Mechanism Of Immune Dysfunction Research Articles

Radiation-induced eCIRP impairs macrophage bacterial phagocytosis.

Macrophages are essential immune cells for host defense against bacterial pathogens after radiation injury. However, the role of macrophage phagocytosis in infection following radiation injury remains poorly examined. Extracellular cold-inducible RNA-binding protein (eCIRP) is a damage-associated molecular pattern that dysregulates host immune system responses such as phagocytosis. We hypothesized that radiation-induced eCIRP release impairs macrophage phagocytosis of bacteria. Adult healthy mice were exposed to 6.5-Gy total body irradiation (TBI). Primary peritoneal macrophages isolated from adult healthy mice were exposed to 6.5-Gy radiation. eCIRP-neutralizing monoclonal antibody (mAb) was added to the cell culture prior to irradiation. Bacterial phagocytosis by peritoneal macrophages was assessed using pHrodo Green-labeled E. coli 7 days after irradiation ex vivo and in vitro. Bacterial phagocytosis was also assessed after treatment with recombinant murine CIRP (rmCIRP). Rac1 and ARP2 protein expression in cell lysates and eCIRP levels in the peritoneal lavage were assessed by Western blotting. Bacterial phagocytosis by peritoneal macrophages was significantly decreased after irradiation compared to controls ex vivo and in vitro. Rac1 and ARP2 expression in the peritoneal macrophages were downregulated after TBI. TBI significantly increased eCIRP levels in the peritoneal cavity. rmCIRP significantly decreased bacterial phagocytosis in a dose-dependent manner. eCIRP mAb restored bacterial phagocytosis by peritoneal macrophages after irradiation. Ionizing radiation exposure impairs bacterial phagocytosis by macrophages after irradiation. Neutralization of eCIRP restores the phagocytic ability of macrophages after irradiation. Our findings elucidate a novel mechanism of immune dysfunction and provide a potential new therapeutic approach for limiting infection after radiation injury.

PLA2G1B is involved in CD4 anergy and CD4 lymphopenia in HIV-infected patients.

The precise mechanism leading to profound immunodeficiency of HIV-infected patients is still only partially understood. Here, we show that more than 80% of CD4+ T cells from HIV-infected patients have morphological abnormalities. Their membranes exhibited numerous large abnormal membrane microdomains (aMMDs), which trap and inactivate physiological receptors, such as that for IL-7. In patient plasma, we identified phospholipase A2 group IB (PLA2G1B) as the key molecule responsible for the formation of aMMDs. At physiological concentrations, PLA2G1B synergized with the HIV gp41 envelope protein, which appears to be a driver that targets PLA2G1B to the CD4+ T cell surface. The PLA2G1B/gp41 pair induced CD4+ T cell unresponsiveness (anergy). At high concentrations in vitro, PLA2G1B acted alone, independently of gp41, and inhibited the IL-2, IL-4, and IL-7 responses, as well as TCR-mediated activation and proliferation, of CD4+ T cells. PLA2G1B also decreased CD4+ T cell survival in vitro, likely playing a role in CD4 lymphopenia in conjunction with its induced IL-7 receptor defects. The effects on CD4+ T cell anergy could be blocked by a PLA2G1B-specific neutralizing mAb in vitro and in vivo. The PLA2G1B/gp41 pair constitutes what we believe is a new mechanism of immune dysfunction and a compelling target for boosting immune responses in HIV-infected patients.

Levamisole-Contaminated Cocaine Use in HIV-Infected and Uninfected Unstably Housed Women.

A growing number of case reports cite serious health complications linked to the cocaine adulterant, levamisole and women are disproportionately affected; however, the clinical effects are not well established. Between April and October of 2010, we conducted a cross-sectional study among 222 homeless and unstably housed women (116 human immunodeficiency virus [HIV]-infected and 106 HIV-uninfected). Immune markers and behavioral factors were compared in separate models by cocaine and levamisole exposure. Overall, 63% of participants were toxicology positive for cocaine/benzoylecgonine, 85% of whom also tested positive for levamisole. Differences in immune markers did not reach levels of significance among HIV-uninfected persons. Compared to HIV-infected persons who were negative for both cocaine and levamisole, the adjusted odds of low white blood cell count were significantly higher among HIV-infected persons positive for both (p = 0.03), but not for those positive for cocaine only. Neutrophil count and HIV viral load did not differ by cocaine and levamisole status among HIV-infected persons. In a separate model, the adjusted odds of testing positive for levamisole were higher among African American women compared to Caucasian and Asian women (p = 0.02). In the context of high levamisole prevalence, results suggest that decreased immune function as a result of levamisole exposure occurs mainly in individuals who are already immune compromised (e.g., HIV-positive), and race/ethnicity appears to be an important factor in understanding levamisole exposure among cocaine-using women. While larger and geographically diverse studies are needed to elucidate these initial findings, results suggest that levamisole may be one mechanism of immune dysfunction in HIV-infected cocaine-using women.

Ischemic Stroke: A Consequence of a Diseased Immune System?

