B-cell Growth Factor Research Articles

Disease-Modifying Agents for Multiple Sclerosis

Multiple sclerosis (MS) is a chronic autoimmune disease of the CNS. Currently, six medications are approved for immunmodulatory and immunosuppressive treatment of the relapsing disease course and secondary-progressive MS. In the first part of this review, the pathogenesis of MS and its current treatment options are discussed. During the last decade, our understanding of autoimmunity and the pathogenesis of MS has advanced substantially. This has led to the development of a number of compounds, several of which are currently undergoing clinical testing in phase II and III studies. While current treatment options are only available for parenteral administration, several oral compounds are now in clinical trials, including the immunosuppressive agents cladribine and laquinimod. A novel mode of action has been described for fingolimod, another orally available agent, which inhibits egress of activated lymphocytes from draining lymph nodes. Dimethylfumarate exhibits immunomodulatory as well as immunosuppressive activity when given orally. All of these compounds have successfully shown efficacy, at least in regards to the surrogate marker contrast-enhancing lesions on magnetic resonance imaging. Another class of agents that is highlighted in this review are biological agents, namely monoclonal antibodies (mAb) and recombinant fusion proteins. The humanized mAb daclizumab inhibits T-lymphocyte activation via blockade of the interleukin-2 receptor. Alemtuzumab and rituximab deplete leukocytes and B cells, respectively; the fusion protein atacicept inhibits specific B-cell growth factors resulting in reductions in B-cells and plasma cells. These compounds are currently being tested in phase II and III studies in patients with relapsing MS. The concept of neuro-protection and -regeneration has not advanced to a level where specific compounds have entered clinical testing. However, several agents approved for conditions other than MS are highlighted. Finally, with the advent of these highly potent novel therapies, rare, but potentially serious adverse effects have been noted, namely infections and malignancies. These are critically reviewed and put into perspective.

Development of a murine model for blastoid variant mantle-cell lymphoma

AbstractBlastoid-variant mantle-cell lymphoma (MCL-BV), unlike most B-cell non-Hodgkin lymphomas (NHL-Bs), is refractory to conventional chemotherapy and associated with a very poor prognosis. Development of new therapies has been hampered by the lack of valid animal models. We have developed a novel murine model of MCL-BV by crossing interleukin 14α (IL-14α) transgenic mice with c-Myc transgenic mice (double transgenic [DTG]). IL-14α is a B-cell growth factor that is expressed in a number of high-grade lymphomas, including MCL-BV. Ninety-five percent of IL-14α transgenic mice develop CD5+ large B-cell lymphomas by 18 months of age. Sixty percent of c-Myc transgenic mice develop pre-B-cell lymphomas by 12 months of age. Close to 100% of DTG mice develop an aggressive, rapidly fatal lymphoma at 3 to 4 months of age that is CD5+, CD19+, CD21−, CD23−, sIgM+. The tumor is found in the blood, bone marrow, liver, spleen, lymph nodes, gastrointestinal tract, and lungs and rarely in the brain, similar to the involvement seen in human MCL-BV. Immunoglobulin gene rearrangements document the monoclonality of the tumor. Cyclin D1 is highly expressed in these tumors, as it is in MCL-BV. DTG represents a novel model for MCL-BV that should reveal important insights into the pathogenesis of the lymphoma and contribute to the development of new forms of therapy.

Circulating cytokines in Norwegian patients with psoriatic arthritis determined by a multiplex cytokine array system

