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Background: The relationship between anti-SARS-CoV-2 humoral immune response, pathogenic inflammation, lymphocytes and fatal COVID-19 is poorly understood., Methods: A longitudinal prospective cohort of hospitalised patients with COVID-19 (n=254) was followed up to 35 days after admission (median, 8 days). We measured early anti-SARS-CoV-2 S1 antibody IgG levels and dynamic (698 samples) of quantitative circulating T-, B- and natural killer lymphocyte subsets and serum interleukin-6 (IL-6) response. We used machine learning to identify patterns of the immune response and related these patterns to the primary outcome of 28-day mortality in analyses adjusted for clinical severity factors., Results: Overall, 45 (18%) patients died within 28 days after hospitalisation. We identified six clusters representing discrete anti-SARS-CoV-2 immunophenotypes. Clusters differed considerably in COVID-19 survival. Two clusters, the anti-S1-IgG lowest T lowest B lowest NK mod IL-6 mod, and the anti-S1-IgG high T low B mod NK mod IL-6 highest had a high risk of fatal COVID-19 (HR 3.36-21.69; 95% CI 1.51-163.61 and HR 8.39-10.79; 95% CI 1.20-82.67; p≤0.03, respectively). The anti-S1-IgG highest T lowest B mod NK mod IL-6 mod and anti-S1-IgG low T highest B highest NK highest IL-6 low cluster were associated with moderate risk of mortality. In contrast, two clusters the anti-S1-IgG high T high B mod NK mod IL-6 low and anti-S1-IgG highest T highest B high NK high IL-6 lowest clusters were characterised by a very low risk of mortality., Conclusions: By employing unsupervised machine learning we identified multiple anti-SARS-CoV-2 immune response clusters and observed major differences in COVID-19 mortality between these clusters. Two discrete immune pathways may lead to fatal COVID-19. One is driven by impaired or delayed antiviral humoral immunity, independently of hyper-inflammation, and the other may arise through excessive IL-6-mediated host inflammation response, independently of the protective humoral response. Those observations could be explored further for application in clinical practice., Competing Interests: Conflict of interest: The authors have nothing to disclose., (Copyright ©The authors 2022.)

Recent studies have suggested that causative variants in telomerase complex genes (TCGs) are present in around 10% of individuals with idiopathic pulmonary fibrosis (IPF) regardless of family history of the disease. However, the studies used a case-control rare variant enrichment study design which is not directly translatable to routine practice. To validate the prevalence results and to establish the individual level, routine clinical practice, and utility of those results we performed next generation sequencing of TCGs on a cohort of well-characterized consecutive individuals with IPF (diagnosis established according to ATS/ERS/JRS/ALAT guidelines). Of 27 IPF patients, three had a family history of idiopathic interstitial pneumonia (familial IPF) and 24 did not (sporadic IPF). Pathogenic/likely-pathogenic variants (according to American College of Medical Genetics criteria) in TCG were found in three individuals (11.1%) of the whole cohort; specifically, they were present in 2 out of 24 (8.3%) of the sporadic and in 1 out of 3 (33.3%) of the patients with familial IPF. Our results, which were established on an individual-patient level study design and in routine clinical practice (as opposed to the case-control study design), are roughly in line with the around 10% prevalence of causative TCG variants in patients with IPF.

Background: Invariant NKT (iNKT) cells are regulatory lymphocytes that may be important in disorders with increased Th1 responses. We utilized a 4-year longitudinal observational study of iNKT cells and SLAM signaling pathway factors, which are important for iNKT development in patients with newly diagnosed sarcoidosis., Methods: Detailed clinical, functional, and radiographic evaluation and determination of iNKT peripheral blood cell counts and expression of SLAM signaling factors was carried out at presentation and after 3 months, 1 year, and 4 years of disease follow-up in 29 patients with pulmonary sarcoidosis. At presentation, we also evaluated the frequencies of pulmonary BALF iNKT cells. We also included 37 control subjects., Results: We demonstrated a marked deficiency of blood and lung iNKT cells and decreased expression of SLAM signaling factors in patients with newly diagnosed sarcoidosis. During 4 years of disease follow-up, there was a significant increase in blood iNKT cell numbers and in expression of SLAM signaling factors, mainly SLAMF1, SLAMF6, and FYN. This increase clearly correlated with improvement in patients' clinical symptoms. At the 4-year endpoint, the disease had gone into remission in the great majority of patients and thus also iNKT cell deficiency. Moreover, at the 4-year endpoint iNKT level reached the iNKT level of the control subjects., Conclusions: Our longitudinal study showed that a disposal of iNKT deficiency in parallel with an increase in expression of SLAM signaling factors characterizes the clinical remission of sarcoidosis.

