Hyperglycemic Memory See article p. 807

Psoriasis Initiators See article p. 839

Aptamers That Block Complement See article p. 861

Better Graft-versus-Tumor Responses See article p. 892

In this Top Read, Xu et al. (p. 861) demonstrate that slow off-rate modified aptamers (SOMAmers) can bind human factor B (FB) and block the alternative pathway (AP) of the complement cascade. Initial screening revealed a SOMAmer, SL1100, with a high affinity to FB. Substituting 2′-O-methyl ribose for 2′-deoxyribose at certain nucleotide positions resulted in two aptamers, SL1102 and SL1103, with high affinity and enhanced nuclease resistance. This family of SOMAmers bind FB and inhibit complement AP in a dose-dependent manner. Analyses of crystal structures indicate that both SL1102 and SL1103 bind FB at the juncture of the CCP1, CCP3, and von Willebrand factor domains, which correspond to the binding site for C3b. Consequently, the binding of SL1102/SL1103 to FB blocks formation of active C3 convertase. These data provide evidence that SOMAmers have the potential to be used as therapeutics in disease states, such as Alzheimer’s disease, which involve complement activation in their pathology.

Psoriasis is a chronic skin disorder that is thought to be initiated by the sustained secretion of IL-23 by skin-resident dendritic cells, which promotes production of type 17 cytokines from T cells to propagate skin inflammation. The triggers of psoriasis have been difficult to identify, but mutations in the Card14 locus have been linked to psoriasis susceptibility. In this Top Read, Zhang et al. (p. 839) use the CARD14-E138A-mutated (Card14E138A/+) psoriasis mouse model crossed with Il17a−/− or Il23−/− mice to investigate triggers of psoriasis. Mice lacking IL-17A still developed skin inflammation, whereas IL-23 deletion was associated with a dramatic decrease in psoriasis-like lesions. Conditional deletion of CARD14-interacting proteins MALT1 or BCL10 in Card14E138A/+ keratinocytes was also associated with a major reduction in skin inflammation and lesion formation, which suggests a role for keratinocytes in initiating psoriasis. Moreover, deletion of MALT1 paracaspase activity ameliorated skin inflammation, further indicating a role for MALT1 in psoriasis pathogenesis and highlighting a pathway that could be targeted therapeutically.

The graft-versus-tumor (GVT) response, mediated by donor-derived lymphocytes, can target and destroy malignant cells. However, donor lymphocyte infusion (DLI) or allogeneic hematopoietic stem cell transplantation (allo-HCT) have been only partially effective in mediating GVT for the treatment of different leukemias and lymphomas. In this Top Read, Ciavattone et al. (p. 892) describe the development of a synthetic MyD88 molecule linked to the ectopic domain of CD8α (CD8α:MyD88), which can be used for costimulation of donor CD8+ T cells to enhance antitumor activity. CD8α:MyD88 treatment of donor T cells augmented GVT responses in vitro and in mouse models of allo-HCT and DLI. These improved GVT responses were associated with increased CD8+ T cell expansion and potentiated their effector functions, including direct killing of tumor cells. CD8α:MyD88 costimulation was also associated with increased but nonlethal graft-versus-host disease in mice treated with donor T cells. Taken together, these results suggest that CD8+ T cell–targeted MyD88 costimulation may be an effective strategy for enhancing GVT responses.

Hyperglycemia is a major factor that drives diabetes-associated complications and elevated inflammation, termed “hyperglycemic memory.” The mechanisms by which hyperglycemia triggers these responses are not well defined, and in this Top Read, Thiem et al. (p. 807) demonstrate that hyperglycemia can induce trained immunity in monocytes and macrophages through epigenetic regulation. Transplantation of bone marrow (BM) from hyperglycemic to normoglycemic mice was associated with elevated TNF-α following LPS treatment, when compared with BM transplantation from normoglycemic mice. A similar proinflammatory response was seen in human monocytes cultured under high glucose conditions and restimulated with LPS. Analysis of CD14+ monocytes from patients with type 1 diabetes and healthy controls revealed upregulation of genes involved in glycolysis and epigenetic enzymes, particularly members of the mixed lineage leukemia (MLL) gene family. Treatment of monocytes under hyperglycemic conditions with an MLL inhibitor reduced proinflammatory responses upon LPS stimulation. In addition, trained immunity in these cells required lactate production. Together, these findings demonstrate that epigenetic training of immune responses in monocytes is critical for hyperglycemia-associated inflammation.