Accelerated Systemic Autoimmunity in the Absence of Somatic Hypermutation in 564Igi: A Mouse Model of Systemic Lupus with Knocked-In Heavy and Light Chain Genes.

564Igi mice have knocked-in immunoglobulin (Ig) heavy (H) and light (L) chain genes that encode an autoantibody recognizing RNA. Previously, we showed that these mice produce pathogenic IgG autoantibodies when activation-induced deaminase (AID) is expressed in pre-B and immature B cells but not when it is expressed only in mature B cells. AID has two functions; it is necessary for somatic hypermutation (SHM) and class switch recombination (CSR).

NEST 2014: views from the trainees-talking about what matters in efforts to diversify the STEM workforce.

This paper summarizes the outcomes of a retreat designed to cultivate interactions between trainees at various training levels and provide them opportunities to share their training perspectives and expectations. Retreat outcomes are used to support the development of better science, technology, engineering, and mathematics training practices by informing the trainers’ perspective.

Mineralocorticoid receptors in immune cells: emerging role in cardiovascular disease.

Mineralocorticoid receptors (MRs) contribute to the pathophysiology of hypertension and cardiovascular disease in humans. As such, MR antagonists improve cardiovascular outcomes but the molecular mechanisms remain unclear. The actions of the MR in the kidney to increase blood pressure are well known, but the recent identification of MRs in immune cells has led to novel discoveries in the pathogenesis of cardiovascular disease that are reviewed here.

Dosage of X-linked Toll-like receptor 8 determines gender differences in the development of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease with a high incidence in females and a complex phenotype. Using 564Igi mice, a model of SLE with knock-in genes encoding an autoreactive anti-RNA Ab, we investigated how expression of Toll-like receptors (TLRs) in B cells and neutrophils affects pathogenesis. We established that TLR signaling through MyD88 is necessary for disease.

A conserved enhancer element differentially regulates developmental expression of CD5 in B and T cells.

We previously identified an enhancer element upstream of the mouse cd5 gene that was required in reporter assays for the induction of cd5 promoter activity by BCR cross-linking. This element is highly conserved in placental mammals. To determine its physiological role, we have now generated mice with a targeted deletion of the enhancer.

Toll-like receptor 7-dependent loss of B cell tolerance in pathogenic autoantibody knockin mice.

Systemic lupus erythematosus (SLE) is characterized by the production of autoantibodies that are frequently directed against nucleic acid-associated antigens. To better understand how B cells reactive with such antigens are regulated, we generated a model system in which heavy and light chain genes encoding 564 immunoglobulin have been targeted to the heavy and light chain loci of the nonautoimmune C57BL/6 mouse strain. This antibody recognizes RNA, single-stranded DNA, and nucleosomes.

Babesia microti primarily invades mature erythrocytes in mice.

Babesia microti is a tick-borne red blood cell parasite that causes babesiosis in people. Its most common vertebrate reservoir is the white-footed mouse. To determine whether B.

CD22 attenuates calcium signaling by potentiating plasma membrane calcium-ATPase activity.

Binding of antigen to the B cell receptor induces a calcium response, which is required for proliferation and antibody production. CD22, a B cell surface protein, inhibits this signal through mechanisms that have been obscure. We report here that CD22 augments calcium efflux after B cell receptor crosslinking.

Age-associated decline in resistance to Babesia microti is genetically determined.

Background: Although infection by the protozoan Babesia microti is rarely symptomatic in immunocompetent young people, healthy individuals aged >50 years may experience life-threatening disease. To determine the basis for this age relationship, we developed a mouse model of babesiosis using a novel clinical isolate of B. microti.

Normal B-1a cell development requires B cell-intrinsic NFATc1 activity.

B-1a cells, an anatomically, phenotypically, and functionally distinct subset of B cells that produce the bulk of natural serum IgM and much of gut-associated IgA, are an important component of the early response to pathogens. Because the induced expression of CD5, a hallmark of B-1a cells, requires a nuclear factor of activated T cells (NFAT)-dependent enhancer, we examined the role of NFAT transcription factors in B-1a development. Here we show that the B-1a compartment is normal in mice lacking NFATc2 but essentially absent in mice lacking NFATc1.

Sialic acid binding domains of CD22 are required for negative regulation of B cell receptor signaling.

CD22, a negative regulator of B cell antigen receptor signaling, binds glycoconjugates terminating in alpha2, 6 sialic acid. The physiological ligand(s) for CD22 remain unknown. We asked whether the sialic acid binding domains are necessary for CD22 to function as a negative regulator.

Two new isotype-specific switching activities detected for Ig class switching.

Ig class switch recombination (CSR) occurs by an intrachromosomal deletional process between switch (S) regions in B cells. To facilitate the study of CSR, we derived a new B cell line, 1.B4.

