Don C. Henderson

Loss of Discrete Memory B Cell Subsets Is Associated with Impaired Immunization Responses in HIV-1 Infection and May Be a Risk Factor for Invasive Pneumococcal Disease

Invasive pneumococcal infection is an important cause of morbidity and mortality in HIV-1-infected individuals. B cells play an important role in maintaining serologic memory after infection. IgM memory B cells are significantly reduced in HIV-1-infected patients and their frequency is similar to that observed in other patient groups (splenectomized individuals and patients with primary Ab deficiency) who are also known to have an increased risk of invasive pneumococcal infection. Antiretroviral therapy does not restore marginal zone B cell percentages. Immunization with the 23-valent polysaccharide pneumococcal vaccine shows that HIV-1-infected patients have impaired total IgM and IgG pneumococcal vaccines compared with healthy controls. Loss of switched memory B cells was associated with impaired tetanus toxoid IgG vaccine responses. Results of this study demonstrate that defects in B cell memory subsets are associated with impaired humoral immune responses in HIV-1 patients who are receiving antiretroviral therapy and may be a contributory factor to the increased risk of invasive pneumococcal infection observed in HIV-1 infection.

Cellular and humoral immunity, mood and exam stress: the influences of self-hypnosis and personality predictors

The effects of self-hypnosis training on immune function and mood were examined in medical students at exam time. Hypnosis involved relaxation and imagery directed at improved immune function and increased energy, alertness and concentration. Hypotheses were made about activated and withdrawn personality differences. Eight high and eight low hypnotically susceptible participants were given 10 sessions of hypnosis, one live and nine tape-recorded, and were compared with control subjects (N=12). CD3, CD4, CD8, CD19 and CD56 NK cells and blood cortisol were assayed. Life-style, activated vs. withdrawn temperament, arousal and anxiety questionnaires were administered. Self-hypnosis buffered the decline found in controls in NK (P<0.002) and CD8 cells (P<0.0.07) and CD8/CD4% (P<0.06) (45-35% order of magnitude differences) while there was an increase in cortisol (P<0.05). The change in NK cell counts correlated positively with changes in both CD8 cells and cortisol. Results were independent of changes in life-style. Energy ratings were higher after hypnosis (P<0.01), and increased calmness with hypnosis correlated with an increase in CD4 counts (P<0.01). The activated temperament, notably the cognitive subscale (speaking and thinking quickly), was predictive of exam levels of T and B lymphocytes (P&z.Lt;0.08-P<0.02), and reaching r=0.72 (P<0.001) in the non-intervention control group. The sizeable influences on cell-mediated immunity achieved by a relatively brief, low cost psychological intervention in the face of a compelling, but routine, stress in young, healthy adults have implications for illness prevention and for patients with compromised immunity.

The impact of self-hypnosis and Johrei on lymphocyte subpopulations at exam time: a controlled study

In a prospective randomised controlled trial, 48 students were randomly assigned to stress reduction training before exams with self-hypnosis, Johrei or a mock neurofeedback relaxation control. Peripheral blood lymphocyte subpopulations and self-reported stress (Perceived Stress Scale) were measured before training and 1-2 months later as exams approached. Absolute number and percentages of CD3(+)CD4(+) and CD3(+)CD8(+) T lymphocytes, CD3(-)CD56(+) Natural Killer cells (NK cells) and NK cell cytotoxic activity was measured from venous blood. Stressed participants showed small but significant declines in both CD3(-)CD56(+) NK cell percentages and NK cell cytotoxic activity levels while CD3(+)CD4(+) T cell percentages increased, changes supported by correlations with perceived stress. The effects of stress were moderated in those who learned Johrei at exam time; 11/12 showed increases in CD3(-)CD56(+) NK cell percentages with decreased percentages of CD3(+)CD4(+) T cells, effects not seen in the relaxation control group. Stress was also buffered in those who learned and practised self-hypnosis in whom CD3(-)CD56(+) NK cell and CD3(+)CD4(+) T cell levels were maintained, and whose CD3(+)CD8(+) T cell percentages, shown previously to decline with exams, increased. The results compliment beneficial effects on mood of self-hypnosis and Johrei. The results are in keeping with beneficial influences of self-hypnosis and provide the first evidence of the suggestive value of the Japanese Johrei procedure for stress reduction, which clearly warrants further investigation.

