Is there a role for locally produced complement in renal disease?
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Animals↗
Biomedical subjects
C van Kooten
Publications and source records attributed to C van Kooten.
Is the proximal tubular cell a proinflammatory cell?
In the past few decades, accumulating evidence has been generated on the central role of the proximal tubular cell in renal injury and dysfunction, such as can be found in some patients with glomerular proteinuria and in chronic renal rejection or following ischaemic insult. Following initial injury or stimulation of the proximal tubular cells, various cascades of mediator systems can be activated leading, for example, to enhanced local production of complement, chemokines, cytokines and matrix components. The locally produced mediators subsequently can lead to amplification of injury either directly or indirectly by enhancement of influx of proinflammatory cells such as macrophages, polymorphonuclear leukocytes and T cells. The concerted production of cytokines and chemokines may tip the balance to a more proinflammatory pathway leading to irreversible interstitial injury of the kidney and loss of renal function.
Chemokines↗
Crosslinking of the human Fc receptor for IgA (FcalphaRI/CD89) triggers FcR gamma-chain-dependent shedding of soluble CD89.
CD89/FcalphaRI is a 55- to 75-kDa type I receptor glycoprotein, expressed on myeloid cells, with important immune effector functions. At present, no information is available on the existence of soluble forms of this receptor. We developed an ELISA for the detection of soluble CD89 (sCD89) forms and investigated the regulation of sCD89 production. PMA/ionomycin stimulation of monocytic cell lines (U937, THP-1, and MM6), but not of neutrophils, resulted in release of sCD89. Crosslinking of CD89 either via its ligand IgA or with anti-CD89 mAbs similarly resulted in sCD89 release. Using CD89-transfected cells, we showed ligand-induced shedding to be dependent on coexpression of the FcR gamma-chain subunit. Shedding of sCD89 was dependent on signaling via the gamma-chain and prevented by addition of inhibitors of protein kinase C (staurosporine) or protein tyrosine kinases (genistein). Western blotting revealed sCD89 to have an apparent molecular mass of 30 kDa and to bind IgA in a dose-dependent fashion. In conclusion, the present data document a ligand-binding soluble form of CD89 that is released upon activation of CD89-expressing cells. Shedding of CD89 may play a role in fine-tuning CD89 immune effector functions.
Antigens, CD↗
Immunoglobulin-binding sites of human FcalphaRI (CD89) and bovine Fcgamma2R are located in their membrane-distal extracellular domains.
To localize the immunoglobulin (Ig)-binding regions of the human Fcalpha receptor (FcalphaRI, CD89) and the bovine Fcgamma2 receptor (bFcgamma2R), chimeric receptors were generated by exchanging comparable regions between these two proteins. FcalphaRI and bFcgamma2R are highly homologous and are more closely related to each other than to other human and bovine FcRs. Nevertheless, they are functionally distinct in that FcalphaRI binds human IgA (hIgA) but not bovine IgG2 (bIgG2), whereas bFcgamma2R binds bIgG2 but not hIgA. FcalphaRI and bFcgamma2R possess extracellular regions consisting of two Ig-like domains, a membrane-distal extracellular domain (EC1), a membrane-proximal EC domain (EC2), a transmembrane region, and a short cytoplasmic tail. Chimeras constructed by exchanging complete domains between these two receptors were transfected to COS-1 cells and assayed for their ability to bind hIgA- or bIgG2-coated beads. The results showed that the Ig-binding site of both FcalphaRI and bFcgamma2R is located within EC1. Supporting this observation, monoclonal antibodies that blocked IgA binding to FcalphaRI were found to recognize epitopes located in this domain. In terms of FcR-Ig interactions characterized thus far, this location is unique and surprising because it has been shown previously that leukocyte FcgammaRs and FcepsilonRI bind Ig via sites principally located in their EC2 domains.
Amino Acid Sequence↗
Synergistic effect of interleukin-1 and CD40L on the activation of human renal tubular epithelial cells.
