsIncreased complement activation was characteristic for hospitalized COVID-19 patients. Complement activation was significantly associated with markers of inflammation, such as interleukin-6, C-reactive protein, and ferritin. Twenty-five patients died during hospital stay due to COVID-19 related illness. Patients with uncontrolled complement activation leading to consumption of C3 and decrease of complement activity were more likely to die, than those who had complement activation without consumption. Cox models identified anaphylatoxin C3a, and C3 overactivation and consumption (ratio of C3a/C3) as predictors of in-hospital mortality [HR of 3.63 (1.55–8.45, 95% CI) and 6.1 (2.1–17.8), respectively].ConclusionIncreased complement activation is associated with advanced disease severity of COVID-19. Patients with SARS-CoV-2 infection are more likely to die when the disease is accompanied by overactivation and consumption of C3. These results may provide observational evidence and further support to studies on complement inhibitory drugs for the treatment of COVID-19.

Plasmacytoid dendritic cells (pDCs) are professional type I interferon (IFN) producing cells that play an essential role in antiviral immunity. In many cell types, detection of intracellular pathogens is mostly dependent on endosomal Toll-like receptors (TLRs) and cytosolic sensors, such as retinoic acid-inducible gene I (RIG-I). However, the possible interplay between these two systems has not yet been elucidated. Here we aimed to study the collaboration of endosomal TLRs and RIG-I in primary human pDCs. We found that under steady-state conditions pDCs express RIG-I at very low level, but the expression of this receptor is rapidly and dramatically up-regulated upon stimulation by the TLR7 ligand imiquimod or the TLR9 ligand type A CpG. We also demonstrated that pDCs are able to sense and respond to 5′-ppp-dsRNA only following activation by endosomal TLRs.Experiments on primary pDCs with functionally blocked IFN-alpha/beta receptor 1 (IFNAR1) and those on human pDC leukemia (pDC-L) cells defective in type I IFN secretion indicated that the up-regulation of RIG-I expression in pDCs upon stimulation by endosomal TLR occurs in a type I IFN-independent manner. Selective phosphorylation of STAT1 on tyrosine 701 could be identified as an early signaling event in this process. Our results show that in contrast to many other cell types, where RIG-I expression is induced by type I IFN, in pDCs a disparate mechanism is responsible for the up-regulation of RIG-I. Our findings also indicate that along with autophagy, an additional mechanism is operating in pDCs to promote the detection of replicating viruses.

Primarily due to recent advances of detection techniques, microchimerism (the proportion of minor variant population is below 1%) has recently gained increasing attention in the field of transplantation. Availability of polymorphic markers, such as deletion insertion or single nucleotide polymorphisms along with a vast array of high sensitivity detection techniques, allow the accurate detection of small quantities of donor- or recipient-related materials. This diagnostic information can improve monitoring of allograft injuries in solid organ transplantations (SOT) as well as facilitate early detection of relapse in allogeneic hematopoietic stem cell transplantation (allo-HSCT). In the present review, genetic marker and detection platform options applicable for microchimerism detection are discussed. Furthermore, current results of relevant clinical studies in the context of microchimerism and SOT or allo-HSCT respectively are also summarized.

The malignant cells proved to express CD4+, CD56+ lineage negative leukemia phenotype characteristically positive for CD36, CD38, CD40, CD45, CD45RA, CD68, CD123, CD184, HLA-DR, BDCA2, and granzyme-B corresponding to the preplasmacytoid dendritic cell developmental stage. The presence of CD11a/CD18, CD84, CD91, CD95, alphavbeta5, CDw197, and the absence of CD52 and CD133 in this case can be regarded as additional features of malignant cells. Completing the immunophenotypes with multidrug resistance function can provide additional information for characterizing pDC leukemia.

Central nervous system involvement is a rare complication of multiple myeloma with extremely poor prognosis as it usually fails to respond to therapy. We present 13 cases diagnosed at two centers in Budapest and review the current literature. The majority of our cases presented with high-risk features initially; two had plasma cell leukemia. Repeated genetic tests showed clonal evolution in 3 cases. Treatments varied according to the era, and efficacy was poor as generally reported in the literature. Only one patient is currently alive, with 3-month follow-up, and the patient responded to daratumumab-based treatment. Recent case reports show promising effectivity of pomalidomide and marizomib.