Serum cytokines play an important role in the pathogenesis of psoriatic arthritis (PsA) by initiating and perpetuating various cellular and humoral autoimmune processes. The aim of this study was to describe a broad spectrum of T- and B-cell cytokines, growth factors and chemokines in patients with PsA and healthy individuals. A novel protein array system, denoted as multiplex cytokine assay was utilized to measure simultaneously the levels of 23 circulating cytokines of patients with PsA and healthy individuals. Additionally, correlational clustering and discriminant function analysis (DFA), two multivariate, supervised analysis methods were employed to identify a subset of biomarkers in order to describe potential functional inter-relationships among these pathological cytokines and identify biomarkers with prognostic and diagnostic utility. Univariate analysis demonstrated that serum levels of a complex set of immune and inflammatory modulating cytokines are significantly up-regulated in patients with PsA relative to unaffected controls including interleukin (IL)-10, IL-13, interferen (IFN)-alpha, epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), fibroblast growth factor [CCL3 macrophage inflammatory protein (MIP)-1alpha], CCL4 (MIP-1beta) and CCL11 (Eotaxin), while granulocyte-colony stimulating factor was significantly reduced in PsA patients. Correlational clustering was able to discriminate among, and hence subclassify, patients with varying levels of disease activity, which may prove useful in guiding therapy in these apparently phenotypically distinct disease subsets. DFA identified EGF, IFN-alpha, VEGF, CCL3 (MIP-1alpha) and IL-12p40 as analytes with the strongest discriminatory power among various PsA patients and controls. Our findings suggest that these factors modulate PsA pathology and the articular involvement in a synergistic manner. Identifying factors could be used in the development of clinical diagnostic tests, which are valuable to guide evidence-based diagnosis and disease management of PsA.

ＩｇＡ腎症に対する扁桃摘出術の臨床効果と予後予測因子の検討

Because upper respiratory tract infections, particularly tonsillitis, often precede IgA nephropathy (IgAN), IgAN is now recognized as a tonsil-related disease, and reports have shown that tonsillectomy is effective in preventing disease progression in IgAN patients. IgA may thus play an important role in IgAN pathogenesis and development. B cell activation factor belonging to the TNF family (BAFF) is expressed by monocytes, macrophages, and dendritic cells, and may be the mechanism by which macrophages and dendritic cells directly regulate human B-cell activation. BAFF acts as a potent B-cell growth factor and costimulator of immunoglobulin production, including IgA. We studied therapeutic effects and serum BAFF levels as prognostic factors. Subjects were 41 patients undergoing tonsillectomy and followed up for at least 1 year. Serum samples were obtained from 38 with IgAN and 29 with recurrent tonsillitis as a properative control groups. The remission group consisted of patients with normal renal function without hematuria and proteinuria. Serum BAFF levels were measured by ELISA kits at our laboratory. Overall remission was 39.0%. The disappearance of hematuria increased for long-term follow-up groups, but proteinuria was unchanged. Serum BAFF levels among the two groups did not differ significantly. Among IgAN patients, higher BAFF levels were associated with higher serum IgA/C3 levels. The correlation was weak (p =0.026, r = 0.407). Using 3.2 ng / ml as a cut off point, we compared cumulative improvement in those with high pretreatment BAFF levels to those with low pretreatment levels. Those with high pretreatment BAFF levels had inferior cumulative improvement in hematuria. Tonsillectomy was effective in improving hematuria. BAFF appears to be a key factor in tonsillectomy among [gAN patients.

Role of interleukin‐7 in bone and T‐cell homeostasis

Initially defined as a B-cell growth factor, the pleiotropic nature of interleukin-7 (IL-7) has increasingly become appreciated. Besides its well-known roles in B- and T-cell lymphopoiesis, IL-7 is now known to regulate the homeostasis of both mature T cells and bone cells. In bone, the precise nature of how IL-7 affects osteoclasts and osteoblasts is controversial, since it has a variety of actions in different target cells. These activities are gender-specific and are dependent on whether IL-7 is delivered systemically or locally. In mature T cells, IL-7 is essential for the survival of nearly all subsets. Naïve T cells are also dependent on IL-7 for survival and homeostatic proliferation in response to lymphopenia. In addition, IL-7 plays a role in the survival of memory CD8+ cells, and at high concentrations, it can compensate for the absence of IL-15. The role of IL-7 on memory CD4+ cells remains controversial and has yet to be firmly established.