BACKGROUND: Renal tubular epithelial cells are a central cell type in tubulointerstitial inflammation because they can produce inflammatory mediators such as cytokines and chemokines. Several signals derived from either monocytes or activated T cells have been reported to regulate the activation of tubular epithelial cells. We studied this regulation in more detail by combined treatment with CD40 ligand and the proinflammatory cytokine interleukin-1 (IL-1) in vitro. METHODS: The regulation of cytokine and chemokine production was studied in primary cultures of human proximal tubular epithelial cells (PTECs). PTECs were activated by coculture with CD40L-transfected murine fibroblasts in combination with recombinant human cytokines. The production of IL-6, IL-8, monocyte chemoattractant protein-1 (MCP-1), and RANTES were measured by specific enzyme-linked immunosorbent assay. RESULTS: The combined activation of PTECs with CD40L and IL-1 resulted in strong synergistic effects on the production of IL-6, IL-8, and RANTES, whereas only an additive stimulation of MCP-1 production was observed. The effects were specific for IL-1 and could be neutralized by the addition of the IL-1R antagonist. Both IL-1alpha and IL-1beta showed similar effects on cytokine production by PTECs. The effects of IL-1 were dose dependent, and kinetic experiments showed that synergistic effects were observed after 24 hours of activation and remained present for at least five days. Reverse transcription-polymerase chain reaction analysis showed that human PTECs could express both IL-1alpha and IL-1beta. The activation of PTECs with IL-1 resulted in an up-regulation of CD40 expression on these cells. CONCLUSIONS: A complex network of regulation exists for the production of cytokines and chemokines by PTECs. The combined treatment results in strong synergistic effects on IL-6, IL-8, and RANTES production. This strengthens the potential role of tubular epithelial cells in inflammatory responses within the kidney.
Animals↗
Decreased IgA1 response after primary oral immunization with live typhoid vaccine in primary IgA nephropathy.
INTRODUCTION: Patients with primary IgA nephropathy (IgAN) have an increased level of immunological memory to certain parenteral recall antigens. We recently found a deficient IgA1 immune response after intranasal challenge with a neo-antigen: cholera toxin subunit B. In the present study, we assessed the specific IgA1 and IgA2 antibody response in plasma, peripheral blood cells and mucosal secretions after primary enteral immunization. METHODS: Twenty eight IgAN patients, 26 patients with non-immunological renal disease and 32 healthy subjects were immunized orally with three sequential doses of live, attenuated, Salmonella typhi Ty21a. The humoral immune response in body fluids and antibody synthesis by circulating B cells was assessed in specific ELISAs and ELIPSAs respectively. RESULTS: Oral immunization resulted in significantly (P<0.0001) increased IgM, IgG, IgA, IgA1 and IgA2 responses in all groups, both in plasma and in circulating B cells in vitro. The IgA1 response in plasma was significantly (P<0.05) lower in IgAN patients, while no significant differences in IgM (P=0.36), IgG (P= 0.79) or IgA2 (P=0.45) responses were found as compared with matched control groups. The amount of IgA1 synthesized by circulating B cells tended to be lower in IgAN patients. No significant IgA response after oral immunization with S. typhi Ty21a was found in saliva (P=0.11) or tears (P=0.10). CONCLUSIONS: These data suggest an IgA1 hyporesponsiveness in patients with IgAN that is not only apparent after primary challenge of the nasal-associated lymphoid tissue but also after presentation to the gut. Previous results after parenteral recall immunization may be explained by assuming that IgAN patients require more frequent and/or longer exposure to IgA1-inducing antigens on their mucosal surfaces before they reach protective mucosal immunity. As a consequence, overproduction of IgA1 antibodies occurs in the systemic compartment, accompanied by an increased number of IgA1 memory cells.
Administration, Oral↗
Blockade of costimulatory pathways of T-cell activation: the solution to acute and chronic rejection?
Understanding of how antigen-specific signals and costimulatory molecules are involved in T-cell activation has resulted in new strategies to interfere with allograft rejection. The present review focuses on the role of two receptor-ligand pairs: CD28 and cytotoxic T lymphocyte associated antigen-4, which interact with the B7 ligands (CD80, CD86); and CD40, which interacts with the CD40L (CD154). On the basis of the extensive tissue distribution of CD40, it is likely that the CD40/CD40L system plays a much broader role.
Acute Disease↗
Role of tubular cells in progressive renal disease.
It is generally accepted that the progressive loss of kidney function results from a pathogenic process that is independent of the original etiology, functioning as a final common pathway. Part of this response is characterized by triggering of interstitial infiltration and induction of tubular damage. As a consequence, tubular epithelial cells (TEC) can become activated and begin to express several inflammatory mediators. In the present review, we will summarize the potential role of TEC in progressive renal disease. Much emphasis will be put on studies using in vitro cultured TEC. These studies have provided more insight into the different signals involved in the regulation of the production of inflammatory mediators like complement, cytokines and chemokines, as well as progression factors like growth factors and matrix component by TEC.
