B-cell Immunoglobulin Secretion Research Articles

Decellularized Bovine Bone Graft for Zygomatic Bone Reconstruction

Reconstruction of large size maxillofacial bone defects following trauma or tumor resection still represents a challenging task for surgeons. Various types of bone materials are used as the grafts for the reconstruction of bone defect: auto, allo, xeno and alloplastic bones. In recent years, using the methods of decellularization has enabled to obtain the natural,biocompatible threedimensional xenograft for the reconstruction of bone defects. Removing DNA from the bone matrix is critical because this DNA may stimulate immune reactions by activating cytokine production and B-cell immunoglobulin secretion after transplantation. For the large maxillofacial bone reconstruction procedures, the decellularized bovine bone graft has proven to be effective, easy to handle and biocompatible, providing excellent final aesthetic and functional results. However, more animal and clinical studies are required to further assess the osteogenic activity and integration of decellularized bone grafts with the native bone.

Circulating T follicular helper cells with increased function during chronic graft-versus-host disease

AbstractChronic graft-versus-host disease (cGVHD) remains a major late complication of allogeneic hematopoietic stem cell transplantation (HSCT). Previous studies have established that both donor B and T cells contribute to immune pathology in cGVHD but the mechanisms responsible for coordinated B- and T-cell responses directed against recipient antigens have not been understood. T follicular helper cells (TFH) play an important role in the regulation of B-cell immunity. We performed extensive phenotypic and functional analysis of circulating TFH (cTFH) and B cells in 66 patients after HSCT. Patients with active cGVHD had a significantly lower frequency of cTFH compared with patients without cGVHD. This was associated with higher CXCL13 plasma levels suggesting increased homing of TFH to secondary lymphoid organs. In patients with active cGVHD, cTFH phenotype was skewed toward a highly activated profile with predominance of T helper 2 (Th2)/Th17 subsets. Activated cTFH in patients with cGVHD demonstrated increased functional ability to promote B-cell immunoglobulin secretion and maturation. Moreover, the activation signature of cTFH was highly correlated with increased B-cell activation and plasmablast maturation in patients after transplant. These studies provide new insights into the immune pathogenesis of human cGVHD and identify TFH as a key coordinating element supporting B-cell involvement in this disease.

Apremilast is a selective PDE4 inhibitor with regulatory effects on innate immunity

Apremilast, an oral small molecule inhibitor of phosphodiesterase 4 (PDE4), is in development for chronic inflammatory disorders, and has shown efficacy in psoriasis, psoriatic arthropathies, and Behçet's syndrome. In March 2014, the US Food and Drug Administration approved apremilast for the treatment of adult patients with active psoriatic arthritis. The properties of apremilast were evaluated to determine its specificity, effects on intracellular signaling, gene and protein expression, and in vivo pharmacology using models of innate and adaptive immunity. Apremilast inhibited PDE4 isoforms from all four sub-families (A1A, B1, B2, C1, and D2), with IC50 values in the range of 10 to 100nM. Apremilast did not significantly inhibit other PDEs, kinases, enzymes, or receptors. While both apremilast and thalidomide share a phthalimide ring structure, apremilast lacks the glutarimide ring and thus fails to bind to cereblon, the target of thalidomide action. In monocytes and T cells, apremilast elevated intracellular cAMP and induced phosphorylation of the protein kinase A substrates CREB and activating transcription factor-1 while inhibiting NF-κB transcriptional activity, resulting in both up- and down-regulation of several genes induced via TLR4. Apremilast reduced interferon-α production by plasmacytoid dendritic cells and inhibited T-cell cytokine production, but had little effect on B-cell immunoglobulin secretion. In a transgenic T-cell and B-cell transfer murine model, apremilast (5mg/kg/day p.o.) did not affect clonal expansion of either T or B cells and had little or no effect on their expression of activation markers. The effect of apremilast on innate immunity was tested in the ferret lung neutrophilia model, which allows monitoring of the known PDE4 inhibitor gastrointestinal side effects (nausea and vomiting). Apremilast significantly inhibited lung neutrophilia at 1mg/kg, but did not induce significant emetic reflexes at doses <30mg/kg. Overall, the pharmacological effects of apremilast are consistent with those of a targeted PDE4 inhibitor, with selective effects on innate immune responses and a wide therapeutic index compared to its gastrointestinal side effects.

