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A PRoliferation-Inducing Ligand (APRIL) in the Pathogenesis of Immunoglobulin A Nephropathy: A Review of the Evidence.

A PRoliferation-Inducing Ligand (APRIL), the thirteenth member of the tumor necrosis factor superfamily, plays a key role in the regulation of activated B cells, the survival of long-lived plasma cells, and immunoglobulin (Ig) isotype class switching. Several lines of evidence have implicated APRIL in the pathogenesis of IgA nephropathy (IgAN). Globally, IgAN is the most common primary glomerulonephritis, and it can progress to end-stage kidney disease; yet, disease-modifying treatments for this condition have historically been lacking. The preliminary data in ongoing clinical trials indicate

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… DCs induce CD40-independent immunoglobulin class switching through BLyS and APRIL. Nat. Immunol. 2002;3:822–829. doi: 10.1038/ni829. 21. Park S.R., Kim P.H., Lee K.S., Lee S.H., Seo G.Y., Yoo Y.C., Lee J., Casali P. …

High-affinity, neutralizing antibodies to SARS-CoV-2 can be made without T follicular helper cells.

T follicular helper (TFH) cells are the conventional drivers of protective, germinal center (GC)–based antiviral antibody responses. However, loss of TFH cells and GCs has been observed in patients with severe COVID-19. As T cell–B cell interactions and immunoglobulin class switching still occur in these patients, noncanonical pathways of antibody production may be operative during SARS-CoV-2 infection. We found that both TFH-dependent and -independent antibodies were induced against SARS-CoV-2 infection, SARS-CoV-2 vaccination, and influenza A virus infection. Although TFH-independent antibod…

B-cell abnormalities in HIV-1 infection: roles for IgG3 and T-bet.

PURPOSE OF REVIEW: Numerous B-cell abnormalities in HIV-1 infection have been described over the past three decades yet have remained poorly defined mechanistically. We review recent studies that describe mechanisms of B-cell dysregulation in chronic HIV-1 infection associated with IgG3 and T-bet. RECENT FINDINGS: HIV-1 infection causes hypergammaglobulinemia and dysregulation of B-cell populations, including the expansion during chronic viremia of functionally impaired tissue-like memory (TLM) B cells. TLM B cells and B cells in other conditions of chronic activation and inflammation with si

USP44 is dispensable for normal hematopoietic stem cell function, lymphocyte development, and B-cell-mediated immune response in a mouse model.

Ubiquitin-specific protease 44 (USP44) is a nuclear protein with deubiquitinase (DUB) catalytic activity that has been implicated as an impo … r normal lymphocyte development. Usp44-deficient B cells show normal activation, proliferation, and immunoglobulin class switching in response to in vitro stimulation, and Usp44-deficient mice mount normal antibody response to immunization. We also tested the effects of USP44 deficiency on disease progression and survival in the Emu-myc model of mouse B-cell lymphoma and observ …

Up-regulation of activation-induced cytidine deaminase and its strong expression in extra-germinal centres in IgG4-related disease.

Immunoglobulin (Ig) G4-related disease (IgG4-RD) is a systemic disorder involving benign mass formation due to fibrosis and intense lymphoplasmacytosis; the chronic inflammation associated with the disease might also contribute to oncogenesis. Activation-induced cytidine deaminase (AID), normally expressed in germinal centre activated B-cells, is an enzyme that edits DNA/RNA and induces somatic hypermutation and Ig class switching. AID expression is strictly controlled under physiological conditions; however, chronic inflammation and some infectious agents induce its up-regulation. AID is over

Genetic associations in type I interferon related pathways with autoimmunity.

Type I interferons play an outstanding role in innate and adaptive immunity by enhancing functions of dendritic cells, inducing differentiation of monocytes, promoting immunoglobulin class switching in B cells and stimulating effector functions of T cells. The increased production of IFNα/β by plasmacytoid dendritic cells could be responsible for not only efficient antiviral defence, but it also may be a pathological factor in the development of various autoimmune disorders. The first evidence of a genetic link between type I interferons and autoimmune diseases was the observation that elevate…

VavP-Bcl2 transgenic mice develop follicular lymphoma preceded by germinal center hyperplasia.