Animals↗
Human mesangial cells in culture and in kidney sections fail to express Fc alpha receptor (CD89).
The mechanism of deposition of IgA in the renal mesangium in primary IgA-nephropathy is poorly understood. It has been suggested that membrane receptors for IgA on mesangial cells (MC) of the kidney may be involved. To obtain more insight in the occurrence of the myeloid receptor for IgA (CD89) on MC, both in situ and in culture, rabbit and goat polyclonal antibodies and mouse monoclonal antibody against recombinant CD89 were raised. Kidney sections from five control subjects and five patients with primary IgA-nephropathy failed to be positive for CD89 in the mesangium, using our polyclonal and monoclonal antibodies. Also, five primary human MC cultures assessed for CD89 expression showed no protein expression of CD89. Furthermore, reverse transcription-PCR failed to detect mRNA expression of CD89 in the cultured MC. It was demonstrated that all five human primary MC bound human IgA in a dose-dependent manner, which was not inhibitable by blocking monoclonal anti-CD89 antibody (My43). In contrast, binding of IgA to U937 cells was blocked efficiently by My43. Finally, incubation of human MC with either human or rat IgA led to increased interleukin-6 production, whereas only human IgA, but not rat IgA, was able to bind to human CD89. Therefore, it is concluded that human MC do not express CD89 (to a significant extent). These results strongly suggest that binding of IgA to human MC occurs via an IgA receptor distinct from CD89.
Animals↗
The DD genotype of the ACE gene polymorphism is associated with progression of diabetic nephropathy to end stage renal failure in IDDM.
BACKGROUND: The insertion-deletion (I/D) polymorphism of the angiotensin converting enzyme gene is a diallelic polymorphism that constitutes a genetic influence on the progression of renal diseases such as IgA nephropathy. Patients with the DD genotype have an accelerated progression towards end stage renal failure in these diseases. The role of the I/D polymorphism in the pathogenesis of diabetic nephropathy in IDDM is unresolved. PATIENTS AND METHODS: We therefore set out to study the contribution of the I/D polymorphism in 79 patients (age 39.5 +/- 7.6 years (mean +/- SD) with end stage renal failure due to diabetic nephropathy, who were recipients of a combined kidney-pancreas transplantation (n = 60), or who were on the waiting list for such a procedure (n = 19). The control series consisted of 82 patients (age 39.5 +/- 9.6 years) without microalbuminuria after fifteen years of IDDM. RESULTS: The ACE genotype distribution in patients was not in accordance with the Hardy-Weinberg equilibrium due to a significant overrepresentation of the DD genotype (X2 = 8.9, p = 0.01). This resulted in a significant increase of the D-allele frequency in the cases compared to controls (X2 = 4.9, p = 0.03). The presence of one D-allele did not increase the risk of end stage renal failure (odds ratio ID/II = 1.0, 95% CI 0.4-2.2). The presence of the DD genotype increased the risk of end stage renal failure twofold compared to the other genotypes (odds ratio 2.1, 95% CI 1.1-4.0). The risk estimate seemed slightly higher in patients with good metabolic control (odds ratio 2.6, 95% CI 1.0-7.1), than in patients with poor control (odds ratio 1.6, 95% CI 0.59-4.3). CONCLUSION: It is concluded that the risk of end-stage renal failure in patients with IDDM is twofold increased in patients with the DD genotype as compared to patients with other genotypes.
Adult↗
Functional analysis of rheumatoid factor-producing B cells from the synovial fluid of rheumatoid arthritis patients.
OBJECTIVE: To understand the regulation of rheumatoid factor (RF) production in rheumatoid arthritis (RA), we studied IgM-RF production by B cells isolated from the synovial fluid (SF). METHODS: Highly purified SF and peripheral blood (PB) B cells were isolated by negative selection in a fluorescence-activated cell sorter (FACS) and then cultured with either L cells, CD40 ligand (CD40L)-transfected L cells, or type B synoviocytes in the presence or absence of interleukin-2 (IL-2), IL-4, or IL-10. Total IgM and IgM-RF were detected after 14 days by enzyme-linked immunosorbent assay. Enzyme-linked immunospot assays were performed to detect cells that spontaneously produced immunoglobulin. SF B cells were also phenotypically characterized by FACS analysis. RESULTS: Terminally differentiated CD20-,CD38+ synovial plasma cells (PC) present in the SF of RA patients secreted IgM-RF in the absence of a stimulus. IgM-RF production markedly increased when SF B cells were cultured in the presence of type B RA synoviocytes together with IL-10, but independently of CD40-CD40L interaction. Although CD20-,CD38+ PC could also be demonstrated in SF B cells from patients with other forms of arthritis, IgM-RF production was restricted to the SF B cell cultures of patients with seropositive RA. The frequency of IgM-RF-producing cells among IgM-producing PC in patients with seropositive RA was estimated to be as much as 50%. CONCLUSION: These data demonstrate that terminally differentiated CD20-,CD38+ IgM-RF-producing B cells are specifically present in the inflamed joints of patients with seropositive RA. There is evidence that the local environment in the rheumatoid joint favors RF production. The relatively high frequency of IgM-RF PC in the SF B cell population provides evidence of a dominant RA-specific antigen-driven response in the development of the synovial PC repertoire.
