Glycogen synthase kinase 3β/CCR6‐positive bone marrow cells correlate with disease activity in multicentric Castleman disease‐TAFRO

Abstract

Multicentric Castleman disease-thrombocytopenia, anasarca, reticulin fibrosis of bone marrow, renal dysfunction and organomegaly (MCD-TAFRO) -is an emergent phenotype characterized by lymphoproliferation, fluid collection, hemocytopenia and multiple organopathy. Although studies have demonstrated an aberrant blood cytokine/chemokine profile referred to as "chemokine storm", the pathogenesis remains unclear. We aimed to identify pathogenic key molecules, potential diagnostic targets and therapeutic markers in MCD-TAFRO using serum cytokine/chemokine profiles. We performed the targeted cytokine/chemokine multiplex analysis in six cases of MCD-TAFRO with remission or non-remission status. We observed significant changes in serum concentrations of CCL2, CCL5, and Chitinase-3-like-1 in the MCD-TAFRO patients with active state compared to inactive state. Ingenuity pathway analysis revealed that glycogen synthase kinase 3 (GSK3) and CCR6, which is expressed in megakaryocytes, were detected as upstream positive regulators for activating MCD-TAFRO status. More GSK3b + CCR6 + cells like megakaryocytes were detected in the bone marrow of patients with MCD-TAFRO than in those with systemic lupus erythematosus, MCD-not otherwise specified or autoimmune haemophagocytic lymphohistiocytosis. The cellularity of GSK3b + CCR6 + cells was correlated with disease activity, including thrombocytopenia and anaemia. In conclusion, GSK3b and CCR6 of bone marrow cells were potentially involved in the pathogenesis of MCD-TAFRO and may act as diagnostic targets and therapeutic markers.

Tacrolimus Treatment for TAFRO Syndrome

“…Bacterial infection [29] Toxic epidermal necrolysis [33] Cyclosporine A Hepatotoxicity [20,30,[34][35][36] Renal toxicity [37] Thrombotic microangiopathy [38] Combination therapy with glucocorticoid Tocilizumab Bacterial infection [20,[39][40][41][42][43] CMV infection [37,[43][44][45][46] Fungal infection [40,42] Cyclosporine A…”

“…Although cyclosporine A has been widely used in the treatment of TAFRO syndrome [13], information regarding cases treated using tacrolimus remains limited. To the best of our knowledge, only four studies have reported the use of tacrolimus treatment for TAFRO syndrome [20,38,55,56] (Table 2), excluding one in which the duration of tacrolimus use was markedly short to evaluate its efficacy [33]. Among these studies, we first described two cases of TAFRO syndrome that were successfully treated using tacrolimus [20].…”

“…Considering the possibility of multiple pathogeneses of TAFRO syndrome, including T-cell and B-cell/plasma cell-dominant variants, it may be reasonable to consider rituximab or tocilizumab as first-line treatments instead of tacrolimus, particularly in patients who are already taking tacrolimus at the onset of TAFRO syndrome. Moreover, Abe et al reported cases of TAFRO syndrome that were refractory to tacrolimus treatment but were effectively treated with cyclosporine A [38]. Both cyclosporine A and tacrolimus exert their immunosuppressive effects by binding to calcineurin on activated T-cells; however, they bind to different binding proteins, cyclophilins, and FK506-binding proteins, respectively [18,19].…”

TAFRO Syndrome and COVID-19

“…Although some researchers have demonstrated that TAFRO syndrome and iMCD-TAFRO are different disease entities, they share similar pathophysiologies involving cytokine storms [ 2 , 4 , 7 ]. For instance, elevated levels of interferon (IFN) γ-inducible protein 10 kDa, IL-10, IL-23, chemokine C-X-C motif chemokine ligand (CXCL) 13, IL-6, and VEGF are reported in iMCD-TAFRO, whereas elevated levels of IL-6 and VEGF are seen in TAFRO syndrome [ 24 , 25 , 26 , 27 , 28 ]. The Janus kinase/signal transducers and activators of transcription (JAK/STAT) and phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathways have been suggested to be involved in the cytokine storms seen in iMCD-TAFRO and TAFRO syndrome [ 4 , 28 ].…”

TAFRO syndrome: A disease that known is half cured

“…Abe et al. also performed proteomic analysis of multiple serum cytokines/chemokines in six patients with MCD‐TAFRO in remission versus nonremission 34 . Significant changes in chemokine and growth factor levels (e.g., CCL2/MCP1, CCL5/RANTES, and CHI3L1) were found after successful treatment of TAFRO syndrome with cyclosporine or tocilizumab.…”