Natural antibodies target virus-antibody complexes to organized lymphoid tissue

Natural antibodies (NA) specific for infectious pathogens are found at low titer (usually <1:40) in the serum of healthy, non-immunized, individuals. Therefore, NA are part of the first line of defence against blood borne microorganisms. They directly neutralize viral infections or lyse pathogens by activating the complement cascade. In addition, recent studies highlighted their role in the pooling of infectious pathogens and other antigens to the spleen. This prevents infection of vital target organs and enhances the induction of adaptive immune responses. Specific T and B-cell responses are exclusively induced in highly organized secondary lymphoid organs including lymph nodes and the spleen. As a consequence, mice with disrupted microorganisation of lymphoid organs have defective adaptive immunity. In addition, some pathogens including lymphocytic choriomeningitis virus (LCMV), Leishmania and HIV developed strategies to destroy the splenic architecture in order to induce an acquired immunosuppression and to establish persistent infection. NA antibodies enhance early neutralizing antibodies in the absence of T help mainly by targeting antigen to the splenic marginal zone. In addition, by activating the complement cascade, NA enhance T cell and T-cell dependent B-cell responses. Therefore, natural antibodies are an important link between innate and adaptive immunity.

Low serum alpha-tocopherol and selenium are associated with accelerated apoptosis in severe sepsis

During sepsis, a severe systemic disorder, micronutrients often are decreased. Apoptosis is regarded as an important mechanism in the development of often significant immunosuppression in the course of the disease. This study aimed to investigate alpha-tocopherol and selenium in reference to apoptosis in patients with sepsis. 16 patients were enrolled as soon as they fulfilled the criteria of severe sepsis. 10 intensive care patients without sepsis and 11 healthy volunteers served as controls. alpha-Tocopherol, selenium and nucleosomes were measured in serum. Phosphatidylserine externalization and Bcl-2 expression were analyzed in T-cells by flow cytometry. Serum alpha-tocopherol and selenium were decreased in severe sepsis but not in non-septic critically ill patients (p < 0.05). Conversely, markers of apoptosis were increased in sepsis but not in critically ill control patients: Nucleosomes were found to be elevated 3 fold in serum (p < 0.05) and phosphatidylserine was externalized on an expanded subpopulation of T-cells (p < 0.05) while Bcl-2 was expressed at lower levels (p < 0.05). The decrease of micronutrients correlated with markers of accelerated apoptosis. Accelerated apoptosis in sepsis is associated with low alpha-tocopherol and selenium. The results support the investigation of micronutrient supplementation strategies in severe sepsis.

Treatment of recurrent rejection in heart transplantation: cytolytic therapy or bolus steroids?

OBJECTIVES: The treatment of recurrent rejection in heart transplant recipients has been a controversial issue for many years. The intent of this retrospective study was to perform a risk-benefit analysis between treatment strategies with bolus steroids only versus anti-thymocyte globulins (RATG; 1.5 mg/kg q 4 days). METHODS: Between 1986 and 1993, 69 of 425 patients (17 male, 52 female; mean age 44 +/- 11 years) who had more than one rejection/patient per month (rej/pt per mo) in the first 3 postoperative months were defined as recurrent rejectors. RESULTS: Repetitive methylprednisolone bolus therapy (70 mg/kg q 3 days) was given in 27 patients (group M; 1.4 +/- 0.2 rej/pt per mo) and RATG therapy for one of the rejection episodes of the 42 remaining patients (group A; 1.5 +/- 0.2 rej/pt per mo). The quality of triple drug immunosuppression in the two study groups was comparable. The rejection-free interval (RFI) following RATG treatment in group A was 21.6 +/- 10 days and 22 +/- 11 in group M. In group M, 3 of 27 patients (11%) had a rejection treatment-related infection (2 bacterial; 1 viral) versus 6 of the 42 patients of group A (14.2%; bacterial 1, viral 5). During postoperative months 3-24, 0.15 +/- 0.12 rej/pat per mo were observed in group M and 0.21 +/- 0.13 rej/pat per mo in group A (n.s.). In this 21-month period cytolytic therapy for rejection was initiated in 8 of the remaining 21 patients of group M (38%) and 15 of the remaining 37 patients of group A (40.5%). The absolute survival and the individual causes of death were not affected by the type of initial treatment of recurrent rejection. The actuarial freedom of graft atherosclerosis is comparable in the two groups with 78% in group A versus 79% in group M free of graft atherosclerosis at 3 years postoperatively. CONCLUSIONS: A comparison of cytolytic therapy versus repeated applications of bolus steroids for treatment of recurrent rejection reveals no significant difference in the long-term patient outcome with respect to the incidence of future rejection episodes and survival.