In human follicular lymphoma the t(14; 18) chromosome translocation activates the antiapoptotic oncogene Bcl2 by linking it to the immunoglobulin heavy chain (IGH) locus. Transgenic mice expressing Bcl2 controlled by an Igh enhancer (E mu) do not develop follicular lymphoma, although they do have an increased incidence of other B-lymphoid neoplasms. We have now analyzed tumorigenesis in mice bearing a Bcl2 transgene controlled by Vav gene regulatory sequences (VavP), which confer expression in multiple hematopoietic lineages. Unlike E mu-Bcl2 mice, many VavP-Bcl2 mice older than 10 months deve

Effect of vitamin A deficiency and Newcastle disease virus infection on IgA and IgM secretion in chickens.

The effect of vitamin A deficiency or the lentogenic La Sota strain of Newcastle disease virus (NDV) infection, or both, on immunoglobulin (IgA and IgM) levels in bile and plasma were investigated. In addition, tissue distribution of IgA-, IgG- and IgM-containing cells was studied to establish the source of these Ig. Chickens (1-d-old) with limited vitamin A reserves were fed ad lib. on diets containing either marginal or adequate levels of vitamin A. At 4 weeks of age, half the chickens in each group were infected with NDV. The number of IgA- and IgM-containing cells was not significantly aff

B-cell activation with CD40L or CpG measures the function of B-cell subsets and identifies specific defects in immunodeficient patients.

Around 65% of primary immunodeficiencies are antibody deficiencies. Functional tests are useful tools to study B-cell functions in vitro. However, no accepted guidelines for performing and evaluating functional tests have been issued yet. Here, we report our experience on the study of B-cell functions in infancy and throughout childhood. We show that T-independent stimulation with CpG measures proliferation and differentiation potential of memory B cells. Switched memory B cells respond better than IgM memory B cells. On the other hand, CD40L, a T-dependent stimulus, does not induce plasma cel

Humoral immunity in pancreatic cancer: B-cell heterogeneity, regulatory networks, and therapeutic opportunities.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a profoundly immunosuppressive tumor microenvironment and remains largely refractory to immunotherapy. Though T-cell-directed strategies have dominated the immunotherapy landscape, there is emerging data to suggest that B-cells and humoral immune products also have a critical role in PDAC pathobiology. However, therapies broadly targeting B-cells have failed in clinical trial, raising important questions regarding the complex, often contradictory roles for humoral immunity in PDAC development. Studies exploring humoral immunity in PDA

Subcutaneous white adipose tissue-derived extracellular vesicles maintain intestinal homeostasis via IgA biosynthesis in aging mice.

Intestinal function and white adipose tissue (WAT) function deteriorate with age, but whether and how their deterioration is intertwined remains unknown. Increased gut permeability, microbiota dysbiosis, and aberrant immune microenvironment are the hallmarks of intestinal dysfunctions in aging. Here, we show that subcutaneous WAT dysfunction triggered aging-like intestinal dysfunctions in mouse models. Removal of inguinal subcutaneous WAT (iWAT) increased intestinal permeability and inflammation and altered gut microbiota composition as well as susceptibility to pathogen infection in mouse mod

PGRN Inhibits Early B-cell Activation and IgE Production Through the IFITM3-STAT1 Signaling Pathway in Asthma.

Progranulin (PGRN) plays a critical role in bronchial asthma and the function of various immune cells. However, the mechanisms by which PGRN influences B-cell receptor (BCR) signaling and immunoglobulin E(IgE) production are not fully understood. The study aimed to elucidate the molecular mechanisms through which PGRN affects BCR signaling, B-cell differentiation, and IgE production. A PGRN knockout mouse model, along with techniques including flow cytometry, the creation of a bone marrow chimeric mouse model, total internal reflection fluorescence (TIRF), and Western blot (WB) analysis is emp

Integrative single-cell analysis reveals distinct adaptive immune signatures in the cutaneous lesions of pemphigus.

Pemphigus, an autoimmune bullous disease affecting the skin and mucosal membranes, is primarily driven by anti-desmoglein (Dsg) autoantibodies. However, the underlying immune mechanisms of this disease remain largely elusive. Here, we compile an unbiased atlas of immune cells in pemphigus cutaneous lesions at single-cell resolution. We reveal clonally expanded antibody-secreting cells (ASCs) that exhibit variable hypermutation and accumulation of IgG4 class-switching in their immunoglobulin genes. Importantly, pathogenic Dsg-specific ASCs are localized within pemphigus lesions and can evolve f

Fusion of parvovirus B19 receptor-binding domain and pneumococcal surface protein A induces protective immunity against parvovirus B19 and Streptococcus pneumoniae.

