Eduardo Fernández-Cruz

Interferon beta-1a therapy enhances CD4 + regulatory T-cell function: An ex vivo and in vitro longitudinal study in relapsing−remitting multiple sclerosis

Interferon beta-1a (IFNâ-1a) has demonstrated efficacy in multiple sclerosis (MS), although its mechanism of action remains only partly understood. We evaluated the ex vivo and in vitro effects of IFNâ-1a (Rebif) on regulatory T-cell (T(Reg)) function in 22 relapsing-remitting MS patients and 16 healthy controls. T(Reg) function was significantly enhanced after 3 and 6 months of IFNbeta-1a therapy. Furthermore, there was a trend towards increasing proportions of total CD4(+)CD25(+) and CD4(+)CD25(+)GITR(+) T(Reg) after 6 months of IFNbeta-1a therapy when compared with baseline. In conclusion, IFNbeta-1a therapy enhances T(Reg) function, and this may be relevant in the inflammatory environment of MS lesions.

Antiphospholipid antibodies and retinal thrombosis in patients without risk factors: a prospective case-control study

PURPOSE To determine the prevalence of antiphospholipid antibodies and other immunologic abnormalities in patients with occlusive retinal vascular events, exempt from conventional risk factors of retinal thrombosis. METHODS Forty patients with retinal vascular occlusion (26 with retinal vein occlusions, eight with arterial occlusions, two with combined venous and arterial occlusions, and four with venous occlusions plus vasculitis), free of main accepted risk factors for retinal thrombosis, were prospectively screened for antiphospholipid antibodies (anticardiolipin-antibodies and lupus anticoagulant) and other immunologic abnormalities. Fourteen patients were younger than 50 years. Prevalence and mean values of antiphospholipid antibodies (aPL) were compared with those in a homogeneous control group of 40 patients. RESULTS The prevalence of antiphospholipid antibodies in the study group was 22.5% (nine of 40). Comparison with control group prevalence (5% [two of 40]) showed a statistically significant difference (P = .04). Six patients in the study group disclosed positivity for IgG-anticardiolipin antibodies, one patient for IgM anticardiolipin antibodies, and two patients for both isotypes IgG and IgM anticardiolipin antibodies. The antibody assay for lupus anticoagulant was negative for all patients. Three patients were diagnosed as having primary antiphospholipid antibody syndrome and are undergoing systemic anticoagulant therapy. Relevant immunologic abnormalities were also found (27.5% with antinuclear antibodies, 35% with elevation of circulating immune complexes, 35% with complement deficiency, 30% with positive rheumatoid factor, and 17.5% with positive C-reactive protein). Thirteen patients (32.5%) had more than four parameters altered. No significant association was found between prevalence or mean values of anticardiolipin antibody and patients younger than 50 years. CONCLUSIONS The high prevalence of anticardiolipin antibodies in patients with vaso-occlusive retinopathy exempt from conventional risk factors, and the relevant diagnostic and therapeutic implications, lead us to recommend a systematic search for specific antiphospholipid antibodies in such patients.

Quantitative Alterations of the Functionally Distinct Subsets of CD4 and CD8 T Lymphocytes in Asymptomatic HIV Infection: Changes in the Expression of CD45RO, CD45RA, CD11b, CD38, HLA-DR, and CD25 Antigens

We determined the representation in asymptomatic human immunodeficiency virus (HIV) infection of the CD45RO+ and CD45RO- CD45RA+ subsets of CD4+ and CD8+ T lymphocytes, CD11b+ and CD11b- subsets of CD8+ T cells, and activated populations of these subsets. Three-color flow cytometry was used to quantitate the different CD4+ and CD8+ T cell populations in 116 asymptomatic HIV+ individuals. In asymptomatic HIV+ infection there was a significant relative increase in the CD4+ CD45RO+ and CD8+ CD45RO+ T cell subsets, which express CD38 and DR antigens, that correlated strongly with the decline in total CD4+ T cells. In addition, we found a loss of CD4+ CD45RO- and CD8+ CD45RO- T cells associated with progression of HIV infection (as measured by the decline in total CD4+ T cells). Studies presented here also indicate that, with the progression of asymptomatic HIV infection, CD8+ CD11b- T lymphocytes showed a significant decrease, whereas CD8+ CD11b+ T cells were significantly increased. This study demonstrates that the progression of HIV infection in asymptomatic patients involves the increase in CD45RO+ subsets of CD4+ and CD8+ T cells, the increase in CD8+ CD11b+ T cells, the decrease in CD45RO- CD45RA+ subsets of CD4 and CD8 T cells, and the decline in CD8+ CD11b- T cells.