Epstein-Barr Virus Lytic Infection Contributes to Lymphoproliferative Disease in a SCID Mouse Model

Most Epstein-Barr virus (EBV)-positive tumor cells contain one of the latent forms of viral infection. The role of lytic viral gene expression in EBV-associated malignancies is unknown. Here we show that EBV mutants that cannot undergo lytic viral replication are defective in promoting EBV-mediated lymphoproliferative disease (LPD). Early-passage lymphoblastoid cell lines (LCLs) derived from EBV mutants with a deletion of either viral immediate-early gene grew similarly to wild-type (WT) virus LCLs in vitro but were deficient in producing LPD when inoculated into SCID mice. Restoration of lytic EBV gene expression enhanced growth in SCID mice. Acyclovir, which prevents lytic viral replication but not expression of early lytic viral genes, did not inhibit the growth of WT LCLs in SCID mice. Early-passage LCLs derived from the lytic-defective viruses had substantially decreased expression of the cytokine interleukin-6 (IL-6), and restoration of lytic gene expression reversed this defect. Expression of cellular IL-10 and viral IL-10 was also diminished in lytic-defective LCLs. These results suggest that lytic EBV gene expression contributes to EBV-associated lymphoproliferative disease, potentially through induction of paracrine B-cell growth factors.

Diverse gene expression pattern during 5-fluorouridine-induced apoptosis

The purpose of this study was to establish experimental conditions to produce apoptosis by the fluorinated pyrimidine 5-fluorouridine and to examine the changes in gene expression that occurred during cell death. HCT-116 colorectal carcinoma cells were exposed to 10 microM 5-fluorouridine alone or in the presence of 1 mM uridine, 30 microM thymidine or both uridine and thymidine. A time-dependent increase in the percentage of apoptotic cells and a decrease in the percentage of viable cells were observed when the cells were treated with 5-fluorouridine in the absence of uridine (p < 0.001) but not in the presence of uridine. cDNA microarray analysis was used to study the expression of 1,200 different genes during apoptosis by 5-flurouridine. The expression of 33 genes was upregulated by 5-fold or greater at 16 and 24 h of 5-fluorouridine exposure. The largest cluster of upregulated genes included a group of genes classified as growth factors, cytokines and chemokines (e.g. interleukin-3, interleukin-4, B-cell growth factor 1 and stem cell growth factor). The expression of MIC-1 increased up to 100-fold during 5-flurouridine exposure. One hundred and twenty-four genes were downregulated by 5-fold or greater following exposure to 5-fluorouridine. The downregulated genes were distributed throughout the six different classifications on the array. Our data demonstrate a diverse pattern of gene expression during the fluorouridine-induced apoptosis and suggest that mechanisms besides a global inhibition of RNA synthesis/ processing contribute to the RNA-directed cytotoxicity of fluoropyrimidines.

Immunologic manipulation for the threatened fetus

Management of the pregnant woman with the antiphospholipid syndrome (APLS) has improved over the last 10 years. The recurrent pregnancy loss that is associated with this disease is managed with prophylactic low dose aspirin and heparin therapy. This therapy leads to a 40% absolute risk reduction in pregnancy loss. However, many women still fail to deliver a live infant despite this therapy so immunologic manipulation of the mother's disease in this group needs to be considered. Intravenous immunoglobulin and plasma exchange may have a role. New immunosuppressive drugs such as tacrolimus have yet to be tried. Monoclonal antibodies to B cells, B-cell growth factors, complement proteins and integrin molecules, all of which appear to play a role in the disease process, may also offer patients some hope. Similarly, biologics such as C1 esterase inhibitor protein, cell surface complement regulator proteins or interleukin-3 need to be tried given their efficacy in models of antibody-induced cell injury.

SLE - Complex cytokine effects in a complex autoimmune disease: tumor necrosis factor in systemic lupus erythematosus

Tumor necrosis factor (TNF) is a proinflammatory cytokine and a B-cell growth factor. It has numerous possible effects on T lymphocytes and dendritic cells, and it influences apoptosis. These differential effects may in part explain why patients under TNF-blocker therapy can develop autoantibodies to nuclear antigens, and may shed some light on the finding that low TNF fosters autoimmune disease in some mouse strains. On the contrary, TNF is increased in the blood and in the inflamed kidneys of systemic lupus erythematosus patients. Several studies in lupus-prone mice other than the F1 generation of New Zealand Black mice crossed with New Zealand White mice suggest that TNF is highly proinflammatory in the efferent limb and is potentially detrimental in lupus organ disease. Therefore, TNF blockade probably constitutes an efficacious therapeutic option.

