Evidence of functional cell-mediated immune responses to nontypeable Haemophilus influenzae in otitis-prone children

Otitis media (OM) remains a common paediatric disease, despite advances in vaccinology. Susceptibility to recurrent acute OM (rAOM) has been postulated to involve defective cell-mediated immune responses to common otopathogenic bacteria. We compared the composition of peripheral blood mononuclear cells (PBMC) from 20 children with a history of rAOM (otitis-prone) and 20 healthy non-otitis-prone controls, and assessed innate and cell-mediated immune responses to the major otopathogen nontypeable Haemophilus influenzae (NTHi). NTHi was a potent stimulator of inflammatory cytokine secretion from PBMC within 4 hours, with no difference in cytokine levels produced between PBMC from cases or controls. In the absence of antigen stimulation, otitis-prone children had more circulating Natural Killer (NK) cells (p<0.01), particularly NKdim (CD56lo) cells (p<0.01), but fewer CD4+ T cells (p<0.01) than healthy controls. NTHi challenge significantly increased the proportion of activated (CD107a+) NK cells in otitis-prone and non-otitis-prone children (p<0.01), suggesting that NK cells from otitis-prone children are functional and respond to NTHi. CD8+ T cells and NK cells from both cases and controls produced IFNγ in response to polyclonal stimulus (Staphylococcal enterotoxin B; SEB), with more IFNγ+ CD8+ T cells present in cases than controls (p<0.05) but similar proportions of IFNγ+ NK cells. Otitis-prone children had more circulating IFNγ-producing NK cells (p<0.05) and more IFNγ-producing CD4+ (p<0.01) or CD8+ T-cells (p<0.05) than healthy controls. In response to SEB, more CD107a-expressing CD8+ T cells were present in cases than controls (p<0.01). Despite differences in PBMC composition, PBMC from otitis-prone children mounted innate and T cell-mediated responses to NTHi challenge that were comparable to healthy children. These data provide evidence that otitis-prone children do not have impaired functional cell mediated immunity

Panel 6 : Vaccines

Objective. To review the literature on progress regarding (1) effectiveness of vaccines for prevention of otitis media (OM) and (2) development of vaccine antigens for OM bacterial and viral pathogens. Data Sources. PubMed database of the National Library of Science. Review Methods. We performed literature searches in PubMed for OM pathogens and candidate vaccine antigens, and we restricted the searches to articles in English that were published between July 2011 and June 2015. Panel members reviewed literature in their area of expertise. Conclusions. Pneumococcal conjugate vaccines (PCVs) are somewhat effective for the prevention of pneumococcal OM, recurrent OM, OM visits, and tympanostomy tube insertions. Widespread use of PCVs has been associated with shifts in pneumococcal serotypes and bacterial pathogens associated with OM, diminishing PCV effectiveness against AOM. The 10-valent pneumococcal vaccine containing Haemophilus influenzae protein D (PHiD-CV) is effective for pneumococcal OM, but results from studies describing the potential impact on OM due to H influenzae have been inconsistent. Progress in vaccine development for H influenzae, Moraxella catarrhalis, and OM-associated respiratory viruses has been limited. Additional research is needed to extend vaccine protection to additional pneumococcal serotypes and other otopathogens. There are likely to be licensure challenges for protein-based vaccines, and data on correlates of protection for OM vaccine antigens are urgently needed. Implications for Practice. OM continues to be a significant health care burden globally. Prevention is preferable to treatment, and vaccine development remains an important goal. As a polymicrobial disease, OM poses significant but not insurmountable challenges for vaccine development.Peer reviewe

Tecniche dell’osservatore

traduction de L. Acquarelli Torino, Einaudi (Techniques of the Observer. On Vision and Modernity in the 19th Century, Cambridge, MIT Press, 1990)

Added value of multiple autoantibody testing for predicting progression to inflammatory arthritis in at-risk individuals

