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EDITORIALS
Metchnikoff’s legacy: the dysplastic nature of innate immunity in myelodysplastic syndromes
Peter L. Greenberg
Stanford Cancer Institute, Stanford, CA, USA
E-mail: PETER L. GREENBERG - peterg@stanford.edu
doi:10.3324/haematol.2021.279419
Over a century ago, Metchnikoff’s seaside investiga- tions into a eukaryotic organism’s response to induced inflammation led to the beginning of our understand- ing of the innate immune system.1 The imbalance of the lym- phoid/macrophage components of this system in myelodsy- plastic syndromes (MDS) generates an adverse immunological mileau for the development of autoimmune disorders in this spectrum of diseases. Given the inherent contribution of myeloidandlymphoidcellstoinnateimmunity,itisnotunex- pected that the dysregulation of these cells has an impact on chronic myeloid clonal blood disorders, particularly MDS.2 The cytopenias and potential for progression of these disor- ders are generated predominantly by their immunological abnormalities, inflammatory bone marrow microenviron- ment, hematopoietic stem cell mutation status and vulnerabil- ity to inhibitory cytokines.
Multiple epidemiological and clinical studies have demon- strated an increased incidence (10-30%) of autoimmune and inflammatory disorders in association with MDS,3-5 ranging from limited hematologic manifestations, such as autoim- mune hemolytic anemia and immune thrombocytopenic purpura, to systemic diseases affecting multiple organs, including vasculitis, connective tissue diseases, inflammatory arthritis and neutrophilic diseases.3-5 Some of these disorders may be associated with adverse outcomes (e.g., vasculitis) or progression of the MDS. Conversely, patients with autoim- mune disorders are more likely to develop MDS than are members of the general population.6
Studies evaluating the deranged biological processes involving innate immunity which underlie the meshing of these neoplastic and autoimmune/inflammatory diseases have provided important insights into the pathogenesis of their co-occurence. Regulatory T cells (Treg) play a critical role in controlling inflammation and autoimmune disorders7 and are present at a high frequency in the bone marrow. In lower- risk MDS, the number of Treg was shown to be decreased, thereby potentially permitting the emergence of autoim- mune responses, including those directed against the dys- plastic clone.8 In addition, it was separately demonstrated that there are interleukin (IL)-17 producing T cells and elevat- ed serum levels of the pro-inflammatory cytokines IL-7, IL- 12, RANTES and interferon-γ in lower-risk MDS. In chronic myelomonocytic leukemia (CMML) and some MDS patients, monocytes demonstrate a strikingly abnormal func- tional imbalance, comprised of >90% classical type mono- cytes,9 which, upon pathogen stimulation, produce high lev- els of a broad range of cytokines, including granulocyte colony-stimulating factor, IL-10, CCL2, IL-6 and S100 inflam- matory proteins. The latter proteins are generated in response to activation of pyroptosis, an inflammasome- mediated process of cell death in myeloid clonal disorders.2 Increased responsiveness of neoplastic CMML hematopoiet- ic precursor cells to microenvironmental inflammatory cytokines, such as granulocyte-macrophage colony-stimulat- ing factor, has also been demonstrated.
The size of a cell population is orchestrated by apoptosis, an ordered form of programmed cell death, which occurs variably during different stages of a disease trajectory. However, in the clinical setting in which inflammatory disor- ders occur, pyroptosis generated by activated inflamma- somes also contributes substantially to cell death in MDS.2 Inflammasomes are a class of intracellular poly-protein com- plexes primarily composed of a sensor, an adaptor protein and an effector.10,11 The nucleotide-binding domain-(NOD) like receptor NLRP3, is a redox-sensitive cytosolic sensor that recruits the ASC (apoptosis-associated speck-like protein containing a caspase-recruitment domain) adaptor protein. NEK7, a member of the NIMA-related kinase (NEK) family, is implicated in the control of inflammasome effector func- tion.12 In response to diverse pathogenic stimuli that trigger a cascade of downstream reactions, disordered cellular homeo- stasis, including mitochondrial dysfunction and toll receptor signaling via reactive oxygen species (ROS) are signals that regulate NEK7-mediated NLRP3 inflammasome activation.10- 12 This interaction in turn causes polymerization of ASC into large cytoplasmic aggregates referred to as ASC specks, per- mitting docking and activation of caspase-1, which produces mature IL-1β and IL-18 (interferon-γ inducing factor) proin- flammatory cytokines that are secreted into the extracellular space as inflammatory effectors of pyroptosis.
In this issue of Haematologica, Wang et al.13 describe the presence in plasma of a marker (ASC specks) of pyroptotic cell death generated by activation of the inflammasome within MDS bone marrow cells from patients treated with recombinant erythropoietin and lenalidomide. The authors used confocal and electron microscopy to visualize and flow cytometry to quantify these specks, which are released upon cytolysis and circulate in peripheral blood for extended peri- ods because of their inherent resistance to degradation. They provide data suggesting the potential utility of such measure- ments to define inflammasome activation, identified by this pyroptotic biomarker (ASC specks) and suggest that this fea- ture, along with assessment of serum erythropoietin levels, may represent a method to detect lower-risk MDS patients whose anemia could benefit from treatment with lenalido- mide and erythropoietin. These findings provide a potential- ly useful approach to clinical assessment of inflammation. However, they require further confirmation, especially regarding their specificity and sensitivity for MDS patients’ responsiveness to therapy.
There is a genetic basis for the inflammatory phenomena contributing to some of the clinical conditions associated with MDS. Both germline and somatic mutations have been associated with myeloid-associated inflammatory diseases, including Schwachman-Diamond syndrome, an autosomal recessive inherited disease with bone marrow failure and inflammatory symptoms, and the myeloid-restricted cryopy- rin-associated periodic syndrome (CAPS), an autoinflamma- tory disease related to mutations in the NLRP3 gene.14 Polymoprhisms in this gene may play a role in the variable
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haematologica | 2022; 107(3