The phospholipid kinase PIKFYVE is essential for Th17 differentiation.

T helper 17 (Th17) cells are effector cells that mediate inflammatory responses to bacterial and fungal pathogens. While the cytokine signaling inputs required to generate Th17s are established, less is known about intracellular pathways that drive Th17 differentiation. Our previously published phosphoproteomic screen identifies that PIKFYVE, a lipid kinase that generates the phosphatidylinositol PtdIns(3,5)P2, is activated during Th17 differentiation.

NADPH oxidase in B cells and macrophages protects against murine lupus by regulation of TLR7.

Loss of NADPH oxidase (NOX2) exacerbates systemic lupus erythematosus (SLE) in mice and humans, but the mechanisms underlying this effect remain unclear. To identify the cell lineages in which NOX2 deficiency drives SLE, we employed conditional KO and chimeric approaches to delete Cybb in several hematopoietic cell lineages of MRL.Faslpr SLE-prone mice.

IL-12 induces a B cell-intrinsic IL-12/IFNγ feed-forward loop promoting extrafollicular B cell responses.

While some infections elicit germinal centers, others produce only extrafollicular responses. The mechanisms controlling these dichotomous fates are poorly understood. We identify IL-12 as a cytokine switch, acting directly on B cells to promote extrafollicular and suppress germinal center responses.

Sliding Window INteraction Grammar (SWING): a generalized interaction language model for peptide and protein interactions.

The explosion of sequence data has allowed the rapid growth of protein language models (pLMs). pLMs have now been employed in many frameworks including variant-effect and peptide-specificity prediction. Traditionally, for protein-protein or peptide-protein interactions (PPIs), corresponding sequences are either co-embedded followed by post-hoc integration or the sequences are concatenated prior to embedding.

Memory B cell subsets have divergent developmental origins that are coupled to distinct imprinted epigenetic states.

Memory B cells (MBCs) are phenotypically and functionally diverse, but their developmental origins remain undefined. Murine MBCs can be divided into subsets by expression of CD80 and PD-L2. Upon re-immunization, CD80/PD-L2 double-negative (DN) MBCs spawn germinal center B cells (GCBCs), whereas CD80/PD-L2 double-positive (DP) MBCs generate plasmablasts but not GCBCs.

B cell-intrinsic Myd88 regulates disease progression in murine lupus.

Nucleic acid-specific Toll-like receptors (TLRs) have been implicated in promoting disease pathogenesis in systemic lupus erythematosus (SLE). Whether such TLRs mediate disease onset, progression, or both remains undefined; yet the answer to this question has important therapeutic implications. MyD88 is an essential adaptor that acts downstream of IL-1 family receptors and most TLRs.

B cell-intrinsic TLR7 expression drives severe lupus in TLR9-deficient mice.

The endosomal Toll-like receptor 7 (TLR7) is a major driver of murine and human systemic lupus erythematosus (SLE). The role of TLR7 in lupus pathogenesis is enhanced when the regulatory role of TLR9 is absent. TLR7 signaling in plasmacytoid DCs (pDC) is generally thought to be a major driver of the IFN response and disease pathology; however, the cell types in which TLR7 acts to mediate disease have not been distinguished.

Age-associated B cells are heterogeneous and dynamic drivers of autoimmunity in mice.

Age-associated B cells (ABCs) are formed under inflammatory conditions and are considered a type of memory B cell (MBC) expressing the transcription factor T-bet. In SLE, ABC frequency is correlated with disease, and they are thought to be the source of autoantibody-secreting cells. However, in inflammatory conditions, whether autoreactive B cells can become resting MBCs is uncertain.

IL-21R signal reprogramming cooperates with CD40 and BCR signals to select and differentiate germinal center B cells.

Both B cell receptor (BCR) and CD40 signaling are rewired in germinal center (GC) B cells (GCBCs) to synergistically induce c-MYC and phosphorylated S6 ribosomal protein (p-S6), markers of positive selection. How interleukin-21 (IL-21), a key T follicular helper (T)-derived cytokine, affects GCBCs is unclear. Like BCR and CD40 signals, IL-21 receptor (IL-21R) plus CD40 signals also synergize to induce c-MYC and p-S6 in GCBCs.

Glucose Requirement of Antigen-Specific Autoreactive B Cells and CD4+ T Cells.

The activation of lymphocytes in patients with lupus and in mouse models of the disease is coupled with an increased cellular metabolism in which glucose plays a major role. The pharmacological inhibition of glycolysis with 2-deoxy-d-glucose (2DG) reversed the expansion of follicular helper CD4+ T cells and germinal center B cells in lupus-prone mice, as well as the production of autoantibodies. The response of foreign Ags was however not affected by 2DG in these mice, suggesting that B and CD4+ T cell activation by autoantigens is uniquely sensitive to glycolysis.

Genetic dissection of TLR9 reveals complex regulatory and cryptic proinflammatory roles in mouse lupus.

In lupus, Toll-like receptor 7 (TLR7) and TLR9 mediate loss of tolerance to RNA and DNA, respectively. Yet, TLR7 promotes disease, while TLR9 protects from disease, implying differences in signaling. To dissect this 'TLR paradox', we generated two TLR9 point mutants (lacking either ligand (TLR9) or MyD88 (TLR9) binding) in lupus-prone MRL/lpr mice.

Persistence of Virus-Specific Antibody after Depletion of Memory B Cells.

