Age-dependent deficiency in saliva and salivary antibodies secretion in Down's syndrome.

OBJECTIVE: Down's syndrome (DS) individuals suffer from an increased susceptibility to infections. Here, we assessed age-related changes in the salivary-specific humoral immunity of DS subjects. DESIGN: Parotid and whole saliva were collected from a young group of DS (YDS, n=30, 23.3+/-4 years), an older group of DS individuals (ODS, n=10, 51.9+/-8 years) and compared to two age-matched groups of healthy volunteers--a young group (YC, n=29, 22.8+/-5 years) and an older group (OC, n=10, 48.4+/-9 years). The levels of total IgA, and specific antibodies to three common oral pathogens (Porphyromonas gingivalis, Actinobacillus (Aggregatibacter) actinomycetemcomitans and Streptococcus mutans) were analysed. RESULTS: The limited increases in IgA concentrations could not compensate the dramatic reduction in the salivary flow rate observed in DS individuals. Therefore, the median secretion rates of the specific antibodies in whole and parotid saliva were 70-77% and 34-60% (respectively) lower in YDS individuals as compared to YC and farther 77-100% and 75-88% (respectively) lower in ODS compared to YDS. In contrast, the antibody secretion rates were similar for parotid saliva, or even increased for whole saliva of OC, compared with YC. Consequently, a dramatic cumulative extreme reduction (>92%) in the bacterial specific salivary antibodies differentiated the adult DS individuals from to their age-matched controls. CONCLUSIONS: Our results indicate a severe immunodeficiency in the secretion rate of the specific salivary IgA response of in DS individuals which intensifies with age.

Salivary LL-37 secretion in individuals with Down syndrome is normal.

Antimicrobial peptides play an important role in the innate immune response. Deficiency in salivary LL-37 antimicrobial peptide has been implicated in periodontitis in patients with morbus Kostman syndrome. Down syndrome is associated with periodontitis, diminished salivary flow, and salivary immunoglobulin deficiency. In the present study, levels of LL-37 and its hCAP18 precursor were measured in saliva samples from young individuals with Down syndrome and compared with levels in those from age-matched healthy controls. LL-37 and human cathelicidin antimicrobial protein (hCAP18) were detected in whole but not in parotid saliva. hCAP18 was more abundant than LL-37. The concentrations of salivary hCAP18 and LL-37 were found to be higher in individuals with Down syndrome than in healthy controls, but their secretion rates were similar. We concluded that, while the adaptive immunity of individuals with Down syndrome is impaired at the oral mucosa, the secretion rate of the LL-37 component of the innate immune system is normal.

The outcome of a preventive dental care programme on the prevalence of localized aggressive periodontitis in Down's syndrome individuals.

BACKGROUND: Periodontal disease in Down's syndrome (DS) individuals develops earlier and is more rapid and extensive than in age-matched normal individuals. The present study evaluated a group of DS patients, who had been participating in a 10-year preventive dental programme, for the impact of the programme on their periodontal status. METHODS: Thirty DS patients (mean age 23.3 +/- 4 years) were compared with 28 age-matched healthy controls (mean age 22.8 +/- 5 years). The hygiene level, gingival condition and periodontal status (periodontal probing depth, clinical attachment level and radiographic alveolar bone loss) were determined. RESULTS: In spite of similar oral hygiene and gingival measures, DS patients, as opposed to the control ones, had a severe periodontal disease. The prevalence, extent and severity of periodontitis in the DS group were significantly greater than in the control group. The teeth most commonly and severely affected were the lower central incisors and the upper first molars. DS patients lost significantly more teeth due to periodontitis. CONCLUSIONS: The clinical and radiographic picture found in the present DS group is characteristic of localized aggressive periodontitis. Within the limitations of this study, it seems that the preventive dental programme had no effect on periodontal destruction progression of localized aggressive periodontitis in DS individuals and that impaired oral hygiene plays a relatively minor role in the pathogenesis of this disease. Future controlled studies are needed to assess the effectiveness of different preventive dental programmes in preventing the progression of periodontitis in DS patients.

CD44 co-stimulates apoptosis in thymic lymphomas and T cell hybridomas.

Thymic lymphomas and hybridomas vary in their sensitivity to dexamethasone (DEX). Identical variance has been demonstrated in our laboratory for apoptosis of such cells by primary thymic epithelial cells or a cell line (TEC). We have also shown that apoptosis induced by TEC was partially mediated by TEC-derived glucocorticoids (GC). We studied the responses of various thymic lymphomas and hybridomas to TEC and DEX. Of these cells, PD1.6 and 2B4 were sensitive whereas B10 were relatively resistant to either inducer. In the present study we found that TEC and DEX synergize in inducing B10 cell apoptosis. B10 cells could also undergo apoptosis by TEC, conditional upon the presence of a TEC-sensitive cell (PD1.6 or 2B4). Contact between TEC and B10 was essential for apoptosis to occur. Thus, TEC may provide two signals, one mediated by GC and the other requiring cell to cell contact. We then analyzed the involvement of co-stimulatory or adhesion molecules in the TEC-induced apoptosis of thymic lymphoma cells. Soluble anti-CD44 antibodies but not anti-CD18, CD2 or CD28, inhibited TEC-induced apoptosis of PD1.6. Dimerization of CD44 by immobilized antibodies augmented DEX-induced apoptosis of all the lymphomas tested. CD44 cross-linkage up-regulated expression of the pro-apoptotic protein Bax, and down-regulated the anti-apoptotic protein, Bclx(L), in the presence of DEX. Taken together, the data suggest that CD44 enhances the apoptotic response of T lymphoma cells to DEX, and that CD44 modulates TEC-induced apoptosis of thymic lymphomas.