Serotype-specific pneumococcal antibodies in breast milk of Gambian women immunized with a pneumococcal polysaccharide vaccine during pregnancy.

Background: In breast-feeding populations, immunization during pregnancy with pneumococcal polysaccharide offers a potentially useful approach to preventing pneumococcal disease in young infants. Methods: Breast milk samples were collected at 0, 2, 4 and 6 months after delivery from Gambian women vaccinated during pregnancy (24–32 weeks gestation) with Pneumovax II (n = 56) or Mengivax A&C (n = 57). Specimens were examined for secretory immunoglobulin A (s-IgA) concentration, subclass distribution and avidity specific to pneumococcal serotypes 4, 6B, 14, 19F and 23F and the antigen mixture in Pneumovax II by enzyme-linked immunosorbent assay. Colostral s-IgA and IgG concentrations in paired maternal sera were compared. Results: Colostral s-IgA concentrations specific to all pneumococcal polysaccharide antigens investigated were significantly higher (P < 0.05) among Pneumovax II vaccinees. Titers specific to serotypes 4, 6B and 14 and the vaccine formula remained significantly higher during 6 months, and those for 19F were higher during 4 months. Significantly higher concentrations of vaccine antigen-specific s-IgA antibody were sustained for 6 months after delivery (P = 0.011). Comparison of colostral s-IgA and IgG in serum revealed a significant correlation only among Mengivax A&C vaccinees for pneumococcal polysaccharide 23F (rs= 0.68; P ≤ 0.0001). Vaccination elicited trends toward increased s-IgA2, reaching significance for serotype 14 and the vaccine formula. Immunization elicited significantly higher s-IgA avidities specific to all pneumococcal polysaccharide antigens studied during 6 months. Conclusions: The public health value of immunization during pregnancy with pneumococcal polysaccharide vaccine in breast-feeding populations warrants further evaluation, particularly in populations with a high incidence of pneumococcal disease in early infancy.

Colostrum Obtained from Women Vaccinated with Pneumococcal Vaccine during Pregnancy Inhibits Epithelial Adhesion of Streptococcus pneumoniae

Prevention of nasopharyngeal colonization may reduce the burden of pneumococcal infection during infancy. Colostrum obtained from Gambian mothers who had been vaccinated with either Pneumovax II or Mengivax A&C (n=8 per group) during pregnancy was examined for inhibition of adherence of Streptococcus pneumoniae serotypes 6B and 14 to pharyngeal epithelial cells in vitro. Pneumococcal adherence was significantly reduced in the presence of breast milk (P< or =.0001 for S. pneumoniae serotype 14; P=.036 for serotype 6B), independent of the concentration of secretory IgA antibodies. Maternal vaccination with polyvalent pneumococcal polysaccharide vaccine boosts the capacity of colostrum to inhibit adherence of pneumococci to pharyngeal epithelial cells. In breast-feeding populations, maternal vaccination might prevent pneumococcal disease in young infants.

CD38 expression on CD8 T cells has a weak association with CD4 T‐cell recovery and is a poor marker of viral replication in HIV‐1‐infected patients on antiretroviral therapy

The aim of the study was to determine whether the expression of CD38 on CD8 T cells can identify patients with virological failure on antiretroviral therapy (ART).

