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Cellular mechanisms underlying sexual dimorphism in the immune response remain largely unknown. Concerning the interactions among the nervous, endocrine and immune systems, we reported that during gestation, a period during which multiple sclerosis (MS) clearly ameliorates, there is a physiological expansion of regulatory T-lymphocytes (T(Reg)). Given that alterations in T(Reg) proportions and suppressive function are involved in MS pathophysiology, we investigated the in vitro effect of sex hormones on T(Reg). Here, we show that both E2 and progesterone (P2) enhance T(Reg) function in vitro, although only E2 further induces a T(Reg) phenotype in activated responder T-cells (CD4(+)CD25(-)) (P < 0.01). E2 receptor beta (ERβ) percentages and mean fluorescence intensity (MFI) on T(Reg) were lower in MS patients than in controls (P < 0.05), in parallel with lower E2 plasma levels (P < 0.05). Importantly, percentages and MFI of ERβ were higher in T(Reg) than in T-responder cells (P < 0.0001) both in MS patients and controls. We show a unique differential pattern of higher ER and PR levels in T(Reg), which may be relevant for the in vivo responsiveness of these cells to sex hormones and hence to MS physiopathology.

The analysis of proliferative responses using 5,6-carboxyfluorescein diacetate succinimidyl ester (CFSE) in flow cytometry is widely used to assess lymphocyte function. The aim of this study was to evaluate nonspecific and specific lymphoproliferative responses using CFSE in heart recipients before and after transplantation and their association with the development of infection. We used four-color flow cytometry to measure the response of peripheral CD3+, CD4+, and CD8+ T cells to phytohemagglutinin mitogen (PHA), tetanus toxoid, hepatitis B, and influenza vaccines using a CFSE proliferation assay in 12 heart recipients and 8 healthy control subjects. Recipients were prospectively evaluated. Immunological studies were performed before and at 3 months after transplantation. A 12-month clinical follow-up examination sought to detect the prevalence of severe infectious complications. Heart recipients (infected [n = 7] and uninfected [n = 5]) disclosed significantly lower percentages of proliferative responses than healthy controls against PHA at both study points. Baseline CD3+, CD4+, and CD8+, antitetanus proliferative responses were significantly lower in infected heart recipients than controls. Patients who developed infections displayed significantly lower percentages of CD3+CFSE and CD8+CFSE cells to PHA mitogen at 3 months after transplantation versus those without infections. In conclusion, nonspecific T-cell reactivity to PHA was lower in heart recipients with posttransplantation infections., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: To investigate whether the incidence of secondary hypogammaglobulinaemia in patients with RA following rituximab was related to patterns of B-cell return and relapse., Methods: CD19(+) B-cell and serum immunoglobulin (sIg) determinations were done every 2 or 3 months in 137 consecutive patients treated with one or more courses of rituximab-based B-cell depletion therapy. The pattern of B-cell return, either concordant or discordant with relapse, was also recorded., Results: There were 119 responders. Before treatment, three patients had low IgM and four had low IgG. After the first cycle, low IgM or IgG was present in 9.2% (11/119) and 11.8% (14/119) of the patients, respectively, increasing to 38.8% (8/18) and 22.2% (4/18) after five cycles. The mean percent maximum sIg decrease/cycle was relatively constant. The CD19(+) B-cell count at repopulation was not correlated with immunoglobulin (Ig) levels after each cycle. Patients discordant for B-cell return and relapse developed significantly lower serum IgM and more low IgM episodes than concordant patients (P < 0.05)., Conclusion: Patients with lower baseline sIg levels tended to develop persistent IgM and IgG hypogammaglobulinaemia, resulting from an accumulation of incremental decreases after repeat cycles. This was not due to lower numbers of returning B cells in those developing low sIgs. The association of low IgM in patients with a discordant pattern of relapse suggests that underlying defects in B cells relating to survival and maturation into Ig-secreting cells, as well as attrition of IgG plasma cells may be contributing to low sIg levels in some patients.

