Functional flow cytometry of monocytes for routine diagnosis of innate primary immunodeficiencies

Transplantation and immunomodulatio

Genetic, immunological, and clinical features of 32 patients with autosomal recessive STAT1 deficiency

Autosomal recessive (AR) STAT1 deficiency is a severe inborn error of immunity disrupting cellular responses to type I, II, and III IFNs, and IL-27, and conferring a predisposition to both viral and mycobacterial infections.We report the genetic, immunological, and clinical features of an international cohort of 32 patients from 20 kindreds: 24 patients with complete deficiency, and 8 patients with partial deficiency. Twenty-four patients suffered from mycobacterial disease (bacillus Calmette Guerin = 13, environmental mycobacteria = 10, or both in 1 patient). Fifty-four severe viral episodes occurred in sixteen patients, mainly caused by Herpesviridae viruses. Attenuated live measles, mumps, and rubella and/or varicella zoster virus vaccines triggered severe reactions in the five patients with complete deficiency who were vaccinated. Seven patients developed features of hemophagocytic syndrome. Twenty-one patients died, and death was almost twice as likely in patients with complete STAT1 deficiency than in those with partial STAT1 deficiency. All but one of the eight survivors with AR complete deficiency underwent hematopoietic stem cell transplantation. Overall survival after hematopoietic stem cell transplantation was 64%. A diagnosis of AR STAT1 deficiency should be considered in children with mycobacterial and/or viral infectious diseases. It is important to distinguish between complete and partial forms of AR STAT1 deficiency, as their clinical outcome and management differ significantly

The expansion of human T-bet(high)CD21(low) B cells is T cell dependent

Accumulation of human CD21(low) B cells in peripheral blood is a hallmark of chronic activation of the adaptive immune system in certain infections and autoimmune disorders. The molecular pathways underpinning the development, function, and fate of these CD21(low) B cells remain incompletely characterized. Here, combined transcriptomic and chromatin accessibility analyses supported a prominent role for the transcription factor T-bet in the transcriptional regulation of these T-bet(high)CD21(low) B cells. Investigating essential signals for generating these cells in vitro established that B cell receptor (BCR)/interferon-gamma receptor (IFN gamma R) costimulation induced the highest levels of T-bet expression and enabled their differentiation during cell cultures with Toll-like receptor (TLR) ligand or CD40L/interleukin-21 (IL-21) stimulation. Low proportions of CD21(low) B cells in peripheral blood from patients with defined inborn errors of immunity (IEI), because of mutations affecting canonical NF-kappa B, CD40, and IL-21 receptor or IL-12/IFN gamma/IFN gamma receptor/signal transducer and activator of transcription 1 (STAT1) signaling, substantiated the essential roles of BCR- and certain T cell-derived signals in the in vivo expansion of T-bet(high)CD21(low) B cells. Disturbed TLR signaling due to MyD88 or IRAK4 deficiency was not associated with reduced CD21(low) B cell proportions. The expansion of human T-bet(high)CD21(low) B cells correlated with an expansion of circulating T follicular helper 1 (cTfh1) and T peripheral helper (Tph) cells, identifying potential sources of CD40L, IL-21, and IFN gamma signals. Thus, we identified important pathways to target autoreactive T-bet(high)CD21(low) B cells in human autoimmune conditions, where these cells are linked to pathogenesis and disease progression.Transplantation and immunomodulatio