ADP-ribosyl Cyclase↗
Effect of anti-neutrophil cytoplasmic antibodies on proteinase 3-induced apoptosis of human endothelial cells.
Wegener's granulomatosis is characterized by crescentic necrotizing glomerulonephritis and systemic vasculitis. Both proteinase 3 (PR3) and anti-neutrophil cytoplasmic antibodies (ANCA), directed against this enzyme, are thought to play a pathogenic role. PR3 has been shown to cause detachment and cytolysis of human umbilical vein endothelial cells (HUVEC) in vitro and to induce apoptosis of bovine pulmonary artery endothelial cells. In the present study we investigated the effect of PR3 and ANCA on the induction of apoptosis of human endothelial cells in vitro. HUVEC were cultured in the absence or presence of varying concentrations of PR3 for different time periods and apoptosis was assessed by three different methods. Staining of the cells with Hoechst 33258 and assessment of nuclear morphology by ultraviolet (UV) light microscopy revealed a dose-dependent induction of apoptosis, as determined by cell counts. A concentration of 8 microg/ml PR3 was found to induce 16% apoptosis after 16 h incubation. Analysis of apoptosis by flow cytometry using the terminal deoxynucleotidyl transferase-mediated dUTP-fluorescein nick-end labelling (TUNEL) method also demonstrated a dose-dependent induction of apoptosis by PR3. DNA fragmentation was confirmed by agarose gel electrophoresis. To investigate the effect of ANCA on PR3-mediated apoptosis, HUVEC were exposed to immunoglobulin G (IgG) from patients with Wegener's granulomatosis or systemic vasculitis, and from normal controls, in the presence or absence of PR3. Enhancement of PR3-mediated apoptosis was found in two of 10 IgG samples with anti-PR3 activity, whereas a reduction in apoptosis was observed in two others. Anti-MPO (myeloperoxidase)-positive IgG, six additional anti-PR3 positive IgG samples and control IgG samples did not have any detectable effect on apoptosis. These studies suggest that ANCA may modulate the relative degree of injury in some cases of Wegener's granulomatosis.
Antibodies, Antineutrophil Cytoplasmic↗
Transforming growth factor-beta 1 regulates chemokine and complement production by human proximal tubular epithelial cells.
Previously it has been demonstrated that human proximal tubular epithelial cells (PTEC) are able to produce chemokines (such as IL-8 and MCP-1) and complement components (such as C2, C3, C4 and factor H), and that production of these proteins is regulated by pro-inflammatory cytokines such as interleukin-1 alpha (IL-1alpha), tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma). Since TGF-beta is also expressed in the renal interstitium during inflammation, we investigated the effect of TGF-beta on the production of chemokines and complement components by PTEC in culture. Transforming growth factor-beta 1 up-regulated IL-8 production by an average of 4.17 +/- 1.0 fold. macrophage chemoattractant phagocyte (MCP-1) production, on the other hand, was down-regulated by TGF-beta 1 by an average of 2.2 +/- 0.7 fold. The production of C3 and C4 was also down-regulated after incubation with TGF-beta 1 (1.9 +/- 0.3- and 3.0 +/- 1.2-fold, respectively). All effects were dose- and time-dependent and were found to be specific for TGF-beta 1, as assessed by inhibition of the effect with a neutralizing antibody against TGF-beta 1. These data, together with the knowledge that TGF-beta, chemokines and complement components play a role in several types of renal disease, suggest that TGF-beta is involved in the regulation of local expression of chemokines and complement components by tubular cells.
Antibodies, Monoclonal↗
Reduced binding of immunoglobulin A (IgA) from patients with primary IgA nephropathy to the myeloid IgA Fc-receptor, CD89.
