Stephen Adelstein

The diagnosis of interstitial lung disease (ILD) requires meticulous evaluation for an underlying connective tissue disease (CTD), with major implications for prognosis and management. CTD associated ILD (CTD-ILD) occurs most commonly in the context of an established CTD, but can be the first and/or only manifestation of an occult CTD or occur in patients who have features suggestive of an autoimmune process, but not meeting diagnostic criteria for a defined CTD—recently defined as “interstitial pneumonia with autoimmune features” (IPAF). The detection of specific autoantibodies serves a critical role in the diagnosis of CTD-ILD, but there remains a lack of data to guide clinical practice including which autoantibodies should be tested on initial assessment and when or in whom serial testing should be performed. The implications of detecting autoantibodies in patients with IPAF on disease behaviour and management remain unknown. The evaluation of CTD-ILD is challenging due to the heterogeneity of presentations and types of CTD and ILD that may be encountered, and thus it is imperative that immunologic tests are interpreted in conjunction with a detailed rheumatologic history and examination and multidisciplinary collaboration between respiratory physicians, rheumatologists, immunologists, radiologists and pathologists.

We commend Oldham et al . [1] for their recent article using the new European Respiratory Society/American Thoracic Society criteria for interstitial pneumonia with autoimmune features (IPAF) to re-characterise a cohort of interstitial lung disease (ILD) patients in their centre. IPAF defines individuals with interstitial pneumonia and features suggestive of a connective tissue disease (CTD), but not meeting established CTD classification criteria [2]. Of their 422 patients with previously diagnosed idiopathic interstitial pneumonia (IIP) or undifferentiated-CTD ILD (UCTD-ILD), approximately one-third met the IPAF criteria, including nearly 20% of those with idiopathic pulmonary fibrosis, 25% with unclassifiable IIP and almost all of those with UCTD-ILD [1]. Importantly, survival was markedly worse in the IPAF group compared with a CTD-ILD cohort [1]. Within the IPAF domains, the presence of at least one clinical criterion was predictive of a favourable outcome, while morphological, multi-compartment involvement carried a significantly increased risk of mortality [1]. There is an urgent need to standardise our approach to connective tissue disease classification in ILD and IPAF

Germinal centers (GC) give rise to high-affinity and long-lived Abs and are critical in immunity and autoimmunity. IL-27 supports GCs by promoting survival and function of T follicular helper cells. We demonstrate that IL-27 also directly enhances GC B cell function. Exposure of naive human B cells to rIL-27 during in vitro activation enhanced their differentiation into CD20⁺CD38⁺CD27^lowCD95⁺CD10⁺ cells, consistent with the surface marker phenotype of GC B cells. This effect was inhibited by loss-of-function mutations in STAT1 but not STAT3. To extend these findings, we studied the in vivo effects of IL-27 signals to B cells in the GC-driven Roquin^san/san lupus mouse model. Il27ra^−/−Roquin^san/san mice exhibited significantly reduced GCs, IgG2a(c)⁺ autoantibodies, and nephritis. Mixed bone marrow chimeras confirmed that IL-27 acts through B cell– and CD4⁺ T cell–intrinsic mechanisms to support GCs and alter the production of pathogenic Ig isotypes. To our knowledge, our data provide the first evidence that IL-27 signals directly to B cells promote GCs and support the role of IL-27 in lupus.