Tissue transglutaminase (TGase2) is a protein-crosslinking enzyme known to be associated with the in vivo apoptosis program. Here we report that apoptosis could be induced in TGase2 ؊/؊ mice; however, the clearance of apoptotic cells was defective during the involution of thymus elicited by dexamethasone, anti-CD3 antibody, or ␥-irradiation, and in the liver after induced hyperplasia. The lack of TGase2 prevented the production of active transforming growth factor-␤1 in macrophages exposed to apoptotic cells, which is required for the up-regulation of TGase2 in the thymus in vivo, for accelerating deletion of CD4؉CD8؉ cells and for efficient phagocytosis of apoptotic bodies. The deficiency is associated with the development of splenomegaly, autoantibodies, and immune complex glomerulonephritis in TGase2 ؊/؊ mice. These findings have broad implications not only for diseases linked to inflammation and autoimmunity but also for understanding the interrelationship between the apoptosis and phagocytosis process.

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Background Descriptions of the pathological features of COronaVIrus Disease-2019 (COVID-19) caused by the novel zoonotic pathogen Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) emanate from tissue biopsies, case reports and small post-mortem studies restricted to the lung and specific organs. Whole body autopsy studies of COVID-19 patients have been sparse. To further define the pathology caused by SARS-CoV-2 across all body organs in both individuals with and without co-morbidities Italian patients who died of COVID-19. Methods We performed autopsies on 22 patients with COVID-19 (18 with co-morbidities and 4 without co-morbidities) who died at the National Institute for Infectious Diseases Lazzaro Spallanzani-IRCCS Hospital, Rome, Italy. Tissues from the lung, heart, liver, kidney, spleen and bone marrow (but not the brain) were examined. Only lung tissues were subject to transmission electron microscopy. Results COVID-19 causes multisystem pathology. Pulmonary and cardiovascular involvement are dominant pathological features. Extra-pulmonary manifestations include hepatic, kidney, splenic and bone marrow involvement, and microvascular injury and thrombosis were also detected. These findings were similar in patients with or without pre-existing medical co-morbidities. Conclusions SARS-CoV-2 infection causes multisystem disease and significant pathology in most organs in patients with and without co-morbidities.