Analysis of a Statewide Early Intervention Program for Young Children with ASD

Journal of Autism and Developmental Disorders - We evaluated the effectiveness of a statewide Medicaid program providing in-home Early Intensive Behavioral Intervention services to young children...     

The role of Bruton’s tyrosine kinase in autoimmunity and implications for therapy

Bruton’s tyrosine kinase (BTK) mediates B cell signaling and is also present in innate immune cells but not T cells. BTK propagates B cell receptor (BCR) responses to antigen-engagement as well as to stimulation via CD40, toll-like receptors (TLRs), Fc receptors (FCRs) and chemokine receptors. Importantly, BTK can modulate signaling, acting as a “rheostat” rather than an “on-off” switch; thus, overexpression leads to autoimmunity while decreased levels improve autoimmune disease outcomes. Autoreactive B cells depend upon BTK for survival to a greater degree than normal B cells, reflected as loss of autoantibodies with maintenance of total antibody levels when BTK is absent. This review describes contributions of BTK to immune tolerance, including studies testing BTK-inhibitors for treatment of autoimmune diseases.     

DNA–histone complexes as ligands amplify cell penetration and nuclear targeting of anti‐DNA antibodies via energy‐independent mechanisms

We have generated three monoclonal cell‐penetrating antibodies (CPAbs) from a non‐immunized lupus‐prone (NZB × NZW)F₁ mouse that exhibited high anti‐DNA serum titres. These CPAbs are polyreactive because they bind to DNA and other cellular components, and localize mainly in the nucleus of HeLa cells, albeit with a distinct nuclear labelling profile. Herein, we have examined whether DNA–histone complexes (DHC) binding to CPAbs, before cell entry, could modify the cell penetration of CPAbs or their nuclear staining properties. By applying confocal microscopy and image analysis, we found that extracellular binding of purified CPAbs to DHC significantly enhanced their subsequent cell‐entry, both in terms of percentages of positively labelled cells and fluorescence intensity (internalized CPAb amount), whereas there was a variable effect on their nuclear staining profile. Internalization of CPAbs, either alone or bound to DHC, remained unaltered after the addition of endocytosis‐specific inhibitors at 37° or assay performance at 4°, suggesting the involvement of energy‐independent mechanisms in the internalization process. These findings assign to CPAbs a more complex pathogenetic role in systemic lupus erythematosus where both CPAbs and nuclear components are abundant.     

Structural characterization of Campylobacter jejuni lipooligosaccharide outer cores associated with Guillain-Barre and Miller Fisher syndromes

Molecular mimicry between lipooligosaccharides (LOS) of Campylobacter jejuni and gangliosides in peripheral nerves plays a crucial role in the pathogenesis of C. jejuni-related Guillain-Barré syndrome (GBS). We have analyzed the LOS outer core structures of 26 C. jejuni strains associated with GBS and its variant, Miller Fisher syndrome (MFS), by capillary electrophoresis coupled with electrospray ionization mass spectrometry. Sixteen out of 22 (73%) GBS-associated and all 4 (100%) MFS-associated strains expressed LOS with ganglioside mimics. GM1a was the most prevalent ganglioside mimic in GBS-associated strains (10/22, 45%), and in eight of these strains, GM1a was found in combination with GD1a mimics. All seven strains isolated from patients with ophthalmoplegia (GBS or MFS) expressed disialylated (GD3 or GD1c) mimics. Three out of 22 GBS-associated strains (14%) did not express sialylated ganglioside mimics because their LOS locus lacked the genes necessary for sialylation. Three other strains (14%) did not express ganglioside mimics because of frameshift mutations in either the cstII sialyltransferase gene or the cgtB galactosyltransferase gene. It is not possible to determine if these mutations were already present during C. jejuni infection. This is the first report in which mass spectrometry combined with DNA sequence data were used to infer the LOS outer core structures of a large number of neuropathy-associated C. jejuni strains. We conclude that molecular mimicry between gangliosides and C. jejuni LOS is the presumable pathogenic mechanism in most cases of C. jejuni-related GBS. However, our findings suggest that in some cases, other mechanisms may play a role. Further examination of the disease etiology in these patients is mandatory.     

Grouping of patients with common variable immunodeficiency based on immunoglobulin biosynthesis: comparison with a classification system on CD4-naïve cells

The present study compared two different systems of classification of patients with common variable immunodeficiency (CVID); one based on in vitro immunoglobulin biosynthesis; and another on CD4-na?ve cell counts. Peripheral blood mononuclear cells (PBMCs) were isolated from 35 patients with CVID and 20 healthy controls. They were stimulated for the secretion of IgM and IgG after stimulation with Staphylococcus aureus Cowan I (SAC) upon supplementation of interleukin-2 (IL-2) or with pokeweed mitogen. T cell subsets were estimated by flow cytometry. By the first system, patients were classified into group A (n=18) with secretion of neither IgG nor IgM; into group B (n=12) with detectable IgM but no IgG secretion; and into group C (n=5) with IgM and IgG secretion similar to controls. By the second system, patients were classified into group I (n=12) with less than 109 CD4-na?ve cells/mul; into group II (n=12) with CD4-na?ve cells within 109-225microl(-1); and into group III (n=11) with more than 225 CD4-na?ve cells/mul. All groups I-III were defective for in vitro release of IgG and IgM. The likelihood ratio for splenomegaly in patients with <225 CD4-na?ve cells/mul was 5.08 (p: 0.024). CD4-na?ve cell counts of patients were positively correlated to serum levels of IgG and IgA of patients. The presented results revealed that the former system described adequately the function of B cells and the latter the clinical status of the patient. Our proposal is that both should be used for the characterization of patients with CVID.     

Serotonergic raphe magnus cell discharge reflects ongoing autonomic and respiratory activities

Serotonergic cells are located in a restricted number of brain stem nuclei, send projections to virtually all parts of the CNS, and are critical to normal brain function. They discharge tonically at a rate modulated by the sleep-wake cycle and, in the case of medullary serotonergic cells in raphe magnus and the adjacent reticular formation (RM), are excited by cold challenge. Yet, beyond behavioral state and cold, endogenous factors that influence serotonergic cell discharge remain largely mysterious. The present study in the anesthetized rat investigated predictors of serotonergic RM cell discharge by testing whether cell discharge correlated to three rhythms observed in blood pressure recordings that averaged >30 min in length. A very slow frequency rhythm with a period of minutes, a respiratory rhythm, and a cardiac rhythm were derived from the blood pressure recording. Cross-correlations between each of the derived rhythms and cell activity revealed that the discharge of 38 of the 40 serotonergic cells studied was significantly correlated to the very slow and/or respiratory rhythms. Very few serotonergic cells discharged in relation to the cardiac cycle and those that did, did so weakly. The correlations between serotonergic cell discharge and the slow and respiratory rhythms cannot arise from baroreceptive input. Instead we hypothesize that they are by-products of ongoing adjustments to homeostatic functions that happen to alter blood pressure. Thus serotonergic RM cells integrate information about multiple homeostatic activities and challenges and can consequently modulate spinal processes according to the most pressing need of the organism.