SummaryComplement is viewed as a critical serum-operative component of innate immunity, with processing of its key component, C3, into activation fragments C3a and C3b confined to the extracellular space. We report here that C3 activation also occurred intracellularly. We found that the T cell-expressed protease cathepsin L (CTSL) processed C3 into biologically active C3a and C3b. Resting T cells contained stores of endosomal and lysosomal C3 and CTSL and substantial amounts of CTSL-generated C3a. While “tonic” intracellular C3a generation was required for homeostatic T cell survival, shuttling of this intracellular C3-activation-system to the cell surface upon T cell stimulation induced autocrine proinflammatory cytokine production. Furthermore, T cells from patients with autoimmune arthritis demonstrated hyperactive intracellular complement activation and interferon-γ production and CTSL inhibition corrected this deregulated phenotype. Importantly, intracellular C3a was observed in all examined cell populations, suggesting that intracellular complement activation might be of broad physiological significance.

Summary Severe disease of SARS-CoV-2 is characterized by vigorous inflammatory responses in the lung, often with a sudden onset after 5–7 days of stable disease. Efforts to modulate this hyperinflammation and the associated acute respiratory distress syndrome rely on the unraveling of the immune cell interactions and cytokines that drive such responses. Given that every patient is captured at different stages of infection, longitudinal monitoring of the immune response is critical and systems-level analyses are required to capture cellular interactions. Here, we report on a systems-level blood immunomonitoring study of 37 adult patients diagnosed with COVID-19 and followed with up to 14 blood samples from acute to recovery phases of the disease. We describe an IFNγ-eosinophil axis activated before lung hyperinflammation and changes in cell-cell co-regulation during different stages of the disease. We also map an immune trajectory during recovery that is shared among patients with severe COVID-19.

Severe COVID-19 is characterized by extensive pulmonary complications, to which host immune responses are believed to play a role. As the major arm of innate immunity, neutrophils are one of the first cells recruited to the site of infection where their excessive activation can contribute to lung pathology. Low-density granulocytes (LDGs) are circulating neutrophils, whose numbers increase in some autoimmune diseases and cancer, but are poorly characterized in acute viral infections. Using flow cytometry, we detected a significant increase of LDGs in the blood of acute COVID-19 patients, compared to healthy controls. Based on their surface marker expression, COVID-19-related LDGs exhibit four different populations, which display distinctive stages of granulocytic development and most likely reflect emergency myelopoiesis. Moreover, COVID-19 LDGs show a link with an elevated recruitment and activation of neutrophils. Functional assays demonstrated the immunosuppressive capacities of these cells, which might contribute to impaired lymphocyte responses during acute disease. Taken together, our data confirms a significant granulocyte activation during COVID-19 and suggests that granulocytes of lower density play a role in disease progression.

Asthma, rhinitis and eczema in Russian Karelia are not only rare but also, to a large extent, have no sIgE component. Therefore, the ability of questionnaires to detect sIgE-mediated atopic conditions in this area of Russia is poor.

The immune response to SARS-CoV2 is under intense investigation, but not fully understood att this moment. Severe disease is characterized by vigorous inflammatory responses in the lung, often with a sudden onset after 5-7 days of stable disease. Efforts to modulate this hyperinflammation and the associated acute respiratory distress syndrome, rely on the unraveling of the immune cell interactions and cytokines that drive such responses. Systems-level analyses are required to simultaneously capture all immune cell populations and the many protein mediators by which cells communicate. Since every patient analyzed will be captured at different stages of his or her infection, longitudinal monitoring of the immune response is critical. Here we report on a systems-level blood immunomonitoring study of 39 adult patients, hospitalized with severe COVID-19 and followed with up to 14 blood samples from acute to recovery phases of the disease. We describe an IFNg-Eosinophil axis activated prior to lung hyperinflammation and changes in cell-cell coregulation during different stages of the disease. We also map an immune trajectory during recovery that is shared among patients with severe COVID-19.

An Eastern vs Western environment appears to exert an effect via opposite alleles on risk of allergic diseases in adult women.

In-ICU CA patients had the lowest one-year survival with the effective cost per survivor three times higher than for OHCAs.

FOXP3, believed to be the regulatory T (Treg)-cell determining factor, is already expressed at the CD4 + CD8 + thymocyte stage, but there is disagreement whether these cells are the precursors of mature CD4 + CD8 À Treg cells. Here, we provide a quantitative analysis of FOXP3 expression in the human thymus. We show that a subset of CD4 + CD8 + cells already expressed as much FOXP3 as the FOXP3 + CD4 + CD8 À cells, and like mature Treg cells were CD127 low . In contrast to earlier data, CD8 + CD4 À thymocytes expressed significantly lower levels of FOXP3 than either the CD4 + CD8 + or CD4 + CD8 À subsets. The CD4 + CD8 + double-positive cells also expressed recombination-activating gene-2, suggesting that they were still immature. Although the FOXP3 + double-positive cells are thus putatively the precursors of the mature CD4 + CD8 À FOXP3 + subset, their frequency did not predict the frequency of more mature Treg cells, and analysis of T-cell antigen receptor repertoire showed clear differences between the two subsets. Although these data do not rule out an independent CD4 + CD8 + Treg cell subset, they are consistent with a model of human Treg cell development in which the upregulation of FOXP3 is an early event, but the first FOXP3 + population is still immature and subject to further selection. The upregulation of FOXP3 may thus not be the final determining factor in the commitment of human thymocytes to the Treg cell lineage. Keywords: suppressor T cell; T-cell receptor; thymic selection; tolerance CD4 + CD25 + regulatory T (Treg) cells have recently emerged as the key controllers of the immune system, capable of suppressing responses against both self and nonself antigens. 1 Although cells with regulatory activity can, under certain circumstances, be also induced peripherally, the best characterized Treg cell subset develops in thymus and has therefore been denoted natural Treg cells. The most reliable marker for natural Treg cells is the forkhead transcription factor FOXP3, postulated to be the Treg cell lineage-determining gene. 2,3 Loss-of-function mutations in FOXP3 lead in mice to the Scurfy phenotype, and in humans to the immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome, both characterized by severe autoimmune manifestations. [1][2][3] In mice, expression of FOXP3 seems to be sufficient and necessary to confer a regulatory phenotype, whereas in human T cells forced expression of FOXP3 leads to hyporesponsiveness but not necessarily to regulatory function. 2-5 Transient, nonregulatory FOXP3 expression has also been reported in activated human T cells, but the expression level is lower than that observed in natural Treg cells. [6][7][8] In human thymocytes and peripheral blood cells analyzed directly ex vivo, the expression of FOXP3 correlates with suppressive function. [9][10][11] In mice, FOXP3 expression is restricted to ab T cells and predominantly to the CD4 + subset, and T-cell antigen receptor (TCR)-mediated signals are thought to be essential for its upregulation. 1,2,12 A...