Variations in Plasmacytoid Dendritic Cell (PDC) and Myeloid Dendritic Cell (MDC) Levels in HIV-Infected Subjects on and off Antiretroviral Therapy

Plasmacytoid and myeloid dendritic cells are reduced in AIDS patients. The number of these circulating cells was assessed cross-sectionally and longitudinally in 27 uninfected and 72 HIV-infected subjects on and off antiretroviral therapy. The plasmacytoid dendritic cell numbers were significantly reduced in the HIV-infected subjects compared to controls (p < 0.001). This reduction correlated directly with CD4+ cell counts (p < 0.001) and inversely with viral load (p < 0.001). These associations were found to a lesser degree for the myeloid dendritic cells. Intra-assay variability of these dendritic cell counts was < 10%. Antiretroviral therapy significantly increased plasmacytoid dendritic cell (p < 0.001) and CD4+ cell (p = 0.05) counts at 8 months by 76.9% and 19%, respectively. The plasmacytoid dendritic cell levels responded more readily to viral load increases and decreases than CD4+ cells. Circulating plasmacytoid dendritic cells may provide important additional information about immune function in HIV-infected subjects receiving or not receiving antiretroviral therapy.     

Early decrease in circulating dendritic cells number after liver transplantation could favor hepatitis C virus recurrence

Cirrhosis and hepatocarcinoma related to hepatitis C virus (HCV) lead to more than 30% of liver transplantations. Host- and virus-related mechanisms, involved in the recurrence of HCV infection of the liver graft, are not yet well known. A weak CD4+ T-cell response was shown to be involved in the outcome of re-infection but whether dendritic cell numbers are modified in patients transplanted for HCV-related disease has never been evaluated. Eight transplanted patients for HCV-related disease and eight non-HCV-infected transplanted controls were included. Blood plasmacytoid dendritic cells and myeloid dendritic cells were quantified before transplantation, at day 7 and 1 month after transplantation. Plasma interferon (IFN)-alpha and interleukin (IL)-12 were concomitantly measured. The results showed a significant decrease in the relative (P < 0.0001) and absolute (P = 0.0002) values of blood plasmacytoid dendritic cells at day 7 after transplantation when compared to the values obtained before transplantation, increasing again 1 month later, in both HCV-infected patients and controls. The same tendency was observed for myeloid dendritic cell relative values (P = 0.0004) and plasma IL-12 (P < 0.05). IFN-alpha appeared to be less often detectable for HCV-infected patients. These results obtained on dendritic cell numbers could explain partially the early and systematic recurrence of HCV infection on the liver graft and contribute to better adapted therapeutic strategies.     

Decreased interferon-alpha production and impaired T helper 1 polarization by dendritic cells from patients with chronic hepatitis C

Patients with chronic hepatitis C (CHC) are unable to prime and maintain vigorous T cell responses that are initiated during the acute phase of hepatitis C virus (HCV) infection. As dendritic cells (DCs) induce and regulate both innate and adaptive immune responses, the aim of this study was to analyse two critical functions of DCs: firstly, production of interferon (IFN)-alpha and, secondly, polarization of T helper 1 lymphocytes. The frequencies of plasmacytoid DC (PDC) and myeloid DC (MDC) were estimated in 63 patients with CHC and 34 normal controls using four-colour flow cytometry. Circulating DCs were isolated from peripheral blood of CHC patients (n = 10) and normal controls (n = 10). These DCs were cultured with herpes simplex virus-1 to evaluate their capacity to produce IFN-alpha. The capacity of DCs to induce polarization of autologous naive CD4(+) T lymphocytes to IFN-gamma-producing effector T lymphocytes was also assessed. The frequencies of PDCs producing intracellular IFN-alpha (P < 0.01) and the levels of IFN-alpha in culture supernatant of PDCs (P < 0.01) were significantly lower in patients with CHC compared to those of normal controls. The numbers of MDC were significantly lower in patients with CHC (8.2 (6.0)/ micro l, median (interquartile range), n = 63) compared to normal control (11.7 (7.8)/ micro l, n = 34) (P < 0.01). Moreover, DCs from patients with CHC induced significantly lower numbers of IFN-gamma-producing effector T lymphocytes compared to that of controls (P < 0.01). This study indicates that the low IFN-alpha-producing capacity and impaired T helper 1 polarization ability of DCs from patients with CHC might be responsible for the typical low anti-HCV immune responses in these patients.     

