Central and peripheral myeloid-derived suppressor cell-like cells are closely related to the clinical severity of multiple sclerosis.

Multiple sclerosis (MS) is a highly heterogeneous demyelinating disease of the central nervous system (CNS) that needs for reliable biomarkers to foresee disease severity. Recently, myeloid-derived suppressor cells (MDSCs) have emerged as an immune cell population with an important role in MS. The monocytic-MDSCs (M-MDSCs) share the phenotype with Ly-6Chi-cells in the MS animal model, experimental autoimmune encephalomyelitis (EAE), and have been retrospectively related to the severity of the clinical course in the EAE. However, no data are available about the presence of M-MDSCs in the CNS of MS patients or its relation with the future disease aggressiveness. In this work, we show for the first time cells exhibiting all the bona-fide phenotypical markers of M-MDSCs associated with MS lesions, whose abundance in these areas appears to be directly correlated with longer disease duration in primary progressive MS patients. Moreover, we show that blood immunosuppressive Ly-6Chi-cells are strongly related to the future severity of EAE disease course. We found that a higher abundance of Ly-6Chi-cells at the onset of the EAE clinical course is associated with a milder disease course and less tissue damage. In parallel, we determined that the abundance of M-MDSCs in blood samples from untreated MS patients at their first relapse is inversely correlated with the Expanded Disability Status Scale (EDSS) at baseline and after a 1-year follow-up. In summary, our data point to M-MDSC load as a factor to be considered for future studies focused on the prediction of disease severity in EAE and MS.

Peripheral myeloid-derived suppressor cells are good biomarkers of the efficacy of fingolimod in multiple sclerosis.

BACKGROUND: The increasing number of treatments that are now available to manage patients with multiple sclerosis (MS) highlights the need to develop biomarkers that can be used within the framework of individualized medicine. Fingolimod is a disease-modifying treatment that belongs to the sphingosine-1-phosphate receptor modulators. In addition to inhibiting T cell egress from lymph nodes, fingolimod promotes the immunosuppressive activity of myeloid-derived suppressor cells (MDSCs), whose monocytic subset (M-MDSCs) can be used as a biomarker of disease severity, as well as the degree of demyelination and extent of axonal damage in the experimental autoimmune encephalomyelitis (EAE) model of MS. In the present study, we have assessed whether the abundance of circulating M-MDSCs may represent a useful biomarker of fingolimod efficacy in EAE and in the clinical context of MS patients. METHODS: Treatment with vehicle or fingolimod was orally administered to EAE mice for 14 days in an individualized manner, starting the day when each mouse began to develop clinical signs. Peripheral blood from EAE mice was collected previous to treatment and human peripheral blood mononuclear cells (PBMCs) were collected from fingolimod to treat MS patients' peripheral blood. In both cases, M-MDSCs abundance was analyzed by flow cytometry and its relationship with the future clinical affectation of each individual animal or patient was assessed. RESULTS: Fingolimod-treated animals presented a milder EAE course with less demyelination and axonal damage, although a few animals did not respond well to treatment and they invariably had fewer M-MDSCs prior to initiating the treatment. Remarkably, M-MDSC abundance was also found to be an important and specific parameter to distinguish EAE mice prone to better fingolimod efficacy. Finally, in a translational effort, M-MDSCs were quantified in MS patients at baseline and correlated with different clinical parameters after 12 months of fingolimod treatment. M-MDSCs at baseline were highly representative of a good therapeutic response to fingolimod, i.e., patients who met at least two of the criteria used to define non-evidence of disease activity-3 (NEDA-3) 12 months after treatment. CONCLUSION: Our data indicate that M-MDSCs might be a useful predictive biomarker of the response of MS patients to fingolimod.

Secondary antibody deficiency is associated with development of infection in kidney transplantation: Results of a multicenter study.

BACKGROUND: We performed a multicenter study to assess the association between secondary antibody deficiency (immunoglobulin G [IgG] hypogammaglobulinemia combined with low levels of specific antibodies) and development of infection in kidney transplantation. METHODS: We prospectively analyzed 250 adult kidney recipients at four centers. The assessment points were before transplantation and 7 and 30 days after transplantation. The immune parameters were as follows: IgG, IgA, and IgM and complement factors C3 and C4 tested by nephelometry; specific IgG antibodies to cytomegalovirus (CMV) and IgG and IgG2 antibodies to pneumococcal polysaccharide (anti-PPS) determined using enzyme-linked immunosorbent assay. The clinical follow-up period lasted 6 months. The clinical outcomes were CMV disease and recurrent bacterial infections requiring antimicrobial therapy. STATISTICS: Multivariate logistic regression. RESULTS: At day 7, IgG hypogammaglobulinemia (IgG levels < 700 mg/dL) combined with low IgG anti-CMV antibody titers (defined as levels < 10 000 units) was present in 12% of kidney recipients. IgG hypogammaglobulinemia combined with low IgG anti-PPS antibody titers (defined as levels < 10 mg/dL) at 1 month after kidney transplantation were recorded in 16% of patients. At day 7 the combination of IgG hypogammaglobulinemia and low anti-CMV titers was independently associated with the development of CMV disease (odds ratio [OR], 6.95; 95% confidence interval [CI], 1.17-41.31; P = .033). At day 30 after transplantation, the combination of IgG < 700 mg/dL and IgG anti-PPS < 10 mg/dL, was independently associated with recurrent bacterial infection (OR, 5.942; 95% CI, 1.943-18.172; P = .002). CONCLUSION: In a prospective multicenter study, early immunologic monitoring of secondary antibody deficiency proved useful for the identification of kidney recipients who developed severe infection.

