Systems Analysis of Immunity to Influenza Vaccination across Multiple Years and in Diverse Populations Reveals Shared Molecular Signatures.

Systems approaches have been used to describe molecular signatures driving immunity to influenza vaccination in humans. Whether such signatures are similar across multiple seasons and in diverse populations is unknown. We applied systems approaches to study immune responses in young, elderly, and diabetic subjects vaccinated with the seasonal influenza vaccine across five consecutive seasons. Signatures of innate immunity and plasmablasts correlated with and predicted influenza antibody titers at 1 month after vaccination with >80% accuracy across multiple seasons but were not associated with the longevity of the response. Baseline signatures of lymphocyte and monocyte inflammation were positively and negatively correlated, respectively, with antibody responses at 1 month. Finally, integrative analysis of microRNAs and transcriptomic profiling revealed potential regulators of vaccine immunity. These results identify shared vaccine-induced signatures across multiple seasons and in diverse populations and might help guide the development of next-generation vaccines that provide persistent immunity against influenza.

Systems biology of vaccination in the elderly.

Aging population demographics, combined with suboptimal vaccine responses in the elderly, make the improvement of vaccination strategies in the elderly a developing public health issue. The immune system changes with age, with innate and adaptive cell components becoming increasingly dysfunctional. As such, vaccine responses in the elderly are impaired in ways that differ depending on the type of vaccine (e.g., live attenuated, polysaccharide, conjugate, or subunit) and the mediators of protection (e.g., antibody and/or T cell). The rapidly progressing field of systems biology has been shown to be useful in predicting immunogenicity and offering insights into potential mechanisms of protection in young adults. Future application of systems biology to vaccination in the elderly may help to identify gene signatures that predict suboptimal responses and help to identify more accurate correlates of protection. Moreover, the identification of specific defects may be used to target novel vaccination strategies that improve efficacy in elderly populations.

CD34-derived human Langerhans cells stimulate a T helper type 2 response independently of extracellular-signal-regulated kinase phosphorylation.

Dendritic cell (DC) subsets can mediate diverse responses, but little is known about the Toll-like receptor (TLR) signalling pathways in different human DC subsets. Despite expressing many TLRs in common, we found that in vitro-derived Langerhans cells (LCs) and monocyte-derived DCs (moDCs) undergo differential signalling events following TLR stimulation. TLR-stimulated LCs did not secrete interleukin (IL)-12p70 and thus induced a T helper type 2 (Th2)-biased response. moDCs secrete high levels of IL-12p70 and induce a Th1 response. Stimulation of moDCs through TLR2 or TLR7/8 was able to induce phosphorylation of the mitogen-activated protein kinase (MAPK) extracellular-signal-regulated kinase (ERK). However, phosphorylated ERK was not induced in TLR-stimulated LCs, suggesting an ERK-independent method of Th2 cell induction. Inhibition of p38 MAPK suppressed moDC maturation, but was much less effective at inhibiting LC maturation. Phosphatidylinositol-3 kinase (PI3K) was also found to play a greater role in moDC survival compared with the LCs. Polymerase chain reaction (PCR) arrays to compare the expression of signalling molecules in LCs and moDCs identified differences in TLR recognition molecules and cytokine response genes, suggesting that differential functional responses are probably mediated at the post-transcriptional level. Thus we have described differences in LC and moDC responses to TLR stimulation, and have identified key differences in ERK phosphorylation and the involvement of MAPK and PI3K.

Secondary antibody deficiency.

Secondary antibody deficiencies are defined by a quantitative or qualitative decrease in antibodies that occur most commonly as a consequence of renal or gastrointestinal immunoglobulin loss, hematological malignancies and corticosteroid, immunosuppressive or anticonvulsant medications. Patients with hematological malignancies or requiring immunosuppressive medications are known to be at increased risk of infection, but few studies directly address this relationship in the context of antibody deficiency. Immunoglobulin replacement therapy has been shown to be effective in reducing infections in primary and some secondary antibody deficiencies. The commonly encountered causes of secondary antibody deficiencies and their association with infection-related morbidity and mortality are discussed. Recommendations are made for screening and clinical management of those at risk.

Primary vs. secondary antibody deficiency: clinical features and infection outcomes of immunoglobulin replacement.

Secondary antibody deficiency can occur as a result of haematological malignancies or certain medications, but not much is known about the clinical and immunological features of this group of patients as a whole. Here we describe a cohort of 167 patients with primary or secondary antibody deficiencies on immunoglobulin (Ig)-replacement treatment. The demographics, causes of immunodeficiency, diagnostic delay, clinical and laboratory features, and infection frequency were analysed retrospectively. Chemotherapy for B cell lymphoma and the use of Rituximab, corticosteroids or immunosuppressive medications were the most common causes of secondary antibody deficiency in this cohort. There was no difference in diagnostic delay or bronchiectasis between primary and secondary antibody deficiency patients, and both groups experienced disorders associated with immune dysregulation. Secondary antibody deficiency patients had similar baseline levels of serum IgG, but higher IgM and IgA, and a higher frequency of switched memory B cells than primary antibody deficiency patients. Serious and non-serious infections before and after Ig-replacement were also compared in both groups. Although secondary antibody deficiency patients had more serious infections before initiation of Ig-replacement, treatment resulted in a significant reduction of serious and non-serious infections in both primary and secondary antibody deficiency patients. Patients with secondary antibody deficiency experience similar delays in diagnosis as primary antibody deficiency patients and can also benefit from immunoglobulin-replacement treatment.

Pseudomonas infection in antibody deficient patients.

Pseudomonas aeruginosa (PA) is commonly isolated from the respiratory secretions of antibody deficiency patients, but the significance of this has not been well studied. We have reviewed our adult antibody deficiency cohort of 179 patients and assessed the prevalence and characteristics of PA infection and the effects of early antibiotic eradication treatments. Of the 34 patients with PA, 55.9% (19) underwent successful eradication and were infection-free, 38.2% (13) had intermittent infection, and 5.9% (2) had chronic PA. PA infection was significantly associated with bronchiectasis (p < 0.0001), with 36.1% (22 out of 61) of patients with bronchiectasis developing a PA infection. Infection status was also significantly associated with chronic sinusitis (p < 0.0001). Most treated PA exacerbations were symptomatic and with colony counts of ≥1000 cfu/ml. Current eradication protocols used at our center involve early treatment at first positive isolate with ciprofloxacin for 3 weeks and nebulized colomycin for 3 months, and if eradication fails, intravenous ceftazidime and gentamycin or colomycin is administered for 2 weeks. Continued sputum surveillance and early eradication treatments upon positive PA culture may help to limit chronic PA infection in antibody deficiency patients.