BACKGROUND: Primary IgA nephropathy (IgAN) is associated with elevated levels of circulating IgA and is characterized by deposition of primarily IgA1 in the renal mesangium. It has not yet been clarified which mechanisms govern the deposition of IgA1 in the mesangium. One of the factors which may play a role in trapping of IgA in the mesangial area is the interaction of IgA with specific IgA receptors (Fc alphaR, CD89) on the mesangial cells. METHODS: In the present study IgA derived from patients with IgAN and controls was investigated for its interaction with human CD89, expressed on the surface of the murine B cell line IIA1.6. RESULTS: IgA binding to CD89 expressing cells was specific, concentration dependent and binding of dIgA and pIgA occurred in a more efficient fashion than that of mIgA. IgA binding to CD89 directly from serum of patients compared to controls showed no significant difference. However these experiments are affected by differences in IgA concentration and combinations of different sizes of IgA. Using purified fractions of mIgA, dIgA, and pIgA isolated from serum, a significantly reduced binding of mIgA to CD89 from patients compared to controls was observed. Finally, the binding of aIgA2 to CD89 was less inhibited using mIgA from patients with IgAN compared to controls. CONCLUSIONS: The reduced binding of mIgA to CD89 seems to contradict a direct role for CD89 in deposition of IgA. However reduced binding of mIgA to CD89 may affect IgA clearance, leading to higher serum IgA. Furthermore, since it has been demonstrated that mIgA can interfere with binding of di- and pIgA, CD89 could still contribute to pIgA deposition in the mesangial area.
Adult↗
IL-4 and IL-13 augment cytokine- and CD40-induced RANTES production by human renal tubular epithelial cells in vitro.
Local production of cytokines by infiltrating monocytes/macrophages and Th1 and Th2 cells is of importance in renal allograft rejection. Activated Th1 cells can produce interleukin-2 (IL-2), interferon-gamma (IFN-gamma), and tumor necrosis factor (TNF), whereas Th2 cells produce IL-4 and IL-13, which inhibit Th1 cells. Furthermore, activated T cells express the costimulatory molecule CD40-ligand. During renal allograft rejection, the chemokine RANTES is detected in both infiltrating mononuclear cells and tubular epithelium. It has been shown previously that stimulation of proximal tubular epithelial cells (PTEC) with cytokines or CD40-ligand results in production of RANTES. The present study investigates the influence of Th1 and Th2 cytokines on RANTES production by activated PTEC. RANTES was not detectable in supernatants of human PTEC stimulated with IL-2, IL-4, IL-10, or IL-13 alone. Likewise, combination of these cytokines with IL-1 alpha, IFN-gamma, or TNF-alpha, respectively, did not result in detectable RANTES production. IL-2 and IL-10 had no significant effect on RANTES production by activated PTEC. IL-4 or IL-13 in combination with IL-1 alpha + IFN-gamma or IFN-gamma + TNF-alpha resulted in a two- to fourfold augmentation of RANTES production, ranging from 2.2 +/- 0.2 to 35 +/- 2 ng/ml in different cell lines. CD40-activated PTEC stimulated with IL-4 or IL-13 produced six to ten times more RANTES (ranging from 7.9 +/- 1.9 to 62 +/- 3.5 ng/ml in different cell lines) compared with CD40-activated cells alone. Because RANTES production is augmented by IL-4 and IL-13, this study suggests that during rejection, direct cellular contact between activated Th2 cells and tubular epithelial cells amplifies the local inflammatory reaction in the kidney.
Bronchi↗
Decreased cytokine-induced IgA subclass production by CD40-ligated circulating B cells in primary IgA nephropathy.