The effects of renal transplantation on circulating dendritic cells

The effects of immunosuppressive agents on T cell function have been well characterized but virtually nothing is known about the effects of renal transplantation on human dendritic cells (DCs). With the use of flow cytometry, we studied the kinetics of myeloid and plasmacytoid DCs in peripheral blood of 24 kidney allograft recipients before and after transplantation, and in 23 donors before and after kidney donation. All patients were treated with tacrolimus, mycophenolate mofetil and prednisone. Surgery resulted in a strong decline in the number of myeloid and plasmacytoid DCs, both in kidney donors and in their recipients. However, in donors this effect was transient, as the numbers of both DC subsets had normalized completely by the third postoperative month. In contrast, the recovery of myeloid DC counts in kidney transplant recipients was only incomplete at the end of the 3-month follow-up, despite tapering of immunosuppression. The seven patients who required additional immunosuppressive treatment because of acute rejection experienced an even more marked decrease in DC counts in the early postoperative period compared with patients who remained rejection-free. Surgical procedures markedly affect the numbers of circulating myeloid and plasmacytoid DCs. Immunosuppressive drugs have important additional in vivo effects on this cell type and impair the reconstitution of the myeloid DC subset in peripheral blood after renal transplantation.     

Decreased interferon-alpha production in HIV-infected patients correlates with numerical and functional deficiencies in circulating type 2 dendritic cell precursors.

Peripheral blood mononuclear cells from patients with human immunodeficiency virus (HIV) infection exhibit a progressively marked decrease in the production of virus-induced interferon (IFN)-alpha, a finding that correlates with and is highly predictive of disease progression and opportunistic infections. The major IFN-alpha producing population has recently been defined as the precursor to type 2 dendritic cells (pDC2) or plasmacytoid DC (pDC). Using four-color flow cytometry, we have enumerated the pDC2 vs non-IFN-alpha producing myeloid DC1 in peripheral blood from HIV-infected patients and healthy controls and related these values to CD4 cell numbers, viral load, and functional activity. The patients had reductions in the numbers of both pDC2 (lin-/HLA-DR+/CD123(bright)) and DC1 (lin1-/HLA-DR+/CD123(dim)/CD11c+), both at an absolute level and as a percentage of cells. The decreases were most evident in patients with decreased CD4 levels. Viral load correlated with the functional frequency of the IFN producing cells but not with absolute pDC2 levels. Using intracellular flow cytometric analysis for IFN-alpha, the patients were demonstrated to have fewer pDC2, as well as a lower percentage of responding cells among those remaining. We conclude that deficient production of IFN-alpha by pDC2 from HIV-infected patients results from both selective loss of these cells and their qualitative dysfunction. Given the central role of DC, and in particular, DC2, in linking innate and adaptive immune responses, these qualitative and quantitative changes in pDC2 are likely to be key contributors to HIV pathogenesis.     

Differential up-regulation of HLA-DM, invariant chain, and CD83 on myeloid and plasmacytoid dendritic cells from peripheral blood

