BK virus (BKV) load in urine alone or in combination with acute graft-versus-host disease (GVHD) was correlated to development of hemorrhagic cystitis (HC). BKV load in combination with acute GVHD discriminated the best, while BKV and viral load alone, but not GVHD, still showed predictive ability for HC.

The influence of conditioning regimen, donor background and HLA matching on development of BK virus (BKV)-associated haemorrhagic cystitis (HC) was examined in 175 allogeneic haematopoietic stem cell transplant (HSCT) patients, undergoing 179 HSCT events. Twentyseven patients presented late-onset HC, and BK viruria was verified in 23/27 HC events. Seventy-one (40%) HSCTs were performed with myeloablative conditioning (MC), 108 (60%) were performed with reduced intensity conditioning (RIC), 66 (37%) were performed with a related donor (RD) grafts and 113 (63%) with an unrelated donor (URD) graft. BK viruria was more common during HC, than non-HC events, after MC as compared to RIC (both Po0.001), and with an HLA-mismatched donor (Po0.01). By multivariate logistical regression analysis, independent risk factors for HC were BKV (OR 6.7; 95% CI 2.0-21.7; P ¼ 0.001), MC (OR 6.0; 95% CI 2.1-17.3; Po0.001) and URD (OR 3.4; 95% CI 1.1-10.6; P ¼ 0.03). However, when analysing HSCT performed with URD or RD grafts separately, BKV (OR 8.5; 95% CI 1.8-19.3; P ¼ 0.004) and MC (OR 5.9; 95% CI 1.3-11.3; P ¼ 0.009) increased the risk for HC only with a URD, but not with an RD graft.

Immune responses need to be controlled tightly to prevent autoimmune diseases, yet underlying molecular mechanisms remain partially understood. Here, we identify biallelic mutations in three patients from two unrelated families in differentially expressed in FDCP6 homolog (DEF6) as the molecular cause of an inborn error of immunity with systemic autoimmunity. Patient T cells exhibit impaired regulation of CTLA-4 surface trafficking associated with reduced functional CTLA-4 availability, which is replicated in DEF6 -knockout Jurkat cells. Mechanistically, we identify the small GTPase RAB11 as an interactor of the guanine nucleotide exchange factor DEF6, and find disrupted binding of mutant DEF6 to RAB11 as well as reduced RAB11 + CTLA-4 + vesicles in DEF6 -mutated cells. One of the patients has been treated with CTLA-4-Ig and achieved sustained remission. Collectively, we uncover DEF6 as player in immune homeostasis ensuring availability of the checkpoint protein CTLA-4 at T-cell surface, identifying a potential target for autoimmune and/or cancer therapy.

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