The classical view of type 1 diabetes assumes that the autoimmune mediated targeting of insulin producing ß-cells is caused by an error of the immune system. Malfunction and stress of beta cells added the target tissue at the center of action. The innate immune system, and in particular islet-resident cells of the myeloid lineage, could function as a link between stressed ß-cells and activation and recognition by the adaptive immune system. We survey the role of islet-resident macrophages and dendritic cells in healthy islet homeostasis and pathophysiology of T1D. Knowledge of islet-resident antigen presenting cells in rodents is substantial, but quite scarce in humans, in particular regarding dendritic cells. Differences in blood between healthy and diseased individuals were reported, but it remains elusive to what extend these contribute to T1D onset. Increasing our understanding of the interaction between ß-cells and innate immune cells may provide new insights into disease initiation and development that could ultimately point to future treatment options. Here we review current knowledge of islet-resident macrophages and dendritic cells, place these in context of current clinical trials, and guide future research.
The protozoan parasite Leishmania (Viannia) braziliensis (L. braziliensis) is the main cause of human tegumentary leishmaniasis in the New World, a disease affecting the skin and/or mucosal tissues. Despite its importance, the study of the unique biology of L. braziliensis through reverse genetics analyses has so far lagged behind in comparison with Old World Leishmania spp. In this study, we successfully applied a cloning-free, PCR-based CRISPR–Cas9 technology in L. braziliensis that was previously developed for Old World Leishmania major and New World L. mexicana species. As proof of principle, we demonstrate the targeted replacement of a transgene (eGFP) and two L. braziliensis single-copy genes (HSP23 and HSP100). We obtained homozygous Cas9-free HSP23- and HSP100-null mutants in L. braziliensis that matched the phenotypes reported previously for the respective L. donovani null mutants. The function of HSP23 is indeed conserved throughout the Trypanosomatida as L. major HSP23 null mutants could be complemented phenotypically with transgenes from a range of trypanosomatids. In summary, the feasibility of genetic manipulation of L. braziliensis by CRISPR–Cas9-mediated gene editing sets the stage for testing the role of specific genes in that parasite’s biology, including functional studies of virulence factors in relevant animal models to reveal novel therapeutic targets to combat American tegumentary leishmaniasis.
Characterization of host-pathogen interactions is a fundamental approach in microbiological and immunological oriented disciplines. It is commonly accepted that host cells start to change their phenotype after engulfing pathogens. Techniques such as real time PCR or ELISA were used to characterize the genes encoding proteins that are associated either with pathogen elimination or immune escape mechanisms. Most of such studies were performed in vitro using primary host cells or cell lines. Consequently, the data generated with such approaches reflect the global RNA expression or protein amount recovered from all cells in culture. This is justified when all host cells harbor an equal amount of pathogens under experimental conditions. However, the uptake of pathogens by phagocytic cells is not synchronized. Consequently, there are host cells incorporating different amounts of pathogens that might result in distinct pathogen-induced protein biosynthesis. Therefore, we established a technique able to detect and quantify the number of pathogens in the corresponding host cells using immunofluorescence-based high throughput analysis. Paired with multicolor staining of molecules of interest it is now possible to analyze the infection profile of host cell populations and the corresponding phenotype of the host cells as a result of parasite load.
Recently, COVID-19 vaccination-induced exacerbation or new-onset of psoriasis have been reported. Underlying immune pathogenesis is unclear and different mechanisms are assumed. Further, clinical- and vaccine-related features and characteristics are partly inconsistent and remain to be elucidated. To add to the understanding of COVID-19 vaccination-triggered psoriasis, we report five cases with exacerbation or new-onset of psoriasis. In our cohort, one patient experienced the new onset of psoriasis, while four had an exacerbation following COVID-19 vaccination. In most patients, exacerbation or new onset occurred after the 2nd or 3rd vaccination. The mean latency from the day of vaccination was 7.2 (1.8) days (SD). The clinical impact with a mean PASI increase following COVID-19 vaccination of 7.2 (5.6) was considered relevant. In most cases, psoriatic lesions almost cleared after applying topical steroids in addition to current treatment, while one patient with psoriatic arthritis required systemic treatment. New onset and exacerbation of psoriasis have also been noted following COVID-19 infections. Hence, the underlying inflammatory response is most likely the culprit agent triggering psoriasis. This underscores that the benefits of COVID-19 vaccination far outweigh the risks, as also in patients with psoriasis.
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