Two main dendritic cell (DC) subsets have been described in peripheral blood, the myeloid subset or DC1 that is characterized by the presence of CD11c and the plasmacytoid subset or DC2 negative for this marker. The two subsets may perform different functions and have been defined as immunogenic (the myeloid subset) or tolerogenic (the plasmacytoid subset). The expression of human leukocyte antigen (HLA)-DM molecules, which act as peptide editors in the antigen presentation process, was studied in freshly isolated plasmacytoid and myeloid DCs from peripheral blood. The expression of the invariant chain (Ii), the major histocompatibility complex class II (MHC-II) : class II-associated Ii peptide (CLIP) complex, and CD83 was also investigated. The results showed that intracellular expression of HLA-DM and the Ii was significantly higher in the plasmacytoid than in the myeloid DC subset. In contrast, a higher fraction of cell expressing MHC-II : CLIP complex was found in the myeloid than in the plasmacytoid DC subpopulation. CD83 was not detected in any of these two subsets. Following culture of these cells with interleukin-3 (IL-3), tumor necrosis factor-alpha (TNFalpha) and/or heat shock protein-70 (HSP-70), the expression of intracellular HLA-DM was up-regulated in the myeloid DCs to levels similar to those found in the plasmacytoid DCs, whilst the Ii was down-regulated in the plasmacytoid subset to similar levels to those expressed in the myeloid DCs. In addition, CD83 was up-regulated in the myeloid (CD11c+) but not in the plasmacytoid (CD11c-) DCs. The expression pattern of these antigen-processing molecules could be related to the immaturity and function attributed to these DC subsets.     

The expression of dendritic cell subsets in severe chronic rhinosinusitis with nasal polyps is altered

Background

Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized as a Th2-driven disease.Activated dendritic cells (DCs) are the main T-cell activators; their role in the chronic inflammatory process of nasal polyposis is still unclear.

Methods

The regulation of DC subsets was analyzed in nasal polyp tissue from CRSwNP patients and compared to inferior turbinate tissue from healthy subjects. Tissue localization and expression of both plasmacytoid and myeloid DCs were assayed by means of immunohistochemistry and flow cytometry. Plasmacytoid DCs were also assayed by PCR, and tissue homogenates were assayed for various inflammatory markers.

Results

The number of plasmacytoid (pDCs) and myeloid (mDCs) dendritic cells was significantly increased in nasal polyp tissue when compared to non-inflamed nasal mucosa. The number of pDCs, but not mDCs, was down-regulated in more severe cases (nasal polyps with asthma) and varied with the cytokine milieu. The amount of pDCs was significantly decreased in IL5+IFNγ – nasal polyp tissue compared to tissues with high IFNγ levels (IL5+IFNγ+). Furthermore, levels of indoleamine 2,3-dioxygenase were increased in nasal polyp compared to inferior turbinate tissue and correlated negatively with the number of pDCs.

Conclusions

There is an altered balance of pDC and mDC numbers in nasal polyp tissue. pDCs seem to be more susceptible to an inflammatory cytokine milieu and may play a crucial role in disease severity.     

Effect of SIVmac infection on plasmacytoid and CD1c+ myeloid dendritic cells in cynomolgus macaques

Dendritic cells (DCs) are known to be essential for the induction and regulation of immune responses. Non-human primates are essential in biomedical research and contribute to our understanding of the involvement of DCs in human infectious diseases. However, no direct single-platform method for quantifying DC precursors has yet been optimized in macaques to give accurate absolute blood counts of these rare-event cell populations in the blood. We adapted a rapid whole-blood assay for the absolute quantification of DCs in cynomolgous macaques by four-colour flow cytometry, using a single-platform assay compatible with human blood. Cynomolgus macaque plasmacytoid DCs (pDCs) and CD1c⁺ myeloid DCs (CD1c⁺ mDCs) were quantified in the blood of 34 healthy macaques and the results obtained were compared with those for blood samples from 11 healthy humans. In addition, circulating absolute numbers of pDCs were quantified in cynomolgus macaques chronically infected with SIVmac. During infection, pDC counts decreased whereas circulating CD1c⁺ mDC counts increased. Information regarding absolute pDC and mDC counts in non-human primates may improve our understanding of the role of these cells in SIV/HIV infection and in other infectious diseases.     