Multiple sclerosis (MS) represents the leading cause of neurological deficit among young adults, affecting women more frequently than men. In MS, the extent of central nervous system lesions is determined by the net balance between self-reactive and regulatory T-cells at any given time, among other factors, as well as by the effect of inflammatory response. Here, we studied both CD4+ and CD8+ T(Reg) in parallel in blood and CSF during MS relapse. A recruitment of both regulatory CD4+ and CD8+ T cells (T(Reg)) within the cerebrospinal fluid (CSF) takes place during MS relapse. Not previously described, the presence of CD4+ T(Reg) in CSF was higher in women than in men, which could account for the sexual dimorphism in the incidence of MS. A direct correlation between plasma oestradiol (E2) and IL-2 levels was observed, in line with a putative circuit of E2 and perforin expression by CD4+ T(Reg) playing a role in MS. Also, serum IFN-alpha was higher in females, with direct correlation with serum E2 levels. This is the first study to analyze perforin expression by CD4+ T(Reg) in MS, which was greatly enhanced in CSF, what points out a relevant role of this molecule in the suppressive effects of the CD4+ T(Reg) in MS, and contributes to the understanding of MS pathophysiology.

Background: CD4+CD25+FoxP3+ regulatory T-cells (nT(Reg)) have been shown to suppress immune responses to autoantigens and to other diverse antigens, this suppression is mainly mediated by a cell contact-dependent mechanism not yet fully defined. It has been reported that both human natural and induced T(Reg) exert cytotoxic activity against autologous target cells, which suggests that the perforin/granzyme pathway may be a relevant candidate mechanism for the suppressive function of T(Reg). Previous reports have shown that oestradiol (E2) modulates T(Reg) percentages and function., Methods: We have evaluated in pregnant and non-pregnant subjects perforin intracellular expression in CD4+CD25+FoxP3+ regulatory T-cells by flow cytometry in whole blood, ex-vivo purified nT(Reg) and ex-vivo purified nT(Reg) after TCR and E2 stimulation. The expression of cellular degranulation markers was also phenotypically determined., Results: We show that E2 expands T(Reg), enhances in vitro T(Reg) function and induces a T(Reg) phenotype in activated responder (CD4+CD25) T-cells, further increasing the expression of perforin on T(Reg) than in vitro T-cell receptor activation alone. We found surface lysosomal-associated membrane glycoproteins (LAMP)-1 and LAMP-2 expression by T(Reg), which is a sign of cell degranulation and therefore of cytotoxicity exerted by these cells., Conclusion: Our data demonstrates the presence of functional T(Reg) cytotoxic properties in biological systems and support the concept that E2 enhances the number and function of T(Reg) suggesting the potential interaction between E2 and immunoregulatory mechanisms., (© 2010 The Authors. European Journal of Clinical Investigation © 2010 Stichting European Society for Clinical Investigation Journal Foundation.)

Recurrent respiratory tract infections (RRTIs) are common clinical conditions in individuals with alterations of the immune function. A prospective open pilot study in a cohort of patients with RRTIs has been performed to assess whether sublingual immunization with a polyvalent bacterial vaccine could exert an immunomodulatory effect on the antigen-specific immunological responses and have an impact on the clinical outcome. Seventeen patients with RRTIs were recruited. An oral polyvalent bacterial preparation (Bactek®) was administered to all patients daily for 6 months. Immunological assessment was performed at baseline and at the end of immunization. Immunological measurements included: T cell-specific proliferations of CD3+CD4+ and CD3+CD8+ to Bactek® antigens, total immunoglobulin levels, antibodies to pneumococcal polysaccharide and tetanus toxoid and B, T and natural killer (NK) cell subsets. There was a significant increase in the proliferative capacity of CD3+CD4+ T cells specific to Bactek® antigens at month 6 in comparison to baseline (P < 0·0001). A significant increase in total CD3+ T cells was also observed (P < 0·05). No significant differences were observed between baseline and month 6 in levels of total immunoglobulins, specific antibodies and B, T or NK cell subsets. A significant reduction in the patient's rate of RRTIs was observed compared with 1 year prior to initiation of therapy (P < 0·0001). The results demonstrate that long-term administration of a sublingual polyvalent bacterial preparation in patients with RRTIs exerts an immune stimulating effect on CD4+ T helper cell responses to bacterial antigens which could be associated with clinical benefit.

