A unique dexamethasone-dependent gene expression profile in the lungs of COVID-19 patients

Background: It is unknown whether the complex immunopathogenesis of COVID-19 acute respiratory distress syndrome (CARDS) differs from that of non-COVID-19 ARDS. Moreover, the effects of systemic dexamethasone (DXM) treatment on pulmonary immunity in COVID-19 remain insufficiently understood. Objective: To understand immune regulation in the lungs of CARDS and critically ill non-COVID-19 patients through gene expression profiling. Methods: Transcriptomic RNA-seq analysis of bronchoalveolar lavage fluid (BALF) from 21 patients: 13 with CARDS (non-DXM or DXM-treated) and 8 with non-COVID-19 ARDS and/or sepsis (all non-DXM-treated). Functional analysis was performed using gene ontology and a blood transcription module, and gene expression of select pro-inflammatory cytokines, interferon-stimulated genes (ISGs) and auto-IFN antibodies were assessed. Results: Median (range) time of COVID-19 symptoms were 11 (8-20) days and BALF was collected 32 (6-65) hours after intubation. We found 550 and 2173 differentially expressed genes in patients with non-DXM-CARDS and DXM-CARDS, respectively. DXM-CARDS was characterized by upregulation of genes related to pulmonary innate and adaptive immunity, notably B-cell and complement pathway activation, antigen presentation, phagocytosis and FC-gamma receptor signalling. Pro-inflammatory genes were not differentially expressed in CARDS vs. non-COVID-19, nor did they differ according to DXM. Most ISGs were specifically upregulated in CARDS, particularly in non-DXM-CARDS. Auto-IFN autoantibodies were detectable in BALF of some CARDS patients. Conclusion: DXM treatment was not associated with regulation of pro-inflammatory pathways in CARDS but with regulation of other specific local innate and adaptive immune responses. These results challenge the concept of a COVID-19 specific cytokine storm.

Nod-Like Receptors in Host Defence and Disease at the Epidermal Barrier

The nucleotide-binding domain and leucine-rich-repeat-containing family (NLRs) (sometimes called the NOD-like receptors, though the family contains few bona fide receptors) are a superfamily of multidomain-containing proteins that detect cellular stress and microbial infection. They constitute a critical arm of the innate immune response, though their functions are not restricted to pathogen recognition and members engage in controlling inflammasome activation, antigen-presentation, transcriptional regulation, cell death and also embryogenesis. NLRs are found from basal metazoans to plants, to zebrafish, mice and humans though functions of individual members can vary from species to species. NLRs also display highly wide-ranging tissue expression. Here, we discuss the importance of NLRs to the immune response at the epidermal barrier and summarise the known role of individual family members in the pathogenesis of skin disease.

Fisiopatologia del rigetto acuto e cronico

Allograft rejection is defined as tissue injury produced by the effector mechanisms of the alloimmune response, leading to deterioration of graft function. There are two types of rejection: T-cell-mediated rejection (TCMR) and antibody-mediated rejection (AMR). Both types of rejection can be early or late, fulminant or indolent, as well as isolated or concomitant and can share pathologic features on biopsy. The immune response to an allograft is an ongoing dialogue between the innate and adaptive immune system, which if unresolved will lead to rejection of the transplanted cells, tissues, or organs. Activation of elements of the innate immune system, triggered by tissue injury sustained during cell isolation or organ retrieval and ischemia reperfusion, will initiate and amplify the adaptive response. T cells require a minimum of two signals for activation: antigen recognition and co-stimulation. Antibody-mediated rejection triggered by alloantibody binding and complement activation is increasingly recognized as a significant contribution to graft loss. Even though one component of the immune system may dominate and lead to rejection, this is usually multifactorial, resulting from the integration of multiple mechanisms. Identifying the molecular pathways that trigger rejection facilitates the identification of targets for the development of immunosuppressive drugs.