Mapping the T helper cell response to acid α-glucosidase in Pompe mice

Pompe disease is a neuromuscular disease caused by an inherited deficiency of the lysosomal enzyme acid α-glucosidase (GAA). The resulting accumulation of glycogen causes muscle weakness with the severe form of the disease resulting in death by cardiorespiratory failure in the first year of life. The only available treatment, enzyme replacement therapy (ERT) with recombinant GAA (rhGAA), is severely hampered by antibody responses that reduce efficacy and cause immunotoxicities. Currently, Pompe mice represent the only pre-clinical model for development of new treatments and for immunological studies. While antibody formation following ERT in this model has been described, the underlying T cell response has not been studied. In order to define the T helper response to rhGAA in Pompe mice, immunodominant CD4(+) T cell epitopes were mapped in GAA(-/-) 129SVE mice using ELISpot. Additionally, cytokine responses and antibody formation against rhGAA during ERT were measured. Among the three CD4(+) T cell epitopes identified, only epitope IFLGPEPKSVVQ, predicted to be the strongest MHC II binder, consistently contributed to IL-4 production. Frequencies of IL-4 producing T cells were considerably higher than those of IL-17 or IFN-γ producing cells, suggesting a predominantly Th2 cell mediated response. This is further supported by IgG1 being the prevalent antibody subclass against rhGAA during ERT and consistent with prior reports on IgE formation and anaphylaxis in this model. These results will facilitate mechanistic studies of the immune response to rhGAA in Pompe mice during development of new therapies and tolerance protocols.     

HBV viremia in newborns of HBsAg(+) predominantly Caucasian HBeAg(−) mothers

BackgroundHepatitis B virus infection is an important public health problem worldwide and eliminating mother-to-infant transmission is important to decrease the prevalence of chronic HBV-infection. Although, immunoprophylaxis given at birth largely prevents mother-to-infant transmission, perinatal HBV viremia has been reported in HBsAg(?) newborns born mainly to HBeAg(+) women in endemic areas.ObjectivesTo examine the incidence of perinatal HBV viremia in newborns of HBsAg(+) predominantly HBeAg(?) mothers.Study designPeripheral blood was obtained at birth from 109 HBsAg(+) mothers and their newborns before the administration of active–passive immunoprophylaxis. Infants were prospectively followed and appropriately vaccinated.ResultsAlthough most (92.7%) of the HBsAg(+) mothers were HBeAg(?), 73.4% had detectable HBV viremia. Neonatal viremia was detected in 3/8 (37.5%) and 24/101 (23.8%) newborns of HBeAg(+) and HBeAg(?) mothers, respectively (p = 0.386). However, HBV–DNA levels were significantly higher in newborns of HBeAg(+) mothers (p = 0.025). No child developed chronic HBV infection, but one child had evidence of subclinical hepatitis.ConclusionsAlthough the clinical significance of low viremia levels in almost one in four newborns of HBsAg(+) mothers in a low endemicity area is unclear, it may enhance our understanding of HBV mother-to-infant transmission.     

Does exposure to antiretroviral therapy affect growth in the first 18 months of life in uninfected children born to HIV-infected women?

Uninfected children born to HIV-infected women are exposed antenatally to antiretroviral therapy, but it is uncertain whether this affects growth in early life. We analyzed weight, height, and occipitofrontal circumference (OFC) in 1912 children from a cohort study: 1304 had no or monotherapy exposure and 608 had combination therapy exposure. The mean z-score for birth weight or OFC did not differ by exposure category in 1513 term children or in 78 born at <34 weeks; the 266 born from 34 to 36 weeks were heavier if exposed to combination therapy. Children with combination therapy exposure born at 34 to 36 weeks reached the 25th centile for weight and OFC earlier than those not exposed born at 34 to 36 weeks (median: birth vs. 3 months; P = 0.003 [weight], P = 0.004 [OFC]), whereas children exposed to combination therapy born at <34 weeks reached the 25th centile for OFC later than those born at <34 weeks not exposed (median: 15 vs. 7 months; P = 0.004). Gestational age and maternal illicit drug use were strongly associated with growth, but the effect of combination therapy exposure was marginal (adjusted coefficients: weight, -0.10 [P = 0.019]; height, -0.12 [P = 0.008]; and OFC, -0.14 [P = 0.001]). Although the effect of combination therapy exposure is minimal, long-term monitoring of these children is important.     

