Clinical and Immunological Insights on Severe, Adverse Neurotropic and Viscerotropic Disease following 17D Yellow Fever Vaccination

Yellow fever (YF) vaccines (17D-204 and 17DD) are well tolerated and cause very low rates of severe adverse events (YEL-SAE), such as serious allergic reactions, neurotropic adverse diseases (YEL-AND), and viscerotropic diseases (YEL-AVD). Viral and host factors have been postulated to explain the basis of YEL-SAE. However, the mechanisms underlying the occurrence of YEL-SAE remain unknown. The present report provides a detailed immunological analysis of a 23-year-old female patient. The patient developed a suspected case of severe YEL-AVD with encephalitis, as well as with pancreatitis and myositis, following receipt of a 17D-204 YF vaccination. The patient exhibited a decreased level of expression of Fc-gamma R in monocytes (CD16, CD32, and CD64), along with increased levels of NK T cells (an increased CD3(+) CD16(+/-) CD56(+/-)/CD3(+) ratio), activated T cells (CD4(+) and CD8(+) cells), and B lymphocytes. Enhanced levels of plasmatic cytokines (interleukin-6 [IL-6], IL-17, IL-4, IL-5, and IL-10) as well as an exacerbated ex vivo intracytoplasmic cytokine pattern, mainly observed within NK cells (gamma interferon positive [IFN-gamma(+)], tumor necrosis factor alpha positive [TNF-alpha(+)], and IL-4 positive [IL-4(+)]), CD8(+) T cells (IL-4(+) and IL-5(+)), and B lymphocytes (TNF-alpha(+), IL-4(+), and IL-10(+)). The analysis of CD4(+) T cells revealed a complex profile that consisted of an increased frequency of IL-12(+) and IFN-gamma(+) cells and a decreased percentage of TNF-alpha(+), IL-4(+), and IL-5+ cells. Depressed cytokine synthesis was observed in monocytes (TNF-alpha(+)) following the provision of antigenic stimuli in vitro. These results support the hypothesis that a strong adaptive response and abnormalities in the innate immune system may be involved in the establishment of YEL-AND and YEL-AVD.

Role of sensory innervation in the rat pulmonary neutrophil recruitment induced by staphylococcal enterotoxins type A and B

Rat airways exposure to Staphylococcal enterotoxin A (SEA) and B (SEB) induces marked neutrophil influx. Since sensory neuropeptides play important roles in cell infiltration, in this study we have investigated its contribution in triggering SEA- and SEB-induced pulmonary neutrophil infiltration. Male Wistar rats were exposed intratracheally with SEA (3 ng/trachea) or SEB (250 ng/trachea). Animals received different in vivo pretreatments, after which the neutrophil counts and levels of substance P and IL-1 in bronchoalveolar lavage fluid were evaluated. Alveolar macrophages and peritoneal mast cells were incubated with SEA and SEB to determine the IL-1 and TNF-alpha levels. Capsaicin pretreatment significantly reduced SEA- and SEB-induced neutrophil influx in bronchoalveolar lavage fluid, but this treatment was more effective to reduce SEA responses. Treatments with SR140333 (tachykinin NK(1) receptor antagonist) and SR48968 (tachykinin NK(2) receptor antagonist) decreased SEA-induced neutrophil influx, whereas SEB-induced responses were inhibited by SR140333 only. Cyproheptadine (histamine/5-hydroxytriptamine receptor antagonist) and MD 7222 (5-HT(3) receptor antagonist) reduced SEA- and SEB-induced neutrophil influx. The substance P and IL-1 levels in bronchoalveolar lavage fluid of SEA-exposed rats were significantly hi.-her than SEB. In addition, SEA (but not SEB) significantly released mast cell TNF-alpha. Increased production of TNF-alpha and IL-1 in alveolar macrophages was observed in response to SEA and SEB. In conclusion, sensory neuropeptides contribute significantly to SEA- and SEB-induced pulmonary neutrophil recruitment, but SEA requires in a higher extent the airways sensory innervation, and participation of mast cells and alveolar macrophage products. (C) 2009 Elsevier B.V. All rights reserved.