Quantitative and functional defects of dendritic cells in classic Kaposi's sarcoma

In this study, we investigated whether dendritic cells (DCs) are altered in classic Kaposi's sarcoma (cKS), a lympho-angioproliferative disorder associated with human herpesvirus-8 (HHV-8) infection. By direct analysis of peripheral blood DCs (PBDCs), we demonstrated that cKS patients have lower frequency of myeloid and plasmacytoid DCs than controls. This reduction was greater in patients with advanced stages of disease. PBDCs from cKS patients also showed up-regulated expression of the scavenger receptor CD91 and impaired IL-12 expression. PB monocytes that represent DC precursors in vivo and in vitro showed the same alterations; accordingly, DCs differentiated in vitro from cKS monocytes were similarly affected. The same alterations were induced by addition of cKS plasma during DC differentiation from control monocytes. These results indicate that PBDCs and their precursors are altered in cKS and suggest that soluble circulating factors participate in this process. The study may provide new insights into the pathogenesis of cKS.     

Functional impairment of dendritic cells in patients infected with hepatitis C virus genotype 1 who failed peginterferon plus ribavirin therapy

Although chronic hepatitis C patients have a lower frequency and functions of dendritic cells (DCs) than healthy subjects, little is known about the serial changes in frequency and functions of DCs following anti-viral treatment and the relationship with treatment outcomes. Twenty patients with hepatitis C virus genotype 1 receiving peginterferon (PEG-IFN) and ribavirin for 24 weeks were enrolled. The frequency and functions of DCs were assayed at baseline and 24 weeks post-treatment. Ten sex and age-matched healthy adults served as controls. Nineteen of the 20 chronic hepatitis C patients completed 24 weeks of combination therapy. Fifteen patients achieved rapid virologic response and 12 achieved sustained virologic response (SVR). The baseline frequency of peripheral blood myeloid DCs and plasmacytoid DCs was significantly lower in chronic hepatitis C patients than in healthy controls. In patients who achieved SVR, the frequency of DCs subsets at the end of follow-up increased to a level comparable to healthy controls. Although no functional defects of DCs was found in chronic hepatitis C patients in comparison with healthy controls, in patients without SVR had a lower CD83 expression and higher interleukin-10 production of DCs than SVR patients. The results suggest that low CD83 expression and high IL-10 production of DCs at the baseline may predict a poor virologic response to 24-week PEG-IFN plus ribavirin therapy in HCV genotype 1 patients.     

Impaired functionality and phenotypic profile of dendritic cells from patients with multiple myeloma

Multiple myeloma (MM) is a B cell cancer characterized by clonal proliferation in the bone marrow and impaired immunity. Because MM is an incurable malignancy, efficient consolidation is needed urgently. Targeting clonotypic B cells by idiotype vaccination has proved the principle to be effective and indicated that future strategies, including dendritic cell-based vaccination, could be a suitable approach. However, as MM patients suffer from a general impaired immunity, which may include dendritic cells (DCs), a careful evaluation of phenotypic traits and functionality of DCs from MM patients is necessary before an efficient vaccine can be developed. This study determined the number, phenotypic profile and functionality of myeloid and plasmacytoid DCs purified directly from blood from MM patients at diagnosis. A reduced number and lower expression of human leucocyte antigen (HLA) molecules was observed on both myeloid and plasmacytoid DCs in MM patients compared to healthy controls. Also, the expression of CCR5, CCR7 and DEC205 was lower in MM patients compared to normal donors. In addition, the capacity to stimulate allogeneic T cell proliferation and to stimulate cytokine production was decreased, suggesting that DCs from these patients are functionally impaired. Finally, the analysis of samples following chemotherapy and transplantation demonstrated an increased expression of HLA molecules, suggesting that this time-point is optimal for harvest and use in vaccination.     

Recruitment of myeloid and plasmacytoid dendritic cells in cervical mucosa during Chlamydia trachomatis infection