The impact of early postoperative cyclosporine serum levels on the incidence of cardiac allograft rejection

The introduction of cyclosporine A (CyA) into the immunosuppressive therapy has significantly improved the results of heart transplantation (HTX). Its nephrotoxicity and hepatotoxicity, however, often limit the perioperative and postoperative use of this drug. The purpose of this retrospective study was to evaluate the effect of early postoperative CyA blood levels on the incidence of early as well as late cardiac rejection and patients' survival. Between October 1985 and June 1991, HTX was performed in 311 patients. Standard immunosuppression consisted of azathioprine (1-2 mg/kg), prednisolone (0.5 to 0.1 mg/kg) and CyA. Rabbit-antithymocyte-globulin (RATG - 1.5 mg/kg) was administered for the first 4 days postoperatively. Moderate rejection was treated with 3 x 500 mg methylprednisolone, severe rejection with RATG (1.5 mg/kg three times a day). Patients were excluded from this study because of a positive cross-matching, early death unrelated to rejection or alternate forms of immunosuppression (n = 111). Follow-up was complete in 200 patients (mean age 44 +/- 11; 18 female, 182 male; 204,233 patient days) with a total of 5380 biopsies. The cohort was divided into group I (no CyA for day 0 to 2; n = 108) and group II (CyA during day 0 to 2; n = 92) according to the onset of CyA therapy. In 101 patients (group A) the mean CyA blood level was less than 150 ng/ml from day 0 to 14 and in 99 patients more than 150 ng/ml (group B).(ABSTRACT TRUNCATED AT 250 WORDS)

Lung growth after experimental pulmonary transplantation

Replacement of the heart and both lungs or single lung transplantation has been performed in a few cases of terminal (cardio) pulmonary disease in childhood. It remains unclear whether pulmonary allografts will meet the demands of a growing organism. Six domestic pigs (mean body weight, 24 kg) underwent left lung transplantation from donors of equal weight. Immunosuppression consisted of cyclosporine, azathioprine, and corticosteroids. After the pigs doubled their body weight, growth of the lung was assessed by bronchography and pulmonary angiography. In transplant animals it took 11 weeks (normal animals, 6 weeks) for their weight to double. At that time, the bronchial tree showed similar growth when compared with nontransplant animals of equal weight. The diameter of the left lower lobe bronchus (9.2 +/- 0.4 mm) was significantly greater than that of animals of 24 kg body weight (7.5 +/- 0.3 mm; p less than 0.01) but comparable to that of normal pigs of similar weight (9.0 +/- 0.5 mm). The same applied for length of the left lower lobe bronchus (transplants, 95 +/- 6.7 mm; controls 24 kg, 67 +/- 2 mm [p less than 0.01]; controls 48 kg, 93 +/- 3 mm). Similar growth tendencies were observed in the pulmonary vascular tree. The diameter of the left lower lobe artery was 9.4 +/- 98 mm in 48 kg transplant pigs, compared with 9.7 +/- 1.2 mm in 24 kg control pigs and 8.5 +/- 0.8 mm in 48 kg control pigs. In one case of recurrent severe pulmonary rejection, the lung did not grow. We conclude from this study that growth is retarded by immunosuppression.(ABSTRACT TRUNCATED AT 250 WORDS)

Growth of lung allografts after experimental transplantation

Heart and lung transplantation has been performed in cases of end-stage cardiopulmonary disease in infants. Nevertheless, it still remains unclear whether lung allografts adjust to a growing organism. In 6 young domestic pigs unilateral left lung allotransplantation was performed. Immunosuppression consisted of a triple drug therapy including cyclosporine, azathioprine, and corticosteroids. Lung growth was studied by using bronchography, pulmonary angiography, and lung histology. After 11 weeks the transplanted animals had doubled their body weight from 24 kg to 48 kg. Non-transplanted animals in contrast doubled their weight within only 6 weeks. The growth retardation was attributed to the immunosuppressive therapy. The bronchial tree and pulmonary vasculature of lung allografts showed a similar growth potential to non-transplanted lungs in animals of equivalent body weight. In one case of recurrent severe rejection of the lung no growth was observed. Therefore it was concluded that lung allografts grow adequately according to the development of the recipient organism. Lung transplantation in children does not seem to be restricted by a limited growth potential of the graft.