Humoral immunity is a major component of the adaptive immune response against viruses and other pathogens with pathogen-specific antibody acting as the first line of defense against infection. Virus-specific antibody levels are maintained by continual secretion of antibody by plasma cells residing in the bone marrow. This raises the important question of how the virus-specific plasma cell population is stably maintained and whether memory B cells are required to replenish plasma cells, balancing their loss arising from their intrinsic death rate.

Heterogeneity and clonality of kidney-infiltrating T cells in murine lupus nephritis.

We previously found that kidney-infiltrating T cells (KITs) in murine lupus nephritis (LN) resembled dysfunctional T cells that infiltrate tumors. This unexpected finding raised the question of how to reconcile the "exhausted" phenotype of KITs with ongoing tissue destruction in LN. To address this, we performed single-cell RNA-Seq and TCR-Seq of KITs in murine lupus models.

Surface phenotypes of naive and memory B cells in mouse and human tissues.

Memory B cells (MBCs) protect the body from recurring infections. MBCs differ from their naive counterparts (NBCs) in many ways, but functional and surface marker differences are poorly characterized. In addition, although mice are the prevalent model for human immunology, information is limited concerning the nature of homology in B cell compartments.

The citrullinated/native index of autoantibodies against hnRNP-DL predicts an individual "window of treatment success" in RA patients.

Background: There is a need for biomarker to identify patients "at risk" for rheumatoid arthritis (risk-RA) and to better predict the therapeutic response and in this study we tested the hypothesis that novel native and citrullinated heterogeneous nuclear ribonucleoprotein (hnRNP)-DL autoantibodies could be possible biomarkers.

Methods: Using protein macroarray and ELISA, epitope recognition against hnRNP-DL was analysed in sera from different developed RA disease and diagnosed SLE patients. Toll-like receptor (TLR) 7/9 and myeloid differentiation primary response gene 88 (MyD88)-dependency were studied in sera from murine disease models.

Roles of Bone Morphogenetic Protein Receptor 1A in Germinal Centers and Long-Lived Humoral Immunity.

In response to T-dependent Ag, germinal centers (GC) generate bone marrow-resident plasma cells (BMPC) and memory B cells (MBC). In this study, we demonstrate that the bone morphogenetic protein receptor 1A (BMPR1A) signaling pathway, which regulates differentiation and self-renewal in multiple stem cell populations, regulates GC dynamics and resultant establishment of BMPC and MBC. Expression studies using quantitative PCR and novel IRES.

A single subcutaneous or intranasal immunization with adenovirus-based SARS-CoV-2 vaccine induces robust humoral and cellular immune responses in mice.

Optimal vaccines are needed for sustained suppression of SARS-CoV-2 and other novel coronaviruses. Here, we developed a recombinant type 5 adenovirus vector encoding the gene for the SARS-CoV-2 S1 subunit antigen (Ad5.SARS-CoV-2-S1) for COVID-19 immunization and evaluated its immunogenicity in mice.

Germinal Center and Extrafollicular B Cell Responses in Vaccination, Immunity, and Autoimmunity.

Activated B cells participate in either extrafollicular (EF) or germinal center (GC) responses. Canonical responses are composed of a short wave of plasmablasts (PBs) arising from EF sites, followed by GC producing somatically mutated memory B cells (MBC) and long-lived plasma cells. However, somatic hypermutation (SHM) and affinity maturation can take place at both sites, and a substantial fraction of MBC are produced prior to GC formation.

The Type II Anti-CD20 Antibody Obinutuzumab (GA101) Is More Effective Than Rituximab at Depleting B Cells and Treating Disease in a Murine Lupus Model.

Objective: Depleting pathogenic B cells could treat systemic lupus erythematosus (SLE). However, depleting B cells in an inflammatory setting such as lupus is difficult. This study was undertaken to investigate whether a type II anti-CD20 monoclonal antibody (mAb) with a different mechanism of action, obinutuzumab (GA101), is more effective than a type I anti-CD20 mAb, rituximab (RTX), in B cell depletion in lupus, and whether efficient B cell depletion results in amelioration of disease.

Affinity-Restricted Memory B Cells Dominate Recall Responses to Heterologous Flaviviruses.

Memory B cells (MBCs) can respond to heterologous antigens either by molding new specificities through secondary germinal centers (GCs) or by selecting preexisting clones without further affinity maturation. To distinguish these mechanisms in flavivirus infections and immunizations, we studied recall responses to envelope protein domain III (DIII). Conditional deletion of activation-induced cytidine deaminase (AID) between heterologous challenges of West Nile, Japanese encephalitis, Zika, and dengue viruses did not affect recall responses.

Comprehensive analyses of B-cell compartments across the human body reveal novel subsets and a gut-resident memory phenotype.

Although human B cells have been extensively studied, most reports have used peripheral blood as a source. Here, we used a unique tissue resource derived from healthy organ donors to deeply characterize human B-cell compartments across multiple tissues and donors. These datasets revealed that B cells in the blood are not in homeostasis with compartments in other tissues.

PIRs mediate innate myeloid cell memory to nonself MHC molecules.

Immunological memory specific to previously encountered antigens is a cardinal feature of adaptive lymphoid cells. However, it is unknown whether innate myeloid cells retain memory of prior antigenic stimulation and respond to it more vigorously on subsequent encounters. In this work, we show that murine monocytes and macrophages acquire memory specific to major histocompatibility complex I (MHC-I) antigens, and we identify A-type paired immunoglobulin-like receptors (PIR-As) as the MHC-I receptors necessary for the memory response.