BackgroundPredicting progression to clinical arthritis in individuals at-risk of developing rheumatoid arthritis is a prerequisite to developing stratification groups for prevention strategies. Selecting accurate predictive criteria is the critical step to define the population at-risk. While positivity for anti-citrullinated protein antibodies (ACPA) remains the main recruitment biomarker, positivity for other autoantibodies (AutoAbs) identified before the onset of symptoms, may provide additional predictive accuracy for stratification.ObjectiveTo perform a multiple AutoAbs analysis for both the prediction and the time of progression to inflammatory arthritis (IA).Methods392 individuals were recruited based on a new musculoskeletal complaint and positivity for ACPA or rheumatoid factor (RF). ELISAs were performed for ACPA, RF, anti-nuclear Ab, anti-carbamylated protein (anti-CarP) and anti-collagen AutoAbs. Logistic and COX regression were used for analysis.ResultsProgression to IA was observed in 125/392 (32%) of cases, of which 78 progressed within 12 months. The AutoAbs ACPA, RF, anti-CarP were individually associated with progression (p77%; area under the curve (AUC) >0.789), compared with prediction using only demographic/clinical data (72.9%, AUC=0.760). Multiple AutoAbs testing provided added value, with +6.4% accuracy for number of positive AutoAbs (AUC=0.852); +5.4% accuracy for AutoAbs levels (ACPA/anti-CarP, AUC=0.832); and +6.2% accuracy for risk-groups based on high/low levels (ACPA/RF/anti-CarP, AUC=0.837). Time to imminent progression was best predicted using ACPA/anti-CarP levels (AUC=0.779), while the number of positive AutoAbs was/status/risk were as good (AUC=0.778).ConclusionWe confirm added value of multiple AutoAbs testing for identifying progressors to clinical disease, allowing more specific stratification for intervention studies.Transplantation and autoimmunit

Anti‐CCP3 Ab improve prediction of clinical arthritis in CCP2+ at risk individuals

Objectives: i) To determine the prevalence of anti‐CCP3 antibodies (Ab) in anti‐CCP2 Ab positive (CCP2+) at‐risk individuals; ii)) To explore the additional value of anti‐CCP3 Ab in CCP2+ at‐risk individuals for predicting progression to inflammatory arthritis (IA). Methods: Anti‐CCP3 Ab were tested on stored serum samples obtained from 347 CCP2+ (BioPlex 2200, BioRad, USA) at‐risk individuals without clinical synovitis. Anti‐CCP2 and anti‐CCP3 titres were categorised as follows: low (LT) and high (HT) for anti‐CCP2, negative/low/strong for anti‐CCP3. Progression to IA was defined as the development of clinical synovitis in ≥1 joint. Only subjects with ≥1 follow‐up visit were included in the progression analysis (n=291). Results: Anti‐CCP3 Ab tended to be either negative (138/347; 39.7%) or strongly positive (189/347; 54.4%), with very few subjects showing a LT (20/347; 5.7%). In contrast, for anti‐CCP2 Ab, more LT were observed (103/347; 29.7%). Eighty‐eight/291 subjects (30.2%) developed IA. The rate of progression of LT and HT anti‐CCP2, when anti‐CCP3 was negative, fell from 7.5% to 3.3%, and from 38.9% to 9.8%, respectively. Progression in anti‐CCP2 HT increased from 38.9% to 48.4% when anti‐CCP3 was strongly positive. The area under the curve was 0.72 for anti‐CCP2 (95%CI=0.66‐0.78) and 0.76 (95%CI=0.70‐0.81) for anti‐CCP3 for assessment of progression. In the multivariate analysis, the odds ratio for the development of IA for anti‐CCP3 was 1.73 (95%CI 1.20‐2.51, p<0.01). Conclusions: Anti‐CCP3 Ab improve the prediction of IA in CCP2+ at‐risk individuals. The impact of anti‐CCP3 Ab status for the risk stratification of HT CCP2+ individuals is particularly notable