Soluble TNF-alpha but not transmembrane TNF-alpha sensitizes T cells for enhanced activation-induced cell death

In addition to its proinflammatory effects, TNF-alpha exhibits immunosuppression. Here, we compared the capacities of transmembrane TNF-alpha (tmTNF) and soluble TNF-alpha (sTNF) in regulating expansion of activated T cells by apoptosis. Splenic CD4(+) T cells from wtTNF, TNF-alpha-deficient (TNF(-/-)) and TNF(-/-) mice expressing a non-cleavable mutant tmTNF showed comparable proliferation rates upon TCR-mediated stimulation. Activation-induced cell death (AICD), however, was significantly attenuated in tmTNF and TNF(-/-), compared with wtTNF CD4(+) T cells. Addition of sTNF during initial priming was sufficient to enhance susceptibility to AICD in tmTNF and TNF(-/-) CD4(+) T cells to levels seen in wtTNF CD4(+) T cells, whereas addition of sTNF only during restimulation failed to enhance AICD. sTNF-induced, enhanced susceptibility to AICD was dependent on both TNF receptors. The reduced susceptibility of tmTNF CD4(+) T cells for AICD was also evident in an in vivo model of adoptively transferred CD4(+) T-cell-mediated colonic inflammation. Hence, the presence of sTNF during T-cell priming may represent an important mechanism to sensitize activated T cells for apoptosis, thereby attenuating the extent and duration of T-cell reactivities and subsequent T-cell-mediated, excessive inflammation.

The immunomodulatory sphingosine 1-phosphate analog FTY720 reduces lesion size and improves neurological outcome in a mouse model of cerebral ischemia

Cerebral ischemia is accompanied by fulminant cellular and humoral inflammatory changes in the brain which contribute to lesion development after stroke. A tight interplay between the brain and the peripheral immune system leads to a biphasic immune response to stroke consisting of an early activation of peripheral immune cells with massive production of proinflammatory cytokines followed by a systemic immunosuppression within days of cerebral ischemia that is characterized by massive immune cell loss in spleen and thymus. Recent work has documented the importance of T lymphocytes in the early exacerbation of ischemic injury. The lipid signaling mediator sphingosine 1-phosphate-derived stable analog FTY720 (fingolimod) acts as an immunosuppressant and induces lymphopenia by preventing the egress of lymphocytes, especially T cells, from lymph nodes. We found that treatment with FTY720 (1mg/kg) reduced lesion size and improved neurological function after experimental stroke in mice, decreased the numbers of infiltrating neutrophils, activated microglia/macrophages in the ischemic lesion and reduced immunohistochemical features of apoptotic cell death in the lesion.

Infection with human herpesvirus 8 and transplant-associated gammopathy

BACKGROUND: The role of human herpesvirus (HHV)-8 in the pathogenesis of multiple myeloma and its pre-malignant state of monoclonal gammopathy is unclear. HHV-8 is transmitted by organ transplantation, representing a unique model with which to investigate primary HHV-8 infection. METHODS: The authors studied the incidence of clonal gammopathy in renal transplant recipients and correlated it with previous and recent HHV-8 infection. RESULTS: Clonal gammopathy was observed in 31 of 162 (19%) HHV-8-seronegative patients, in 5 of 17 (29%) HHV-8-seropositive patients, and in 9 of 24 (38%) HHV-8 seroconverters within 5 years after transplantation. Gammopathy was often transient, and no progression to myeloma was observed. Two patients with persistent gammopathy developed B-cell lymphoma. In a logistic regression model, HHV-8 serostatus of the graft recipient was significantly associated with subsequent development of gammopathy, with a relative risk (RR) of 1.9 and a 95% confidence interval (CI) of 0.5 to 6.4 for an HHV-8-seropositive recipient and an RR of 2.9 and a 95% CI of 1.01 to 8.0 for seroconverters as compared with baseline (HHV-8 seronegative). Other significant variables were cytomegalovirus (CMV) serostatus and the intensity of immunosuppression (RR of 10.4 and 95% CI of 2.6-41.7 for a CMV-negative recipient with a CMV-positive donor vs. a CMV-negative recipient with a CMV-negative donor and RR of 17.6 and 95% CI of 2.0-150.8 if OKT3 was used vs. no use of antilymphocytic substances). CONCLUSIONS: Transplant recipients with HHV-8 infection are more likely to develop clonal gammopathy. However, this risk is much lower than the risk conferred by CMV infection and antilymphocytic therapy, arguing against a major role of HHV-8 infection in the pathogenesis of clonal plasma cell proliferation.

