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Today, HIV-infected children who have access to treatment face a chronic rather than a progressive and fatal disease. As a result, new challenges are emerging in the field. Recent lines of evidence outline several factors that can differently affect the ability of the immune system to fully reconstitute and to mount specific immune responses in children receiving HAART. In this paper, we review the underlying mechanisms of immune reconstitution after HAART initiation among vertically HIV-infected children analyzing the possible causes of suboptimal responses. [ABSTRACT FROM AUTHOR]

During an immune response antigen-primed B-cells increase their antigen responsiveness by affinity maturation mediated by somatic hypermutation of the genes encoding the antigen-specific B-cell receptor (BCR) and by selection of higher-affinity B cell clones. Unlike the BCR, the T-cell receptor (TCR) cannot undergo affinity maturation. Nevertheless, antigen-primed T cells significantly increase their antigen responsiveness compared to antigen-inexperienced (naïve) T cells in a process called functional aviditymaturation. This paper covers studies that describe differences in T-cell antigen responsiveness during T-cell differentiation along with examples of the mechanisms behind functional avidity maturation in T cells. [ABSTRACT FROM AUTHOR]

Osteoblasts support hematopoietic cell development, including B lymphopoiesis. We have previously shown that the nuclear factor of activated T cells (NFAT) negatively regulates osteoblast differentiation and bone formation. Interestingly, in smooth muscle, NFAT has been shown to regulate the expression of vascular cellular adhesion molecule-1 (VCAM-1), a mediator of cell adhesion and signaling during leukocyte development. To examine whether NFAT signaling in osteoblasts regulates hematopoietic development in vivo, we generated a mouse model expressing dominant-negative NFAT driven by the 2.3 kb fragment of the collagen-αI promoter to disrupt NFAT activity in osteoblasts (dnNFATOB). Bone histomorphometry showed that dnNFATOB mice have significant increases in bone volume (44%) and mineral apposition rate (131%) and decreased trabecular thickness (18%). In the bone microenvironment, dnNFATOB mice displayed a significant increase (87%) in Lineage-cKit+Sca-1+ (LSK) cells and significant decreases in B220+CD19-IgM- pre-pro-B cells (41%) and B220+CD19+IgM+ immature B cells (40%). Concurrent with these findings, LSK cell differentiation into B220+ cells was inhibited when cocultured on differentiated primary osteoblasts harvested from dnNFATOB mice. Gene expression and protein levels of VCAM-1 in osteoblasts decreased in dnNFATOB mice compared to controls. These data suggest that osteoblast-specific NFAT activity mediates early B lymphopoiesis, possibly by regulating VCAM-1 expression on osteoblasts. [ABSTRACT FROM AUTHOR]

Systemic autoimmune and rheumatic diseases (SAIRDs) are thought to develop due to the failure of autoimmune regulation and tolerance. Current therapies, such as biologics, have improved the clinical results of SAIRDs; however, they are not curative treatments. Recently, new discoveries have been made in immune tolerance and inflammation, such as tolerogenic dendritic cells, regulatory T and B cells, Th 17 cells, inflammatory and tolerogenic cytokines, and intracellular signaling pathways. They lay the foundation for the next generation of the therapies beyond the currently used biologic therapies. New drugs should target the core processes involved in disease mechanisms with the aim to attain complete cure combined with safety and low costs compared to the biologic agents. Re-establishment of autoimmune regulation and tolerance in SAIRDs by the end of the current decade should be the final and realistic target. [ABSTRACT FROM AUTHOR]

Alterations of B cell subpopulations have been described up to date as characterizing advanced stage of HIV-1 infection. However, whether such defects are relevant in subjects with a preserved number of CD4+ T cells (>350 cells/μL) is unclear. In a crosssectional study, we investigated if signs of B cells exhaustion and impaired viral immune surveillance are present in a cohort of 43 asymptomatic HIV-1-infected patients with preserved CD4+ T cell counts (>350 cells/μL) and highly active antiretroviral therapy (HAART) untreated. A dramatic expansion of exhausted tissue-like memory B cells (CD10-CD21lowCD27-) was observed. B cells alteration was related to an increase in Torque teno virus (TTV) load, used as surrogate marker of immune function. Successfully HAART-treated patients showed normalization of B cell subpopulations frequency and TTV load. These results provide new insights on B cell in HIV-1 infection and show that development of B cell abnormalities precedes CD4+ T cell decline. [ABSTRACT FROM AUTHOR]

Enterovirus 71 (EV71) has induced fatal encephalitis in hundreds of thousands of infants and young children in the Asia-Pacific region since the past decade. Lymphocyte and antibody responses have been suspected to aggravate EV71-induced neurological symptoms, so anti-inflammatory agents have been used to treat patients with neurological symptoms. In the present study, we found that mice deficient in CD4+ T cells were resistant to EV71 infection as wild-type mice, whereas mice deficient in B cells were highly susceptible to viral infection. Compensation of CD4 T-cell function by other immune cells was not likely, because wild-type mice depleted of CD4+ T cells were also resistant to viral infection. Infected CD4 T-cell-deficient mice produced virus-specific neutralizing antibodies, IgMand IgG.Moreover, adoptive transfer of the virus-specific antibody produced by infected CD4 T-celldeficient mice protected B-cell-deficient mice from infection by reducing tissue viral loads. Collectively, our results show that the CD4 T-cell-independent antibody response promotes the survival of EV71-infected mice and suggest great potential for the use of vaccines and neutralizing antibodies to reduce fatal symptoms in patients. [ABSTRACT FROM AUTHOR]