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Summary: We characterized Mycobacterium bovis BCG isolates found in lung and brain samples from a previously vaccinated patient with IFNγR1 deficiency. The isolates collected displayed distinct genomic and phenotypic features consistent with host adaptation and associated changes in antibiotic susceptibility and virulence traits. Background: We report a case of a patient with partial recessive IFNγR1 deficiency who developed disseminated BCG infection after neonatal vaccination (BCG-vaccine). Distinct M. bovis BCG-vaccine derived clinical strains were recovered from the patient’s lungs and brain. Methods: BCG strains were phenotypically (growth, antibiotic susceptibility, lipid) and genetically (whole genome sequencing) characterized. Mycobacteria cell infection models were used to assess apoptosis, necrosis, cytokine release, autophagy, and JAK-STAT signaling. Results: Clinical isolates BCG-brain and BCG-lung showed distinct Rv0667 rpoB mutations conferring high- and low-level rifampin resistance; the latter displayed clofazimine resistance through Rv0678 gene (MarR-like transcriptional regulator) mutations. BCG-brain and BCG-lung showed mutations in fadA2, fadE5, and mymA operon genes, respectively. Lipid profiles revealed reduced levels of PDIM in BCG-brain and BCG-lung and increased TAGs and Mycolic acid components in BCG-lung, compared to parent BCG-vaccine. In vitro infected cells showed that the BCG-lung induced a higher cytokine release, necrosis, and cell-associated bacterial load effect when compared to BCG-brain; conversely, both strains inhibited apoptosis and altered JAK-STAT signaling. Conclusions: During a chronic-disseminated BCG infection, BCG strains can evolve independently at different sites likely due to particular microenvironment features leading to differential antibiotic resistance, virulence traits resulting in dissimilar responses in different host tissues.

Mycobacterium genavense is a challenging opportunistic pathogen to diagnose and manage in patients with human immunodeficiency virus (HIV). Persistent immunosuppression or protracted immune reconstitution inflammatory syndrome can lead to complicated clinical courses. We describe 3 cases of M. genavense in patients with HIV representing the spectrum between disease burden and strength of immune response.

Dedicator-of-cytokinesis 8 (DOCK8) deficiency, a primary immunodeficiency disease, can be reversed by allogeneic hematopoietic stem cell transplantation (HSCT); however, there are few reports describing the use of alternative donor sources for HSCT in DOCK8 deficiency. We describe HSCT for patients with DOCK8 deficiency who lack a matched related or unrelated donor using bone marrow from haploidentical related donors and post-transplantation cyclophosphamide (PT/Cy) for graft-versus-host disease (GVHD) prophylaxis. Seven patients with DOCK8 deficiency (median age, 20 years; range, 7 to 25 years) received a haploidentical related donor HSCT. The conditioning regimen included 2 days of low-dose cyclophosphamide, 5 days of fludarabine, 3 days of busulfan, and 200 cGy total body irradiation. GVHD prophylaxis consisted of PT/Cy 50 mg/kg/day on days +3 and +4 and tacrolimus and mycophenolate mofetil starting at day +5. The median times to neutrophil and platelet engraftment were 15 and 19 days, respectively. All patients attained >90% donor engraftment by day +30. Four subjects developed acute GVHD (1 with maximum grade 3). No patient developed chronic GVHD. With a median follow-up time of 20.6 months (range, 9.5 to 31.7 months), 6 of 7 patients are alive and disease free. Haploidentical related donor HSCT with PT/Cy represents an effective therapeutic approach for patients with DOCK8 deficiency who lack a matched related or unrelated donor. Published by Elsevier Inc. on behalf of the American Society for Blood and Marrow Transplantation.

