Biomedical subjects

Virginia Pascual

Publications and source records attributed to Virginia Pascual.

26 records · Page 2Linked to original sources

PubMed2003

Human germinal center B cells differ from naive and memory B cells by their aggregated MHC class II-rich compartments lacking HLA-DO.

To generate memory B cells bearing high-affinity antibodies, naive B cells first encounter antigen in the T cell-rich areas of secondary lymphoid organs. There, they are activated by antigen-specific T cells and become germinal center (GC) founder B cells. GC founders enter the GC to become centroblasts that proliferate and mutate their BCR. Centroblasts differentiate into centrocytes that undergo selection, which requires both the recognition/capture of antigen on follicular dendritic cells and the presentation of processed antigen to GC T cells. Because at each stage of differentiation B cells act as antigen-presenting cells, we analyzed their content of HLA-DR(+)-rich compartments (MIIC), as well as their expression of HLA-DM, which catalyzes peptide loading of class II molecules, and HLA-DO, which interacts with HLA-DM and focuses MHC class II peptide loading on antigens internalized by the BCR. Naive and memory B cells concentrate HLA-DR, -DM and -DO into compartments dispersed under the cell surface, which are identified by their expression of lysosome-associated membrane protein (Lamp)-1 as late endosomes/lysosomes. GC founders and GC B cells express larger Lamp-1(+)DR(+) compartments that are concentrated in the juxta-nuclear region. These compartments express lower levels of HLA-DM and virtually no HLA-DO. Upon induction of a GC founder phenotype through the prolonged (days) co-ligation of BCR and CD40, the naive B cell's peripheral DR(+)DM(+)Lamp-1(+) compartments aggregate in a polar fashion close to the nucleus. Furthermore, HLA-DO expression virtually disappears, whereas low levels of HLA-DM remain co-localized with HLA-DR. Anti-kappa/lambda antibodies, used as surrogate antigens, are promptly (minutes) endocytosed in naive, memory and GC B cells. Then, naive and memory B cells target the surrogate antigen to their peripheral HLA-DO(+) MIIC, while GC B cells target it to their HLA-DO(-) MIIC aggregates. Taken together, our results show that human GC B cells differ from naive and memory B cells by their aggregated MIIC that lack HLA-DO.

Animals↗

PubMed2003

The central role of dendritic cells and interferon-alpha in SLE.

PURPOSE OF REVIEW: Until recently, systemic lupus erythematosus has been viewed mainly as a B-cell disease resulting from altered T cell-B cell interactions. The recognition of the fundamental role of dendritic cells in the control of tolerance and immunity led to the hypothesis that systemic lupus erythematosus may be driven through unabated dendritic cell activation. This review summarizes the recently uncovered role of dendritic cell subsets and one of their products, interferon-alpha, in the pathophysiology of systemic lupus erythematosus. RECENT FINDINGS: CD14+ monocytes isolated from the blood of patients with systemic lupus erythematosus, but not those from healthy individuals, act as dendritic cells. Their activation is driven by circulating interferon-alpha that may come from one of the dendritic cell subsets (ie, plasmacytoid dendritic cells that infiltrate systemic lupus erythematosus skin lesions). Although only a fraction of patients with active systemic lupus erythematosus show circulating interferon-alpha, blood mononuclear cells from all of them display an interferon-alpha signature. SUMMARY: The disease model that the authors propose places interferon-alpha at the center of the immunologic abnormalities observed in systemic lupus erythematosus, and poses interferon-alpha and/or interferon-alpha-producing cells as novel targets for therapy in this disease. The authors surmise that type I interferon antagonists will bring systemic lupus erythematosus patients the relief that tumor necrosis factor antagonists brought to patients with rheumatoid arthritis.

Dendritic Cells↗

PubMed2003

Dendritic cells: controllers of the immune system and a new promise for immunotherapy.

The immune system is controlled by dendritic cells (DCs). Just as lymphocytes comprise different subsets, DCs comprise several subsets that differentially control lymphocyte function. In humans, the myeloid pathway includes Langerhans cells (LCs) and interstitial DCs (intDCs). While both subsets produce IL-12, only intDCs make IL-10 and induce B cell differentiation. Another pathway includes plasmacytoid DCs, which promptly secrete large amounts of IFN-alpha/beta viral encounter. Thus, insights into in vivo DC functions are important to understand the launching and modulation of immunity.

Dendritic Cells↗

PubMed2003

Dendritic cells: controllers of the immune system and a new promise for immunotherapy.

