Alexander Panda

Aging of the innate immune system

The innate immune system is composed of a network of cells including neutrophils, NK and NKT cells, monocytes/macrophages, and dendritic cells that mediate the earliest interactions with pathogens. Age-associated defects are observed in the activation of all of these cell types, linked to compromised signal transduction pathways including the Toll-like Receptors. However, aging is also characterized by a constitutive pro-inflammatory environment (inflamm-aging) with persistent low-grade innate immune activation that may augment tissue damage caused by infections in elderly individuals. Thus, immunosenescence in the innate immune system appears to reflect dysregulation, rather than exclusively impaired function.

Age-associated decrease in TLR function in primary human dendritic cells predicts influenza vaccine response.

We evaluated TLR function in primary human dendritic cells (DCs) from 104 young (age 21–30 y) and older (≥65 y) individuals. We used multicolor flow cytometry and intracellular cytokine staining of myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) and found substantial decreases in older compared with young individuals in TNF-α, IL-6, and/or IL-12 (p40) production in mDCs and in TNF-α and IFN-α production in pDCs in response to TLR1/2, TLR2/6, TLR3, TLR5, and TLR8 engagement in mDCs and TLR7 and TLR9 in pDCs. These differences were highly significant after adjustment for heterogeneity between young and older groups (e.g., gender, race, body mass index, number of comorbid medical conditions) using mixed-effect statistical modeling. Studies of surface and intracellular expression of TLR proteins and of TLR gene expression in purified mDCs and pDCs revealed potential contributions for both transcriptional and posttranscriptional mechanisms in these age-associated effects. Moreover, intracellular cytokine production in the absence of TLR ligand stimulation was elevated in cells from older compared with young individuals, suggesting a dysregulation of cytokine production that may limit further activation by TLR engagement. Our results provide evidence for immunosenescence in DCs; notably, defects in cytokine production were strongly associated with poor Ab response to influenza immunization, a functional consequence of impaired TLR function in the aging innate immune response.

Human innate immunosenescence: causes and consequences for immunity in old age

The past decade has seen an explosion in research focusing on innate immunity. Through a wide range of mechanisms including phagocytosis, intracellular killing and activation of proinflammatory or antiviral cytokine production, the cells of the innate immune system initiate and support adaptive immunity. The effects of aging on innate immune responses remain incompletely understood, particularly in humans. Here we review advances in the study of human immunosenescence in the diverse cells of the innate immune system, including neutrophils, monocytes, macrophages, natural killer and natural killer T (NKT) cells and dendritic cells-with a focus on consequences for the response to infection or vaccination in old age.

Dysregulation of human Toll-like receptor function in aging.

Studies addressing immunosenescence in the immune system have expanded to focus on the innate as well as the adaptive responses. In particular, aging results in alterations in the function of Toll-like receptors (TLRs), the first described pattern recognition receptor family of the innate immune system. Recent studies have begun to elucidate the consequences of aging on TLR function in human cohorts and add to existing findings performed in animal models. In general, these studies show that human TLR function is impaired in the context of aging, and in addition there is evidence for inappropriate persistence of TLR activation in specific systems. These findings are consistent with an overarching theme of age-associated dysregulation of TLR signaling that likely contributes to the increased morbidity and mortality from infectious diseases found in geriatric patients.

Influenza vaccination during pregnancy and factors for lacking compliance with current CDC guidelines.

Background. The Center for Disease Control and Prevention (CDC) and the American College of Obstetricians and Gynecologists (ACOG) recommend influenza vaccination for all pregnant women during the influenza season. However, the actual rate of vaccination is substantially below the target levels. Given the recent emergence of novel influenza strains, there is an important need to address knowledge gaps in women and their healthcare providers to improve vaccination coverage for pregnant women during inter-pandemic and pandemic periods. This study attempted to identify potentially remediable attitudinal factors among women and their physicians that may present barriers to influenza vaccination and then assess the impact of interventions to increase the influenza vaccination rate in pregnant women. Methods. This prospective study initially analyzed patient and physician knowledge regarding the influenza vaccine in pregnancy and then examined the impact of several interventions aimed to increase immunization rates implemented over the following year. Influenza vaccination rates were assessed before and after the interventions. Results. Five hundred twenty patients were enrolled in the study during the influenza season 2007/2008. Only 19% of those patients reported receiving the influenza vaccination and only 28% recalled that the vaccine was offered. Following this, in the summer and fall of 2008, we performed a physician education program and distributed posters advertising the influenza vaccine to all offices offering prenatal care in our area in order to increase patient awareness of the need for the vaccine. In the following influenza season, we again reassessed the vaccination rate and patients knowledge and awareness of the vaccine in 480 postpartum women. Influenza vaccination rates increased from 19% to 31%. After the intervention, 51% of patients recalled that the vaccine was offered to them during the pregnancy as opposed to only 28% the year prior. Conclusion. Understanding the specific barriers to vaccination that our population faced was helpful in designing the interventions to improve knowledge and acceptance of influenza vaccination in pregnancy, which led to an increased vaccination rates in women.

Long-term Follow-up of a Fenestrated Amplatzer Atrial Septal Occluder in Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a progressive disease, with right-heart failure being the main cause of death. In patients refractory to conventional drug therapy, atrial septostomy can serve as palliative treatment or as a bridge to transplantation. A 41-year-old woman with a 15-year history of PAH associated with a corrected atrial septal defect presented with severe deterioration of symptoms. Echocardiography confirmed reocclusion of an atrial septal stoma that had been created several months before. After performing a repeat atrial septostomy, we implanted a custom-made atrial septostomy device, an Amplatzer septal occluder that had been fenestrated to serve as a custom-made atrial septostomy device. This resulted in an improvement in cardiac output and a marked symptomatic relief. During the 6-year follow-up, the patient was clinically stable with limited but constant exercise tolerance, under specific medical therapy. Repeated echocardiography confirmed long-term patency of the device.