The presence of CD56/CD16 in T-cell acute lymphoblastic leukaemia correlates with the expression of cytotoxic molecules and is associated with worse response to treatment

Some cases of T-cell acute lymphoblastic leukaemia (ALL) express markers found in natural-killer (NK) cells, such as CD56 and CD16. Out of 84 T-cell ALL cases diagnosed at our Institution, CD56 and/or CD16 was detected in 24 (28.5%), which we designated T/NK-ALL group. Clinical features, laboratory characteristics, survival and expression of cytotoxic molecules were compared in T/NK-ALL and T-ALL patients. Significant differences were observed regarding age (24.9 vs. 16.4 years in T/NK-ALL and T-ALL, respectively, P = 0.006) and platelet counts (177 x 10(9)/l vs. 75 x 10(9)/l in T/NK-ALL and T-ALL, respectively, P = 0.03). Immunophenotypic analysis demonstrated that CD34, CD45RA and CD33 were more expressed in T/NK-ALL patients, whereas CD8 and terminal deoxynucleotidyl transferase were more expressed in T-ALL patients (P < 0.05). The mean overall survival (863 vs. 1869 d, P = 0.02) and disease-free survival (855 vs. 2095 d, P = 0.002) were shorter in patients expressing CD56/CD16. However, multivariate analysis identified CD56/CD16 as an independent prognostic factor only for DFS. Cytotoxic molecules were highly expressed in T/NK-ALL compared to T-ALL. Perforin, granzyme B and TIA-1 were detected in 12/17, 4/17 and 7/24 T/NK-ALL patients and in 1/20, 0/20 and 1/20 T-ALL respectively (P < 0.001, P = 0.036 and P = 0.054). Therefore, the presence of CD56/CD16 was associated with distinct clinical features and expression of cytotoxic molecules in the blasts.

Frequency of insertion/deletion polymorphism in exon 8 of HLA-G and kidney allograft outcome

Human leukocyte antigen-G (HLA-G) is a non-classical major histocompatibility complex (MHC) class Ib molecule predominantly expressed in cytotrophoblasts, where it acts as a specific immunosuppressor. Literature data have shown that grafts in some settings, such as cardiac and liver/kidney-associated transplantations, express HLA-G and this expression is associated with less severe rejection and also reduces the incidence of rejection. Fourteen-base pair deletion/insertion polymorphism has been reported in exon 8 of the 3`-untranslated region of HLA-G. This polymorphism within exon 8 of the HLA-G gene might influence transcription activity, which in turn may influence the stability of HLA-G transcripts. This influences the stability of the HLA-G protein and therefore is of potential functional relevance. In order to determine a possible correlation between the 14-bp insertion/deletion polymorphism and kidney allograft outcome, we isolated genomic DNA from 83 patients who had received isolated kidney allografts, and we classified the 83 specimens into two groups, grafts presenting Banff features of rejection group and a non-rejection group, and compared them with a control group of 97 healthy subjects. The 14-bp polymorphism at exon 8 was genotyped in all groups. There was no significant difference in allelic frequencies of 14-bp insertion/deletion polymorphism between normal controls and kidney transplant patients. In the RG, the homozygous genotype +14/+14 bp (P = 0.0238) was significantly increased in the group with acute rejection compared with the healthy control group. Analysis of other HLA-G polymorphisms and functional studies on immune regulation are essential to elucidate the role of HLA-G in kidney allografts.

Role of neurokinin-1 expressing neurons in the locus coeruleus on ventilatory and cardiovascular responses to hypercapnia

We assessed the role of NK-1 receptors (NK1R) expressing neurons in the locus coeruleus (LC) on cardiorespiratory responses to hypercapnia. To this end, we injected substance P-saporin conjugate (SP-SAP) to kill NK-1 immunoreactive (NK1R-ir) neurons or SAP alone as a control. Immunohistochemistry for NK1R, tyrosine hydroxylase (TH-ir) and Glutamic Acid Decarboxylase (GAD-ir) were performed to verify if NK1R-expressing neurons, catecholaminergic and/or GABAergic neurons were eliminated. A reduced NK1R-ir in the LC (72%) showed the effectiveness of the lesion. SP-SAP lesion also caused a reduction of TH-ir (66%) and GABAergic neurons (70%). LC SP-SAP lesion decreased by 30% the ventilatory response to 7% CO(2) and increased the heart rate (fH) during hypercapnia but did not affect MAP. The present data suggest that different populations of neurons (noradrenergic, GABAergic, and possibly others) in the LC express NK1R modulating differentially the hypercapnic ventilatory response, since catecholaminergic neurons are excitatory and GABAergic ones are inhibitory. Additionally, NK1R-ir neurons in the LC, probably GABAergic ones, seem to modulate fH during CO(2) exposure, once our previous data demonstrated that catecholaminergic lesion does not affect this variable. (C) 2010 Elsevier B.V. All rights reserved.