BACKGROUND: In IgA nephropathy (IgAN), the abnormalities in the IgA immune system are apparently restricted to the IgA1 subclass in the systemic compartment, as evidenced by the antigen-specific responses to recall antigens. Since precursors of IgA producing B cells in human peripheral blood belong predominantly to the mucosal compartment, we took the opportunity to assess the capacity of circulating B cells in peripheral blood (PBMC) of 20 IgAN patients and matched controls to produce IgA, IgA1, and IgA2. METHODS: Supernatants from T cell- (immobilized anti-CD3) and B cell-specific (CD40 ligation) activated cultures were assessed for immunoglobulin isotypes by ELISA. In addition, we compared the sensitivity of T and B cells to various cytokines (IL-2, IL-10, TGF-beta) in both culture systems. RESULTS: In contrast to significantly higher plasma IgA1 levels (P < 0.01), no significant differences in salivary IgA1 (P = 0.73) and IgA2 (P = 0.96) levels or ratios (P = 0.91) were found. In the absence of exogenous cytokines, none of the different culture systems led to significant differences in IgA or IgA subclass synthesis by PBMCs of patients and controls. However, in IgAN patients, the addition of IL-2 did not enhance the production of the IgA subclasses as was found in controls. Furthermore IL-10 led to significantly (P < 0.05) lower IgA1 and IgA2 synthesis in patients than in controls. TGF-beta induced suppression of all isotypes in patients and controls. None of the different conditions resulted in a selectively enhanced production of any one of the IgA subclasses. When both IL-10 and TGF-beta were added to the cultures, IgM was the predominant immunoglobulin synthesized both in patients and controls with a significantly (P < 0.05) lower synthesis of IgM, IgG, IgA1, and IgA2 in patients. CONCLUSION: These in vitro data suggest that PBMCs from patients contain more mature and further differentiated B cells. However, there was no selective IgA or IgA1 dysregulation of circulating B cells in IgAN. These results do not confirm the widely believed paradigm that patients with IgAN are primary hyperresponders.
Adult↗
High CD40 membrane expression in AIDS-related lymphoma B cell lines is associated with the CD45RA+, CD45RO+, CD95+ phenotype and high levels of its soluble form in culture supernatants.
CD40 is a membrane glycoprotein expressed on normal and neoplastic B lymphocytes. Stimulation through CD40 regulates important cellular functions, but the effects depend on its membrane density. While extensive studies have characterized CD40 in non-Hodgkin lymphomas of immunocompetent individuals, little is known on the characteristics of this molecule in lymphomas arising in immunocompromised hosts. The aim of this study was to characterize the pattern of CD40 expression in an in vitro model constituted by AIDS small non-cleaved lymphoma (SNCCL) cell lines. The analysis of CD45 isoforms, a group of molecules alternatively spliced during B cell differentiation, has been chosen to correlate this process to the number of CD40 molecules per cell in these cell lines. Since Apo 1/Fas expression is upregulated on B lymphocytes after CD40 ligation and this expression is functionally relevant, we wanted to know whether a different CD40 pattern in AIDS-SNCCL cell lines could influence CD95 expression. We have shown that 3 of these cell lines (PA 682, Es III, and HBL-2) have high membrane CD40 expression (> 100,000 molecules/cell); they release large amounts of soluble CD40 (sCD40) in culture supernatants (>500 pg/ml), are CD45RA/RO double labelled, and express the Apo 1/Fas (CD95) antigen. On the contrary, low CD40 membrane antigen cell lines (BRGIgA, HBL-2, NC 71, AS 283A, and LAM C3+, < 50,000 molecules/cell) release low amounts of sCD40 (<300 pg/ml), are CD45RA+ but CD45RO-, and do not express CD95. EBV has no role in CD40 and CD45 isoform behaviour, because EBV superinfection of the EBV negative, low membrane CD40 HBL-2 cell line does not modify CD40 membrane expression, sCD40 production, or CD45 isoform and CD95 expression. Our data suggest that membrane CD40 in AIDS-SNCCL cell lines might be a key element in the regulation of their pathophysiology by influencing the expression of CD45 isoforms and of CD95, and by the release of its soluble form.
Antigens, CD↗
CD40 ligation on human cord blood CD34+ hematopoietic progenitors induces their proliferation and differentiation into functional dendritic cells.
Human CD34+ multilineage progenitor cells (CD34HPC) from cord blood and bone marrow express CD40, a member of the tumor necrosis factor-receptor family present on various hematopoietic and nonhematopoietic cells. As hyper-IgM patients with mutated CD40 ligand (CD40L) exhibit neutropenia, no B cell memory, and altered T cell functions leading to severe infections, we investigated the potential role of CD40 on CD34HPC development. CD40-activated cord blood CD34HPC were found to proliferate and differentiate independently of granulocyte/macrophage colony-stimulating factor, into a cell population with prominent dendritic cell (DC) attributes including priming of allogeneic naive T cells. DC generated via the CD40 pathway displayed strong major histocompatibility complex class II DR but lacked detectable CD1a and CD40 expression. These features were shared by a dendritic population identified in situ in tonsillar T cell areas. Taken together, the present data demonstrate that CD40 is functional on CD34HPC and its cross-linking by CD40L+ cells results in the generation of DC that may prime immune reactions during antigen-driven responses to pathogenic invasion, thus providing a link between hematopoiesis, innate, and adaptive immunity.
Animals↗