A Biomarker Panel (Bioscore) Incorporating Monocytic Surface and Soluble TREM-1 Has High Discriminative Value for Ventilator-Associated Pneumonia: A Prospective Observational Study

Introduction Ventilator-associated pneumonia (VAP) increases mortality in critical illness. However, clinical diagnostic uncertainty persists. We hypothesised that measuring cell-surface and soluble inflammatory markers, incorporating Triggering Receptor Expressed by Myeloid cells (TREM)-1, would improve diagnostic accuracy. Methods A single centre prospective observational study, set in a University Hospital medical-surgical intensive Care unit, recruited 91 patients into 3 groups: 27 patients with VAP, 33 ventilated controls without evidence of pulmonary sepsis (non-VAP), and 31 non-ventilated controls (NVC), without clinical infection, attending for bronchoscopy. Paired samples of Bronchiolo-alveolar lavage fluid (BALF) and blood from each subject were analysed for putative biomarkers of infection: Cellular (TREM-1, CD11b and CD62L) and soluble (IL-1β, IL-6, IL-8, sTREM-1, Procalcitonin). Expression of cellular markers on monocytes and neutrophils were measured by flow cytometry. Soluble inflammatory markers were determined by ELISA. A biomarker panel (‘Bioscore’), was constructed, tested and validated, using Fisher’s discriminant function analysis, to assess its value in distinguishing VAP from non VAP. Results The expression of TREM-1 on monocytes (mTREM-1) and neutrophils (nTREM-1) and concentrations of IL-1β, IL-8, and sTREM-1 in BALF were significantly higher in VAP compared with non-VAP and NVC (p<0.001). The BALF/blood mTREM-1 was significantly higher in VAP patients compared to non-VAP and NVC (0.8 v 0.4 v 0.3 p<0.001). A seven marker Bioscore (BALF/blood ratio mTREM-1 and mCD11b, BALF sTREM-1, IL-8 and IL-1β, and serum CRP and IL-6) correctly identified 88.9% of VAP cases and 100% of non-VAP cases. Conclusion A 7-marker bioscore, incorporating cellular and soluble TREM-1, accurately discriminates VAP from non-pulmonary infection.

Pneumococcal vaccination and HIV infection

Bacterial infections are a common cause of morbidity in HIV disease, both in industrialized countries where Pneumocystis carinii pneumonia (PCP) prophylaxis has led to the emergence of bacterial pathogens as the leading cause of respiratory illness in some centres1, and in the developing world, where the incidence in the general population is already high2. In common with HIV-negative subjects, Streptococcus pneumoniae is the primary respiratory pathogen and the most frequent non-mycobacterial isolate from blood culture. Pneumococcal disease occurs signi® cantly more frequently in individuals infected with HIV with pneumococcal pneumonia rates 5.5± 17.5 fold3,4 greater than population-based estimates in the USA and an increase of up to 100-fold for bacteraemic pneumococcal infection5. The annual rate of infection in a study of Kenyan HIV-positive female sex workers was 42.5/1000 indicating the extent of the problem in developing countries6. The increasing global problem of penicillinresistant S. pneumoniae7 highlights the need for improved preventive strategies as well as treatment options. The observations that pneumococcal penicillin resistance appears to be associated with HIV infection8± 10 and that the majority of strains reported to show reduced sensitivity are of serotypes included in the currently available 23 valent pneumococcal polysaccharide vaccine underscores the potential bene® t of immunization. Pneumococcal vaccination for HIV-infected individuals is currently recommended in the USA11 and by the Department of Health in the UK12 although uptake in the past has been low13.

Tryptophan and quality of life in colorectal cancer.

We tested the hypothesis that reduced tryptophan availability due to immunological stimulation in colorectal cancer impairs quality of life (QoL) by measuring serum tryptophan levels, and correlating them with serum immunological markers and with QoL indices. Serum tryptophan level was significantly reduced in cancer patients compared with healthy controls. Serum tryptophan/kynurenine ratio and neopterin level were significantly increased in cancer, with a significant correlation between the two variables. Reduced serum tryptophan correlated significantly with worse QoL scores. The results support the hypothesis that in colorectal cancer, QoL impairment may be due to serum tryptophan depletion mediated by immunological activation.