Intravenous immunoglobulin therapy (IVIG) is the treatment of choice for many immune-mediated diseases, yet its mechanisms of action are incompletely elucidated. We investigated the possibility that IVIG played a direct role in the expansion of regulatory T cells (Treg) that recognize the heavy chain constant region of immunoglobulin G (Fc) as a mechanism for the recovery of Kawasaki disease (KD), a T cell mediated pediatric vasculitis of the coronary arteries. We successfully generated Fc-specific Treg clones from sub-acute KD subjects that did not develop arterial complications after IVIG and defined an unusual functional phenotype: Fc-specific Treg secrete IL-10 and small amounts of IL-4 but not TGF-β. Antigen presentation studies demonstrated that these Treg clones can be activated by autologous B cells that express IgG on their cell surface in the absence of exogenous Fc. The IgG molecule has to be canonically processed and presented by autologous MHC molecules to be recognized by Treg. In support of the importance of this novel Treg population in downsizing vascular inflammation, KD patients with dilated coronary arteries or aneurysms despite IVIG treatment failed to expand Fc-specific Treg. Our results point to a specificity of a previously un-described Treg population for the clinical benefit provided by IVIG therapy in children.
We administered a large battery of neuropsychological tests to an heterogeneous cohort of genetically defined spinocerebellar ataxia (SCA) patients in order to assess their cognitive profile and to compare cognitive impairment among different SCA genotypes, particularly between SCA with the classical pattern of olivo-ponto-cerebellar atrophy (SCA1 and SCA2) and those with a relatively "pure" olivo-cerebellar atrophy (SCA6 and SCA8). Our data revealed a neuropsychological picture characterized by fronto-parietal involvement with mnestic, linguistic, visuospatial, attentional, executive, and mood changes, in agreement with the cerebellar cognitive affective syndrome definition. We found a homogeneous neuropsychological profile among SCA subgroups with a prominent role of frontal dysfunction—particularly, attention, memory, and executive functions. We analyzed the possible interactions between neuropsychological pattern and clinical, demographical, and genetic variables. We found the presence of a cognitive impairment at the early stages of the disease, without visuospatial alterations, which appeared later. Age and education represented the most important demographic factors to predict the neuropsychological performance in SCA and in controls, but their effect in patients had definitely more impact. In our sample education could represent a protective factor and a marker of an enriched environment or a better developmental cognitive differentiation. We demonstrated that in our patients there was a distinct subgroup of high functional subjects and that triplet repeats modulated the effect of aging on cognition and progression of motor disability.
Serological responses to hepatitis B virus-X determinants have been noted in human sera, but conflicting findings concerning the correlation of anti-HBx antibodies with different stages of hepatitis B virus infection or pathological sequelae have been reported. Using an adenovirus-based eukaryotic vector, the 17 kD X protein was efficiently expressed in 293 cells. Cellular extracts containing the eukaryotic X protein have been used to screen for anti-HBx antibodies by immunoblot analysis in a large panel of sera from patients affected by hepatitis B virus chronic hepatitis, hepatocellular carcinoma and acute viral hepatitis. Sera from 32 of 171 (19%) chronic hepatitis B virus patients were positive for anti-HBx antibodies. Only one of thirty-two (3%) HBsAg-negative, anti-HBs/anti-HBc-positive chronic hepatitis serum was anti-HBx positive. Very few sera from primary hepatocellular carcinoma patients showed positivity for anti-HBx (8 of 149 or 5%). Anti-HBx were also detected in 8 of 48 (17%) acute viral hepatitis patients. In the four cases that were followed up weekly, anti-HBx antibodies appeared 3 to 4 wk after the onset of the clinical signs. To compare the X protein expressed in eukaryotic and prokaryotic cells as a substrate for anti-HBx antibody detection, 171 sera were screened with HBx fusion proteins expressed in Escherichia coli. The prokaryotic cell extract test seems to be more sensitive. During the chronic phase of hepatitis B virus infection, the presence of anti-HBx antibodies detected with the eukaryotic cell extract correlates with the presence of well-established markers of ongoing viral replication: serum hepatitis B virus-DNA (p less than 0.001) and intrahepatic HBcAg expression (p less than 0.001).
Abstract We characterized a novel population of tolerogenic myeloid dendritic cells (tmDCs) defined as CD11c + CD11b + CD14 + CD4 + and immunoglobulin‐like transcript receptor (ILT)‐4 + that are significantly more abundant in the circulation of infants and young children than in adults. TmDCs secrete the immunosuppressive lymphokine interleukin (IL)‐10 when stimulated with the heavy constant region of immunoglobulins (Fc) and express high levels of the adenosine A 2A receptor (A 2A R), which, when activated by adenosine, inhibits the release of pro‐inflammatory cytokines from most immune cells. Here we show that stimulation of the A 2A R on tmDCs by regadenoson or N ‐ethylcarboxamidoadenosine (NECA) rapidly increases cyclic AMP accumulation and enhances IL‐10 production under Fc stimulatory conditions. In co‐culture experiments, tmDCs inhibit the differentiation of naïve T cells to a pro‐inflammatory phenotype. In conclusion, although DCs are classically viewed as antigen presenting cells that activate T cells, we show an independent role of tmDCs in pediatric immune regulation that may be important for suppressing T cell responses to neoantigens in infants and young children.
T cell clones derived from cerebrospinal fluid (CSF) of patients with multiple sclerosis (MS) were analysed for their capacity to produce interleukin 2 (IL-2), interleukin 4 (IL-4), interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha). They were also compared with liver-infiltrating T cell clones from patients with chronic active hepatitis. All the CSF T clones (both CD4+ and CD8+) produced large amounts of IFN-gamma and particularly of TNF-alpha, that was synthesized in a significantly larger amount than compared clones. Moreover, they were capable of secreting IL-2, but not IL-4. From our results, we conclude that first, the CSF CD4+ T clones could constitute a subset with functional properties similar to the T helper 1 (Th1)/inflammatory cell subset of the mouse; and second, the large amounts of TNF produced by CSF T cell clones strongly suggests a significant role for this cytokine as well as of IFN-gamma in MS immunopathogenesis.
A high proportion of CD8 positive cells and inverted CD4/CD8 ratio were found in peripheral blood mononuclear cells and in freshly isolated kidney-graft infiltrating cells in two patients who underwent irreversible acute rejection. Seventy seven T cell clones were generated from the T cell blasts infiltrating rejected kidney allografts. The majority of T cell clones obtained showed CD8 phenotype in accordance to uncloned graft infiltrating cells. All clones (both CD8 and CD4) displayed cytolytic activity evaluated by lectin-dependent cell-mediated cytotoxicity and natural killer (NK) activities. None of the clones presented lymphokine activated killer phenomenon. These data suggest that the graft infiltrate is characterized by T cell clones with cytolytic potential and that these T cell clones may be responsible for the killing of graft cells by a CTL or NK type mechanism.