Severe impairment of secretory Ig production in parotid saliva of Down Syndrome individuals.

Infections associated with Down Syndrome (DS) are prevalent in the mucosal-gastrointestinal and respiratory systems, for reasons that are uncertain. The purpose of the present study was to assess the levels of parotid salivary immunoglobulins (Ig) in a group of DS individuals as a possible factor in the susceptibility of mucosal surfaces to infections. Twenty-nine DS and 10 age- and sex-matched healthy individuals were included. Salivary flow rate and IgA, IgG, and IgM concentrations were recorded. The secretion rates of IgA and IgG were diminished by 83% (p < 0.001) and 75% (p = 0.05), respectively, whereas the secretion rate of IgM was not statistically significantly lower. Analysis of the data suggests that DS individuals are immunodeficient in the humoral mucosal immune response. This may explain, in part, the high incidence of recurrent infections in target organs of the secretory immune system in DS subjects.

A link between parotid salivary Ig level and recurrent respiratory infections in young Down's syndrome patients.

The purpose of the present investigation was to assess the correlation between recurrent respiratory infections and the levels of salivary Ig in a group of young Down's syndrome (DS) individuals. Twenty-three DS and 10 age- and sex-matched healthy individuals were included. DS individuals who had experienced three or more upper respiratory tract infections (n = 10) in the previous 12 months were compared to DS individuals who had not experienced recurrent respiratory infections (n = 13) and to healthy controls (n = 10). A statistically significant reduction in the Ig salivary secretion rate was recorded in the subgroup with recurrent respiratory infections. No significant differences were seen between the subgroup without recurrent respiratory infections and controls. It is suggested that the secretory immune system provides local immune protection against pathogens in the respiratory tract. Detection of salivary Ig levels may serve as a predictor of the susceptibility of DS individuals to recurrent respiratory tract infections.

The growth and metastasis of human, HER-2/neu-overexpressing tumor cell lines in male SCID mice.

HER-2/neu is overexpressed on a variety of human adenocarcinomas and overexpression has been associated with a poor prognosis. For this reason, HER-2 has become an attractive target for immunotherapy. To facilitate testing of anti-HER-2-monoclonal antibodies (MAbs) and immunotoxins (ITs), we have evaluated the in vivo growth and metastatic spread of three HER-2-overexpressing human breast cancer cell lines (BT474, MDA-MB-453 and HCC1954) and one ovarian cancer cell line (SKOV3.ip1) in pre-irradiated male SCID mice using subcutaneous (s.c.), intravenous (i.v.) and intraperitoneal (i.p.) routes of injection. All the cell lines tested grew as s.c. tumors and the growth of BT474 and MDA-MB-453 cells after s.c. injection was improved by co-inoculation with Matrigel. Metastases to the lungs were detectable by PCR or histopathology after s.c. injection of BT474 and to a much lesser extent after s.c. injection of HCC1954, MD-MB-453 and SKOV3.ip1 cells. I.p. injection of HCC1954 and SKOV3.ip1 cells produced fatal ascites while i.v. injection of SKOV3.ip1, but not BT474 or MDA-MB-453 cells, resulted in infiltration of lungs and death within 9-11 weeks.

p53 and thymic 'death by neglect': thymic epithelial cell-induced apoptosis of CD4+8+ thymocytes is p53-independent.

The involvement of the tumor suppressor protein, p53, in thymic epithelial cell-induced apoptosis of CD4+8+ (double positive) thymocytes, was studied in an in vitro model consisting of a thymic epithelial cell line (TEC) and thymocytes. p53 expression was not augmented in double positive (DP) thymocytes upon co-culturing with TEC, although extensive apoptosis was observed. In the same cells, p53 expression was upregulated in response to low ionizing irradiation, which was accompanied with massive apoptosis. Moreover, TEC induced apoptosis in two DP thymomas, derived from p53(-/-) mice, and in a double positive thymoma clone expressing mutant p53. The extent and kinetics of TEC-induced apoptosis was not affected by the status of p53 in the thymocytes tested. We conclude that thymic epithelial cell-induced apoptosis of immature DP thymocytes is p53-independent and apparently, involves a different apoptotic pathway than that triggered by DNA damage.