The mobilization of myeloid dendritic cells (mDCs) and plasmacytoid dendritic cells (pDCs) to the cervix during chlamydial infection is not fully understood, and the role of these cells in immunopathogenesis is largely unknown. As an effective vaccine to control chlamydial infection is currently unavailable, understanding the regulation of the local immune response becomes a necessity. Therefore, mDC and pDC populations were analysed in peripheral blood and cervical samples of controls and Chlamydia -positive women, with or without mucopurulent cervicitis (MPC). Cervical cytokines and C-reactive protein levels in serum were quantified by ELISA and the chlamydial infectious load by culture. Chlamydia trachomatis infection mobilized both mDCs and pDCs to the cervical mucosa. pDCs were recruited more often in women with MPC (p <0.05) and they correlated significantly with the chlamydial load, C-reactive protein levels and cervical interleukin-8 (IL-8) levels. Upregulation of surface expression of co-stimulatory molecules (CD80, CD83 and CD86) on cervical mDCs and pDCs was observed during chlamydial infection but was significant only for mDCs. Significantly higher levels of IL-1β, IL-6 and IL-8 were observed in Chlamydia- positive women with MPC; however, after therapy, IL-8 levels decreased significantly. Median numbers of mDCs after therapy were significantly higher in the cervix and blood of infected women as compared to the numbers of pDCs, which were found to be lower in the cervix after therapy. These results thus suggest that during chlamydial infection, both mDCs and pDCs are recruited to the cervix, but their number and possible immunological functions may differ with the pathological condition. pDCs were associated more often with MPC and inflammatory factors, suggesting that they may possibly be involved in the immunopathogenesis of infections due to Chlamydia .     

Chemokine receptor expression on dendritic cells is normal in HIV-infected patients with a stable response to art, but chemokine levels remain elevated

The development of strategies to optimize T‐cell responses in previously immunodeficient HIV patients with a stable virological response to ART requires an understanding of the factors that affect responsiveness. Chemokines direct the migration of dendritic cells (DC) to non‐lymphoid tissues infected by secondary pathogens and to lymph nodes where they prime T‐cells. Quantitation of mRNA is a sensitive technique enabling assessment of chemokine receptors by CD14⁺ monocytes, myeloid (m)DCs, plasmacytoid (p)DCs, and M‐DC8⁺ cells. MDC8⁺ cells invariably expressed less CCR2, CCR5, and CXCR4 than the other cells, but expression of CCR2, CCR5, CCR6, CCR7, CXCR3, and CXCR4 was similar in patients and healthy controls. However plasma levels of CXCL10, CCL5, and CCL2 remained higher in patients than controls. Overall, it appears that chemokine directed migration of DC may not limit immune responses in these patients. J. Med. Virol. 83:1128–1133, 2011. © 2011 Wiley‐Liss, Inc.     

Aberrant composition of the dendritic cell population in hepatic lymph nodes of patients with hepatocellular carcinoma

Patients with hepatocellular carcinoma (HCC) are characterized by a weak T-cell response to their tumor, and chronic carriers of hepatitis B virus or hepatitis C virus have a poor T-cell response against the virus. These inadequate T-cell responses may be due to insufficient activation of the T cells by dendritic cells (DCs). Because lymph nodes (LNs) are the primary site of antigen-specific T-cell activation, we hypothesized that hepatic LNs of patients with HCC and/or chronic viral hepatitis might have aberrant compositions of their DC populations. To address this hypothesis, we enumerated mature myeloid DCs (MDCs) and plasmacytoid DCs (PDCs) in hepatic LNs by quantitative immunohistochemistry. Patients with HCC and chronic viral hepatitis and patients with chronic viral hepatitis without HCC were compared with patients with liver inflammation of nonviral etiology and with organ donors with healthy livers. The numbers of PDCs and mature MDCs in hepatic LNs of patients with chronic viral hepatitis did not differ from those of patients with liver inflammation of nonviral etiology nor from individuals with healthy livers. However, hepatic LNs of patients with HBV or HCV infection complicated by HCC showed a 1.5-fold reduction in numbers of mature MDCs and a 4-fold increase in numbers of PDCs in their T-cell areas compared with those of patients with viral hepatitis only (P <.01). In conclusion, patients with HCC have an aberrant composition of the DC population in their hepatic LNs. This may be one of the causes of the inadequate T-cell response against HCC in these patients.     

