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The transcription factors TCF1 and LEF1 promote self-renewal and regulatory functions in B-1a cells.

Inborn errors of the alternative NF-κB pathway in humans impair the development of AIRE-expressing medullary thymic epithelial cells, thereby underlying the production of autoantibodies against type I IFNs and predisposition to viral diseases

Dysregulated immune features in a patient with a homozygous loss-of-function mutation in PDCD1 suggest that IL-6, IL-23, STAT3 and RORγT might be potential targets for treatment of PD-1 blockade-induced autoimmunity.

The wide diversity of clinical and immunological phenotypes of patients with RAG deficiency, combined with structural characterization of the RAG protein complex, have provided new mechanistic insights into RAG protein function.

A recent study suggests that exposure to the mold Aspergillus induces the production of antibodies that neutralize interferon-γ (IFN-γ), which increases the risk of mycobacterial disease.

Patients who express a hyperactive mutant of the kinase PI3K exhibit defective humoral immunity. Preite et al. show that overactive PI3K leads to defective class-switched antigen-specific responses to immunization, despite augmented germinal-center formation and reactivity to commensal microbes and self antigens.

Here, the authors describe biallelic loss-of-function variants in human SHARPIN in individuals with autoinflammation and immunodeficiency, termed sharpenia. They also successfully treat one of these individuals with TNF inhibitors.

A quantitative morphological framework for the human thymus reveals the establishment of the lobular cytokine network, canonical thymocyte trajectories and thymic epithelial cell distributions in fetal and paediatric thymic development.

Human TNF is required for respiratory-burst-dependent immunity to Mycobacterium tuberculosis in macrophages but seems to be largely redundant physiologically.

Transcriptomic, proteomic and immune repertoire profiling reveals distinct peripheral features of MIS-C and pediatric COVID-19, including elevated soluble spike protein levels, more pronounced type II IFN-dependent gene expression and a higher B cell mutation rate in patients with MIS-C.

Mutations that impact the function of the Arp2/3 complex are known to cause inborn errors of immunity. Here the authors describe biallelic null mutations in the ARPC5 subunit of Arp2/3 that disrupt actin function and cytokine signaling, causing infections, autoimmunity, inflammation and dysmorphisms.

A study of two childhood cases of herpes simplex encephalitis shows that TMEFF1 interacts with the HSV-1 cell-surface receptor NECTIN-1, preventing HSV-1 from fusing with the cell membrane and entering cortical neurons.

Chen et al. generate lung bud organoids from human pluripotent stem cells that recapitulate early lung development, such as branching airway formation and early alveolar structures, which could potentially be used to model lung disease.

Patients with partial recombination-activating gene (RAG) deficiency (pRD) present variable late-onset autoimmune clinical phenotypes. Walter and colleagues identified a restricted primary B cell antigen receptor repertoire enriched for autoreactivity and clonal persistence in pRD. They described dysregulated B cell maturation with expansion of T-bet⁺ B cells revealing how RAG impacts stringency of tolerance and B cell fate in the periphery.

An autoimmune-prone state of steady-state cytokinopathy, hyperactivated CD4 T cells and ongoing B cell activation contributes to a breach in immune tolerance in individuals with Down’s syndrome.

The study of individuals with primary immunodeficiencies (PIDs) has helped to define mechanisms that control the development and function of the immune system. This Review focuses on recently characterized PIDs and describes the genetic defects that are associated with these disorders.

De Ravin et al. report an unplanned interim analysis of a secondary safety outcome for an ongoing clinical trial on lentiviral gene therapy for the treatment of X-linked Severe Combined Immunodeficiency (NCT01306019). Vector induced alternative splicing events are identified that cause aberrant fusion transcripts, leading to clonal dominance in a single patient and clonal expansion in others. This can be mitigated by the removal of the lentivector cryptic splice acceptor.

Herpes simplex virus-1 encephalitis is linked to variants in a small nucleolar RNA, suggesting a new mechanism for antiviral immunity in cortical neurons.

WASP is a novel tumor-suppressor gene in ALK-driven anaplastic large cell lymphoma through modulation of CDC42 and MAPK signaling and provides a rationale for combination therapy.

Deficiency in Wiskott-Aldrich syndrome protein (WASP) has been associated with autoimmune colitis, but the underlying mechanism is still unclear. Here the authors show that WASP deficiency is associated with defective WASP/DOCK8 complex formation, altered IL-10 signalling, and impaired anti-inflammatory macrophage functions.

Whole-genome sequencing analysis of individuals with primary immunodeficiency identifies new candidate disease-associated genes and shows how the interplay between genetic variants can explain the variable penetrance and complexity of the disease.

Dock8 deficiency leads to defects in humoral immunity. Geha and colleagues show that Dock88 interacts with MyD88 to bridge TLR9 signaling to the Src-Syk-STAT3 pathway to promote B cell proliferation and differentiation.

The linear ubiquitination complex (LUBAC) is poorly understood in humans. Casanova and colleagues identify natural mutations in a component of human LUBAC and use this to dissect its function in vivo and in vitro.

Neurons and oligodendrocytes differentiated from induced pluripotent stem cells (iPSCs) of patients with inherited TLR3 and UNC-93B deficiencies are found to be more susceptible to infection by HSV-1 than control cells because they fail to induce a normal interferon response, whereas neural stem cells and astrocytes are not susceptible.

Raif Geha, Louis Kunkel, Waleed Al-Herz and colleagues report a mutation in TFRC (encoding transferrin receptor 1, TfR1) that causes combined immunodeficiency characterized by impaired function of T and B cells in homozygous patients. Iron citrate rescued the lymphocyte defects in patient-derived cells and in a mouse model, demonstrating the importance of TfR1-mediated iron internalization in adaptive immunity.

ISG15 deficiency in humans leads to a failure to maintain adequate levels of USP18, triggering an increase in type I interferon production and signalling, and promoting auto-inflammatory disease.

Severe combined immunodeficiencies comprise a group of rare, monogenic diseases that are characterized by an early onset and a profound block in T lymphocyte development. In this Primer, Fischer and colleagues explain the pathogenesis of this disorder with a focus on current and future treatment strategies.

The COVID Human Genetic Effort examines the molecular, cellular and immunological determinants of the various SARS-CoV-2-related disease manifestations by searching for causal errors of immunity.