The role of human interleukin-6 in B-cell isotype regulation and differentiation

Human Interleukin-6 (IL-6) is a cytokine secreted by T cells, as well as a variety of other cell types, which exhibits B-cell differentiating activity. The recent cloning of the gene that codes for this molecule has allowed us the opportunity to study the function of this molecule alone and in conjunction with other lymphokines in human B-cell isotype-regulation and differentiation. Recombinant human IL-6 enhances immunoglobulin (Ig) M and G secretion by B-cells activated by Staphylococcal A Cowan strain (SAC) and enhances IgM, IgG, and IgA secretion by B-cells activated by pokeweed mitogen. IL-6 also augments immunoglobulin secretion of differing isotypes from various Epstein-Barr Virus transformed B-cell lines. However, IL-6 does not alter the secreted isotype of naive surface IgM-positive B-cells. As human T-cells secrete other lymphokines in association with IL-6 after activation we examined the interaction of Interleukin-2 (IL-2) gamma-interferon (IFN-γ) and Interleukin-4 (IL-4) with IL-6 on B-cell immunoglobulin secretion. IL-2 and IL-4 synergized with IL-6 in augmenting immunoglobulin secretion by SAC-activated B-cells. IFN-γ significantly inhibited the Ig secretion of SAC-activated B-cells cocultured with IL-6 alone or in combination with IL-2. These results demonstrate that human recombinant IL-6 augments immunoglobulin secretion of isotype-committed B-cells but it does not induce a change in the isotype secreted. In addition, this lymphokine synergizes with IL-2 and IL-4 in supporting Ig secretion. However, IFN-γ significantly inhibits IL-6 induced Ig Secretion.

Helper Inducer T Cells in the Lungs of Sarcoidosis Patients: Analysis of Their Pathogenic and Clinical Significance

Phenotypic analysis of helper CD4+TQ1- cell population, the major helper T-cell subset for B-cell responses, was carried out in BAL fluid of sarcoidosis patients. Most of the BAL CD4+ cells lacked TQ1 membrane antigen. A correlation between the number of helper CD4+TQ1- cells and IgM and IgA levels was observed in 27 sarcoidosis patients' BAL. A role of CD4+TQ1- cells in modulating lung B-cell immunoglobulin secretion in sarcoidosis was confirmed by the fact that BAL IgG level and helper T-cell number correlated well in patients with low-intensity alveolitis. Results showed an inverse correlation between symptom duration and BAL IgM levels and CD4+TQ1- cell number. The number of helper cells was above normal in patients who had symptoms for less than 12 months and within normal range in those who had symptoms for more than that. The pathogenic and clinical relevance of these data is discussed.

Myelin Basic Protein‐Specific RNA Levels in Interleukin‐2‐Stimulated Oligodendrocytes

In the immune system, T- and B-cell proliferation, as well as B-cell immunoglobulin secretion, is induced by interleukin-2 (IL-2), a T-cell-derived lymphokine. IL-2 also influences the growth of glial cells, specifically, the proliferation and maturation of oligodendrocytes. Studies were conducted to investigate further IL-2-induced maturation of oligodendrocytes through its effect on the regulation of the myelin basic protein (MBP) gene. A cDNA probe specific for rat MBP and a double-antibody radioimmunoassay for MBP were used to quantitate MBP mRNA and protein levels in oligodendrocytes under different experimental conditions. We demonstrate that both MBP mRNA and protein levels are increased in IL-2-stimulated oligodendrocytes. MBP mRNA levels increase within 8 h after IL-2 stimulation, peak between 24 and 48 h, and then decline slightly. MBP protein levels increase 24 h after stimulation and peak at 72 h. MBP mRNA transcripts in the range of 2.0-2.4 kilobases are present in cultured rat oligodendrocytes, which are similar to the MBP mRNA transcripts detected in whole rat and mouse brain. These mRNA transcripts are specifically increased in quantity after oligodendrocyte stimulation with IL-2. These results suggest that one component of oligodendrocyte differentiation/maturation--MBP mRNA and protein expression--can be regulated in part by IL-2.

Immunoregulatory T-cell dysfunction in polyclonal gammopathy.

The mechanisms responsible for the increased serum immunoglobulines in polyclonal gammopathy states are unknown. We have studied the regulation of peripheral blood B-cell immunoglobulin synthesis and secretion, by T cells of either blood or bone marrow compartments, in 20 patients with polyclonal gammopathy and 27 controls with normal serum immunoglobulin levels. When compared to B-T-cell cocultures of normals, cocultures of polyclonal gammopathy patients had significantly higher levels of immunoglobulin secretion (P less than 0.01). Normal T cells but not T cells from patients with polyclonal gammopathy suppressed B-cell immunoglobulin secretion (P less than 0.01) and not the number of cytoplasmic immunoglobulin-positive cells of the polyclonal gammopathy patients. T cells from patients with polyclonal gammopathy enhanced normal B-cell immunoglobulin secretion (P less than 0.05) but not the number of cytoplasmic immunoglobulin-positive cells. Controls' bone marrow T cells were more efficient than blood T cells in suppressing polyclonal gammopathy B cells (P less than 0.02). T cells in polyclonal gammopathy are predominantly helper cells and could play a role in the enhanced immunoglobulin secretion of B cells. Bone marrow T cells are more efficient than blood T cells in regulating B cells. It seems that T cells predominantly regulate B-cell immunoglobulin secretion and not the number of B cells with cytoplasmic Ig.