Interferon-complement loop in transplant-associated thrombotic microangiopathy

Abstract

Transplant-associated thrombotic microangiopathy (TA-TMA) is an important cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). The complement inhibitor eculizumab improves TA-TMA, but not all patients respond to therapy, prompting a search for additional targetable pathways of endothelial injury. TA-TMA is relatively common after HSCT and can serve as a model to study mechanisms of tissue injury in other thrombotic microangiopathies. In this work, we performed transcriptome analyses of peripheral blood mononuclear cells collected before HSCT, at onset of TA-TMA, and after resolution of TA-TMA in children with and without TA-TMA after HSCT. We observed significant upregulation of the classical, alternative, and lectin complement pathways during active TA-TMA. Essentially all upregulated genes and pathways returned to baseline expression levels at resolution of TA-TMA after eculizumab therapy, supporting the clinical practice of discontinuing complement blockade after resolution of TA-TMA. Further analysis of the global transcriptional regulatory network showed a notable interferon signature associated with TA-TMA with increased STAT1 and STAT2 signaling that resolved after complement blockade. In summary, we observed activation of multiple complement pathways in TA-TMA, in contrast to atypical hemolytic uremic syndrome (aHUS), where complement activation occurs largely via the alternative pathway. Our data also suggest a key relationship between increased interferon signaling, complement activation, and TA-TMA. We propose a model of an “interferon-complement loop” that can perpetuate endothelial injury and thrombotic microangiopathy. These findings open opportunities to study novel complement blockers and combined anti-complement and anti-interferon therapies in patients with TA-TMA and other microangiopathies like aHUS and lupus-associated TMAs.

Complement activation and endothelial perturbation parallel COVID-19 severity and activity

“…However, the activation of the classical pathway by antibodies against the different viral epitopes cannot be excluded. Moreover, interferon may regulate the synthesis of complement components by various cell types [ 28 , 29 ], and the larger availability of complement components may fuel the increase in the levels of activation products. Interferon may activate complement in a rare vasculopathy, Degos Disease [ 30 ] but to date there is no evidence for such mechanisms in COVID-19.…”

Thinking Beyond HLH: Clinical Features of Patients with Concurrent Presentation of Hemophagocytic Lymphohistiocytosis and Thrombotic Microangiopathy

“…Our previous gene expression analysis in autologous stem cell recipients showed upregulation of interferon-responsive complement genes at the onset of TA-TMA that resolved after therapy with complement blocking Additional information is listed in Supplemental Table 1 a Clinically attributed to HLH diagnosis b Perinatal intraventricular hemorrhage (IVH) Fig. 1 Outcomes of patients with HLH based on treatment received agent eculizumab [32]. High levels of IFNγ promote the formation of neutrophil extracellular traps (NETs), leading to complement activation via complement factor P (CFP) [33].…”

From COVID-19 to clot: the involvement of the complement system

“…Eculizumab is a long-acting humanized monoclonal antibody targeted against complement protein C5. It inhibits the cleavage of C5 into C5a and C5b and hence prevents the generation of the terminal complement complex C5b-9 ( Figure 1), which is involved in cell lysis (Jodele et al, 2020). Eculizumab has also been successfully used to protect against microvascular thrombosis in patients with atypical hemolytic uremic syndrome (Legendre et al, 2013) Diurno et al (2020) presented a case series aimed at reporting preliminary data obtained with anti-complement C5 therapy with eculizumab in COVID-19 patients admitted to intensive care unit with severe pneumonia or acute respiratory distress syndrome in Napoli, Italy.…”