Early intravenous immunoglobulin replacement in hypogammaglobulinemic heart transplant recipients: results of a clinical trial.

BACKGROUND: Immunoglobulin G (IgG) hypogammaglobulinemia (HGG) is a risk factor for development of severe infections after heart transplantation. We performed a clinical trial to preliminarily evaluate the efficacy and safety of early administration of intravenous immunoglobulin (IVIG) for prevention of severe infection in heart recipients with post-transplant IgG HGG. METHODS: Twelve heart recipients with IgG HGG detected in a screening phase of the clinical trial (IgG <500 mg/dL) were recruited. Patients received IVIG (Flebogamma 5%), as follows: 2 doses of 200 mg/kg followed by up to 5 additional doses of 300 mg/kg to maintain IgG >750 mg/dL. IgG and specific antibody titers to distinct microorganisms were tested during follow-up. The primary outcome measure was development of severe infection during the study period. Data on the primary outcome were matched with those of 13 recipients with post-transplant HGG who were not included in the clinical trial and with those of 11 recipients who did not develop HGG during the same study period. RESULTS: Mean time to detection of HGG was 15 days. IgG and specific antibody reconstitution (anti-cytomegalovirus, anti-Haemophilus influenza, and anti-hepatitis B surface antigen antibodies) was observed in IVIG-treated patients. Severe infection was detected in 3 of 12 (25%) IVIG-treated recipients, in 10 of 13 (77%) HGG non-IVIG patients, and in 2 of 11 (18%) non-HGG patients (log-rank, 15.31; P=.0005). No severe IVIG-related side effects were recorded. CONCLUSION: Data from this study demonstrate that prophylactic IVIG replacement therapy safely modulates HGG and specific antimicrobial antibodies. Our data also preliminarily suggest that IVIG replacement therapy might decrease the incidence of severe infection in heart recipients with HGG.

Alterations of naïve and memory B-cell subsets are associated with risk of rejection and infection in heart recipients.

Rejection and infection are relevant causes of mortality in heart recipients. We evaluated the kinetics of the maturation status of B lymphocytes and its relationship with acute cellular rejection and severe infection in heart recipients. We analyzed B-cell subsets using 4-color flow cytometry in a prospective follow-up study of 46 heart recipients. Lymphocyte subsets were evaluated at specific times before and up to 1 year after transplantation. Higher percentages of pretransplant class-switched memory B cells (CD19+CD27+IgM-IgD- >14%) were associated with a 74% decrease in the risk of severe infection [Cox regression relative hazard (RH) 0.26, 95% confidence interval (CI), 0.07-0.86; P = 0.027]. Patients with higher percentages of naïve B cells at day 7 after transplantation (CD19+CD27-IgM+IgD+ >58%) had a 91% decrease in the risk of developing acute cellular rejection (RH 0.09; 95% CI, 0.01-0.80; P = 0.02). Patients with infections showed a strong negative correlation between baseline serum B-cell-activating factor (BAFF) concentration and absolute counts of memory class-switched B cells (R = -0.81, P = 0.01). The evaluation of the immunophenotypic maturation status of B lymphocytes could prove to be a useful marker for identifying patients at risk of developing rejection or infection after heart transplantation.

Regulatory Cells in Multiple Sclerosis: From Blood to Brain.

Multiple sclerosis (MS) is a chronic, autoimmune, and neurodegenerative disease of the central nervous system (CNS) that affects myelin. The etiology of MS is unclear, although a variety of environmental and genetic factors are thought to increase the risk of developing the disease. Historically, T cells were considered to be the orchestrators of MS pathogenesis, but evidence has since accumulated implicating B lymphocytes and innate immune cells in the inflammation, demyelination, and axonal damage associated with MS disease progression. However, more recently the importance of the protective role of immunoregulatory cells in MS has become increasingly evident, such as that of myeloid-derived suppressor cells (MDSCs), regulatory T (Treg) and B (Breg) cells, or CD56bright natural killer cells. In this review, we will focus on how peripheral regulatory cells implicated in innate and adaptive immune responses are involved in the physiopathology of MS. Moreover, we will discuss how these cells are thought to act and contribute to MS histopathology, also addressing their promising role as promoters of successful remyelination within the CNS. Finally, we will analyze how understanding these protective mechanisms may be crucial in the search for potential therapies for MS.