Cloning of the Rat IL-5Rα Gene: Analysis of 5′-Upstream Region and Expression by B Cells

Although rats are widely used for the analysis of allergic reactions and parasitic infections where IL-5 is involved, nothing is currently known of the expression of IL-5 receptor in this species. In this study, the cDNA sequence, genomic structure and the transcriptional regulation of the rat IL-5Rα were analyzed. The rat IL-5Rα gene, which we localized to chromosome 4q34-q41, spans more than 25 kb and consists of 12 exons. Promoter activity was seen in different cell lines and analysis by deletion experiments allowed to identify two negative regulatory regions which did not differ when tested either with IL-5Rα-negative or positive cells. Finally, the investigation of the expression of IL-5Rα showed that it is expressed in lung, spleen, liver, and purified rat B cells from normal rat. This can provide an explanation for the role of rat IL-5 as B-cell growth factor and a relevant model in order to better understand the activity of IL-5 on human B cells.

Essential role for T cells in human B-cell lymphoproliferative disease development in severe combined immunodeficient mice.

Epstein-Barr virus (EBV)-positive B-cell lymphoproliferative disease (BLPD)-like lesions develop in severe combined immunodeficient (SCID) mice inoculated with peripheral blood mononuclear cells (PBMCs) from EBV-seropositive donors. We used this model to investigate the pathogenesis of EBV-associated BLPD. Tumour incidence fell from 81% to 11% when only B cells were inoculated, suggesting a key role for T cells in tumour formation. This was further underlined by the reduction in tumour incidence from 76% to 7% when PBMCs were depleted of CD4 positive (+ve) helper T cells. Tumour outgrowth was also reduced when PBMC were depleted of CD8 +ve, CD45RA +ve or CD45RO +ve T cells. The majority of PBMC-derived tumours analysed by reverse transcriptase-polymerase chain reaction (RT-PCR) expressed mRNA for interleukin (IL) 2, 4, 6, 10 and interferon (IFN) gamma. This is the cytokine pattern seen in activated T cells and includes B-cell growth factors. In situ hybridization studies confirmed that the tumour cells themselves express the growth factors, which is consistent with autocrine-stimulated tumour growth. Our results suggest the following sequence of events: (1) T cells are essential for the initial outgrowth of tumorigenic EBV +ve B cells in vivo; (2) the neoplasm sustains its growth in an autocrine, cytokine-stimulated manner; and (3) established tumours become independent of T-cell help.

Preparation of recombinant rat interleukin-5 by baculovirus expression system and analysis of its biological activities

Rat interleukin-5 (IL-5) cDNA was subcloned from peritoneal cells collected 4 h after intraperitoneal injection of Ascaris suum antigen solution into the immunized rats. Cysteine proteinase-deleted (CPd) rat IL-5 recombinant virus was constructed by inserting rat IL-5 cDNA into CPd virus having a deletion in the cysteine proteinase gene of the silkworm Bombyx mori nuclear polyhedrosis virus. On infection with the CPd rat IL-5 recombinant virus, the silkworm B. mori larvae produced rat IL-5 as a dimeric form in hemolymph. Recombinant rat IL-5 was purified more than 95.5% by anion-exchange chromatography and hydrophobic chromatography. The purified recombinant rat IL-5 promoted the proliferation of T88-M cells in a concentration-dependent manner, and its effect was inhibited by an anti-murine IL-5 neutralizing polyclonal antibody. When bone marrow cells from normal rats were incubated with recombinant rat IL-5 in medium containing methylcellulose, the colony formation by eosinophilic cells was induced. Furthermore, when rat peritoneal eosinophils were incubated with recombinant rat IL-5, the spontaneous decrease in the eosinophil viability was inhibited in time- and concentration-dependent manners. In addition, the recombinant rat IL-5-induced eosinophil survival was inhibited by an anti-murine IL-5 neutralizing polyclonal antibody. These findings suggest that rat IL-5 acts as B-cell growth factor II (BCGF-II), eosinophil differentiation factor (EDF), and eosinophil survival-enhancing factor.