Common variable immunodeficiency revisited: normal generation of naturally occurring dendritic cells that respond to Toll‐like receptors 7 and 9

Patients with common variable immunodeficiency (CVID) have reduced numbers and frequencies of dendritic cells (DCs) in blood, and there is also evidence for defective activation through Toll‐like receptors (TLRs). Collectively, these observations may point to a primary defect in the generation of functional DCs. Here, we measured frequencies of plasmacytoid DCs (pDCs) and myeloid DCs (mDCs) in peripheral blood of 26 CVID patients and 16 healthy controls. The results show that the patients have reduced absolute counts of both subsets. However, the decreased numbers in peripheral blood were not reflected in reduced frequencies of CD34⁺ pDC progenitors in the bone marrow. Moreover, studies at the single cell level showed that DCs from CVID patients and healthy controls produced similar amounts of interferon‐α or interleukin‐12 and expressed similar levels of activation markers in response to human cytomegalovirus and ligands for TLR‐7 and TLR‐9. The study represents the most thorough functional characterization to date, and the first to assess bone marrow progenitor output, of naturally occurring DCs in CVID. In conclusion, it seems unlikely that CVID is secondary to insufficient production of naturally occurring DCs or a defect in their signalling through TLR‐7 or TLR‐9.     

Vitamin D status and the immune assessment in 22q11.2 deletion syndrome

22q11.2 deletion syndrome (22q11.2DS) is characterized by a heterogeneous phenotype, including alterations in phospho-calcium metabolism and immunodeficiency. We analyzed vitamin D status and the immune assessment, focusing on T cell subpopulations and dendritic cells (DCs) in a cohort of 17 pediatric 22q11.2DS patients and 17 age-matched healthy subjects. As antigen-presenting cells, DCs are the main target of vitamin D, promoting a tolerogenic T cell response. Patients were subdivided into three groups according to the parameters of phospho-calcium metabolism and serum levels of 25OHD: normal values, vitamin D deficiency and hypoparathyroidism. Different degrees of T cell deficiency, ranging from normal to partial T cell numbers, were observed in the cohort of patients. The group with vitamin D deficiency showed a significant reduction of naive T cells and a significant increase of central memory T cells compared to controls. In this group the number of circulating DCs was significantly reduced. DC decrease affected both myeloid and plasmacytoid DC subsets (mDCs and pDCs), with the most relevant reduction involving pDCs. A direct correlation between 25OHD levels and recent thymic emigrant (RTE) and DC number was identified. Despite the limited cohort analyzed, our results show that deficiency of the pDC subset in patients with 22q11.2DS may be included among the causative factors of the progressive increase of risk of autoimmune diseases in these patients. As most patients suffer from increased susceptibility to infections and heightened prevalence of autoimmune disorders, we suggest a potential role of vitamin D supplementation in preventing autoimmune or proinflammatory diseases in 22q11.2DS.     

Disparate effects of acute and chronic infection with SIVmac239 or SHIV-89.6P on macaque plasmacytoid dendritic cells

Blood plasmacytoid dendritic cells (pDCs) contribute to both innate and adaptive immune responses by secreting high levels of IFN-alpha following acute bacterial and viral infections and indirectly by augmenting cell-mediated immunity. Cross-sectional studies have shown that the number of circulating pDCs in HIV patients, compared to that in uninfected individuals, is reduced. However, since the time of infection is usually unknown in HIV-infected patients, pDC-virus interactions that occur immediately after virus exposure are poorly understood. The current study investigated pDC dynamics during acute and chronic infections of macaques with either SIVmac239 or the pathogenic SIV-HIV chimera, SHIV-89.6P, as models for HIV infection. In three rhesus and three pig-tailed macaques infected intravenously with SIVmac239, the percentages of pDCs in blood declined 2- to 6-fold during the first 6 weeks after infection and remained depressed throughout the disease course. Surprisingly, no consistent, comparable decline in peripheral blood pDCs was observed in six macaques infected with SHIV-89.6P. In this latter group, percentages of pDCs did not correlate with CD4(+) T cells, but there was an inverse relationship with viral load. In addition, when compared to na?ve controls, the percentages of pDCs were reduced in spleens and peripheral lymph nodes of SIVmac239- but not SHIV-89.6P-infected animals that had progressed to AIDS. Proviral DNA was detected during the acute phase in pDCs isolated from macaques infected with either virus. These results imply that, even though macaque pDCs can be infected by both SIVmac239 and SHIV-89.6P, the subsequent effects on in vivo pathogenesis differ. The underlying mechanism(s) for these differences is unclear, but the selection of SIV or SHIV as a challenge virus might influence the outcome of some studies, such as those evaluating vaccines or the therapeutic efficacy of drugs.     

