Pulmonary involvement of ANCA-associated vasculitis in adult Chinese patients

Objective The aim of this study was to clarify the clinical characteristics and long-term outcomes of ANCA-associated vasculitis (AAV) patients with pulmonary involvement from a single Chinese cohort. Methods Newly diagnosed AAV patients with pulmonary involvement, as defined by CT, were recruited from January 2010 to June 2020. Clinical data and CT images were collected retrospectively. Baseline CTs were evaluated and re-classified into four categories: interstitial lung disease (ILD), airway involvement (AI), alveolar hemorrhage (AH), and pulmonary granuloma (PG). Results A total of 719 patients were newly diagnosed with AAV, 366 (50.9%) of whom combined with pulmonary involvement at baseline. Among the AAV cases with pulmonary involvement, 55.7% (204/366) had ILD, 16.7% (61/366) had AI alone, 14.8% (54/366) had PG, and 12.8% (47/366) had AH alone. During follow-up of a median duration of 42.0 months, 66/366 (18.0%) patients died, mainly died from infections. Survival, relapse, and infection were all significantly different based on the radiological features. Specifically, the ILD group tends to have a poor long-term prognosis, the PG group is prone to relapse, and the AI group is apt to infection. The AH group has a high risk of both early infection and relapse, thus a poor short-term prognosis. Conclusion AAV patients with diverse radiological features have different clinical characteristics and outcomes. Therefore, the intensity of immunosuppressive therapy must be carefully valued by considering the baseline CT findings among AAV patients with pulmonary involvement.

Pulmonary Involvement of ANCA-associated Vasculitis in Adult Chinese Patients.

Objective: The aim of this study was to clarify the clinical characteristics and long-term outcomes of ANCA-associated vasculitis (AAV) patients with pulmonary involvement from a single Chinese cohort. Methods: Newly diagnosed AAV patients with pulmonary involvement, as defined by CT, were recruited from January 2010 to June 2020. Clinical data and CT images were collected retrospectively. Baseline CTs were evaluated and re-classified into four categories: interstitial lung disease (ILD), airway involvement (AI), alveolar hemorrhage (AH), and pulmonary granuloma (PG). Results: A total of 719 patients were newly diagnosed with AAV, 366 (50.9%) of whom combined with pulmonary involvement at baseline. Among the AAV cases with pulmonary involvement, 55.7% (204/366) had ILD, 16.7% (61/366) had AI alone, 14.8% (54/366) had PG, and 12.8% (47/366) had AH alone. During follow-up of a median duration of 42.0 months, 66/366 (18.0%) patients died, mainly died from infections. Survival, relapse, and infection were all significantly different based on the radiological features. Specifically, the ILD group tends to have a poor long-term prognosis, the PG group is prone to relapse, and the AI group is apt to infection. The AH group has a high risk of both early infection and relapse, thus a poor short-term prognosis.Conclusion: AAV patients with diverse radiological features have different clinical characteristics and outcomes. Therefore, the intensity of immunosuppressive therapy must be carefully valued by considering the baseline CT findings among AAV patients with pulmonary involvement.

The M2a Macrophage Phenotype Accompanies Pulmonary Granuloma Resolution in Mmp12 Knock-Out Mice Instilled with Multiwall Carbon Nanotubes

Sarcoidosis is a chronic disease with unknown etiology and pathophysiology, characterized by granuloma formation. Matrix Metalloproteinase-12 (MMP12) is an elastase implicated in active granulomatous sarcoidosis. Previously, we reported that oropharyngeal instillation of multiwall carbon nanotubes (MWCNT) into C57Bl/6 mice induced sarcoid-like granulomas and upregulation of MMP12. When Mmp12 knock-out (KO) mice were instilled with MWCNT, granuloma formation occurred 10 days post-instillation but subsequently resolved at 60 days. Thus, we concluded that MMP12 was essential to granuloma persistence. The aim of the current study was to identify potential mechanisms of granuloma resolution in Mmp12KO mice. Strikingly, an M2 macrophage phenotype was present in Mmp12KO but not in C57Bl/6 mice. Between 10 and 60 days, macrophage populations in MWCNT-instilled Mmp12KO mice demonstrated an M2c to M2a phenotypic shift, with elevations in levels of IL-13, an M2 subtype-regulating factor. Furthermore, the M2 inducer, Apolipoprotein E (ApoE), and Matrix Metalloproteinase-14 (MMP14), a promoter of collagen degradation, were upregulated in 60-day MWCNT-instilled Mmp12KO mice. In conclusion, alveolar macrophages express two M2 phenotypes in Mmp12KO mice: M2c at 10 days when granulomas form, and M2a at 60 days when granulomas are resolving. Findings suggest that granuloma resolution in 60-day Mmp12KO mice requires an M2a macrophage phenotype.