Background: Studies in primary HIV-1 infection and advanced HIV-1 disease have demonstrated that HIV-1 DNA associated with peripheral blood mononuclear cells (PBMC HIV-1 DNA) has predictive value for disease progression., Objectives: To analyse in asymptomatic HIV-1 chronic infection the predictive value of PBMC HIV-1 DNA for virological failure., Study Design: In 115 individuals who had previously participated in study STIR-2102, we retrospectively analysed the PBMC HIV-1 DNA by quantitative real-time PCR. Antiretroviral naïve patients (baseline pre-ART) received 6 weeks of ART prior to randomisation (baseline post-ART). The predictive value of PBMC HIV-1 DNA, HIV-1 RNA in plasma and CD4+ T cells, at baselines pre-ART and post-ART, was determined by Kaplan-Meier and Proportional Hazards Regression analyses., Results: At baseline post-ART, 82% of patients showed suppression of HIV-1 RNA, however they maintained significant amounts of HIV-1 DNA (geometric mean: 690 copies/10(6) PBMC). Pre-ART and post-ART levels of HIV-1 DNA and pre-ART levels of HIV-1 RNA showed predictive value (Log-Rank test: p<0.001, p<0.001, p=0.003, respectively). In a multivariate model post-ART PBMC HIV-1 DNA was the stronger predictive variable (adjusted HR, 2.51 [95% CI, 1.33-4.73, p=0.004]) independently of HIV-1 RNA (HR 1.74 [95% CI, 1.16-2.61, p=0.007])., Conclusions: PBMC HIV-1 DNA is an effective prognostic marker for virological outcome in individuals with asymptomatic HIV-1 chronic infection., (Copyright (c) 2010 Elsevier B.V. All rights reserved.)

Development of polyfunctional T lymphocyte responses is critical in the immunological response against HIV-1. Fifty-four HIV-1 infected patients receiving antiretroviral treatment (ART) and immunization with an HIV-1 immunogen or placebo, periodically every 3 months throughout a period of 36 months, were evaluated for the purposes of analysing the development of HIV-1-specific CD4+ and CD8+ responses. A significant increase of proliferating and IFN-gamma producing CD8+ HIV-1-specific T cells, of HIV-1-specific precursor frequencies for CD8+ and for CD4+ T cells and of Gag/pol-specific memory CTL precursors (CTLp) was observed in the immunogen group in comparison to placebo. IL-2 intracellular expression and IFN-gamma and TNF-alpha co-expression in HIV-1-specific CD8+ T cells were also substantially increased in the immunized group. A negative correlation between viral load and CD3+CD4+CFSElow HIV-1-specific lymphoproliferative response and frequency of Gag/pol-specific CTLp was solely observed in the HIV-1 immunogen group. Long-term immunization in patients receiving ART helps to develop HIV-1-specific polyfunctional T cell responses.

The human immunodeficiency virus-1 (HIV-1) preferentially infects CD4+ cells, leading to their destruction. In contrast to other viral infections, the immune system is unable to keep the HIV infection under permanent control in most cases. This failure ultimatively results in immunodeficiency with occurrence of AIDS-defining diseases. In recent years, highly active antiretroviral therapy (HAART) has become available, and the number of AIDS cases and deaths have decreased dramatically. However, limitations of HAART become more apparent, demanding greater emphasis on search for alternative approaches. Stimulation and modulation of the immune response to HIV are new and promising strategies. A prerequisite, however, is the knowledge about immunologic defense mechanisms against HIV. In this article, the major factors of innate and acquired immune responses to HIV are described.