Discontinuation of enfuvirtide in heavily pretreated HIV-infected individuals

BACKGROUND: Enfuvirtide was shown to be highly effective in treatment- experienced patients. Data on discontinuation of enfuvirtide and switch to new antiretroviral drugs are scarce. We aimed to evaluate the efficacy and the impact of discontinuing and/or switching enfuvirtide on virologic and clinical parameters in clinical practice. METHODS: All HIV-infected individuals participating in the Swiss HIV Cohort Study who were treated with enfuvirtide for at least 4 weeks in combination with an optimized background antiretroviral regimen were included in this study. RESULTS: A total of 151 patients were analyzed. The median baseline CD4 cell count was 108 cells/microL (interquartile range [IQR] 50-206) and HIV RNA was 4.7 log10 copies/mL (IQR 4.1-5.2). Virologic suppression, defined as a viral load below 50 copies/mL at 12 months, was achieved by 57.6% of patients. Overall, a median CD4 cell increase of 121 cells/microL (IQR 50-189) from baseline was noted. Up to 50% of patients discontinued enfuvirtide within the first year of treatment, mainly because of the patient's choice. After discontinuation of enfuvirtide, high rates of virologic failure and clinical progression were observed, notably when CD4 cell count at stopping enfuvirtide was below 100 cells/microL and no switch to new potent antiretroviral drugs such as darunavir, maraviroc, or raltegravir was performed. CONCLUSIONS: Enfuvirtide provides high virologic and immunologic response in treatment-experienced patients in the setting of clinical practice. Enfuvirtide should not be discontinued but should be replaced by new potent antiretrovirals, particularly in case of severe immunosuppression.

HIV infection disrupts the sympatric host-pathogen relationship in human tuberculosis

The phylogeographic population structure of Mycobacterium tuberculosis suggests local adaptation to sympatric human populations. We hypothesized that HIV infection, which induces immunodeficiency, will alter the sympatric relationship between M. tuberculosis and its human host. To test this hypothesis, we performed a nine-year nation-wide molecular-epidemiological study of HIV-infected and HIV-negative patients with tuberculosis (TB) between 2000 and 2008 in Switzerland. We analyzed 518 TB patients of whom 112 (21.6%) were HIV-infected and 233 (45.0%) were born in Europe. We found that among European-born TB patients, recent transmission was more likely to occur in sympatric compared to allopatric host-pathogen combinations (adjusted odds ratio [OR] 7.5, 95% confidence interval [95% CI] 1.21-infinity, p = 0.03). HIV infection was significantly associated with TB caused by an allopatric (as opposed to sympatric) M. tuberculosis lineage (OR 7.0, 95% CI 2.5-19.1, p<0.0001). This association remained when adjusting for frequent travelling, contact with foreigners, age, sex, and country of birth (adjusted OR 5.6, 95% CI 1.5-20.8, p = 0.01). Moreover, it became stronger with greater immunosuppression as defined by CD4 T-cell depletion and was not the result of increased social mixing in HIV-infected patients. Our observation was replicated in a second independent panel of 440 M. tuberculosis strains collected during a population-based study in the Canton of Bern between 1991 and 2011. In summary, these findings support a model for TB in which the stable relationship between the human host and its locally adapted M. tuberculosis is disrupted by HIV infection.

