At a Glance Commentary: Scientific knowledge on the Subject: severe SARS-CoV-2 infections leading to the Coronavirus disease 2019 (COVID-19) and the acute respiratory distress syndrome (ARDS) are associated with high mortality and prolonged durations of intensive care unit stay. Profound lymphopenia and elevated serum levels of pro-inflammatory cytokines, also characterized as cytokine storm, have been associated with clinical severity. However, few data compared the immunopathology of COVID-19 ARDS to that of non-COVID-19 ARDS, so that specific traits of the immune responses to severe SARS-CoV-2 infections have not been well identified. What This Study Adds to the Field: COVID-19 ARDS patients showed a phenotype of impaired adaptive immune response with profound lymphopenia and impaired/delayed lymphocyte activation. We also report a "chemokine signature" with increased serum concentrations of IP-10 and GM-CSF in COVID-19 patients. Serum concentrations of IP-10 and GM-CSF and nasopharyngeal viral loads were associated with outcomes in COVID-19 patients. Such results highlight the contribution of myeloid cells and impaired adaptive immune

We examined 807 productive IGHV-IGHD-IGHJ gene rearrangements from mantle cell lymphoma (MCL) cases, by far the largest series to date. The IGHV gene repertoire was remarkably biased, with IGHV3-21, IGHV4-34, IGHV1-8, and IGHV3-23 accounting for 46.3% of the cohort. Eightyfour of 807 (10.4%) cases, mainly using the IGHV3-21 and IGHV4-34 genes, were found to bear stereotyped heavy complementaritydetermining region 3 (VH CDR3) sequences and were placed in 38 clusters. Notably, the MCL stereotypes were distinct from those reported for chronic lymphocytic leukemia. Based on somatic hypermutation (SHM) status, 238/807 sequences (29.5%) carried IGHV genes with 100% germ line identity; the remainder (569/807; 70.5%) exhibited different SHM impact, ranging from minimal (in most cases) to pronounced. Shared replacement mutations across the IGHV gene were identified for certain subgroups, especially those using IGHV3-21, IGHV1-8, and IGHV3-23.Comparison with other entities, in particular CLL, revealed that several of these mutations were "MCL-biased." In conclusion, MCL is characterized by a highly restricted immunoglobulin gene repertoire with stereotyped VH CDR3s and very precise SHM targeting, strongly implying a role for antigen-driven selection of the clonogenic progenitors. Hence, an antigen-driven origin of MCL could be envisaged, at least for subsets of cases. (Blood. 2011; 118(11):3088-3095) IntroductionMantle cell lymphoma (MCL) is an aggressive B-cell malignancy that represents 5%-10% of non-Hodgkin lymphomas. The median overall survival is 3-5 years, and at present, conventional treatment is not curative and long-term remission is rare. However, subsets of MCL patients follow a more indolent clinical course without disease progression for a relatively long period. 1 The cytogenetic hallmark of MCL is the chromosomal translocation t(11;14)(q13;q32). This aberration leads to the juxtaposition of the CCDN1 locus on chromosome 11 to the immunoglobulin heavy chain (IGH) locus on chromosome 14. As a consequence, cyclin D1 is constitutively overexpressed, causing gross cell cycle deregulation. 2 In addition to the primary t(11;14), several secondary genomic aberrations can be identified in most MCL cases, 2,3 supporting early findings that cyclin D1 overexpression must be accompanied by other genetic abnormalities to promote lymphomagenesis. 2,4 Various gene expression changes that may cooperate with cyclin D1 deregulation also have been described in MCL, mainly involved in DNA repair pathways and the control of cell cycle and apoptosis. 4,5 That notwithstanding, alterations in the local tumor microenvironment also may play an important role in regulating the growth and survival of MCL neoplastic cells. 2,5,6 In B-cell malignancies, immunogenetic analysis of the clonogenic B-cell receptors (BcRs) offers valuable insight into both the ontogenetic derivation and the possible involvement of antigen selection. In particular, a biased repertoire of immunoglobulin heavy variable (IGHV) genes is generally considered as evid...