Antigen-specific antibody responses in B-1a and their relationship to natural immunity.

B-1a cells are primarily thought of as natural antibody-producing cells. However, we now show that appropriate antigenic stimulation induces IgM and IgG B-1a antibody responses and long-lived T-independent antigen-specific B-1a memory that differs markedly from canonical B-2 humoral immunity. Thus, we show here that in the absence of inflammation, priming with glycolipid (FtL) from Francisella tularensis live vaccine strain induces splenic FtL-specific B-1a to mount dominant IgM and activation-induced cytidine deaminase-dependent IgG anti-FtL responses that occur within 3-5 d of FtL priming and fade within 1 wk to natural antibody levels that persist indefinitely in the absence of secondary FtL immunization. Equally surprising, FtL priming elicits long-term FtL-specific B-1a memory cells (IgM>>IgG) that migrate rapidly to the peritoneal cavity and persist there indefinitely, ready to respond to appropriately administrated secondary antigenic stimulation. Unlike B-2 responses, primary FtL-specific B-1a responses and establishment of persistent FtL-specific B-1a memory occur readily in the absence of adjuvants, IL-7, T cells, or germinal center support. However, in another marked departure from the mechanisms controlling B-2 memory responses, rechallenge with FtL in an inflammatory context is required to induce B-1a secondary antibody responses. These findings introduce previously unexplored vaccination strategies for pathogens that target the B-1a repertoire.

Antigen-specific memory in B-1a and its relationship to natural immunity.

In the companion article by Yang and colleagues [Yang Y, et al. (2012) Proc Natl Acad Sci USA, 109, 10.1073/pnas.1121631109], we have shown that priming with glycolipid (FtL) from Francisella tularensis live-vaccine strain (i) induces FtL-specific B-1a to produce robust primary responses (IgM >>IgG); (ii) establishes persistent long-term production of serum IgM and IgG anti-FtL at natural antibody levels; and (iii) elicits FtL-specific B-1a memory cells that arise in spleen but rapidly migrate to the peritoneal cavity, where they persist indefinitely but divide only rarely. Here, we show that FtL rechallenge alone induces these PerC B-1a memory cells to divide extensively and to express a unique activation signature. However, FtL rechallenge in the context of a Toll-like receptor 4 agonist-stimulated inflammatory response readily induces these memory cells to migrate to spleen and initiate production of dominant IgM anti-FtL secondary responses. Thus, studies here reveal unique mechanisms that govern B-1a memory development and expression, and introduce B-1a memory as an active participant in immune defenses. In addition, at a practical level, these studies suggest previously unexplored vaccination strategies for pathogen-associated antigens that target the B-1a repertoire.

A randomized controlled pilot trial of oral N-acetylcysteine in children with autism.

BACKGROUND: An imbalance in the excitatory/inhibitory systems with abnormalities in the glutamatergic pathways has been implicated in the pathophysiology of autism. Furthermore, chronic redox imbalance was also recently linked to this disorder. The goal of this pilot study was to assess the feasibility of using oral N-acetylcysteine (NAC), a glutamatergic modulator and an antioxidant, in the treatment of behavioral disturbance in children with autism. METHODS: This was a 12-week, double-blind, randomized, placebo-controlled study of NAC in children with autistic disorder. Subjects randomized to NAC were initiated at 900 mg daily for 4 weeks, then 900 mg twice daily for 4 weeks and 900 mg three times daily for 4 weeks. The primary behavioral measure (Aberrant Behavior Checklist [ABC] irritability subscale) and safety measures were performed at baseline and 4, 8, and 12 weeks. Secondary measures included the ABC stereotypy subscale, Repetitive Behavior Scale-Revised, and Social Responsiveness Scale. RESULTS: Thirty-three subjects (31 male subjects, 2 female subjects; aged 3.2-10.7 years) were randomized in the study. Follow-up data was available on 14 subjects in the NAC group and 15 in the placebo group. Oral NAC was well tolerated with limited side effects. Compared with placebo, NAC resulted in significant improvements on ABC irritability subscale (F = 6.80; p < .001; d = .96). CONCLUSIONS: Data from this pilot investigation support the potential usefulness of NAC for treating irritability in children with autistic disorder. Large randomized controlled investigations are warranted.

Distinct plasma profile of polar neutral amino acids, leucine, and glutamate in children with Autism Spectrum Disorders.

The goal of this investigation was to examine plasma amino acid (AA) levels in children with Autism Spectrum Disorders (ASD, N = 27) and neuro-typically developing controls (N = 20). We observed reduced plasma levels of most polar neutral AA and leucine in children with ASD. This AA profile conferred significant post hoc power for discriminating children with ASD from healthy children. Furthermore, statistical correlations suggested the lack of a typical decrease of glutamate and aspartate with age, and a non-typical increase of isoleucine and lysine with age in the ASD group. Findings from this limited prospective study warrant further examination of plasma AA levels in larger cross-sectional and longitudinal cohorts to adequately assess for relationships with developmental and clinical features of ASD.

T-independent type II immune responses generate memory B cells.

Unlike T-dependent immune responses against protein antigens, T-independent responses against polysaccharides confer long-lasting humoral immunity in the absence of recall responses and are not known to generate memory B cells. Here we report that polysaccharide antigens elicit memory B cells that are phenotypically distinct from those elicited by protein antigens. Furthermore, memory B cell responses against polysaccharides are regulated by antigen-specific immunoglobulin G antibodies. As the generation and regulation of immunologic memory is central to vaccination, our findings help explain the mode of action of the few existing polysaccharide vaccines and provide a rationale for a wider application of polysaccharide-based strategies in vaccination.

Cloning and developmental expression of Baf57 in Xenopus laevis.

Mammalian and Drosophila homologues of Baf57 have been previously isolated as being a subunit of SWI/SNF-like chromatin remodeling complexes. Here, we report the cloning and developmental expression of Xenopus Baf57. We isolated XBaf57 by using an expression cloning approach to identify novel modulators of Xenopus Smad7. XBaf57 co-operates with XSmad7 by increasing the expression of neural markers in ectodermal explants. XBaf57 is expressed in the ectoderm and pre-involuting mesoderm during gastrula stages and in the central nervous system during neurula and tailbud stages. These results raise the possibility that XBaf57 (or XBaf57-containing chromatin remodelling complexes) may be involved in the process of neural induction during Xenopus embryonic development.