Monitoring of early humoral immunity to identify lung recipients at risk for development of serious infections: A multicenter prospective study.

BACKGROUND: Infection is still a leading cause of death during the first year after lung transplantation. We performed a multicenter study among teaching hospitals to assess monitoring of early humoral immunity as a means of identifying lung recipients at risk of serious infections. METHODS: We prospectively analyzed 82 adult lung recipients at 5 centers in Spain. Data were collected before transplantation and at 7 and 30 days after transplantation. Biomarkers included IgG, IgM, IgA, complement factors C3 and C4, titers of antibodies to pneumococcal polysaccharide antigens (IgG, IgA, IgM) and antibodies to cytomegalovirus (IgG), and serum B-cell activating factor (BAFF) levels. The clinical follow-up period lasted 6 months. Clinical outcomes were bacterial infections requiring intravenous anti-microbial agents, cytomegalovirus (CMV) disease, and fungal infections requiring therapy. RESULTS: We found that 33 patients (40.2%) developed at least 1 serious bacterial infection, 8 patients (9.8%) had CMV disease, and 10 patients (12.2%) had fungal infections. Lower IgM antibody levels against pneumococcal polysaccharide antigens at Day 7 (defined as <5 mg/dl) were a risk factor for serious bacterial infection (adjusted odds ratio [OR] 3.96; 95% confidence interval [CI] 1.39 to 11.26; p = 0.0099). At Day 7 after transplantation, IgG hypogammaglobulinemia (defined as IgG <600 mg/dl) was associated with a higher risk of CMV disease (after adjustment for CMV mismatch: OR 8.15; 95% CI 1.27 to 52.55; p = 0.028) and fungal infection (adjusted OR 8.03, 95% CI 1.51 to 42.72; p = 0.015). Higher BAFF levels before transplantation were associated with a higher rate of development of serious bacterial infection and acute cellular rejection. CONCLUSION: Early monitoring of specific humoral immunity parameters proved useful for the identification of lung recipients who are at risk of serious infections.

Evaluation of humoral immunity profiles to identify heart recipients at risk for development of severe infections: A multicenter prospective study.

BACKGROUND: New biomarkers are necessary to improve detection of the risk of infection in heart transplantation. We performed a multicenter study to evaluate humoral immunity profiles that could better enable us to identify heart recipients at risk of severe infections. METHODS: We prospectively analyzed 170 adult heart recipients at 8 centers in Spain. Study points were before transplantation and 7 and 30 days after transplantation. Immune parameters included IgG, IgM, IgA and complement factors C3 and C4, and titers of specific antibody to pneumococcal polysaccharide antigens (anti-PPS) and to cytomegalovirus (CMV). To evaluate potential immunologic mechanisms leading to IgG hypogammaglobulinemia, before heart transplantation we assessed serum B-cell activating factor (BAFF) levels using enzyme-linked immunoassay. The clinical follow-up period lasted 6 months. Clinical outcome was need for intravenous anti-microbials for therapy of infection. RESULTS: During follow-up, 53 patients (31.2%) developed at least 1 severe infection. We confirmed that IgG hypogammaglobulinemia at Day 7 (defined as IgG <600 mg/dl) is a risk factor for infection in general, bacterial infections in particular, and CMV disease. At Day 7 after transplantation, the combination of IgG <600 mg/dl + C3 <80 mg/dl was more strongly associated with the outcome (adjusted odds ratio 7.40; 95% confidence interval 1.48 to 37.03; p = 0.014). We found that quantification of anti-CMV antibody titers and lower anti-PPS antibody concentrations were independent predictors of CMV disease and bacterial infections, respectively. Higher pre-transplant BAFF levels were a risk factor of acute cellular rejection. CONCLUSION: Early immunologic monitoring of humoral immunity profiles proved useful for the identification of heart recipients who are at risk of severe infection.

Potential role of serum BAFF as a biomarker in HIV infection.

We evaluated the potential role of serum B-cell activating factor (BAFF) as a biomarker in HIV infection and analyzed the relationship between BAFF concentration and the immunophenotypic activation status of T-cells. We tested the hypothesis that higher serum BAFF concentrations are associated with risk for development of AIDS in HIV positive individuals. Forty-one HIV patients (CDC category A 17, category B 24) were evaluated retrospectively. Serum BAFF concentrations were assessed using a commercial enzyme-linked immunosorbent assay. Cox regression was used to estimate the probability for development of AIDS. Patients with higher BAFF concentrations (> 2100 pg/mL) were at greater risk of developing AIDS (relative hazard 5.69; p = 0.0033). BAFF levels were independently associated with risk of AIDS after adjustment by clinical risk factors. Serum BAFF was correlated with activated T-cell subsets and with neopterin levels. BAFF is a good candidate for further evaluation as a nonspecific surrogate marker in HIV infection.