Cellular tropism and viral interleukin-6 expression distinguish human herpesvirus 8 involvement in Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease.

Human herpesvirus 8 (HHV-8) infection has been implicated in the etiology of Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman's disease (MCD), three diseases that frequently develop in immunocompromised, human immunodeficiency virus-positive individuals. One hypothesis that would account for different pathological manifestations of infection by the same virus is that viral genes are differentially expressed in heterogeneous cell types. To test this hypothesis, we analyzed the localization and levels of expression of two viral genes expressed in latent and lytic infections and the viral homologue of interleukin-6 (vIL-6). We show that PEL parallels KS in the pattern of latent and lytic cycle viral gene expression but that the predominant infected cell type is a B cell. We also show that MCD differs from KS not only in the infected cell type (B-cell and T-cell lineage) but also in the pattern of viral gene expression. Only a few cells in the lesion are infected and all of these cells express lytic-cycle genes. Of possibly greater significance is the fact that in a comparison of KS, PEL, and MCD, we found dramatic differences in the levels of expression of vIL-6. Interleukin-6 is a B-cell growth and differentiation factor whose altered expression has been linked to plasma cell abnormalities, as well as myeloid and lymphoid malignancies. Our findings support the hypothesis that HHV-8 plays an important role in the pathogenesis of PEL and MCD, in which vIL-6 acts as an autocrine or paracrine factor in the lymphoproliferative processes common to both.

Effects of interleukin 3, interleukin 7, and B-cell growth factor on proliferation and drug resistance in vitro in childhood acute lymphoblastic leukemia.

Growth factors have been reported to enhance the cytotoxicity of anticancer agents. In our study we investigated the capacities of interleukin 3 (IL-3), interleukin 7 (IL-7), low-molecular-weight B-cell growth factor (lmw-BCGF), and IL-3 + 7 to induce proliferation and to modulate the drug resistance of childhood acute lymphoblastic leukemia (ALL) cells. Proliferation was assessed with the methyl-thiazole-tetrazolium (MTT) assay and other parameters. Cellular resistance to cytarabine, thioguanine, and prednisolone was measured using the MTT assay. In 19 samples containing >90% leukemic cells the proliferative response and the modulation of drug resistance was markedly heterogeneous between patient samples and between growth factors. All growth factors were able to stimulate proliferation significantly after 5 days of culture. lmw-BCGF was the most potent growth factor in this respect. Cytotoxicity of cytarabine and thioguanine was significantly increased by IL-7, that of thioguanine by IL-3 as well. IL-7 enhanced the cytotoxicity of thioguanine significantly more than IL-3 and lmw-BCGF and that of cytarabine more than IL-3. Cytotoxicity of prednisolone was not significantly influenced by any growth factor. In individual cases, growth factors reduced the cytotoxicity of the drugs. IL-3 + 7 did not add activity to the most potent single growth factor in both proliferation and drug resistance measurements. This study shows that IL-3, IL-7, and lmw-BCGF generally induce and occasionally inhibit proliferation of ALL cells. Furthermore, they may either increase or decrease cytotoxicity of anticancer drugs. This heterogeneous response to growth factors concerning induction of proliferation and modulation of drug resistance should be taken into account in their clinical use.

Sequential changes in CGRP-like immunoreactivity in NIDDM model Otsuka Long-Evans Tokushima Fatty (OLETF) rat pancreatic islets.