Increased levels of activated subsets of CD4 T cells add to the prognostic value of low CD4 T cell counts in a cohort of HIV-infected drug users.

ObjectiveTo identify subsets of CD4 T lymphocytes that can predict the development of AIDS and to assess whether increased levels of these cellular markers could provide additional independent prognostic information to the CD4 T cell count and plasma HIV-1-RNA levels. Design and methodsIn a prospective study, a cohort of 85 HIV-positive intravenous drug users [clinical categories of the CDC classification A (n = 48) and B (n = 37)] were followed for a period of 37 ± 13 months. Memory and activated CD4 and CD8 T cells were quantitated by three-colour flow cytometry at baseline and expressed as a percentage of total CD4 and CD8 lymphocytes. Clinical evaluations were performed at 6 month intervals. The relationships between these lymphocyte subsets and progression to AIDS were studied using Kaplan–Meier plots and proportional hazards regression models. ResultsAfter adjustment for the level of CD4 T cells and plasma HIV-1-RNA levels, the elevation in the subset CD4+CD38+DR+ was the marker within the functionally distinct subsets of CD4 T lymphocytes with additional prognostic value in bivariate Cox regression models. In multivariate models, increased percentages of CD4+CD38+DR+ T cells provided the strongest independent prognostic information for progression to AIDS (relative hazard, 1.07;P < 0.0001). ConclusionOur results suggest that high levels of CD4+CD38+HLA-DR+ T cells reflect the increasing degree of CD4 T cell activation during the progression of HIV infection, and could be used together with the CD4 T cell and HIV-RNA levels to evaluate more accurately the progressive cellular immune impairment associated with the risk of progression to AIDS.

Immunological and serological markers predictive of progression to AIDS in a cohort of HIV-infected drug users.

We have performed a prospective 33-month follow-up of the evolution of HIV infection in a cohort of 76 HIV-positive intravenous drug users (IVDUs). We report on immunological and serological variables that proved to be highly predictive of development to AIDS. In a stepwise multivariate analysis of the actuarial progression rate we found the number of CD4+ lymphocytes to be the most powerful predictor of progression to AIDS. We found no independent predictive effects associated with any other variable with predictive power: loss of antibody to p24 antigen, anergy, HIV p24 antigenaemia, loss of antibody to p53 (reverse transcriptase), decreased number of CD8+ T cells, loss of antibody to p31, loss of antibody to p17, beta 2-microglobulin level, loss of antibodies to gp41 and p64, or immunoglobulin A level. We have found that our data differ from those obtained in studies in homosexual men in the different prognostic value of those predictive markers. Our findings should help to identify high risk of progression to clinical AIDS among IVDUs, thereby assisting in the selection of patients for prophylaxis and therapy.

Relationship of Virologic, Immunologic, and Clinical Parameters in Infants with Vertically Acquired Human Immunodeficiency Virus Type 1 Infection