Temporal trends in the characteristics of children at antiretroviral therapy initiation in southern Africa: the IeDEA-SA Collaboration

BACKGROUND Since 2005, increasing numbers of children have started antiretroviral therapy (ART) in sub-Saharan Africa and, in recent years, WHO and country treatment guidelines have recommended ART initiation for all infants and very young children, and at higher CD4 thresholds for older children. We examined temporal changes in patient and regimen characteristics at ART start using data from 12 cohorts in 4 countries participating in the IeDEA-SA collaboration. METHODOLOGY/PRINCIPAL FINDINGS Data from 30,300 ART-naïve children aged <16 years at ART initiation who started therapy between 2005 and 2010 were analysed. We examined changes in median values for continuous variables using the Cuzick's test for trend over time. We also examined changes in the proportions of patients with particular disease severity characteristics (expressed as a binary variable e.g. WHO Stage III/IV vs I/II) using logistic regression. Between 2005 and 2010 the number of children starting ART each year increased and median age declined from 63 months (2006) to 56 months (2010). Both the proportion of children <1 year and ≥10 years of age increased from 12 to 19% and 18 to 22% respectively. Children had less severe disease at ART initiation in later years with significant declines in the percentage with severe immunosuppression (81 to 63%), WHO Stage III/IV disease (75 to 62%), severe anemia (12 to 7%) and weight-for-age z-score<-3 (31 to 28%). Similar results were seen when restricting to infants with significant declines in the proportion with severe immunodeficiency (98 to 82%) and Stage III/IV disease (81 to 63%). First-line regimen use followed country guidelines. CONCLUSIONS/SIGNIFICANCE Between 2005 and 2010 increasing numbers of children have initiated ART with a decline in disease severity at start of therapy. However, even in 2010, a substantial number of infants and children started ART with advanced disease. These results highlight the importance of efforts to improve access to HIV diagnostic testing and ART in children.

Rituximab as a treatment option for refractory endogenous anterior uveitis

BACKGROUND To report on anti-CD20 antibody therapy in a patient with uveitis refractive to immunosuppression therapy. METHODS Case report with ophthalmoscopic, optical coherence tomography and fluorescein-angiographic findings. RESULTS A 49-year-old woman was suffering from bilateral, noninfectious chronic anterior uveitis refractive to corticosteroids and immunosuppressive drugs. Bilateral visual acuity was 20/100 due to cataract and cystoid macular edema (CME). After treatment with rituximab, vision and CME improved, and uveitis was stable until the final visit (follow-up at 12 months). CONCLUSION The case report suggests that rituximab may be helpful for selected patients with chronic anterior uveitis refractive to corticosteroids and immunosuppressive medication.

Aeromonas salmonicida subsp. salmonicida in the light of its type-three secretion system

Aeromonas salmonicida subsp. salmonicida is an important pathogen in salmonid aquaculture and is responsible for the typical furunculosis. The type-three secretion system (T3SS) is a major virulence system. In this work, we review structure and function of this highly sophisticated nanosyringe in A. salmonicida. Based on the literature as well as personal experimental observations, we document the genetic (re)organization, expression regulation, anatomy, putative functional origin and roles in the infectious process of this T3SS. We propose a model of pathogenesis where A. salmonicida induces a temporary immunosuppression state in fish in order to acquire free access to host tissues. Finally, we highlight putative important therapeutic and vaccine strategies to prevent furunculosis of salmonid fish.

Risk of tuberculosis following HIV seroconversion in high-income countries

Background Few data exist on tuberculosis (TB) incidence according to time from HIV seroconversion in high-income countries and whether rates following initiation of a combination of antiretroviral treatments (cARTs) differ from those soon after seroconversion. Methods Data on individuals with well estimated dates of HIV seroconversion were used to analyse post-seroconversion TB rates, ending at the earliest of 1 January 1997, death or last clinic visit. TB rates were also estimated following cART initiation, ending at the earliest of death or last clinic visit. Poisson models were used to examine the effect of current and past level of immunosuppression on TB risk after cART initiation. Results Of 19 815 individuals at risk during 1982–1996, TB incidence increased from 5.89/1000 person-years (PY) (95% CI 3.77 to 8.76) in the first year after seroconversion to 10.56 (4.83 to 20.04, p=0.01) at 10 years. Among 11 178 TB-free individuals initiating cART, the TB rate in the first year after cART initiation was 4.23/1000 PY (3.07 to 5.71) and dropped thereafter, remaining constant from year 2 onwards averaging at 1.64/1000 PY (1.29 to 2.05). Current CD4 count was inversely associated with TB rates, while nadir CD4 count was not associated with TB rates after adjustment for current CD4 count, HIV-RNA at cART initiation. Conclusions TB risk increases with duration of HIV infection in the absence of cART. Following cART initiation, TB incidence rates were lower than levels immediately following seroconversion. Implementation of current recommendations to prevent TB in early HIV infection could be beneficial.