Rationale: A hallmark of pulmonary tuberculosis (TB) is the formation of granulomas. However, the immune factors that drive the formation of a protective granuloma during latent TB, and the factors that drive the formation of inflammatory granulomas during active TB, are not well defined. Objectives: The objective of this study was to identify the underlying immune mechanisms involved in formation of inflammatory granulomas seen during active TB. Methods: The immune mediators involved in inflammatory granuloma formation during TB were assessed using human samples and experimental models of Mycobacterium tuberculosis infection, using molecular and immunologic techniques. Measurements and Main Results: We demonstrate that in human patients with active TB and in nonhuman primate models of M. tuberculosis infection, neutrophils producing S100 proteins are dominant within the inflammatory lung granulomas seen during active TB. Using the mouse model of TB, we demonstrate that the exacerbated lung inflammation seen as a result of neutrophilic accumulation is dependent on S100A8/A9 proteins. S100A8/A9 proteins promote neutrophil accumulation by inducing production of proinflammatory chemokines and cytokines, and influencing leukocyte trafficking. Importantly, serum levels of S100A8/A9 proteins along with neutrophil-associated chemokines, such as keratinocyte chemoattractant, can be used as potential surrogate biomarkers to assess lung inflammation and disease severity in human TB. Conclusions: Our results thus show a major pathologic role for S100A8/A9 proteins in mediating neutrophil accumulation and inflammation associated with TB. Thus, targeting specific molecules, such as S100A8/A9 proteins, has the potential to decrease lung tissue damage without impacting protective immunity against TB.

Rationale: Hypersensitivity pneumonitis (HP) exhibits a diverse outcome. Patients with acute/subacute HP usually improve, whereas patients with chronic disease often progress to fibrosis. However, the mechanisms underlying this difference are unknown. Objectives: To examine the T-cell profile from patients with subacute HP and chronic HP. Methods: T cells were obtained by bronchoalveolar lavage from 25 patients with subacute HP, 30 patients with chronic HP, and 8 control subjects. T-cell phenotype and functional profile were evaluated by flow cytometry, cytometric bead array, and immunohistochemistry. Measurements and Main Results: Patients with chronic HP showed higher CD4+:CD8+ ratio (median, 3.05; range, 0.3–15; subacute HP: median, 1.3; range, 0.1–10; control: median, 1.3; range, 0.7–2.0; P < 0.01), and a decrease of γδT cells (median, 2.0; range, 0.5–3.4; subacute HP: median, 10; range, 4.8–17; control: median, 15; range, 5–19; P < 0.01). Patients with chronic HP exhibited an increase in the terminally differentiated memory CD4+ and CD8+ T-cell subsets compared with patients with subacute HP (P < 0.05). However, memory cells from chronic HP showed lower IFN-γ production and decreased cytotoxic activity by CD8+ T lymphocytes. Chronic HP displayed a Th2-like phenotype with increased CXCR4 expression (median, 6%; range, 1.7–36, vs. control subjects: median, 0.7%; range, 0.2–1.4; and subacute HP: median, 2.2%; range, 0.1–5.3; P < 0.01), and decreased CXCR3 expression (median, 4.3%; range, 1.4–25%, vs. subacute HP: median, 37%; range, 4.9–78%; P < 0.01). Likewise, supernatants from antigen-specific–stimulated cells from chronic HP produced higher levels of IL-4 (80 ± 63 pg/ml vs. 25 ± 7 pg/ml; P < 0.01), and lower levels of IFN-γ (3,818 ± 1671 pg/ml vs. 100 ± 61 pg/ml; P < 0.01) compared with subacute HP. Conclusions: Our findings indicate that patients with chronic HP lose effector T-cell function and exhibit skewing toward Th2 activity, which may be implicated in the fibrotic response that characterizes this clinical form.

Pigeon breeders disease (PBD) is caused by the exposure of a susceptible host to avian antigens. However, genetic factors determining individual predisposition are unknown. In this work, polymorphisms of the major histocompatibility complex (MHC) class II alleles and tumor necrosis factor alpha (TNF- α ) promoter were evaluated in 44 patients with PBD, 99 healthy unrelated controls (HC), and 50 exposed but asymptomatic subjects (EAS). MHC typing was performed by PCR-specific sequence oligonucleotide analysis, and TNF- α polymorphism at − 238 and − 308 positions by amplification refractory mutation system-PCR. PBD patients showed a significant increase of the alleles HLA-DRB1*1305 (p < 0.001, OR = 15.4, 95% CI = 3.18–102.6 [HC], and OR = 17.05, 95% CI = 2.25–357.8 [EAS]) and HLA-DQB1*0501 (p < 0.05, OR = 2.93, 95% CI = 1.21–7.15 [HC], and OR = 2.96, 95% CI = 1.0–9.14 [EAS]). A decrease of HLA-DRB1*0802 was also noticed in patients when compared with both control groups (p < 0.05). Haplotype analysis revealed an increase of DRB1*1305–DQB1*0301 and a decrease of DRB1*0802–DQB1*0402. PBD patients had an increased frequency of TNF-2^{− 308} compared with both control groups (p < 0.05). Patients exhibiting the TNF-2^{− 308} allele were younger (33.9 ± 14.6 versus 44.2 ± 10.4 yr; p < 0.05), and displayed more lymphocytes in their bronchoalveolar lavages (88.0 ± 12.1 versus 68.9 ± 17.2; p < 0.05). These results suggest that genetic factors located within the MHC region contribute to the development of PBD.

SARS-CoV-2 virus has infected more than 92 million people worldwide resulting in the Coronavirus disease 2019 (COVID-19). Using a rhesus macaque model of SARS-CoV-2 infection, we have characterized the transcriptional signatures induced in the lungs of juvenile and old macaques following infection. Genes associated with Interferon (IFN) signaling, neutrophil degranulation and innate immune pathways are significantly induced in macaque infected lungs, while pathways associated with collagen formation are downregulated, as also seen in lungs of macaques with tuberculosis. In COVID-19, increasing age is a significant risk factor for poor prognosis and increased mortality. Type I IFN and Notch signaling pathways are significantly upregulated in lungs of juvenile infected macaques when compared with old infected macaques. These results are corroborated with increased peripheral neutrophil counts and neutrophil lymphocyte ratio in older individuals with COVID-19 disease. Together, our transcriptomic studies have delineated disease pathways that improve our understanding of the immunopathogenesis of COVID-19.