Lyons et al. show that STAT3 negatively regulates TGF-β signaling via ERBIN and that cell-intrinsic deregulation of TGF-β pathway activation promotes the IL-4/IL-4Rα/GATA3 axis to support atopic phenotypes in humans., Nonimmunological connective tissue phenotypes in humans are common among some congenital and acquired allergic diseases. Several of these congenital disorders have been associated with either increased TGF-β activity or impaired STAT3 activation, suggesting that these pathways might intersect and that their disruption may contribute to atopy. In this study, we show that STAT3 negatively regulates TGF-β signaling via ERBB2-interacting protein (ERBIN), a SMAD anchor for receptor activation and SMAD2/3 binding protein. Individuals with dominant-negative STAT3 mutations (STAT3mut) or a loss-of-function mutation in ERBB2IP (ERBB2IPmut) have evidence of deregulated TGF-β signaling with increased regulatory T cells and total FOXP3 expression. These naturally occurring mutations, recapitulated in vitro, impair STAT3–ERBIN–SMAD2/3 complex formation and fail to constrain nuclear pSMAD2/3 in response to TGF-β. In turn, cell-intrinsic deregulation of TGF-β signaling is associated with increased functional IL-4Rα expression on naive lymphocytes and can induce expression and activation of the IL-4/IL-4Rα/GATA3 axis in vitro. These findings link increased TGF-β pathway activation in ERBB2IPmut and STAT3mut patient lymphocytes with increased T helper type 2 cytokine expression and elevated IgE.

Background Sjögren’s syndrome (SS) is an autoimmune disease characterized by immune attack on the salivary and lacrimal glands. Given the known cytokine activation and type I interferon gene expression signature found in SS, we hypothesized that anticytokine autoantibodies might be detectable by Luciferase immunoprecipitation systems in some SS patients and correlate with clinical symptoms. Results Luciferase immunoprecipitation systems was used to screen for serum anti-cytokine autoantibodies in 57 primary SS patients and 25 healthy volunteers. Autoantibodies were detected against GMCSF, interferon-γ, -α and, -ω in one, two, two and six patients with SS, respectively. None of the healthy volunteers showed anticytokine autoantibodies and none of the SS or control subjects showed autoantibodies against interferon-λ. One 51-year old female SS subject with the highest anti-interferon-α and -ω autoantibody levels had stable autoantibody levels over the course of a year. In vitro functional testing of serum autoantibodies from this subject demonstrated partially neutralizing activity for interferon-α signaling. Clinical information on this individual revealed a low focus score and high levels of unstimulated salivary flow, suggesting the possibility that interferon-α autoantibody neutralizing activity may have contributed to the milder sicca symptoms. Conclusion Overall, these findings demonstrate that a subset of SS patients (16%) harbor autoantibodies against GMCSF, interferon-γ, interferon-ω, and interferon-α. These data support the observation that high levels of interferon-α autoantibodies may attenuate disease symptoms in SS.

Treatment of PML with Pembrolizumab A patient with variable immunodeficiency and progressive multifocal leukoencephalopathy was treated with five pembrolizumab infusions. The CSF JC viral load went...

Monozygotic twins with GATA2 deficiency: same haploidentical-related donor, different severity of GvHD

Heterozygous GATA2 mutation is associated with immunodeficiency, lymphedema, and myelodysplastic syndrome. Disease presentation is variable, often coinciding with loss of circulating dendritic cells, monocytes, B cells, and natural killer (NK) cells. Nonetheless, in a proportion of patients carrying GATA2 mutation, NK cells persist. We found that peripheral blood NK cells in symptomatic patients uniformly lacked expression of the transcription factor promyelocytic leukemia zinc finger (PLZF), as well as expression of intracellular signaling proteins FceRγ, spleen tyrosine kinase (SYK), and EWS/FLI1-Activated Transcript 2 (EAT-2) in a variegated manner. Moreover, consistent with an adaptive identity, NK cells from patients with GATA2 mutation displayed altered expression of cytotoxic granule constituents and produced interferon-γ upon Fc-receptor engagement but not following combined interleukin-12 (IL-12) and IL-18 stimulation. Canonical, PLZF-expressing NK cells were retained in asymptomatic carriers of GATA2 mutation. Developmentally, GATA-binding protein-2 (GATA-2) was expressed in hematopoietic stem cells, but not in NK-cell progenitors, CD3-CD56bright, canonical, or adaptive CD3-CD56dim NK cells. Peripheral blood NK cells from individuals with GATA2 mutation proliferated normally in vitro, whereas lineage-negative progenitors displayed impaired NK-cell differentiation. In summary, adaptive NK cells can persist in patients with GATA2 mutation, even after NK-cell progenitors expire. Moreover, our data suggest that adaptive NK cells are more long-lived than canonical, immunoregulatory NK cells.