Natural killer T (NKT) cells, a unique subgroup of lymphocytes with features of both T and natural killer (NK) cells, represent a bridge between innate and adaptive immunity. They have the ability to either promote or suppress immune responses. With these immunoregulatory functions, NKT cells have emerged as an important subset of lymphocytes with a protective role in some disorders, such as infections, cancer, and possibly sarcoidosis, and a pathogenic role in others, such as asthma, chronic obstructive pulmonary disease and hypersensitivity pneumonitis. Immunotherapeutic interventions to modulate the immune response by targeting iNKT cell functions has become a challenging field and has shown promising results for the development of new therapies., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Invariant natural killer T (NKT) cells might contribute to the amplified and prolonged T-cell immune response that characterizes sarcoidosis. Therefore, we want to investigate the frequency and distribution of pulmonary invariant NKT cells in corticosteroid-naïve patients with sarcoidosis. We used multi-parameter flow cytometry with antibodies against CD3, CD4, CD8, CD14, CD19, CD45, CD16/56, TCR Valpha24, and TCR Vbeta11, on bronchoalveolar lavage fluid (BALF), to examine the frequency and distribution of pulmonary invariant NKT cells in 47 newly diagnosed sarcoidosis patients and in 8 control subjects. The frequencies of BALF Valpha24 Vbeta11 invariant NKT cells were significantly lower in patients with sarcoidosis in comparison to control subjects. Moreover, lower invariant NKT cell frequencies in patients with sarcoidosis significantly correlated with exaggerated BALF lymphocytosis and CD4 T cell responses. This study demonstrated a pulmonary deficiency in the frequency of a subset of T cells with immunoregulatory function in patients with sarcoidosis., (Copyright 2009 Elsevier Ltd. All rights reserved.)

Background: Natural killer T (NKT) cells, a newly identified subgroup of T cells with immunoregulatory function, may be implicated in the pathogenesis of interstitial lung disease (ILD)., Methods: We used multiparameter flow cytometry with antibodies to CD3, CD4, CD8, CD14, CD19, CD45, CD16/56, CD56, CD161, and Valpha24 invariant T-cell receptor (TCR) in BAL fluid (BALF) to examine the frequency and distribution of pulmonary NKT cells in several cases of ILD. We included 57 patients with sarcoidosis and 17 patients with hypersensitivity pneumonitis., Results: We found significantly higher frequencies of pulmonary NKT cells in patients with hypersensitivity pneumonitis in comparison to the other study patients with ILD (median proportion of NKT cells, 11%; range, 3 to 38%; vs 3%; range, 0 to 16%; p < 0.0001). In contrast, there was no difference in the proportion of conventional natural killer cells. We found that a major subset of NKT cells in the BALF of patients with hypersensitivity pneumonitis was a CD8+CD56+ population that did not express the invariant TCR., Conclusions: These results suggest the involvement of NKT cells in the pathogenesis of hypersensitivity pneumonitis.

Background: Sarcoidosis is a systemic autoimmune disease where an inflammatory reaction involving alveolar macrophages, T-helper lymphocytes, and epitheloid cells is mounted against unknown antigens. A genetic predisposition for sarcoidosis is supposed by studies in twins, by geographical and racial distribution. In the current investigation we compared the expression patterns between slow onset and acute sarcodosis using a whole-genome cDNA array., Methods: Bronchoalveolar lavage was performed in six patients with slow onset sarcoidosis and four patients with acute sarcoidosis (Löfgren's disease) and obtained cells were used for gene expression profiling. The results were confirmed by RT- and Taqman-PCR. In addition, protein expression was examined on paraffin sections of sarcoid granulomas by immunohistochemistry., Results: In T-helper lymphocytes and alveolar macrophages we found an upregulation of genes belonging to the phosphoinositol-3-kinase/v-akt murine thymoma viral oncogene homolog/signal transducer and activator of transcription 3 pathway, as well as a downregulation of genes of the extrinsic and intrinsic apoptotic signaling cascades. In addition an upregulation of the genes encoding fatty acid binding protein 4 and 5, as well as peroxisome proliferative activated receptor delta in Löfgren's disease was detected. Differences in gene expression between slow onset sarcoidosis and Löfgren's syndrome were found mainly within genes of the major histocompatibility complex., Conclusions: In sarcoidosis enhanced cell proliferation and decreased apoptosis result in accumulation and prolonged survival of antigen-primed T-helper lymphocytes and activated macrophages. This is enhanced in Löfgren's disease, probably by hyper-stimulation via the peroxisome proliferation signaling, providing a larger pool of antigen-primed immune cells.