Subset-dependent modulation of dendritic cell activity by circovirus type 2

Viral interactions with dendritic cells (DCs) have important consequences for immune defence function. Certain single-stranded DNA viruses that associate with a number of species, including humans and pigs, exhibit interesting characteristics in this context. Porcine circovirus type 2 (PCV2) can persist within myeloid DCs in the absence of virus replication. Internalization was observed with both conventional blood DCs and plasmacytoid DCs [natural interferon-producing cells (NIPCs)], as well as DC precursors. This PCV2-DC interaction neither induced nor inhibited DC differentiation. The maturation of myeloid DCs induced by a cocktail of interferon-alpha/tumour necrosis factor-alpha (IFN-alpha/TNF-alpha), and the ability to process and present antigen to T lymphocytes, remained intact in the presence of PCV2. The virus was clearly internalized by the DCs, a process noted with both mature and immature cells. This suggested a non-macropinocytic uptake, confirmed by an insensitivity to wortmannin but sensitivity to cytochalasin D, chlorpromazine and bafilomycin. Nevertheless, PCV2 was immunomodulatory, being effected through the reaction of NIPC to danger signals. When NIPCs responded to the CpG-oligonucleotide (CpG-ODN), their costimulatory function which induces myeloid DC maturation was clearly impaired by the presence of PCV2. This was caused by a PCV2-induced inhibition of the IFN-alpha and TNF-alpha normally produced following interaction with CpG-ODN. Thus, the immunomodulatory activity of PCV2 is mediated through the disruption of NIPC function. This would impair the maturation of associated myeloid DC and have major implications for the efficient recognition of viral and bacterial danger signals, favouring the establishment of infections additional to that of PCV2.     

Psoriasis in humans is associated with down-regulation of galectins in dendritic cells

We have investigated the expression and role of galectin‐1 and other galectins in psoriasis and in the Th1/Th17 effector and dendritic cell responses associated with this chronic inflammatory skin condition. To determine differences between psoriasis patients and healthy donors, expression of galectins was analysed by RT‐PCR in skin samples and on epidermal and peripheral blood dendritic cells by immunofluorescence and flow cytometry. In the skin of healthy donors, galectin‐1, ‐3 and ‐9 were expressed in a high proportion of Langerhans cells. Also, galectins were differentially expressed in peripheral blood dendritic cell subsets; galectin‐1 and galectin‐9 were highly expressed in peripheral myeloid dendritic cells compared with plasmacytoid dendritic cells. We found that non‐lesional as well as lesional skin samples from psoriasis patients had low levels of galectin‐1 at the mRNA and protein levels, in parallel with low levels of IL‐10 mRNA compared with skin from healthy patients. However, only lesional skin samples expressed high levels of Th1/Th17 cytokines. The analysis of galectin‐1 expression showed that this protein was down‐regulated in Langerhans cells and dermal dendritic cells as well as in peripheral blood CD11c⁺ DCs from psoriasis patients. Expression of galectin‐1 correlated with IL‐17 and IL‐10 expression and with the psoriasis area and index activity. Addition of galectin‐1 to co‐cultures of human monocyte‐derived dendritic cells with autologous T lymphocytes from psoriasis patients attenuated the Th1 response. Conversely, blockade of galectin binding increased IFNγ production and inhibited IL‐10 secretion in co‐cultures of monocyte‐derived dendritic cells with CD4⁺ T cells. Our results suggest a model in which galectin‐1 down‐regulation contributes to the exacerbation of the Th1/Th17 effector response in psoriasis patients. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.