We have investigated the relationship among the HIV-1 biologic phenotype, replicative capacity of virus isolates, HIV-RNA copy number in plasma, p24 antigenemia, CD4+ T lymphocyte counts in peripheral blood, and the clinical status in a cohort of 13 HIV-infected children younger than 12 mo of age, born of HIV-1 seropositive mothers. Six out of 13 HIV-1 isolates from these patients were classified as rapid/high and seven as slow/low. We have found a significantly positive correlation between the replication rate of HIV isolates and their capacity to induce syncytia in vitro. Most of the serial HIV-1 isolates obtained from infants with AIDS had the rapid/high phenotype and induced syncytia, whereas only two out of 23 HIV-1 isolates obtained from infants without AIDS showed these properties. In sequential analysis of HIV-1 isolates from infants with AIDS, the presence of viral isolates with rapid/high and SI phenotype was associated with higher levels of HIV-1 RNA in plasma, CD4+ T cell depletion, and clinical progression. By contrast, infants whose viruses exhibited nonsyncytium-inducing phenotype throughout the follow-up showed lower levels of HIV RNA, stable CD4+ T cell counts, and mild symptomatic HIV infection. Our findings indicate that infants who carried viruses with more cytopathic biologic phenotype and who had higher viral RNA coy numbers in blood were more likely to have lower CD4+ T cell counts and more likely to have AIDS.

Circulating dendritic cells subsets and regulatory T-cells at multiple sclerosis relapse: Differential short-term changes on corticosteroids therapy

Glucocorticoids remain the treatment of choice for MS relapses. However, little is known on the effect of intravenous methylprednisolone (IVMP) on dendritic cells (DCs) and regulatory T-cells (TReg). Our main goal was to quantify circulating myeloid and plasmacytoid DCs (mDCs and pDCs), and TReg at MS relapse versus healthy controls; and to analyse the short-term changes after IVMP for MS relapse. MS patients at relapse compared to controls showed higher %CD4+CD25high+ TReg (p<0.01). After 5-days of IVMP, activated T-lymphocytes (p=0.001), pDCs (p<0.0001), and CD11c+ mDCs (p<0.0001) decreased. By contrast, CD4+CD25+ and CD4+CD25high+ TReg further increased (p<0.0001 both). Changes on these subsets may play a relevant role in the immunosuppressive activity of this drug.

Intravenous Immunoglobulin Treatment Increased Live Birth Rate in a Spanish Cohort of Women with Recurrent Reproductive Failure and Expanded CD56+ Cells

Natural killer (NK, CD3− CD56+/CD16+) and NKT‐like cells (CD3+ CD56+/CD16+) activity is considered among the key factors for reproductive success. In the absence of immunological screening, beneficial effects of intravenous immunoglobulin (IVIG) in preventing recurrent reproductive failure (RRF) have not been reported. Here, we analyse the IVIG influence on pregnancy success in women with RRF and circulating NK or/and NKT‐like cells expansion.

Efficacy and safety of Etanercept, high-dose intravenous gammaglobulin and plasmapheresis combined therapy for lupus diffuse proliferative nephritis complicating pregnancy:

We report one case of pregnancy-onset severe diffuse proliferative nephritis in a patient with systemic lupus erythematosus (SLE), who was successfully treated with a combination of anti-tumour necrosis factor (TNF)-alpha, plasmapheresis and high-dose intravenous gammaglobulin. No flares were observed either in clinical symptoms or in laboratory examinations during pregnancy or after delivery. Her autoantibodies except fluorescent anti-nuclear antibodies were negative. We suggest that a combination of anti-TNF-alpha, plasmapheresis and high-dose intravenous gammaglobulin may be a safe and effective therapy for pregnant patients suffering severe lupus nephritis.

Outcomes of splenectomy in patients with common variable immunodeficiency (CVID): a survey of 45 patients

Splenectomy has been used in patients with common variable immunodeficiency disorders (CVID), mainly in the context of refractory autoimmune cytopenia and suspected lymphoma, but there are understandable concerns about the potential of compounding an existing immunodeficiency. With increasing use of rituximab as an alternative treatment for refractory autoimmune cytopenia, the role of splenectomy in CVID needs to be re‐examined. This retrospective study provides the largest cohesive data set to date describing the outcome of splenectomy in 45 CVID patients in the past 40 years. Splenectomy proved to be an effective long‐term treatment in 75% of CVID patients with autoimmune cytopenia, even in some cases when rituximab had failed. Splenectomy does not worsen mortality in CVID and adequate immunoglobulin replacement therapy appears to play a protective role in overwhelming post‐splenectomy infections. Future trials comparing the effectiveness and safety of rituximab and splenectomy are needed to provide clearer guidance on the second‐line management of autoimmune cytopenia in CVID.