IMPORTANCE Amyotrophic lateral sclerosis (ALS) has an immune component, but previous human studies have not examined immune changes over time.OBJECTIVES To assess peripheral inflammatory markers in participants with ALS and healthy control individuals and to track immune changes in ALS and determine whether these changes correlate with disease progression.

Aspergillus fumigatus, a ubiquitous airborne fungus, can cause invasive infection in immunocompromised individuals but also triggers allergic bronchopulmonary aspergillosis in a subset of otherwise healthy individuals repeatedly exposed to the organism. This study addresses a critical gap in our understanding of the immunoregulation in response to repeated exposure to A. fumigatus conidia. C57BL/6 mice were challenged intranasally with A. fumigatus conidia weekly, and leukocyte composition, activation, and cytokine production were examined after two, four, and eight challenges. Approximately 99% of A. fumigatus conidia were cleared within 24 h after inoculation, and repeated exposure to A. fumigatus conidia did not result in hyphal growth or accumulation of conidia with time. After 2 challenges, there was an early influx of neutrophils and regulatory T (T reg ) cells into the lungs but minimal inflammation. Repeated exposure promoted sustained expansion of the draining lymph nodes, while the influx of eosinophils and other myeloid cells into the lungs peaked after four exposures and then decreased despite continued A. fumigatus challenges. Goblet cell metaplasia and low-level fibrosis were evident during the response. Repeated exposure to A. fumigatus conidia induced T cell activation in the lungs and the codevelopment by four exposures of T H 1, T H 2, and T H 17 responses in the lungs, which were maintained through eight exposures. Changes in CD4 T cell polarization or T reg numbers did not account for the reduction in myeloid cell numbers later in the response, suggesting a non-T-cell regulatory pathway involved in dampening inflammation during repeated exposure to A. fumigatus conidia.

CD11b؉ myeloid cells was diminished in IL-17A ؊/؊ mice. Collectively, these data indicate that IL-17A enhances host defenses against a moderately virulent strain of C. neoformans through effects on leukocyte recruitment, IFN-␥ production by CD4 and CD8 T cells, and the activation of lung myeloid cells.

The alveolar epithelium is characteristically abnormal in fibrotic lung disease, and we recently established a direct link between injury to the type II alveolar epithelial cell (AEC) and the accumulation of interstitial collagen. The mechanisms by which damage to the epithelium induces lung scarring remain poorly understood. It is particularly controversial whether an insult to the type II AEC initiates an inflammatory response that is required for the development of fibrosis. To explore whether local inflammation occurs following a targeted epithelial insult and contributes to lung fibrosis, we administered diphtheria toxin to transgenic mice with type II AEC-restricted expression of the diphtheria toxin receptor. We employed immunophenotyping techniques and diphtheria toxin receptor-expressing, chemokine-receptor-2 deficient (CCR2−/−) mice to determine the participation of lung leukocyte subsets in pulmonary fibrogenesis. Our results demonstrate that targeted type II AEC injury induces an inflammatory response that is enriched for CD11b+ non-resident exudate macrophages (ExM) and their precursors, Ly-6Chigh monocytes. CCR2-deficiency abrogates the accumulation of both cell populations and protects mice from fibrosis, weight loss, and death. Further analyses revealed that the ExM are alternatively-activated and that ExM and Ly-6Chigh monocytes express mRNA for IL-13, TGF-β, and the collagen genes, COL1A1 and COLIIIA1. Furthermore, the accumulated ExM and Ly-6Chigh monocytes contain intracellular collagen as detected by immunostaining. Together, these results implicate CCR2 and the accumulation of ExM and Ly-6Chigh monocytes as critical determinants of pulmonary fibrosis induced by selective type II AEC injury.