Browsing by Author "Silva, S. L."
Now showing 1 - 7 of 7
Results Per Page
Sort Options
- ALTERATIONS IN NEURODEVELOPMENT OCCUR BY MODERATED LEVELS OF UNCONJUGATED BILIRUBIN AND INCREASE WHEN NEURONS ARE CO-CULTURED WITH ASTROCYTESPublication . Falcao, A.; Fernandes, A.; Silva, S. L.; Vaz, A. R.; Brito, M. A.; Henrique, D.; Silva, R. F.; Brites, D.
- First use of thymus transplantation therapy for FOXN1 deficiency (nude/SCID) : a report of 2 casesPublication . Markert, M. L.; Marques, J. G.; Neven, B.; Devlin, B. H.; McCarthy, E. A.; Chinn, I. K.; Albuquerque, A. S.; Silva, S. L.; Pignata, C.; de Saint Basile, G.; Victorino, R. M.; Picard, C.; Debre, M.; Mahlaoui, N.; Fischer, A.; Sousa, A. E.FOXN1 deficiency is a primary immunodeficiency characterized by athymia, alopecia totalis, and nail dystrophy. Two infants with FOXN1 deficiency were transplanted with cultured postnatal thymus tissue. Subject 1 presented with disseminated Bacillus Calmette-Guérin infection and oligoclonal T cells with no naive markers. Subject 2 had respiratory failure, human herpes virus 6 infection, cytopenias, and no circulating T cells. The subjects were given thymus transplants at 14 and 9 months of life, respectively. Subject 1 received immunosuppression before and for 10 months after transplantation. With follow up of 4.9 and 2.9 years, subjects 1 and 2 are well without infectious complications. The pretransplantation mycobacterial disease in subject 1 and cytopenias in subject 2 resolved. Subject 2 developed autoimmune thyroid disease 1.6 years after transplantation. Both subjects developed functional immunity. Subjects 1 and 2 have 1053/mm(3) and 1232/mm(3) CD3(+) cells, 647/mm(3) and 868/mm(3) CD4(+) T cells, 213/mm(3) and 425/mm(3) naive CD4(+) T cells, and 10 200 and 5700 T-cell receptor rearrangement excision circles per 100 000 CD3(+) cells, respectively. They have normal CD4 T-cell receptor β variable repertoires. Both subjects developed antigen-specific proliferative responses and have discontinued immunoglobulin replacement. In summary, thymus transplantation led to T-cell reconstitution and function in these FOXN1 deficient infants.
- Human FOXN1-deficiency is associated with αβ double-negative and FoxP3+ T-cell expansions that are distinctly modulated upon thymic transplantationPublication . Albuquerque, A. S.; Marques, J. G.; Silva, S. L.; Ligeiro, D.; Devlin, B. H.; Dutrieux, J.; Cheynier, R.; Pignata, C.; Victorino, R. M.; Markert, M. L.; Sousa, A. E.Forkhead box N1 (FOXN1) is a transcription factor crucial for thymic epithelium development and prevention of its involution. Investigation of a patient with a rare homozygous FOXN1 mutation (R255X), leading to alopecia universalis and thymus aplasia, unexpectedly revealed non-maternal circulating T-cells, and, strikingly, large numbers of aberrant doublenegative ab T-cells (CD4negCD8neg, DN) and regulatory-like T-cells. These data raise the possibility that a thymic rudiment persisted, allowing T-cell development, albeit with disturbances in positive/negative selection, as suggested by DN and FoxP3+ cell expansions. Although regulatory-like T-cell numbers normalized following HLA-mismatched thymic transplantation, the abDN subset persisted 5 years post-transplantation. Involution of thymus allograft likely occurred 3 years post-transplantation based on sj/bTREC ratio, which estimates intrathymic precursor T-cell divisions and, consequently, thymic explant output. Nevertheless, functional immune-competence was sustained, providing new insights for the design of immunological reconstitution strategies based on thymic transplantation, with potential applications in other clinical settings.
