Immunological markers and clinical characteristics of pulmonary inflammation

Interstitial lung diseases (ILD) includes a broad spectrum of disorders affecting the lung parenchyma. Common to these conditions is the exacerbated pulmonary immunological response leading to inflammation, disordered tissue healing, and, in a proportion of patients, chronic pulmonary fibrosis. Current treatments consist mainly of immunosuppressive agents, however, they often fail to control the disease progression. Thus, there is a need for more effective treatment modalities. The development of such new therapies, however, requires an in depth understanding of the underlying immunopathological disease mechanisms.

The studies included in this thesis had two overall aims: first to describe the normal pulmonary cellular composition as reflected by bronchoalveolar lavage fluid (BALF), and second, to further characterize the immunological mechanisms and the pulmonary response to treatment in two disorders commonly associated with ILD, namely sarcoidosis and rheumatoid arthritis (RA).

Normal BALF cellular differential counts were established based on samples from 295 healthy individuals. Subgroup analysis demonstrated that BALF composition was independent of age, gender, season and sample collection site.

In sarcoidosis, the BALF cellular characteristics typical for the disease, namely the increased cluster of differentiation (CD) 4/CD8 T cell ratio, was not reflected in the lymph nodes (LNs). Furthermore, compared to LNs and blood, there was an accumulation of activated and differentiated T cells in BALF. This indicates that, in sarcoidosis, the lung is the primary target for the immune response. In treatment refractory sarcoidosis, the extracorporeal removal of leukocytes through granulocyte and monocyte apheresis (GMA) treatment, was associated with significant immunomodulation. Particularly, there was an increase in blood regulatory T cells. This has also been observed after GMA treatment in other inflammatory conditions, where it has been associated with a good clinical response.

In early RA, after six months of disease-modifying atirheumatic drug (DMARD) treatment, there was a radiological disease progression in one third of patients exhibiting ILD at baseline. Furthermore, there was an increase in airways obstruction, with all patients suffering a large decline in the forced expiratory volume in one second. This indicates that early RA may be associated with an underlying inflammation of both lung parenchyma and airways.

In conclusion, both sarcoidosis and RA are associated with an exacerbated pulmonary immune response. In sarcoidosis, the immune reaction seems to be focused to the lung, indicating an airborne disease trigger. In early RA, systemic inflammation appears to be accompanied by inflammation of both airways and lung parenchyma, with an inadequate response to DMARDs. In both diseases, there is a need for more effective therapies. GMA could be an interesting alternative in sarcoidosis. In RA, therapeutic efforts aiming to reduce the pulmonary inflammatory reaction, should be encouraged.

List of scientific papers

I. Olsen HH, Grunewald J, Tornling G, Sköld CM, Eklund A. Bronchoalveolar lavage results are independent of season, age, gender and collection site. PLoS One 2012;7(8):e43644. Epub 2012 Aug 31.
https://doi.org/10.1371/journal.pone.0043644

II. Darlington P, Haugom-Olsen H, von Sivers K, Wahlström J, Runold M, Svjatoha V, Porwit A, Eklund A, Grunewald J. T-cell phenotypes in bronchoalveolar lavage fluid, blood and lymph nodes in pulmonary sarcoidosis – indication for an airborne antigen as the triggering factor in sarcoidosis. J Intern Med 2012;272:465-471.
https://doi.org/10.1111/j.1365-2796.2012.02543.x

III. Olsen HH, Muratov V, Cederlund K, Lundahl J, Eklund A, Grunewald J. Therapeutic granulocyte and monocyte apheresis (GMA) for treatment refractory sarcoidosis: a pilot study of clinical effects and possible mechanisms of action. Clin Exp Immunol 2014;177:712-719.
https://doi.org/10.1111/cei.12360

IV. Olsen HH, Reynisdottir G, Pawlowski J, Harju A, Karimi R, Klareskog L, Sköld CM, Nyrén S, Catrina AI, Eklund A, Grunewald J. Pulmonary manifestations in early rheumatoid arthritis: A six month follow up study. [Manuscript]