T helper cell populations: As flexible as the skin?

T helper cells can be defined by the cytokines they produce and are divided into Th1, Th2, Th17, T(FH) or regulatory T cells. Th17 cells have been shown to produce, in addition to IL-17, IL-22. In the current issue of the European Journal of Immunology, an article by Larsen et al. (Eur. J. Immunol. 2011. 41: 2596-2605) provides evidence that human T helper cells, like murine cells, can also express IL-22 in the absence of the other T helper cell signature cytokines. Moreover, they show that these IL-22-producing cells, namely Th22 cells, can be found in the skin of psoriasis patients, where they might contribute to the pathogenesis of this inflammatory skin disease. Finally, they show that, molecularly, Th22 cells are related to Th17 cells, and might therefore be derived from the latter. In this Commentary, the development of the pro-inflammatory T helper populations in the skin are discussed and a model that explains the development of Th22 cells found in the skin of psoriasis patients is proposed.     

Are there gender and race differences in cellular immunity patterns over age in infected and uninfected children born to HIV-infected women?

This study investigated whether age-related patterns of immunologic markers in 1488 uninfected (9789 measurements) and 186 infected (3414 measurements) children differed by gender and race. CD4+, CD8+, and absolute lymphocytes by HIV infection status, gender, and race were assessed using linear mixed-effects natural cubic spline models, allowing for prematurity and maternal CD4+ cell count. In uninfected children, levels of all 3 markers peaked twice in the first few months of life, declining to adult levels by around 8 years of age; uninfected boys and uninfected black children had significantly reduced CD4+ and absolute lymphocyte counts; the gender difference was especially pronounced in black children. Infected children had substantially lower levels and distinctly different patterns; with, e.g., by age 6 months CD4+ cell counts nearly 1200 per mm3 lower than in uninfected infants. Levels also significantly differed by gender and race for infected children, although for gender in the opposite direction. The gender and race differences in CD4+ levels were not explained by a general lymphocytosis nor were they confounded by treatment. These substantial differences in immunologic markers may reflect underlying genetic influence on the cellular immune system and may have implications for clinical decisions about therapeutic management.     

Rapid evolution of HIV-1 to functional CD8⁺ T cell responses in humanized BLT mice

The development of mouse/human chimeras through the engraftment of human immune cells and tissues into immunodeficient mice, including the recently described humanized BLT (bone marrow, liver, thymus) mouse model, holds great promise to facilitate the in vivo study of human immune responses. However, little data exist regarding the extent to which cellular immune responses in humanized mice accurately reflect those seen in humans. We infected humanized BLT mice with HIV-1 as a model pathogen and characterized HIV-1-specific immune responses and viral evolution during the acute phase of infection. HIV-1-specific CD8(+) T cell responses in these mice were found to closely resemble those in humans in terms of their specificity, kinetics, and immunodominance. Viral sequence evolution also revealed rapid and highly reproducible escape from these responses, mirroring the adaptations to host immune pressures observed during natural HIV-1 infection. Moreover, mice expressing the protective HLA-B*57 allele exhibited enhanced control of viral replication and restricted the same CD8(+) T cell responses to conserved regions of HIV-1 Gag that are critical to its control of HIV-1 in humans. These data reveal that the humanized BLT mouse model appears to accurately recapitulate human pathogen-specific cellular immunity and the fundamental immunological mechanisms required to control a model human pathogen, aspects critical to the use of a small-animal model for human pathogens.     