- Monocyte activation is a feature of common variable immunodeficiency irrespective of plasma lipopolysaccharide levelsPublication . Barbosa, R. R.; Silva, S. P.; Silva, S. L.; Tendeiro, R.; Melo, A. C.; Pedro, E.; Barbosa, M. P.; Santos, M. C.; Victorino, R. M.; Sousa, A. E.Common variable immunodeficiency disorders (CVID), the most frequent cause of symptomatic primary immunodeficiency, are defined by impaired antibody production. Notwithstanding, T cell activation and granulomatous manifestations represent the main causes of CVID morbidity even in patients receiving immunoglobulin (Ig) G replacement therapy. Additionally, gut pathology is a frequent feature of CVID. In this study, we investigated monocyte imbalances and their possible relationship with increased microbial translocation in CVID patients. Monocyte subsets were defined according to CD14 and CD16 expression levels and evaluated in terms of human leucocyte antigen D-related (HLA-DR), CD86 and programmed death-1 molecule ligand 1 (PD-L1) expression by flow cytometry, in parallel with the quantification of plasma lipopolysaccharide (LPS) and serum levels of soluble CD14 (sCD14), LPS-binding protein (LBP) and anti-LPS antibodies. CVID patients (n=31) featured significantly increased levels of serum sCD14 and an expansion of CD14(bright) CD16(+) monocytes in direct correlation with T cell and B cell activation, the latter illustrated by the frequency of the CD21(low) CD38(low) subset. Such alterations were not observed in patients lacking B cells due to congenital agammaglobulinaemia (n=4). Moreover, we found no significant increase in circulating LPS or LBP levels in CVID patients, together with a relative preservation of serum anti-LPS antibodies, in agreement with their presence in commercial IgG preparations. In conclusion, CVID was associated with monocyte imbalances that correlated directly with T cell activation markers and with B cell imbalances, without an association with plasma LPS levels. The heightened monocyte activated state observed in CVID may represent an important target for complementary therapeutic strategies.
- PREVENTIVE EFFECTS OF BILE ACIDS ON BILIRUBIN-INDUCED APOPTOSIS OF HUMAN BRAIN MICROVASCULAR ENDOTHELIAL CELLSPublication . Correia, M.; Cardoso, F. L.; Sousa, D.; Pamela, I.; Vaz, A. R.; Silva, S. L.; Falcao, A. S.; Fernandes, A.; Silva, R. F. M.; Kim, K. S.; Brites, D.; Brito, M. A.
- Primary B-cell deficiencies reveal a link between human IL-17-producing CD4 T-cell homeostasis and B-cell differentiation.Publication . Barbosa, R. R.; Silva, S. P.; Silva, S. L.; Melo, A. C.; Pedro, E.; Barbosa, M. P.; Pereira-Santos, M. C.; Victorino, R. M.; Sousa, A. E.IL-17 is a pro-inflammatory cytokine implicated in autoimmune and inflammatory conditions. The development/survival of IL-17-producing CD4 T cells (Th17) share critical cues with B-cell differentiation and the circulating follicular T helper subset was recently shown to be enriched in Th17 cells able to help B-cell differentiation. We investigated a putative link between Th17-cell homeostasis and B cells by studying the Th17-cell compartment in primary B-cell immunodeficiencies. Common Variable Immunodeficiency Disorders (CVID), defined by defects in B-cell differentiation into plasma and memory B cells, are frequently associated with autoimmune and inflammatory manifestations but we found no relationship between these and Th17-cell frequency. In fact, CVID patients showed a decrease in Th17-cell frequency in parallel with the expansion of activated non-differentiated B cells (CD21(low)CD38(low)). Moreover, Congenital Agammaglobulinemia patients, lacking B cells due to impaired early B-cell development, had a severe reduction of circulating Th17 cells. Finally, we found a direct correlation in healthy individuals between circulating Th17-cell frequency and both switched-memory B cells and serum BAFF levels, a crucial cytokine for B-cell survival. Overall, our data support a relationship between Th17-cell homeostasis and B-cell maturation, with implications for the understanding of the pathogenesis of inflammatory/autoimmune diseases and the physiology of B-cell depleting therapies.
- Reduced BAFF-R and increased TACI expression in common variable immunodeficiencyPublication . Barbosa, R. R.; Silva, S. L.; Silva, S. P.; Melo, A. C.; Pereira-Santos, M. C.; Barata, J. T.; Hammarström, L.; Cascalho, M.; Sousa, A. E.Purpose B-cell survival and differentiation critically depend on the interaction of BAFF-R and TACI with their ligands, BAFF and APRIL. Mature B-cell defects lead to Common Variable Immunodeficiency (CVID), which is associated with elevated serum levels of BAFF and APRIL. Nevertheless, BAFF-R and TACI expression in CVID and their relationship with ligand availability remain poorly understood. Methods and Results We found that BAFF-R expression was dramatically reduced on B cells of CVID patients, relative to controls. BAFF-R levels inversely correlated with serum BAFF concentration both in CVID and healthy subjects. We also found that recombinant BAFF stimulation reduced BAFF-R expression on B cells without decreasing transcript levels. On the other hand, CVID subjects had increased TACI expression on B cells in direct association with serum BAFF but not APRIL levels. Moreover, splenomegaly was associated with higher TACI expression, suggesting that perturbations of TACI function may underlie lymphoproliferation in CVID. Conclusions Our results indicate that availability of BAFF determines BAFF-R and TACI expression on B cells, and that BAFF-R expression is controlled by BAFF binding. Identification of the factors governing BAFF-R and TACI is crucial to understanding CVID pathogenesis, and B-cell biology in general, as well as to explore their potential as therapeutic targets.