Factors involved in the development of LFs

There is a certain overlap between the pathways involved in the development of SLOs and inducible LFs. The development of SLOs is dependent on specialised cells called lymphoid tissue inducer (LTi) cells that drive lymphotoxin dependent expression of the homeostatic chemokines CCL19, CCL21 and CXCL13. Although these homeostatic chemokines are also important for the formation of LFs, the necessity for LTi cells in the development of LFs is controversial. Indeed, a recent study by Rangel-Moreno et al1 showed that in neonatal mice, endotoxin induced ectopic pulmonary lymphoid tissue can form in the absence of LTi cells. Instead, T cells producing the cytokine interleukin 17 were sufficient for their formation through induction of lymphotoxin independent expression of CXCL13. Given the association of Th17 cells with chronic inflammation and autoimmunity, the formation of LFs in these conditions could in principle also be a component of interleukin 17 mediated pathology (figure 1).

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Figure 1

Possible functions and triggers for pulmonary lymphoid follicles (LFs). (A) LF formation is linked with inflammation that is driven by irritants or infections. The chemokines CXCL13 and CCL21 are key participants in the formation and organisation of the follicles. (B) One role of LFs could be to enhance immune responses against pathogens by providing a local site for expansion and differentiation of adaptive immune cells. (C) An alternative, but not mutually exclusive, hypothesis is that LFs form during chronic inflammation and provide a site and reservoir for autoreactive cells that act to enhance disease. DC, ; FDC, ; HEV, ; IL-17, interleukin 17; TLR

Relevance of LFs to disease

The formation of pulmonary lymphoid aggregates can be triggered by a variety of stimuli, such as microbial infections and inflammation. Consequently, pulmonary LFs are rarely found in healthy adults whereas they are enriched in chronic disease such as chronic obstructive pulmonary disease (COPD). The landmark paper by Hogg et al2 provided a compelling association between the progression of COPD and the frequency of airways containing LFs, although their role in the disease itself remains elusive. One can speculate that these LFs develop to limit or counteract infection of the airways, which can follow breach of the epithelial barrier in diseased lungs. On the other hand, the breakdown products of the lung tissue that accumulate in the lungs could also be presented within the LFs, giving rise to B and T cell responses directed against self-antigens and thus perpetuate the ongoing disease.

There are conflicting reports regarding the presence of autoantibodies in COPD patients. One of the major caveats in such studies is the definition of an appropriate self-antigen as this may vary, even between subjects exhibiting similar disease severity in terms of clinical symptoms. Moreover, many of these studies measure levels of circulating autoantibodies in the serum of patients. As COPD is seldom linked to systemic autoimmunity, the production of autoantibodies might be localised within the LFs and thus evaluation of their levels within the airways would be more relevant. Van der Strate et al3 have demonstrated that B cells within pulmonary LFs of COPD patients exhibit an antigen specific oligoclonal activation. Building on the potential for B cell mediated pathology in COPD, Feghali-Bostwick et al4 showed the presence of immune complexes and complement within diseased lungs. In addition, they found increased levels of autoantibodies directed against the pulmonary epithelium that also displayed pathogenic potential, as measured by their ability to mediate antibody dependent cell mediated cytotoxicity. Although these studies allude to a role for LFs in driving immunopathology in COPD, conclusive mechanistic evidence is still lacking.

In addition to chronic inflammation, infections are also known to trigger the formation of LFs. In these situations, LFs could serve as a site for induction of specific immune responses. In fact, such localised responses in addition to being protective might also be less pathogenic in comparison with systemic immune responses. Wiley et al5 studied the role of LFs in the context of protective immunity. They found that induction of LFs by instillation of protein nano cage particles enhances immune responses to primary viral infections while curtailing the extent of bystander damage to the lungs. Of note, this effect mediated by the LFs was not specific and resulted in protection against different viral infections.