Immune response to purified protein derivative in infants from helminth-sensitized mothers — A cases series

BackgroundMaternal exposure to antibodies, cytokines or parasitic antigens during gestation may alter the degree of immune competence of offspring. Here we describe the production of cytokines and chemokines, and the ability to activation of the immune response in infants from mothers sensitized to helminths.MethodsIt were selected five infants born to helminth-seropositive mothers but who were negative for current helminth infection. Whole blood was cultured without stimulus, with phytohemagglutinin mitogen (5 μg/ml, 24 h) or with purified protein derivative (PPD) (1 μg/ml, 24 h), and the supernatant was assessed for presence of Th1/Th2 cytokines (IFN-γ, TNF-α, IL-10, IL-5, IL-4 and IL-2) and chemokines (CXCL10, CCL2, CXCL9, CCL5 and CXCL8) by cytometric bead array.ResultsAll infants produced CCL5. Two infants demonstrated a mixed profile of Th1 (CXCL9) and Th2 (CCL2) chemokines in the presence of CXCL10, while one infant showed skewing towards Th2 without CXCL10 and two of them had been impaired immune response (children from sensitized to Schistosoma mansoni mothers).ConclusionInfants with Th1 and Th2 profile chemokines demonstrated a good response to vaccination, indicated by CXCL10 levels, but not infants predominantly Th2-skewed profile. These results highlight that children from mothers sensitized to S. mansoni may lead to ineffective immune response to PPD, while mothers sensitized to Ascaris lumbricoides showed no such impairment.     

With a little help from my old T cell: Memory follicular T helper cells driving autoimmunity?

It has long been known that the B cell repertoire includes cells that are capable of producing autoantibodies and that these cells can be found in humans and also in wild type strains of laboratory mice; however, normally, these B cells do not give rise to plasma cells, and thus do not fulfil their autoimmune potential. In this issue of the European Journal of Immunology, Nusser et al. [Eur. J. Immunol. 2014. 44: 2893–2902] dissect the mechanism by which these B cells are activated and autoantibodies are produced. The authors demonstrate that T cells, most likely antigen‐specific, which accumulate with age or as a result of homeostatic proliferation, provide essential help to these autoreactive B cells. Hence, this study reveals a previously under appreciated mechanism, by which T cells, possibly generated with age after exposure to a variety of antigens, break immunological tolerance and lead to the generation of autoantibodies that could contribute to the development of autoimmune diseases.     

T helper type 1 cells in asthma: friend or foe?

A large body of research supports a pathogenic role for T helper 2 cells in asthma, although T helper 1 cell-type responses may also contribute. Using the principle of T helper cell cross-regulation, investigators have attempted to regulate the pathological effects of T helper 2 cells using regimens that may promote T helper 1 cell-type inflammation. In this review, we propose that the use of factors that promote T helper 1 cell differentiation and activation to treat asthma may be counterproductive, and that alternate regulatory approaches should be explored.     

T cell‐mediated immune responses in human newborns: ready to learn?

Infections with intracellular pathogens are often more severe or more prolonged in young infants suggesting that T cell-mediated immune responses are different in early life. Whereas neonatal immune responses have been quite extensively studied in murine models, studies of T cell-mediated immunity in human newborns and infants are scarce. Qualitative and quantitative differences when compared with adult immune responses have been observed but on the other hand mature responses to certain vaccines and infectious pathogens were demonstrated during the postnatal period and even during foetal life. Herein, we review the evidence suggesting that under appropriate conditions of stimulation, protective T cell-mediated immune responses could be induced by vaccines in early life.     

Germ cell tumours in neonates and infants: a distinct subgroup?

