To B or Not to B: Germinal Center Responses in Progressive Fibrotic Interstitial Lung Disease

Inflammation and remodeling of the lung parenchyma are defining features of interstitial lung diseases (ILDs), the most common of which is idiopathic pulmonary fibrosis (IPF). IPF was initially hypothesized to be driven by inflammation. However, clinical trials demonstrating an increased rate of hospitalization and death in patients treated with prednisone and azathioprine have called this hypothesis into question (1).

In the decade since, the underlying mechanisms of IPF have been an intense area of investigation, leading to the identification of epithelial cell injury, dysregulated wound repair, and progressive fibrosis as critical events in the development of IPF. High-dimensional, single-cell analyses and complementary mechanistic studies have established innate immunity—namely, profibrotic macrophages—as key to IPF development and progression (2, 3). Whether adaptive immune responses drive IPF pathogenesis remains an open question. Numerous studies have associated dysregulated lymphocytes and autoantibodies with outcomes in patients with IPF. The confusing and sometimes contradictory results of these studies suggest complex mechanisms are at play and highlight the need to study specific lymphocyte subsets (4).

In contrast to IPF, both humoral and cellular adaptive immune responses have been convincingly linked to the development of other ILD subtypes. For example, activation of T-helper type 1 (Th1) cells is believed to be the primary driver of granuloma formation and inflammation in chronic hypersensitivity pneumonitis, whereas specific autoantibodies are strongly associated with the risk and pattern of ILD in connective tissue disease–associated ILD (5, 6). Regardless of ILD subtype, the development of progressive pulmonary fibrosis significantly impacts survival (7). Therefore, understanding whether common adaptive immune mechanisms contribute to ILD progression is a compelling area of investigation, particularly in light of recent advances in targeted immunotherapy.

In this issue of the Journal (pp. 1823–1834) Velez and colleagues present their work “Active antigen-specific adaptive immune responses are shared among patients with progressive fibrotic interstitial lung disease” (8), building on their prior finding that enlargement of mediastinal lymph nodes predicts mortality in ILD (9). Lymph nodes are the primary site for the initiation, propagation, and regulation of adaptive immune responses, suggesting a potential link to antigen-driven adaptive immune responses and progressive ILD. In this study, explanted lung lymph nodes and lung tissue from 50 patients undergoing lung transplantation for progressive fibrotic ILD and tissue from 36 lung donors without any known lung disease were analyzed using spectral flow cytometry (8).

There are several notable findings of this work. First, lymph nodes from patients with ILD had evidence of T-cell activation and enhanced germinal center (GC) reactions, regardless of ILD subtype. Specifically, T-follicular helper cells, GC B cells, and T-follicular regulatory cells (Tfrs) were enriched in ILD samples, compared with donor controls. In addition to patients with IPF, the ILD cohort included patients with immune-mediated ILD, including connective tissue disease–associated ILD, interstitial pneumonia with autoimmune features, and chronic hypersensitivity pneumonitis. Somewhat surprisingly, GC populations were expanded to an equivalent extent in patients with IPF compared with those with non-IPF ILD. However, it is important to note that the authors did not include patient medication history in their analysis. It is therefore possible—even likely—that the use of immunomodulatory agents differed between patients with IPF and those with underlying autoimmunity. Nevertheless, these data provide convincing evidence of an ongoing, adaptive immune response in patients with ILD with progressive fibrosis.

Second, the authors identified potentially important associations between immune responses in lymph nodes and lung function. Although GC B cells correlated with rapid lung function decline, Tfr cell frequency correlated with a slower decline in lung function. As Tfr cells suppress B-cell responses within GCs, these findings raise the intriguing possibility that Tfr cells may protect against pathological GC B-cell responses. Furthermore, they suggest that a nuanced understanding of adaptive immune responses in progressive fibrosis will be required to develop effective immunotherapy for fibrotic lung diseases.

Finally, the authors asked whether antibodies to a recently identified novel autoantigen, ABLIM1 (actin-binding LIM protein 1), could be detected in a separate, larger ILD cohort (10). ABLIM1 is expressed in multiple epithelial cell subsets, including aberrant basaloid cells with a dedifferentiated phenotype characterized by KRT17 expression. ABLIM1 binds to actin and serves as a scaffolding protein, and it has recently been shown to possess E3 ubiquitin ligase activity that can affect NF-κB signaling (11). However, the normal function of ABLIM1 in the lung is unknown. Strikingly, autoantibodies to ABLIM1 were found in >70% of patients with IPF and >80% of patients with non-IPF ILD, compared with only 2% of healthy control subjects. These data raise several interesting questions and potential avenues for future investigation.

The development of autoantibodies to ABLIM1 in progressive ILD suggests that epithelial injury may lead to the initial and sustained exposure of an otherwise protected antigen. Aberrant basaloid cells are expanded in fibrotic lung disease, localize to the periphery of fibroblastic foci, and drive extracellular matrix production (12, 13). Could these cells be a source of ABLIM1 or one of the many other autoantigens that have been associated with ILD? Sequencing of B- and T-cell receptors may help in identifying whether clonal populations are present in fibrosing ILD, as well as the antigen(s) driving GC responses. Does the adaptive immune response to ABLIM1 or other autoantigens contribute to ongoing epithelial cell injury and tissue remodeling, or is it just a marker of injury and disease progression? How would antibodies against an intracellular antigen, like ABLIM1, contribute to lung injury and fibrosis?

Perhaps the most important question raised by this work is whether targeted immunosuppression (e.g., rituximab) could be effective in progressive fibrotic ILD, particularly IPF. Corticosteroids suppress both proinflammatory responses and regulatory cells, suggesting that clinical trials of immunosuppression in IPF may have failed to demonstrate benefit because of their lack of specificity and the complex mechanisms by which adaptive immunity contributes to fibrosis.

Overall, this is a well-executed study with several novel findings. The authors should be commended for tackling a difficult question. Samples from patients with ILD are challenging to obtain and study. Nevertheless, they performed sophisticated immunologic analyses on samples from a relatively large number of individuals, and they provide strong evidence for immune activation in progressive fibrotic lung disease, including IPF. Although this study makes significant contributions to our understanding of the adaptive immune response in end-stage fibrotic disease, further mechanistic studies are needed to establish a pathogenic role for adaptive responses and to inform future trials of targeted immunotherapy.