Severe pulmonary infection or vigorous cyclic deformation of the alveolar epithelial type I (AT I) cells by mechanical ventilation leads to massive extracellular ATP release. High levels of extracellular ATP saturate the ATP hydrolysis enzymes CD39 and CD73 resulting in persistent high ATP levels despite the conversion to adenosine. Above a certain level, extracellular ATP molecules act as danger-associated molecular patterns (DAMPs) and activate the pro-inflammatory response of the innate immunity through purinergic receptors on the surface of the immune cells. This results in lung tissue inflammation, capillary leakage, interstitial and alveolar oedema and lung injury reducing the production of surfactant by the damaged AT II cells and deactivating the surfactant function by the concomitant extravasated serum proteins through capillary leakage followed by a substantial increase in alveolar surface tension and alveolar collapse. The resulting inhomogeneous ventilation of the lungs is an important mechanism in the development of ventilation-induced lung injury. The high levels of extracellular ATP and the upregulation of ecto-enzymes and soluble enzymes that hydrolyse ATP to adenosine (CD39 and CD73) increase the extracellular adenosine levels that inhibit the innate and adaptive immune responses rendering the host susceptible to infection by invading microorganisms. Moreover, high levels of extracellular adenosine increase the expression, the production and the activation of pro-fibrotic proteins (such as TGF-β, α-SMA, etc.) followed by the establishment of lung fibrosis.

Hyperinflammation plays an important role in severe and critical COVID-19. Using inconsistent criteria, many researchers define hyperinflammation as a form of very severe inflammation with cytokine storm. Therefore, COVID-19 patients are treated with anti-inflammatory drugs. These drugs appear to be less efficacious than expected and are sometimes accompanied by serious adverse effects. SARS-CoV-2 promotes cellular ATP release. Increased levels of extracellular ATP activate the purinergic receptors of the immune cells initiating the physiologic pro-inflammatory immune response. Persisting viral infection drives the ATP release even further leading to the activation of the P2X7 purinergic receptors (P2X7Rs) and a severe yet physiologic inflammation. Disease progression promotes prolonged vigorous activation of the P2X7R causing cell death and uncontrolled ATP release leading to cytokine storm and desensitisation of all other purinergic receptors of the immune cells. This results in immune paralysis with co-infections or secondary infections. We refer to this pathologic condition as hyperinflammation. The readily available and affordable P2X7R antagonist lidocaine can abrogate hyperinflammation and restore the normal immune function. The issue is that the half-maximal effective concentration for P2X7R inhibition of lidocaine is much higher than the maximal tolerable plasma concentration where adverse effects start to develop. To overcome this, we selectively inhibit the P2X7Rs of the immune cells of the lymphatic system inducing clonal expansion of Tregs in local lymph nodes. Subsequently, these Tregs migrate throughout the body exerting anti-inflammatory activities suppressing systemic and (distant) local hyperinflammation. We illustrate this with six critically ill COVID-19 patients treated with lidocaine.

Stretching the alveolar epithelial type I (AT I) cells controls the intercellular signaling for the exocytosis of surfactant by the AT II cells through the extracellular release of adenosine triphosphate (ATP) (purinergic signaling). Extracellular ATP is cleared by extracellular ATPases, maintaining its homeostasis and enabling the lung to adapt the exocytosis of surfactant to the demand. Vigorous deformation of the AT I cells by high mechanical power ventilation causes a massive release of extracellular ATP beyond the clearance capacity of the extracellular ATPases. When extracellular ATP reaches levels >100 μM, the ATP receptors of the AT II cells become desensitized and surfactant impairment is initiated. The resulting alteration in viscoelastic properties and in alveolar opening and collapse time-constants leads to alveolar collapse and the redistribution of inspired air from the alveoli to the alveolar ducts, which become pathologically dilated. The collapsed alveoli connected to these dilated alveolar ducts are subject to a massive strain, exacerbating the ATP release. After reaching concentrations >300 μM extracellular ATP acts as a danger-associated molecular pattern, causing capillary leakage, alveolar space edema, and further deactivation of surfactant by serum proteins. Decreasing the tidal volume to 6 mL/kg or less at this stage cannot prevent further lung injury.

