Defective peripheral B cell selection in common variable immune deficiency patients with autoimmune manifestations.

Common variable immune deficiency (CVID) is a heterogeneous disorder characterized by recurrent infections, low levels of serum immunoglobulins, and impaired vaccine responses. Autoimmune manifestations are common, but B cell central and peripheral selection mechanisms in CVID are incompletely understood. Here, we find that receptor editing, a measure of central tolerance, is increased in transitional B cells from CVID patients and that these cells have a higher immunoglobulin κ:λ ratio in CVID patients with autoimmune manifestations than in those with infection only.

Clonal relationships of memory B cell subsets in autoimmune mice.

Immunological memory protects our body from re-infection and it is composed of a cellular and a humoral arm. The B-cell branch with its memory B cells (MBCs), plasma cells and antibodies, formed either in a germinal centre (GC) -dependent or -independent manner, ensure that we can rapidly mount a recall immune response. Previous work in immunised wildtype (WT) mice have identified several subsets of MBCs whereas less is known under autoimmune conditions.

Lipid Nanoparticles Deliver the Therapeutic VEGFA mRNA In Vitro and In Vivo and Transform Extracellular Vesicles for Their Functional Extensions.

Lipid nanoparticles (LNPs) are currently used to transport functional mRNAs, such as COVID-19 mRNA vaccines. The delivery of angiogenic molecules, such as therapeutic VEGF-A mRNA, to ischemic tissues for producing new blood vessels is an emerging strategy for the treatment of cardiovascular diseases. Here, the authors deliver VEGF-A mRNA via LNPs and study stoichiometric quantification of their uptake kinetics and how the transport of exogenous LNP-mRNAs between cells is functionally extended by cells' own vehicles called extracellular vesicles (EVs).

CD27 on human memory B cells-more than just a surface marker.

Immunological memory protects the human body from re-infection with an earlier recognized pathogen. This memory comprises the durable serum antibody titres provided by long-lived plasma cells and the memory T and B cells with help from other cells. Memory B cells are the main precursor cells for new plasma cells during a secondary infection.

Ectopic Germinal Centres with B and T Cells and Follicular Dendritic Cell Networks in Urethral Stricture Tissue: Possible Avenue for Immunological Treatments.

Background: The underlying cause of a urethral stricture can sometimes be obscure. It is possible that an injury to the urethra induces an immunological cascade that generates scar tissue and fibrosis, eventually resulting in a stricture. If such immunological reactions could be better elucidated, immunological therapies could possibly emerge.

The Interplay between CD27 and CD27 B Cells Ensures the Flexibility, Stability, and Resilience of Human B Cell Memory.

Memory B cells (MBCs) epitomize the adaptation of the immune system to the environment. We identify two MBC subsets in peripheral blood, CD27 and CD27 MBCs, whose frequency changes with age. Heavy chain variable region (VH) usage, somatic mutation frequency replacement-to-silent ratio, and CDR3 property changes, reflecting consecutive selection of highly antigen-specific, low cross-reactive antibody variants, all demonstrate that CD27 and CD27 MBCs represent sequential MBC developmental stages, and stringent antigen-driven pressure selects CD27 into the CD27 MBC pool.

Lack of Gut Secretory Immunoglobulin A in Memory B-Cell Dysfunction-Associated Disorders: A Possible Gut-Spleen Axis.

B-1a B cells and gut secretory IgA (SIgA) are absent in asplenic mice. Human immunoglobulin M (IgM) memory B cells, which are functionally equivalent to mouse B-1a B cells, are reduced after splenectomy. To demonstrate whether IgM memory B cells are necessary for generating IgA-secreting plasma cells in the human gut.

Dissecting Integrin Expression and Function on Memory B Cells in Mice and Humans in Autoimmunity.

Immunological memory ensures life-long protection against previously encountered pathogens, and in mice and humans the spleen is an important reservoir for long-lived memory B cells (MBCs). It is well-established that integrins play several crucial roles in lymphocyte survival and trafficking, but their involvement in the retention of MBCs in secondary lymphoid organs, and differences between B cell subsets in their adhesion capacity to ICAM-1 and/or VCAM-1 have not yet been confirmed. Here, we use an autoimmune mouse model, where MBCs are abundant, to show that the highest levels of LFA-1 and VLA-4 amongst B cells are found on MBCs.

Long-Lived Plasma Cells in Mice and Men.

Even though more than 30 years have passed since the eradication of smallpox, high titers of smallpox-specific antibodies are still detected in the blood of subjects vaccinated in childhood. In fact, smallpox-specific antibody levels are maintained in serum for more than 70 years. The generation of life-long immunity against infectious diseases such as smallpox and measles has been thoroughly documented.

Dysregulated miR-155 and miR-125b Are Related to Impaired B-cell Responses in Down Syndrome.

Children with Down Syndrome (DS) suffer from immune deficiency with a severe reduction in switched memory B cells (MBCs) and poor response to vaccination. Chromosome 21 (HSA21) encodes two microRNAs (miRs), miR-125b, and miR-155, that regulate B-cell responses. We studied B- and T- cell subpopulations in tonsils of DS and age-matched healthy donors (HD) and found that the germinal center (GC) reaction was impaired in DS.

Age-associated B cells expanded in autoimmune mice are memory cells sharing H-CDR3-selected repertoires.