We describe the changes in B cells and calcitonin gene-related peptide (CGRP)-like immunoreactivity in the pancreatic islets of Otsuka Long-Evans Tokushima Fatty (OLETF) rats, an animal model of human non-insulin-dependent diabetes mellitus (NIDDM). In the OLETF rat pancreatic islets, CGRP immunoreactivity was seen in the nerve fibers with multiple varicosities and in endocrine cells that were identical to somatostatin-containing cells, but some somatostatin-immunoreactive cells lacked CGRP immunoreactivity. In the OLETF rats, plasma insulin levels were significantly higher than in the control rats (Long-Evans Tokushima Otsuka; LETO) only at 7 weeks of age. From 7 through 32 weeks of age, OLETF rats had a greater B-cell area than LETO rats. The length of CGRP-immunoreactive nerve fibers per area and the numbers of CGRP-immunoreactive cells per area did not differ between the groups at 7 weeks of age. After 16 weeks of age, both of these CGRP parameters in the OLETF rats became increasingly higher than in the LETO rats. These results suggest that CGRP is a B-cell growth factor and probably an inhibitory factor for insulin secretion.

Human Herpesvirus Type 8 Interleukin-6 Homologue Is Functionally Active on Human Myeloma Cells

Seroepidemiology and polymerase chain reaction studies have strongly suggested that human herpesvirus type 8 (HHV-8) is associated with Kaposi's sarcoma, Castleman's disease, and body cavity-based lymphoma. The genome of HHV-8 harbors a viral analogue of the interleukin-6 (IL-6) gene. The amino acid sequence of the viral IL-6 (vIL-6) protein is 24.7% identical to human IL-6 (hIL-6). IL-6 as a B-cell growth and differentiation factor is known to play an essential role in the pathophysiology of B-cell tumors. Thus, it seems possible that virus-encoded IL-6 contributes to malignant growth of HHV-8–positive B-cell lymphatic tumors. We have tested a preparation of HHV-8–derived IL-6 for the ability to promote the proliferation of the human myeloma cell line INA-6, which is strictly dependent on exogenous IL-6 for growth and survival. Viral IL-6 significantly induced DNA synthesis of INA-6 cells, but required much more protein on a weight basis when compared with hIL-6 for maximal proliferation. The proliferative effect of vIL-6 was almost completely inhibited by a combination of anti–IL-6 receptor (IL-6R) and anti-gp130 antibodies or IL-6R superantagonist Sant7 and anti-gp130 antibodies. This report demonstrates that vIL-6 has proliferative activity on human cells and that the IL-6R and gp130 are involved in vIL-6 signaling in the myeloma cell line INA-6.

Human Herpesvirus Type 8 Interleukin-6 Homologue Is Functionally Active on Human Myeloma Cells

AbstractSeroepidemiology and polymerase chain reaction studies have strongly suggested that human herpesvirus type 8 (HHV-8) is associated with Kaposi's sarcoma, Castleman's disease, and body cavity-based lymphoma. The genome of HHV-8 harbors a viral analogue of the interleukin-6 (IL-6) gene. The amino acid sequence of the viral IL-6 (vIL-6) protein is 24.7% identical to human IL-6 (hIL-6). IL-6 as a B-cell growth and differentiation factor is known to play an essential role in the pathophysiology of B-cell tumors. Thus, it seems possible that virus-encoded IL-6 contributes to malignant growth of HHV-8–positive B-cell lymphatic tumors. We have tested a preparation of HHV-8–derived IL-6 for the ability to promote the proliferation of the human myeloma cell line INA-6, which is strictly dependent on exogenous IL-6 for growth and survival. Viral IL-6 significantly induced DNA synthesis of INA-6 cells, but required much more protein on a weight basis when compared with hIL-6 for maximal proliferation. The proliferative effect of vIL-6 was almost completely inhibited by a combination of anti–IL-6 receptor (IL-6R) and anti-gp130 antibodies or IL-6R superantagonist Sant7 and anti-gp130 antibodies. This report demonstrates that vIL-6 has proliferative activity on human cells and that the IL-6R and gp130 are involved in vIL-6 signaling in the myeloma cell line INA-6.