BACKGROUND: Parvovirus B19 (B19) is a well-known cause of fifth disease in children, but infection during pregnancy may cause hydrops fetali … in splenic cells from mice immunized with RBD-PspA, suggesting that PspA-specific T cells supported immunoglobulin class switching of both RBD- and PspA-specific B cells. CONCLUSIONS: RBD-PspA should be an effective bivalent vaccine against B19 and S. pneumoniae infections.

Increased estrogen to androgen ratio enhances immunoglobulin levels and impairs B cell function in male mice.

Sex steroids, such as estrogens and androgens, are important regulators of the humoral immune response. Studies in female mice have demonstrated that alteration of circulating estrogen concentration regulates antibody-mediated immunity. As males have normally little endogenous estrogen, we hypothesized that in males high estrogens and low androgens affect the immune system and enhance the allergic inflammatory response. Here, we studied transgenic male mice expressing human aromatase (AROM+). These animals have a high circulating estrogen to androgen ratio (E/A), causing female traits such as

Downregulation of FOXP1 is required during germinal center B-cell function.

B-cell maturation and germinal center (GC) formation are dependent on the interplay between BCL6 and other transcriptional regulators. FOXP1 is a transcription factor that regulates early B-cell development, but whether it plays a role in mature B cells is unknown. Analysis of human tonsillar B-cell subpopulations revealed that FOXP1 shows the opposite expression pattern to BCL6, suggesting that FOXP1 regulates the transition from resting follicular B cell to activated GC B cell. Chromatin immunoprecipitation-on-chip and gene expression assays on B cells indicated that FOXP1 acts as a transcri

Epidemiology: clues to the pathogenesis of Burkitt lymphoma.

The two major epidemiological clues to the pathogenesis of Burkitt lymphoma (BL) are the geographical association with malaria--BL incidence relates to the malaria transmission rate--and early infection by Epstein-Barr virus (EBV). Both agents cause B cell hyperplasia, which is almost certainly an essential component of lymphomagenesis in BL. The critical event in lymphomagenesis is the creation of a MYC translocation, bringing the MYC gene into juxtaposition with immunoglobulin genes and causing its ectopic expression, thereby driving the proliferation of BL cells. It is highly likely that su

Absence of IgD-CD27(+) memory B cell population in X-linked hyper-IgM syndrome.

The present study analyzed peripheral blood B cell populations separated by IgD and CD27 expression in six males with X-linked hyper-IgM syndrome (XHIM). Costimulation of mononuclear cells from most of the patients induced no to low levels of class switching from IgM to IgG and IgA with Staphylococcus aureus Cowan strain (SAC) plus IL-2 or anti-CD40 mAb (anti-CD40) plus IL-10. Measurable levels of IgE were secreted in some of the patients after stimulation with anti-CD40 plus IL-4. Costimulation with SAC plus IL-2 plus anti-CD40 plus IL-10 yielded secretion of significant levels of IgG in addi

IgG subclass antibody to Mycobacterium leprae 18,000 MW antigen is restricted to IgG1 and IgG3 in leprosy.

IgG subclass responses to Mycobacterium leprae 18,000 MW recombinant antigen (18K) were determined in sera from untreated leprosy patients u … 3, P < 0.001) but not in tuberculoid leprosy patients (r = 0.007, P > 0.10) which may be related to immunoglobulin class switching of IgG3 to IgG1 rather than selective shifts in T-helper subsets. Our results therefore, do not support the hypothesis that activation of Th2 cells occurs in lepromatous leprosy; this issue needs further examination.

VH gene analysis of primary cutaneous B-cell lymphomas: evidence for ongoing somatic hypermutation and isotype switching.

Primary cutaneous B-cell lymphomas are B-cell non-Hodgkin's lymphomas that arise in the skin. The major subtypes discerned are follicle center cell lymphomas, immunocytomas (marginal zone B-cell lymphomas), and large B-cell lymphomas of the leg. In this study, we analyzed the variable heavy chain (VH) genes of 7 of these lymphomas, ie, 4 follicle center cell lymphomas (diffuse large-cell lymphomas) and 3 immunocytomas. We show that all these lymphomas carry heavily mutated VH genes, with no obvious bias in VH gene usage. The low ratios of replacement versus silent mutations observed in the fra