Human germ cell tumours (GCTs) constitute a heterogeneous group of tumours that can be classified into four major subgroups. One of these subgroups encompasses (immature) teratomas and yolk sac tumours of patients under the age of 5 years. In this paper we review the various clinical, histological and cytogenetical aspects of these infantile GCTs. The primordial germ cell (PGC) has been suggested to be the cell of origin for GCTs. Infantile GCTs, however, have been suggested to originate from PGCs at a different stage of maturation than adult GCTs. The cytogenetic constitution of infantile GCTs also appears to differ from the adult GCTs and includes recurrent losses of lp and 6q. Recently, two cases of infantile GCT were detected with constitutional 12q13 translocations. These exceptional cases may be instrumental in the search for candidate genes related to infantile and/or adult GCT development.     

Are dendritic cells central to regulatory T cell function?

The role of dendritic cells (DCs) as sentinels and inducers of immunity has been amply documented in the past 35 years. More recently, experimental evidence has suggested that DCs may also be critical to maintain tolerance to self-antigens. These opposing functions are complementary and would ensure the integrity of the organism in an environment full of pathogens. In this review, we summarize the observations supporting the hypothesis that DCs induce and maintain tolerance by a mechanism involving regulatory T cells.     

Disproportion of helper T cell subsets in peripheral blood of patients with primary Sjögren's syndrome

We studied the proportions of Th1 and Th2 cells in peripheral blood of 15 patients with primary Sj?gren's syndrome (p-SS), by using a procedure to enumerate the cells synthesizing cytokines such as INF-gamma or IL-4 in cytoplasm of CD4+ lymphocytes. The frequency of Th1 (INF-gamma containing) cells in p-SS patients was significantly reduced as compared to normal control (20.57+/-7.48% vs 28.78+/-11.56%, p < 0.05), while that of Th2 (IL-4 containing) cells was not different from normal control (3.33+/-0.98% vs 2.85+/-1.88%). The ratio of Th1 to Th2 cells in p-SS patients was significantly decreased as compared to normal control (6.60+/-3.15 vs 11.55+/-6.72, p < 0.05). There was no difference in frequency of Th1 or of Th2 cells between 8 patients given small amounts of prednisolone (PSL) and 7 patients not given PSL (21.44+/-9.39% vs 19.57+/-5.05%, 3.12+/-0.80% vs 3.56+/-1.17%). The percentage of Th1 cells was not different between 7 patients with glandular symptoms (G) and 8 patients with extraglandular symptoms (EG) (18.61+/-9.63% vs 22.27+/-5.02%). Although the frequency of Th2 cells was higher in EG-patients than that in G-patients (3.84+/-0.78% vs 2.74+/-0.86%) with tendency of elevated IgG level in sera, the ratio of Th1 to Th2 cells was not different among them (6.26+/-2.84 vs 6.99+/-3.64). These results suggest that the reduced ratio of Th1 to Th2 cells is essential and is related to the dysfunction of cellular immunity in p-SS.     

Why are children born to teen mothers at risk for adverse outcomes in young adulthood? Results from a 20-year longitudinal study

This 20-year longitudinal study showed that the young adult offspring of teen mothers are at risk for a range of adverse outcomes including early school leaving, unemployment, early parenthood, and violent offending. We tested how much the effect of teen childbearing on offspring outcomes could be accounted for by social selection (in which a woman's characteristics that make her an inadequate parent also make her likely to bear children in her teens) versus social influence (in which the consequences of becoming a teen mother also bring harm to her children, apart from any characteristics of her own). The results provided support for both mechanisms. Across outcomes, maternal characteristics and family circumstances together accounted for approximately 39% of the effect of teen childbearing on offspring outcomes. Consistent with a social-selection hypothesis, maternal characteristics accounted for approximately 18% of the effect of teen childbearing on offspring outcomes; consistent with a social-influence hypothesis, family circumstances accounted for 21% of the teen childbearing effect after controlling for maternal characteristics. These results suggest that public policy initiatives should be targeted not only at delaying childbearing in the population but at supporting individual at-risk mothers and their children.