The immune system is meant to protect against invading microbes. Although this system is effective against many microbes, some can use molecular mimicry to turn the immune system against the host and activate autoimmune responses. The resulting autoimmunity has significant implications for public health and healthcare costs. It is well known that regulatory T cells (Tregs) are crucial for self-tolerance and that their function is impaired after exposure to self-antigens or antigens with molecular mimicry, leading to the activation of autoimmune responses. How molecular mimicry disrupts Tregs in this manner remains under debate. This review contributes to the field of the pathogenesis of autoimmunity by proposing that purinergic signaling in the lymph nodes, with extracellular ATP, ADP, and adenosine as ligands, plays a pivotal role in this process. Repeated or high-dose microbial infection causes the release of large amounts of extracellular ATP sufficient to reach the threshold of extracellular ATP levels for activating P2X7 purinergic receptors (P2X7Rs) on dendritic cells and Tregs. This hampers the ability of Tregs to suppress autoimmune responses. Crucially, P2X7Rs are activated at very high extracellular ATP levels, thus only after repeated or high-dose infection with microbes. Arguably, in contrast to the rapid elimination of microbes with foreign antigens, the clearance of invading microbes that employ molecular mimicry requires the activation of P2X7Rs at the expense of self-tolerance. Because all processes required to activate autoimmune responses occur in secondary lymphoid organs, this article hypothesizes that, contrary to current convention, microbes do not need to enter organs to initiate autoimmunity. However, some types of microbes can prevent P2X7R-induced Treg disruption by converting extracellular ATP to adenosine, mitigating autoimmune responses resulting in chronic diseases with less severe inflammation. The proposed hypothesized mechanism has potential implications for the understanding and treatment of autoimmune disorders.

Background Systemic autoinflammatory diseases (SAIDs) are a diverse group of rare disorders with partially overlapping clinical features. However, their genetic makeup and treatment responses vary widely. Although inflammasome dysregulation is central to many SAIDs, recent studies suggest that additional immune pathways may also contribute to disease activity. Methods We integrated bulk transcriptomic and plasma proteomic data from SAID patients and negative controls, generated using the NovaSeq 6000 and SomaScan platform, respectively. We assessed the expression patterns of four inflammation-related genes (IL1B, IL6, IL18 and BLNK) and evaluated differential expression between patients and controls, and between initial and follow-up samples. We constructed protein-protein interaction (PPI) networks of the transcripts and proteins, then performed a functional enrichment analysis to identify gene sets that were significantly enriched in each PPI network. Results Transcriptomic profiling identified 1,805 differentially expressed transcripts. BLNK showed significant inverse correlations with IL1B and IL18, whereas BLNK and IL6 were correlated with B-cell proportions. Among the top 50 upregulated transcripts, three enriched groups were identified: associated with secretory granules, haemoglobin complexes and adaptive immune responses. Differential proteomic analysis identified 1217 differentially abundant proteins; the top 50 upregulated proteins were categorised into four groups related to complement activation, the acute-phase response, neutrophil migration and extracellular matrix organisation. Finally, we observed transcriptomic and proteomic expression changes during follow-up. Conclusions Our analyses reveal the diverse inflammatory signatures observed across patients. These findings underscore the complexity of SAID pathophysiology and could help refine hypotheses regarding disease mechanisms and patient stratification.

Immune responses in systemic autoinflammatory disease (SAID) were investigated by multi-omics analysis, integrating RNA expression and proteomic data. By identifying the top 10 co-expressed transcripts of IL1B and BLNK, we demonstrated the simultaneous activation of pro- and anti-inflammatory pathways in 338 SAID patients, with less activation in 68 negative controls. Our findings highlight the role of adaptive immune system-related genes in SAID, suggesting a reciprocal relationship between innate and adaptive immunity. Notably, negative controls exhibited active immune responses despite the absence of symptoms, an important consideration for data interpretation. In addition, we demonstrated how transcriptomic and proteomic profiling using heatmaps can verify treatment response, using the top 30 transcripts from 19 ANA-positive SAID patients and the top 30 proteins from 60 SAID patients with follow-up samples. These findings advance our understanding of the pathology of SAID and provide a valuable framework for treatment monitoring.