Antibiotic resistance and penicillin tolerance in ano-vaginal group B streptococci

Objectives. We sought to determine the prevalence of group B streptococcus (GBS) colonisation and to characterise antibiotic resistance patterns. Methods. Vaginal and ano-rectal cultures were evaluated for GBS colonisation, and antibiotic susceptibility profiles were determined to 15 antibiotics according to the guidelines of the National Committee for Clinical Laboratory Standards. Results. Our GBS prevalence was 30%. All isolates were sensitive to amoxicillin/clavulanic acid, ampicillin, ampicillin/sulbactam, cefotaxime, ceftriaxone, cefuroxime-sodium, imipenem, linezolid, penicillin G and vancomycin. Thirty-two percent of the isolates were resistant to azithromycin, 21% to clindamycin, 25% to erythromycin and 23% to tetracycline. Conclusions. The relatively high rates of resistance to four of the 15 antibiotics tested confirm that for women allergic to penicillin and colonised with GBS, antibiotic sensitivities should be determined. We noticed increasing resistance to clindamycin over a 7-year period. Ongoing surveillance of local antibiotic resistance patterns at the institutional level is important in determining optimal prophylaxis as resistance patterns differ between institutions and are increasing.

Dendritic cells in the circulation of women with preeclampsia demonstrate a pro-inflammatory bias secondary to dysregulation of TLR receptors

Toll-like receptors (TLRs) are central components of the innate immune system that recognize both microbial ligands and host products released during tissue damage. Data from epidemiologic studies and animal models suggest that inappropriate activation of the immune system plays a critical role in the development of preeclampsia. This study evaluates in a systematic fashion the expression and function of TLRs in the circulation of patients with preeclampsia compared to healthy pregnant controls. We evaluated TLR expression and function in primary dendritic cells (DCs) of 30 patients with preeclampsia and 30 gestational age-matched healthy pregnant controls. DCs were stimulated with the different TLR ligands engaging TLR1/2, TLR2/6, TLR3, TLR4, TLR5, TLR7, TLR8 and TLR9. The expression of TLR-induced production of TNF-α, IFN-α, IL-6, and IL-12 were measured by multicolor flow cytometry. Basal expression of TLR3, TLR4 and TLR9 was significantly increased in DCs isolated from women with preeclampsia. Preeclamptic DCs also expressed significantly higher basal levels of cytokines. In contrast, preeclamptic DCs demonstrated a less robust response to stimulation with various TLR ligands as compared with healthy pregnant controls. Under basal conditions, DCs from preeclamptic individuals express higher levels of select TLRs and produce more pro-inflammatory cytokines as compared with healthy controls. As such, the ability of these cells to mount an inflammatory reaction in response to a TLR ligand is limited. These data demonstrate a dysregulated pattern of TLR expression and cytokine production in DCs from PE patients that may limit further activation by TLR engagement.

Bronchogenic Cyst of the Interatrial Septum Presenting as Atrioventricular Block

Bronchogenic cysts are congenital lesions that are a remnant from abnormal budding of the embryonic foregut. These cysts are usually single; most cases are either asymptomatic or present with respiratory symptoms. A 43-year-old woman presented with intermittent type II atrioventricular block during cholecystectomy. The cardiac evaluation including transthoracic and transesophageal echocardiography and magnetic resonance imaging revealed a cystic homogeneous mass within the interatrial septum. The patient underwent surgical resection of the mass and closure of the septal defect. Histopathology identified ciliated columnar epithelium, consistent with the diagnosis of a bronchogenic cyst.

Longitudinal expression of Toll-like receptors on dendritic cells in uncomplicated pregnancy and postpartum

OBJECTIVE Toll-like receptors (TLRs) are integral parts of the innate immune system and have been implicated in complications of pregnancy. The longitudinal expression of TLRs on dendritic cells in the maternal circulation during uncomplicated pregnancies is unknown. The objective of this study was to prospectively evaluate TLRs 1-9 as expressed on dendritic cells in the maternal circulation at defined intervals throughout pregnancy and postpartum. STUDY DESIGN This was a prospective cohort of 30 pregnant women with uncomplicated pregnancies and 30 nonpregnant controls. TLRs and cytokine expression was measured in unstimulated dendritic cells at 4 defined intervals during pregnancy and postpartum. Basal expression of TLRs and cytokines was measured by multicolor flow cytometry. The percent-positive dendritic cells for each TLRs were compared with both nonpregnant and postpartum levels with multivariate linear regression. RESULTS TLRs 1, 7, and 9 were elevated compared with nonpregnant controls with persistent elevation of TLR 1 and interleukin-12 (IL-12) into the postpartum period. Concordantly, levels of IL-6, IL-12, interferon alpha, and tumor necrosis factor alpha increased during pregnancy and returned to levels similar to nonpregnant controls during the postpartum period. The elevated levels of TLR 1 and IL-12 were persistent postpartum, challenging notions that immunologic changes during pregnancy resolve after the prototypical postpartum period. CONCLUSION Normal pregnancy is associated with time-dependent changes in TLR expression compared with nonpregnant controls; these findings may help elucidate immunologic dysfunction in complicated pregnancies.