Dendritic cells (DCs) can be utilized either as vectors or as targets for therapy. Patients with metastatic melanoma received CD34-DC vaccine that contains Langerhans' cells and interstitial DCs. DCs were pulsed with MART1, tyrosinase, MAGE3, gp100 and Flu-MP peptides, and KLH. DCs induced an immune response to control antigens in 16/18 patients. An enhanced immune response to 1 or more melanoma antigens (MelAgs) was seen in these 16 patients. The two patients failing to respond experienced rapid tumour progression. Six out of seven patients with immunity to two or fewer MelAgs had progressive disease 10 weeks after study entry, in contrast to tumour progression in only 1/10 patients with immunity to > two MelAgs. Since tumour immunotherapy targets autologous antigens we can learn from systemic autoimmunity such as systemic lupus erythematosus (SLE). As opposed to normal monocytes, SLE monocytes induce proliferation of allogeneic CD4+ T cells. SLE sera induce monocyte differentiation towards DCs in an IFNalpha-dependent mechanism. Spiking autologous serum with IFNalpha reproduces DC differentiation. 50% of SLE patients have high serum levels of IFNalpha, which could explain T/B lymphopenia. Yet, plasmacytoid DCs, a major IFNalpha source, are 80% decreased. pDCs and IFNalpha may play a role in SLE pathogenesis and therapy.

Animals↗

PubMed2002

Blood dendritic cells and DC-poietins in systemic lupus erythematosus.

Dendritic cells (DCs) control immunity and tolerance. Hence, we surmised that systemic lupus erythematosus (SLE), a systemic autoimmune disease with autoreactive T and B cells, might be due to alterations in DC homeostasis. Taken together, our results demonstrate profound alterations of DCs and DC-poietins homeostasis in SLE. Elevated levels of interferon-alpha (IFN) in serum of SLE patients coexist with decreased numbers of cells producing IFN-alpha, i.e., plasmacytoid dendritic cells (PDCs). Decreased numbers of circulating DCs correlate with increased levels of soluble tumor necrosis factor (TNF) receptors, thus suggesting the potential role of TNF pathway in the observed DC alterations. Finally, increased FMS-like tyrosine kinase 3-ligand (FLT3-L) and its correlation with soluble TNF receptors suggest a physiologic response to compensate low DC numbers. Although IFN-alpha remains at the center of immunologic aberrations in SLE, it remains to be determined whether increased shedding of soluble TNF receptors could also be ascribed to IFN-alpha.

Adolescent↗

PubMed2002

The interplay of dendritic cell subsets in systemic lupus erythematosus.

Dendritic cells (DC) control immunity and tolerance. Hence, we surmised that systemic lupus erythematosus (SLE), a systemic autoimmune disease with autoreactive T and B cells, might be due to DC alterations. Based on our findings, we are proposing a model of SLE where autoimmune responses are driven by unabated activation of myeloid DC through IFN-alpha produced by plasmacytoid DC. Thus, interplay between DC subsets might represent a key component of SLE pathogenesis.

Autoantibodies↗

PubMed2002

Faces of eosinophilic fasciitis in childhood.

Eosinophilic fasciitis is a rare connective tissue disease in children characterized by hardening and thickening of the skin and soft tissues, peripheral eosinophilia, elevated erythrocyte sedimentation rate, and hypergammaglobulinemia. In this study, we report three pediatric patients with eosinophilic fasciitis whose clinical presentation and response to therapy differed from those reported in the literature. All three patients were female. Two of them had Raynaud's phenomenon as an initial feature, and the third had hepatosplenomegaly. Muscle involvement with weakness was present in two patients, as documented not only by increased aldolase levels at the time of presentation but also by inflammatory changes in the muscle biopsy. Serum immunoglobulin G levels were increased only in the most severely involved patient. Peripheral eosinophilia was present in all three cases. All three patients responded well to prednisone therapy. Two patients had a uni-phasic course, and one required further therapy to control a postinfection relapse. In summary, we found that Raynaud's phenomenon and hepatosplenomegaly can be part of the spectrum of clinical manifestations of childhood eosinophilic fasciitis. Identification as eosinophilic fasciitis and not scleroderma, despite hand involvement and Raynaud's phenomenon, can suggest that the illness may be steroid responsive.

Journal Article↗

PubMedDate not supplied

Dramatic improvement of pyoderma gangrenosum with infliximab in a patient with PAPA syndrome.

Infliximab, a chimeric antitumor necrosis factor alpha monoclonal antibody (anti-TNF alpha), has been recently shown to have a beneficial effect on pyoderma gangrenosum associated with inflammatory bowel disease. Patients with the syndromic triad of pyogenic sterile arthritis, pyoderma gangrenosum, and acne, an autoinflammatory process caused by mutations in the CD2 binding protein-1 (CD2BP1) gene, can have severe pyoderma gangrenosum. We describe a 14-year-old patient with this syndrome who was unresponsive to multiple therapies. A dramatic improvement in his pyoderma gangrenosum was observed after one infusion of infliximab, and a second infusion led to its resolution. Our observation extends the therapeutic use of infliximab to this component of PAPA syndrome.

Acne Vulgaris↗