Impact of different genetic mutations on granulocyte development and G-CSF responsiveness in congenital neutropenia.

Congenital neutropenia (CN) is a genetic disorder characterized by persistent or intermittent low peripheral neutrophil counts, thus increasing susceptibility to bacterial and fungal infections. Various forms of CN, caused by distinct genetic mutations, exhibit differential responses to granulocyte colony-stimulating factor (G-CSF) therapy, with the underlying mechanisms not fully understood. This study presents an in-depth comparative analysis of clinical and immunological features in 5 CN patient groups (severe congenital neutropenia [SCN]1, SCN3, cyclic neutropenia [CyN], warts, hypogammaglobulinaemia, infections and myelokathexis [WHIM], and Shwachman-Bodian-Diamond Syndrome [SBDS]) associated with mutations in ELANE, HAX1, CXCR4, and SBDS genes.

MZB1-mediated IgA secretion suppresses the development and progression of colorectal cancer triggered by gut inflammation.

Colorectal cancer (CRC) ranks among the top causes of mortality globally. Gut inflammation is one crucial risk factor that augments CRC development since patients suffering from inflammatory bowel disease have an increased incidence of CRC. The role of immunoglobulin (Ig)A in maintaining gut homeostasis and preventing inflammation has been well established.

B cell abnormalities and autoantibody production in patients with partial RAG deficiency.

Mutations in the recombination activating gene 1 () and in humans are associated with a broad spectrum of clinical phenotypes, from severe combined immunodeficiency to immune dysregulation. Partial (hypomorphic) RAG deficiency (pRD) in particular, frequently leads to hyperinflammation and autoimmunity, with several underlying intrinsic and extrinsic mechanisms causing a break in tolerance centrally and peripherally during T and B cell development. However, the relative contributions of these processes to immune dysregulation remain unclear.

DNA repair mechanisms that promote insertion-deletion events during immunoglobulin gene diversification.

Insertions and deletions (indels) are low-frequency deleterious genomic DNA alterations. Despite their rarity, indels are common, and insertions leading to long complementarity-determining region 3 (CDR3) are vital for antigen-binding functions in broadly neutralizing and polyreactive antibodies targeting viruses. Because of challenges in detecting indels, the mechanism that generates indels during immunoglobulin diversification processes remains poorly understood.

Design and Protocol for Beijing Hospital Takayasu Arteritis (BeTA) Biobank.

Background: Although hundreds of studies have been conducted, our understanding of the pathogenesis, indications for surgical intervention, and disease markers of Takayasu arteritis (TAK) are still limited. Collection of biological specimens, clinical data and imaging data will facilitate translational research and clinical studies. In this study, we aim to introduce the design and protocol for the Beijing Hospital Takayasu Arteritis (BeTA) Biobank.

LAPTM5 mediates immature B cell apoptosis and B cell tolerance by regulating the WWP2-PTEN-AKT pathway.

Elimination of autoreactive developing B cells is an important mechanism to prevent autoantibody production. However, how B cell receptor (BCR) signaling triggers apoptosis of immature B cells remains poorly understood. We show that BCR stimulation up-regulates the expression of the lysosomal-associated transmembrane protein 5 (LAPTM5), which in turn triggers apoptosis of immature B cells through two pathways.

Glia maturation factor-γ is involved in S1P-induced marginal zone B-cell chemotaxis and optimal IgM production to type II T-independent antigen.

Marginal zone B cells (MZBs) represent a unique B-cell sub-population that rapidly differentiate into IgM-secreting plasma cells in response to T-independent (T-I) antigen. Sphingosine 1-phosphate (S1P) promotes MZB localization to the marginal zone. However, intracellular molecules involved in MZB localization and migration remain largely unknown.

RAG1 splicing mutation causes enhanced B cell differentiation and autoantibody production.

Hypomorphic RAG1 or RAG2 mutations cause primary immunodeficiencies and can lead to autoimmunity, but the underlying mechanisms are elusive. We report here a patient carrying a c.116+2T>G homozygous splice site mutation in the first intron of RAG1, which led to aberrant splicing and greatly reduced RAG1 protein expression.

Role of Polymeric Immunoglobulin Receptor in IgA and IgM Transcytosis.

Transcytosis of polymeric IgA and IgM from the basolateral surface to the apical side of the epithelium and subsequent secretion into mucosal fluids are mediated by the polymeric immunoglobulin receptor (pIgR). Secreted IgA and IgM have vital roles in mucosal immunity in response to pathogenic infections. Binding and recognition of polymeric IgA and IgM by pIgR require the joining chain (J chain), a small protein essential in the formation and stabilization of polymeric Ig structures.

CTLA-4 expression by B-1a B cells is essential for immune tolerance.

CTLA-4 is an important regulator of T-cell function. Here, we report that expression of this immune-regulator in mouse B-1a cells has a critical function in maintaining self-tolerance by regulating these early-developing B cells that express a repertoire enriched for auto-reactivity. Selective deletion of CTLA-4 from B cells results in mice that spontaneously develop autoantibodies, T follicular helper (Tfh) cells and germinal centers (GCs) in the spleen, and autoimmune pathology later in life.

B Cell Lymphoma.

B cell development and activation are accompanied by dynamic genetic alterations including V(D)J rearrangements and immunoglobulin-gene somatic hypermutation and class-switch recombination. Abnormalities in these genetic events can cause chromosomal translocations and genomic mutations, leading to altered expression and function of genes involved in B cell survival or proliferation and consequently B lymphomagenesis. In fact, B cell lymphoma accounts for 95% of the lymphomas.

Primary Antibody Deficiencies.

Primary antibody deficiencies (PADs) are the most common types of inherited primary immunodeficiency diseases (PIDs) presenting at any age, with a broad spectrum of clinical manifestations including susceptibility to infections, autoimmunity and cancer. Antibodies are produced by B cells, and consequently, genetic defects affecting B cell development, activation, differentiation or antibody secretion can all lead to PADs. Whole exome and whole genome sequencing approaches have helped identify genetic defects that are involved in the pathogenesis of PADs.

Regulation of Humoral Immune Responses and B Cell Tolerance by the IgM Fc Receptor (FcμR).

Immunoglobulin (Ig) M is the first antibody isotype produced during an immune response and is critical for host defense against infections. Recent studies have revealed that IgM also plays an important role in immune regulation and immunological tolerance. Mice lacking secretory IgM not only exhibit impaired production of antigen-specific IgG and are more susceptible to bacterial and viral infections, but also produce autoantibodies and are prone to develop autoimmune diseases.

B Cell Development and Maturation.

Since the identification of B cells in 1965 (Cooper  et al. 1965), three has been tremendous progress in our understanding of B cell development, maturation and function. A number of B cell subpopulations, including B-1, B-2 and regulatory B cells, have been identified.

Aortic intimal intussusception during acute type B aortic dissection endovascular repair.

Aortic intimal intussusception (AoII) is rare, especially during the endovascular repair of acute uncomplicated type B aortic dissection. Here we present a case of 47-year-old man who suffered AoII during the endovascular repair of type B aortic dissection. An abdominal aortic stent was inserted to recanalize the aorta, but failed.