Selenium reverses Pteridium aquilinum-induced immunotoxic effects

We have previously shown that bracken fern (Pteridium aquilinum) has immunomodulatory effects on mouse natural killer (NK) cells by reducing cytotoxicity. Alternatively, it has been demonstrated that selenium can enhance NK cell activity. Therefore, the aims of the present study were to evaluate if ptaquiloside, the main toxic component found in P. aquilinum, is responsible for the immunotoxic effects observed in mice, and if selenium supplementation could prevent or even reverse these effects. Male C57BL/6 mice were administered the P. aquilinum extract by daily gavage for 30 days, and histological analyses revealed a significant reduction in splenic white pulp area that was fully reversed by selenium treatment. In addition, mice administered ptaquiloside by daily gavage for 14 days demonstrated the same reduction of NK cell activity as the P. aquilinum extract, and this reduction was prevented by selenium co-administration. Lastly, non-adherent splenic cells treated in vitro with an RPM! extract of P. aquilinum also showed diminished NM cell activity that was not only prevented by selenium co-treatment but also fully reversed by selenium post-treatment. The results of this study clearly show that the immunosuppressive effects of P. aquilinum are induced by ptaquiloside and that selenium supplementation can prevent as well as reverse these effects. (C) 2010 Elsevier Ltd. All rights reserved.

The immunomodulatory effects of Ipomoea cornea in rats vary depending on life stage

Ipomoea cameo Jacq. ssp. fistulosa (Mart. Ex Choisy; Convolvulaceae; I. cameo) possesses a toxic component: an indolizidine alkaloid swainsonine (SW) that has immunomodulatory effects due to its inhibition of glycoprotein metabolism. It is also known that SW is excreted into both the amniotic fluid and milk of female rats exposed to I. cameo. Thus, the aim of this study was to determine whether SW exposure, either in utero or from the milk of dams treated with I. cornea, modulates offspring immune function into adulthood. In addition, adult (70 days old) and juvenile rats (21 days old) were exposed to I. cameo in order to evaluate several other immune parameters: lymphoid organs relative weight and cellularity, humoral and cellular immune responses. Offspring exposed to I. cornea during lactation developed rheumatoid arthritis (RA) in adulthood after an immunogenic challenge. In addition, both adult and juvenile rats exposed to I. cameo showed discrepancies in several immune parameters, but did not exhibit any decrease in humoral immune response, which was enhanced at both ages. These findings indicate that SW modulates immune function in adult rats exposed to SW during lactation and in juvenile and adult rats exposed to SW as juveniles and adults, respectively.

CDKN2A is not the principal target of deletions on the short arm of chromosome 9 in neuroendocrine (Merkel cell) carcinoma of the skin

The majority of small-cell lung cancers (SCLCs) express p16 but not pRb, Given our previous study showing loss of pRb in Merkel cell carcinoma (MCC)/neuroendocrine carcinoma of the skin and the clinicopathological similarities between SCLC acid MCC, we wished to determine if this was also the case in MCC, Twenty-nine MCC specimens from 23 patients were examined for deletions at 10 loci on 9p and I on 9p. No loss of heterozygosity (LO H) was peen in 9 patients including 2 for which tumour and cell line DNAs were examined. Four patients had LOH for all informative loci on 9p, Ten tumours showed more limited regions of loss on 9p, and from these 2 common regions of deletion were determined, Half of all informative cases had LOH at D95168, the most telomeric marker examined, and 3 specimens showed loss of only D9S168, A second region (InFNA-D9S126) showed L0H in 10(44%) cases, and case MCC26 showed LOH for only D9S126, implicating genes centromeric of the CDKN2A locus. No mutations in the coding regions of p16 were seen in 7 cell lines tested, and reactivity to anti-p16 antibody was seen in all Il tumour specimens examined and in 6 of 7 cell lines from 6 patients. Furthermore, all cell lines examined reacted with anti-p 14' antibody, These results suggest that neither transcript of the CDKN2A locus is the target of deletions on 9p in MCC and imply the existence of tumour-suppressor genes mapping both centromeric and telomeric of this locus. (C) 2001 Wiley-Liss, Inc.