Pulmonary granuloma is not always the tuberculosis hallmark: pathological findings of different tuberculosis stages in New and Old World Nonhuman Primates naturally infected with the Mycobacterium tuberculosis Complex

Herein we present the pathological findings of different tuberculosis stages in Old and New World monkeys kept under human care in Rio de Janeiro, Brazil and naturally infected with Mycobacterium tuberculosis Complex. Fifteen nonhuman primates from five different colonies were incorporated into the study. There are 60% (9/15) Old World Monkeys and 40% (6/15) New World Monkeys. According to the gross and histopathologic findings, the lesions in nonhuman primates of this study are classified into the chronic-active, extrapulmonary, early-activation or latent-reactivation tuberculosis stage. Among the Old World Monkey, 66.7% (6/9) of nonhuman primates, all rhesus monkeys (Macaca mulatta), showed severe granulomatous pneumonia. In all Old World Monkeys cases, typical granulomas were seen in at least one organ regardless of the stage of the disease. In the New World Monkeys, the typical pulmonary granulomas were seen in 16.7% (1/6) of the cases, just in the latent-reactivation stage in Uta Hick’s Bearded Saki (Chiropotes utahickae). In this study, 66.7% (6/9) of Old World Monkeys (OWM) and 83.3% (5/6) of New World Monkeys (NWM) showed pulmonary changes at the histological evaluation. The tuberculosis diagnosis in the nonhuman primates in this study was based on pathological, immunohistochemical, molecular, and bacteriological culture. Although the typical presentation was observed in some cases, the absence of pulmonary granuloma did not exclude the tuberculosis occurrence in nonhuman primates of the Old and New World. Tuberculosis should be included as a cause of interstitial pneumonia with foamy macrophages infiltration in the New World nonhuman primates. Due to the high sensitivity of immunohistochemistry with Anti-Mycobacterium tuberculosis, we suggest the addition of this technique as a diagnostic tool of tuberculosis in the nonhuman primates even when the typical changes are not seen.

Studies in a Murine Granuloma Model of Instilled Carbon Nanotubes: Relevance to Sarcoidosis

Poorly soluble environmental antigens, including carbon pollutants, are thought to play a role in the incidence of human sarcoidosis, a chronic inflammatory granulomatous disease of unknown causation. Currently, engineered carbon products such as multiwall carbon nanotubes (MWCNT) are manufactured commercially and have been shown to elicit acute and chronic inflammatory responses in experimental animals, including the production of granulomas or fibrosis. Several years ago, we hypothesized that constructing an experimental model of chronic granulomatosis resembling that associated with sarcoidosis might be achieved by oropharyngeal instillation of MWCNT into mice. This review summarizes the results of our efforts to define mechanisms of granuloma formation and identify potential therapeutic targets for sarcoidosis. Evidence is presented linking findings from the murine MWCNT granuloma model to sarcoidosis pathophysiology. As our goal was to determine what pulmonary inflammatory pathways might be involved, we utilized mice of knock-out (KO) backgrounds which corresponded to deficiencies noted in sarcoidosis patients. A primary example of this approach was to study mice with a myeloid-specific knock-out of the lipid-regulated transcription factor, peroxisome proliferator-activated receptor gamma (PPARγ) which is strikingly depressed in sarcoidosis. Among the major findings associated with PPARγ KO mice compared to wild-type were: (1) exacerbation of granulomatous and fibrotic histopathology in response to MWCNT; (2) elevation of inflammatory mediators; and (3) pulmonary retention of a potentially antigenic ESAT-6 peptide co-instilled with MWCNT. In line with these data, we also observed that activation of PPARγ in wild-type mice by the PPARγ-specific ligand, rosiglitazone, significantly reduced both pulmonary granuloma and inflammatory mediator production. Similarly, recognition of a deficiency of ATP-binding cassette (ABC) lipid transporter ABCG1 in sarcoidosis led us to study MWCNT instillation in myeloid-specific ABCG1 KO mice. As anticipated, ABCG1 deficiency was associated with larger granulomas and increased levels of inflammatory mediators. Finally, a transcriptional survey of alveolar macrophages from MWCNT-instilled wild-type mice and human sarcoidosis patients revealed several common themes. One of the most prominent mediators identified in both human and mouse transcriptomic analyses was MMP12. Studies with MMP12 KO mice revealed similar acute reactions to those in wild-type but at chronic time points where wild-type maintained granulomatous disease, resolution occurred with MMP12 KO mice suggesting MMP12 is necessary for granuloma progression. In conclusion, these studies suggest that the MWCNT granuloma model has relevance to human sarcoidosis study, particularly with respect to immune-specific pathways.