Astrocyte activation is associated with inflammatory demyelination in multiple sclerosis. Lu et al. show the key role for DRD2/PTS/PKCδ axis in the modulation of astrocyte activation. Its therapeutic inhibition may provide a potent lever to alleviate autoimmune diseases.
Pathogenic autoantibodies to IFN-γ act through the impedance of receptor assembly and Fc-mediated response
The pathogenic anti–IFN-γ autoantibodies belong to three groups based on their epitopes, leading to two signal-related neutralization modes by preventing IFN-γ binding to the receptor or IFN-γ–induced receptor dimerization. Moreover, anti–IFN-γ autoantibodies selectively induce Fc-mediated responses, potentiating their pathogenic functions.
This study shows that CD38 is a new member of the IgM-BCR coreceptor; it associates with CD19 in unstimulated B cells and with CD19 and IgM after BCR stimulation. Targeting CD38 with an antibody impairs B cell proliferation and survival, and formation of IgM:CD19 synapses.
Developing high-affinity decoy receptors to treat multiple myeloma and diffuse large B cell lymphoma
Miao et al. demonstrate the dichotomous activities of APRIL and BAFF in MM and DLBCL, which can be safely targeted by an engineered decoy receptor designed to trap both ligands with ultra-high binding affinity.
Plasma and memory antibody responses to Gamma SARS-CoV-2 provide limited cross-protection to other variants
This paper describes the plasma and memory antibody response in a cohort of SARS-CoV-2 Gamma-infected individuals in Brazil. Potent antibody neutralization was shown to be limited to Gamma and Beta, and epitope recognition skewed to Class 3 epitopes.
Augmenting neurogenesis rescues memory impairments in Alzheimer’s disease by restoring the memory-storing neurons
Deficits in hippocampal neurogenesis cause cognitive impairments in Alzheimer’s disease by compromising memory storage. Augmenting neurogenesis rescues memory by recruiting more new neurons with restored spine density and transcription profile. AD-linked genes regulate the memory-storing neurons.
Biallelic PAX5 mutations cause hypogammaglobulinemia, sensorimotor deficits, and autism spectrum disorder
A mouse model carrying biallelic Pax5 mutations identified in a patient with hypogammaglobulinemia and autism spectrum disorder shows a B cell developmental arrest and autistic-like behavior caused by abnormal development of the cerebellum and loss of ventral midbrain GABAergic neurons.
Brief Definitive Report
Karo-Atar et al. demonstrate direct regulation of the intestinal stem cell compartment by an enteric helminth, resulting in expansion of fetal-like stem cells and inhibition of secretory cells. They establish how a helminth parasite co-opts a tissue development program to counter type 2 immune-mediated expulsion.
Deseke et al. use soluble γδ TCRs and CRISPR/Cas9-mediated screening to identify the MHC class II surface receptor HLA-DR as the cognate TCR ligand of a CMV-induced Vδ1+ γδ T cell clone, which is cross-recognizing leukemia cells.
Using monoclonal antibodies built from SARS-CoV-2–specific memory B cells, Hale et al. demonstrate that IgM antibodies outperform IgG in neutralization assays against mutated variants. The authors suggest that IgM antibodies may be useful therapeutically, and that IgM memory B cells may be underappreciated protectors against rapidly evolving pathogens.
Technical Advances and Resources
Single-cell RNA sequencing of zebrafish hematopoiesis provides new insights into zebrafish B- and T-cell development and cellular diversity within the primary lymphoid organs (kidney marrow and thymus). This work advances the current understanding of zebrafish immunology and will facilitate future genetic and developmental studies.