Age-associated B cells (ABCs) represent a distinct cell population expressing low levels of CD21 (CD21 ). The Ig repertoire expressed by ABCs in aged mice is diverse and exhibits signs of somatic hypermutation (SHM). A CD21 B-cell population is expanded in autoimmune diseases, e.

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.

Absence of surrogate light chain results in spontaneous autoreactive germinal centres expanding V(H)81X-expressing B cells.

Random recombination of antibody heavy- and light-chain genes results in a diverse B-cell receptor (BCR) repertoire including self-reactive BCRs. However, tolerance mechanisms that prevent the development of self-reactive B cells remain incompletely understood. The absence of the surrogate light chain, which assembles with antibody heavy chain forming a pre-BCR, leads to production of antinuclear antibodies (ANAs).

Surrogate light chain is required for central and peripheral B-cell tolerance and inhibits anti-DNA antibody production by marginal zone B cells.

Selection of the primary antibody repertoire takes place in pro-/pre-B cells, and subsequently in immature and transitional B cells. At the first checkpoint, μ heavy (μH) chains assemble with surrogate light (SL) chain into a precursor B-cell receptor. In mice lacking SL chain, μH chain selection is impaired, and serum autoantibody levels are elevated.

Uncoupling of natural IgE production and CD23 surface expression levels.

CD23, the low affinity receptor for immunoglobulin E (IgE), has been proposed to play a critical role in the regulation of IgE production, based on altered IgE levels in CD23-deficient mice and transgenic mouse models, as well as in mouse strains with mutations in the CD23 gene, e.g. 129 substrains.

Measurements in the Blood of BDNF for RA Patients and in Response to Anti-TNF Treatment Help Us to Clarify the Magnitude of Centrally Related Pain and to Explain the Relief of This Pain upon Treatment.

Brain-derived neurotrophic factor (BDNF) is a neurotrophin with functions related to neuronal survival/proliferation processes and inflammation. BDNF is also an important central pain mediator. The levels of BDNF have been found to be high for RA patients with severe disease and to become lowered in response to anti-TNF treatment.

Mechanism of estradiol-induced block of voltage-gated K+ currents in rat medial preoptic neurons.

The present study was conducted to characterize possible rapid effects of 17-β-estradiol on voltage-gated K(+) channels in preoptic neurons and, in particular, to identify the mechanisms by which 17-β-estradiol affects the K(+) channels. Whole-cell currents from dissociated rat preoptic neurons were studied by perforated-patch recording. 17-β-Estradiol rapidly (within seconds) and reversibly reduced the K(+) currents, showing an EC(50) value of 9.

The pre-B cell receptor checkpoint.

B lymphocytes are essential antibody-producing cells of the immune system. During the development of progenitor B cells to mature B cells that express a membrane-bound antibody, the B cell receptor (BCR), the cells undergo selection at several checkpoints, which ensures that a diverse antibody repertoire is generated and that the BCRs recognise foreign-, but not self-, antigens. In this review, we consider the pre-BCR checkpoint.

New insight into the non-neuronal cholinergic system via studies on chronically painful tendons and inflammatory situations.

For certain parts of the body, it is nowadays accepted that there is a cholinergic system that is not related to cholinergic innervation, i.e. a non-neuronal cholinergic system.

Unexpected finding of a marked non-neuronal cholinergic system in human knee joint synovial tissue.

The cholinergic anti-inflammatory pathway is a newly discovered pathway. Another recent concept is the existence of a non-neuronal cholinergic system that has, so far, been defined for human tendons, intestine, airways and urinary bladder. The existence of such a system in joint synovial tissue is yet to be described.

BDNF in RA: downregulated in plasma following anti-TNF treatment but no correlation with inflammatory parameters.

The involvement of brain-derived neurotrophic factor (BDNF) in rheumatoid arthritis (RA) is largely unknown. The distribution of BDNF and its associated receptors, TrkB and p75, in the synovial tissue of patients with RA was examined and contrasted with that in patients with osteoarthritis (OA). Additionally, levels of BDNF in both synovial tissue and synovial fluid were measured.

Expression patterns of neurotrophins and neurotrophin receptors in articular chondrocytes and inflammatory infiltrates in knee joint arthritis.

Background: It is likely that neurotrophins (NTs) are of great importance for the articular cartilage and the inflammation process in arthritis.

Methods: The immunohistochemical expression of the NTs nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) and the associated receptors p75, TrkA and TrkB was examined in the knee joint of arthritic and healthy mice.

Results: Immunoreactions for NGF and BDNF were detected in cells and nerve fiber varicosities in the inflammatory infiltrates of the synovial tissue of arthritic joints but not in synovial tissue of controls.

Levels of gastrin-releasing peptide and substance P in synovial fluid and serum correlate with levels of cytokines in rheumatoid arthritis.

It is well known that cytokines are highly involved in the disease process of rheumatoid arthritis (RA). Recently, targeting of neuropeptides has been suggested to have potential therapeutic effects in RA. The aim of this study was to investigate possible interrelations between five neuropeptides (bombesin/gastrin-releasing peptide (BN/GRP), substance P (SP), vasoactive intestinal peptide, calcitonin-gene-related peptide, and neuropeptide Y) and the three cytokines tumour necrosis factor (TNF)-alpha, IL-6, and monocyte chemoattractant protein-1 in synovial fluid of patients with RA.