Interleukin-7 (IL-7) Enhances Class Switching to IgE and IgG4 in the Presence of T Cells Via IL-9 and sCD23

AbstractInterleukin-7 (IL-7) is a B-cell growth factor produced by both bone marrow stroma cells and follicular dendritic cells (FDCs) located in primary lymphoid follicles and germinal centers. In this study, we have evaluated the role of IL-7 on human Ig class switching. IL-7 was added to peripheral blood mononuclear cells (PBMCs) or tonsillar B cells in the absence or presence of IL-4 and/or anti-CD40 monoclonal antibody (MoAb). Alone, IL-7 did not affect Ig production by PBMCs or by anti-CD40 MoAb-stimulated B cells. Rather, IL-7 potentiated IL-4–induced IgE and IgG4 production by PBMCs. In parallel, IgG3 production was also enhanced but to a lesser extent, whereas the production of the other isotypes was unaltered. The activity of IL-2, IL-9, or IL-15, which share usage of the common γ chain for signaling, was also assessed. IL-9, like IL-7, potentiated mainly IgE and IgG4 production by IL-4–stimulated PBMCs. IL-15, in contrast, was ineffective, whereas IL-2 enhanced the production of all isotypes. More precisely, IL-7 potentiation of IgE and IgG4 production required the presence of T cells and was accompanied by an increase of the expression of two soluble molecules favoring preferentially IgE and IgG4 synthesis: CD23 (sCD23) and IL-9. Moreover, neutralizing anti-CD23 and anti–IL-9 antibodies partly inhibited the increase of IgE synthesis induced by IL-7. Thus, IL-7 produced locally in the germinal centers by FDCs may interact with T cells and potentiate human IgE and IgG4 switching by favoring IL-9 and sCD23 production.

Increased production of B-cell growth factor by T lymphocytes in Graves' thyroid: possible role of CD4+ CD29+ cells.

The possible role of B-cell growth factor (BCGF) in the abnormal activation of B cells in Graves' disease was investigated by measuring the production of BCGF by, and analyzing lymphocyte subsets of, peripheral blood cells and thyroid infiltrates from 10 patients with Graves' disease and peripheral blood cells from 9 healthy controls. Medium from peripheral blood and intrathyroidal T cells cultured in the absence or presence of phytohemagglutinin (PHA) was subjected to a bioassay with a cell line, KS-3.F10, responsive only to BCGF. The percentages of activated (DR+CD4+ and DR+CD8+) T cells in the thyroid of Graves' patients were significantly higher than those in the peripheral blood of patients or controls, whereas the percentage of naive (CD4+CD45RA+) T cells was lower. The percentage of B (CD20+) cells in peripheral blood was increased in patients compared with controls. BCGF production by T cells from the thyroid or peripheral blood of Graves' patients, in the absence or presence of PHA, was significantly greater than that by peripheral T cells from healthy controls. PHA-stimulated BCGF production by peripheral T cells of Graves' patients showed a significant negative correlation with the percentage of DR+CD8+ cells in peripheral blood, whereas spontaneous and PHA-stimulated BCGF production by intrathyroidal T cells from Graves' patients showed a positive correlation with the serum concentrations of triiodothyronine (T3) or thyroxine (T4). The different distributions of CD4+ T-cell subsets between thyroid and peripheral blood suggest an important role for intrathyroidal helper/suppressor-inducer (CD4+CD29+) cells in the increased production of BCGF and consequent exacerbation of autoimmunity in Graves' disease.

Enhanced follicular dendritic cell-B cell interaction in HIV and SIV infections and its potential role in polyclonal B cell activation.

Human immunodeficiency virus (HIV) infections have been characterized by both polyclonal Bcell activation and enhanced responsiveness to B-cell growth factors on one hand and the loss of specific antibody (Ab) responses and refractoriness to the normal signals for B-cell activation on the other. Histopathological studies of lymph node from HIV- and simian immunodeficiency virus (SIV)-infected individuals have indicated initial follicular hyperplasia and the appearance of large irregular germinal centers that undergo progressive involution concomitant with follicular dendritic-cell (FDC) disruption. During this process, follicular dendritic-cell -enriched lymph-node-cell cultures exhibit increased ability to induce cluster formation (“in vitro germinal centers”), lymphocyte proliferation and antibody production compared to uninfected controls. This paper discusses how enhanced FDC-B-cell interaction within SIV-infected germinal centers may result in a reduced ability to select high-affinity B cells and alter the dynamics of antibodyproducing- cell and memory-cell generation resulting in the observed hyperactivity.