The Trypanosoma cruzi trans-sialidase is a T cell-independent B cell mitogen and an inducer of non-specific Ig secretion.

Polyclonal lymphocyte activation and hypergammaglobulinemia characterize the acute phase of many parasitic diseases, including Chagas' disease, a debilitating condition caused by Trypanosoma cruzi. Polyclonal lymphocyte activation correlates with disease susceptibility inT. cruzi infection.

Origins and functions of B-1 cells with notes on the role of CD5.

Whether B-1a (CD5+) cells are a distinct lineage derived from committed fetal/neonatal precursors or arise from follicular B-2 cells in response to BCR ligation and other, unknown signals remains controversial. Recent evidence indicates that B-1a cells can derive from adult precursors expressing an appropriate specificity when the (self-) antigen is present. Antibody specificity determines whether a B cell expressing immunoglobulin transgenes has a B-2, B-1a or marginal zone (MZ) phenotype.

Cutting edge commentary: origins of B-1 cells.

The origin of B-1a cells, a minority population of B cells that express CD5, are abundant in coelomic cavities, and often produce autoantibodies, has been the subject of study for many years. Accumulating evidence demonstrates that the hypothesis that only B cells arising in fetal or neonatal tissues have the potential to become B-1a cells cannot be true. Rather, B cell receptor-mediated signaling initiated by ligation of autoantigen has now been shown to be required for induction of the B-1a phenotype.

Bruton's tyrosine kinase links the B cell receptor to nuclear factor kappaB activation.

The recognition of antigen by membrane immunoglobulin M (mIgM) results in a complex series of signaling events in the cytoplasm leading to gene activation. Bruton's tyrosine kinase (BTK), a member of the Tec family of tyrosine kinases, is essential for the full repertoire of IgM signals to be transduced. We examined the ability of BTK to regulate the nuclear factor (NF)-kappaB/Rel family of transcription factors, as the activation of these factors is required for a B cell response to mIgM.

Regulation of nuclear localization and transcriptional activity of TFII-I by Bruton's tyrosine kinase.

Bruton's tyrosine kinase (Btk) is required for normal B-cell development, as defects in Btk lead to X-linked immunodeficiency (xid) in mice and X-linked agammaglobulinemia (XLA) in humans. Here we demonstrate a functional interaction between the multifunctional transcription factor TFII-I and Btk. Ectopic expression of wild-type Btk enhances TFII-I-mediated transcriptional activation and its tyrosine phosphorylation in transient-transfection assays.

The ability of CD40L, but not lipopolysaccharide, to initiate immunoglobulin switching to immunoglobulin G1 is explained by differential induction of NF-kappaB/Rel proteins.

Antibodies of the immunoglobulin G1 class are induced in mice by T-cell-dependent antigens but not by lipopolysaccharide (LPS). CD40 engagement contributes to this preferential isotype production by activating NF-kappaB/Rel to induce germ line gamma1 transcripts, which are essential for class switch recombination. Although LPS also activates NF-kappaB, it poorly induces germ line gamma1 transcripts.

An NFAT-dependent enhancer is necessary for anti-IgM-mediated induction of murine CD5 expression in primary splenic B cells.

CD5 is a 67-kDa membrane glycoprotein the expression of which in murine splenic B cells is induced by surface IgM cross-linking. To analyze this induction, we transiently transfected primary splenic B cells with luciferase reporter constructs driven by various wild-type and mutated CD5 5'-flanking sequences. The transfected cells were subsequently cultured in medium with or without F(ab')2 anti-IgM (anti-IgM), and luciferase expression was assayed.

B cell antigen receptor-evoked calcium influx is enhanced in CD22-deficient B cell lines.

CD22 is a B cell membrane glycoprotein that, upon Ag receptor engagement, becomes rapidly tyrosyl phosphorylated and associates with several signaling molecules including Lyn, Syk, PLCgamma1, and the protein-tyrosine phosphatase, SHP-1. Two allelic forms of murine CD22 exist: CD22.1 is expressed in strains such as NZB and DBA/2, whereas CD22.

Protein-tyrosine phosphatase SHP-1 is dispensable for FcgammaRIIB-mediated inhibition of B cell antigen receptor activation.

The inhibitory Fc receptor, FcgammaRIIB, provides a signal that aborts B cell antigen receptor activation, blocking extracellular calcium influx. Because the protein-tyrosine phosphatase SHP-1 binds tyrosyl phosphorylated FcgammaRIIB and FcgammaRIIB-mediated inhibition is defective in motheaten (me/me) mice, which do not express SHP-1, it was proposed that SHP-1 mediates FcgammaRIIB signaling in B cells (D'Ambrosio, D., Hippen, K.