The lung in systemic lupus erythematosus

IFN-driven autoimmune lung inflammation

In recent years a type I IFN (IFNα and IFNβ) gene signature in the peripheral blood of SLE patients has been described which correlates with increased disease activity. Elevated IFNα is observed in over 50% of patients and correlates with disease severity, flare and tissue involvement (specifically skin, kidney, and central nervous system). In the lung, type I IFNs are induced in response to infection and injury (such as that associated with smoking, etc.), with lung epithelial cells and cells of the innate immune system being involved; depending on the stimulus IFNs in the lung exacerbate inflammation via inducing chemokine expression and production of inflammatory cytokines (presumably by upregulating signaling components that will enhance their expression) and will promote adaptive immune responses via enhancing antigen presentation and costimulatory molecule upregulation. As mentioned above, type I IFNs can help break tolerance and drive the production of autoantibodies. Deposition of circulating autoantibodies and immune complexes on lung tissue has been suggested as a leading cause of inflammation in the lung in SLE and rheumatoid arthritis (RA).

Type I IFNs (IFNα and IFNβ) are produced in response to RNA and DNA detection primarily: both Toll-like receptors (TLRs) and cytosolic RNA and DNA sensors are involved (discussed in detail in Chapter 23 ). One IFN-inducing pathway that has recently been associated with lung involvement is the cGAS-STING pathway. cGAS is an intracellular, cytosolic DNA sensor which once activated produces cyclic dinucleotides which then activate the ER-resident adaptor protein STING (stimulator of interferon genes). STING homodimerizes and activates the IRF3 kinase TBK1, resulting in IRF3 activation and nuclear translocation and subsequent activation of IFNβ gene expression. Activating mutations in the gene encoding STING, TMEM173, give rise to enhanced expression of IFNβ and a systemic autoinflammatory/autoimmune disease termed SAVI (STING associated vasculopathy with onset in infancy). SAVI is part of a collection of autoinflammatory/autoimmune diseases termed interferonopathies which all feature single gene mutations in regulators of the cGAS-STING pathway. ^{, 22} However, despite the similarities in IFN dysregulation among the interferonopathies, clinically only SAVI and another novel syndrome called COPA syndrome, are associated with lung involvement. Thus, perhaps another mechanism may be at play here.

Recently endoplasmic reticulum (ER) stress has emerged as a driver of autoimmune lung inflammation. ER stress responses in lung epithelia leads to the release of cytokines that aid recruitment of cells to the damaged area and remodeling of the local environment. A recent report identified ER stress as the principle mechanism behind a hereditary autoimmune syndrome of severe lung disease, where mutations in COPA disrupt protein transport, causing ER stress and subsequent activation of inflammation and recruitment of Th17 cells to the lung. Interestingly, ER stress has been shown to prime IFN production via the activation of the transcription factor IRF3, indicating the potential for cross-talk between IFN and ER stress pathways and potential relevance to IFN driven diseases such as SLE. The clinical features of SAVI and COPA syndrome are discussed in detail further.

Immune complex involvement

The most common conditions associated with immune complexes (ICs) are autoimmune diseases such as SLE and RA. Patients with SLE have various lab abnormalities including high titer autoantibodies against DNA, ribonucleoprotein complexes, Smith antigen, Ro/SSA and La/SSB (reviewed in [28]). Autoantibodies associated with lung disease in SLE include anti-Smith, anti-RNP, and anti-SSA1 (or TRIM21/Ro52). Anti-SSA1/TRIM21 is associated with poor outcome in a number of interstitial lung diseases including SLE. Interestingly SSA-1 or TRIM21 is an interferon regulated gene, indicating in patients with high levels of type I IFN then levels of this autoantigen are high. Immune complexes are antigen-antibody complexes formed by binding of IgM or IgG to soluble antigen. They mediate their effects in two ways primarily: triggering complement activation via the classical pathway involving recognition of antibody by C1q, activation of C3 and generation of the C5b-9 membrane attack complex, binding to Fcγ receptors on monocytes, resident macrophages and neutrophils to enhance phagocytosis, release or produce reactive oxygen species (ROS) production and degranulation of neutrophils to release proteases, inflammatory cytokines and ROS to further exacerbate inflammation . Immune complexes can also trigger neutrophil NETosis—a process whereby neutrophils release decondensed chromatin (DNA and histones) and granular contents to the extracellular space. Thus immune complex-mediated inflammation and injury is at the heart of lung involvement in diseases such as SLE and RA.

Neutrophils and NETosis

SLE patients have a specific inflammatory subset of neutrophils called low density neutrophils (LDNs) or granulocytes that are primed to be activated by immune complexes and IFNs. They produce IL-1β and also IFN in response to being activated and are also highly susceptible to undergoing NETosis—targeted release of self-DNA from within the neutrophil as a result of decondensation of nucleosomes. Release of histones and self-DNA from neutrophils during NETosis is highly inflammatory and damaging to the lung — both acting as a source of autoantigens (histones and self-DNA) but also driving IFN production through recognition of self-DNA by DNA sensing cGAS-STING pathway. Extracellular histones can also drive cytotoxicity of alveolar epithelial cell lines, exacerbating lung damage and inflammation.

Acute lung inflammation that drives alveolar hemorrhage is driven primarily by the release of inflammatory cytokines and chemokines that result in stimulating an influx of neutrophils into the airways. Recently work from our group showed that an inflammatory cytokine IL-16 plays a role in this process. IL-16 is released during systemic inflammation and induces CXCL10 expression from alveolar epithelial cells, promoting the influx of neutrophils in a mouse model of IFN-driven disease. Our work also showed that enhanced IL-16 levels associated with lung involvement in SLE patients, suggesting IL-16 may act as a marker or driver of IFN-driven autoimmune lung inflammation. As to whether IL-16 contributes to altered neutrophil function in SLE is currently under investigation.

Thus, many mechanisms that are known to drive tissue pathology in SLE– immune complex deposition, neutrophil activation and NETosis, dysregulation of IFN production and signaling contribute to autoimmune lung inflammation, and specifically SLE-associated lung inflammation. The relative contribution of RNA/DNA sensing pathways in regulating these responses and driving exacerbation of lung inflammation and process of fibrosis remains underappreciated and under studied. As discussed below in detail our analysis of monogenic diseases such as COPA syndrome and SAVI may provide additional information that may better guide therapeutic intervention and management.

Pulmonary infection

Of all the pulmonary manifestations in SLE, infection is the most common and needs to be excluded. Infection can mimic lung disease, which is part of the connective tissue disease (CTD) process and often requires immunosuppressive therapy; also, infection is associated with appreciable morbidity and mortality. Both typical and atypical pathogenic organisms, including fungal and mycobacterial species, may be the cause. Due to a patient's immunocompromised state, the clinical presentation may be insidious, particularly if opportunistic organisms are the culprit. Rigorous evaluation that often includes bronchoalveolar lavage (BAL) to exclude infection in SLE patients with any suggestive or unexplained pulmonary abnormality is mandatory. (See Chapter 45 for a thorough review of infectious complications associated with SLE.)

Nonpulmonary involvement as a cause of respiratory symptoms

A comprehensive evaluation is needed to exclude nonrespiratory causes of dyspnea and/or cough. For example, cardiac ischemia, cardiomyopathy, valvular heart disease, pericardial disease, anemia, and deconditioning are important etiologies to consider and need to be excluded. Cough may be more likely due to gastroesophageal reflux disease, esophageal dysmotility, or aspiration; these frequently-encountered comorbid conditions require thorough assessment and appropriate management.