Stroke is a leading cause of long-term disability and the second leading cause of death globally. Approximately 795,000 strokes are reported each year in the US, 87 percent of which are ischemic. [1] The direct medical cost associated with stroke in 2009 was approximately $22.8 billion, with an additional $13.8 billion in indirect costs associated with lost productivity, unemployment, rehabilitation, and follow-up care [1]. The incidence of stroke is expected to increase dramatically over the next decade primarily because of an increase in the elderly population and increased incidence of stroke among the middle-aged population. We must develop and implement improved acute and long-term care options to mitigate the increasing burden of stroke. This special edition was designed to address innovative areas of stroke research that are expected to have a tremendous impact on current and future clinical care of stroke patients. Historically, ischemic stroke has been studied and treated as a disease of the cerebrovascular system. However, there is a well-characterized and understudied immunological response to ischemic stroke that provides an opportunity for targeting novel therapeutic and rehabilitation strategies. In the opening articles, Doll et al. and Famakin describe the innate and adaptive immune response to stroke and suggests the time window for targeting the immune response to stroke may be longer than previously expected. Studies are needed to follow stroke patients over the course of their injury and recovery to identify time specific patterns of cytokine responses and potential avenues for anti-inflammatory treatment beyond the acute care period. In the third article by Schulze et al, we are reminded of the significant contribution the catecholamine and steroid responses have on guiding the immune response to stroke recovery. Petrone et al. also describes the effects of estrogen on the immune response and how this modulation of the immune response may account for sex differences in ischemic stroke incidence and severity. Continued study in this area will not only be important for stroke, but also other types of brain injuries (traumatic, blast, neurodegenerative) that inevitably alter the hormonal balance and subsequently have immunological consequences. It is interesting to consider whether a common mechanism of immune dysfunction underlies many complex diseases, such as stroke, heart disease, myocardial infarction, and atherosclerosis. While it is possible that the immune system is similarly altered, gene-environment interactions may control the timing or severity of the dysfunction, and epigenetic modifications may provide a common molecular mechanism to link the immune response among different disease states. In their review, Saban et al. propose a new theoretical model to guide ischemic stroke research to further understand the extent to which epigenetic signatures bridge the psycho-social environment. Our knowledge of the epigenetic control of the immunological consequences of ischemic stroke is limited and requires a new approach to clinical and pre-clinical studies. The question remains whether we can truly model the human condition of ischemic stroke. Given the advances in genomic technology, systems modeling, and biomedical engineering we must re-invent stroke research and begin to utilize human patients as the best model to study the condition. Thus, new collaborations between scientists, clinicians, engineers and patients will be the key to future success. We hope this special edition broadens your horizons to the possibility of ischemic stroke being an immunological disease. Before we can begin to make significant improvements in clinical care of stroke, we must strengthen our research collaborations and be creative in our approach. Our patients depend on it.

Increased Myeloid-Derived Suppressor Cells in Gastric Cancer Correlate with Cancer Stage and Plasma S100A8/A9 Proinflammatory Proteins

Immune dysfunction may contribute to tumor progression in gastric cancer (GC) patients. One mechanism of immune dysfunction is the suppression of T cell activation and impairment of the efficacy of cancer immunotherapy by myeloid-derived suppressor cells (MDSCs). We assessed the phenotype and immunosuppressive function of MDSCs in GC patients. We further investigated the role of S100A8/A9 in GC and the relationship between S100A8/A9 and MDSC function. Lastly, the effect of MDSCs on survival rates and its potential as a prognostic factor in GC patients were investigated. MDSCs from PBMCs of GC patients were identified by comparing the expression of specific surface markers with PBMCs from healthy individuals. The ability of MDSCs to suppress T lymphocyte response and the effect of S100A8/A9 and RAGE blocking were tested in vitro by (autologous) MLR. GC patients had significantly more MDSCs than healthy individuals. These MDSCs suppressed both T lymphocyte proliferation and IFN-γ production and had high arginase-I expression. Levels of S100A8/A9 in plasma were higher in GC patients compared with healthy individuals, and they correlated with MDSC levels in the blood. Blocking of S100A8/A9 itself and the S100A8/A9 receptor RAGE on MDSCs from GC patients abrogated T cell effector function. We found that high levels of MDSCs correlated with more advanced cancer stage and with reduced survival (p = 0.006). S100A8/A9 has been identified as a potential target to modulate antitumor immunity by reversing MDSC-mediated immunosuppression.

Slowing down with age: lung DCs do it too

Decline in immune function with age has been attributed to defects or alterations in both the innate and the adaptive immune system. In this issue of the JCI, Zhao and coworkers provide evidence for a novel mechanism of immune dysfunction in aging mice. They show that migration of respiratory DCs from the site of virus replication to the draining lymph nodes in response to infection with several different respiratory viruses is markedly diminished with increasing age. The impaired DC migration was a result of increased levels of the lipid mediator prostaglandin D(2) (PGD(2)) in the respiratory tract with age and could be partially reversed by blockade of PGD(2) synthesis or action.

Requirement for labile Zn2+ in phagocytosis by murine macrophages

IntroductionSystemic Zn2+ deficiency impairs the ability to fight infection. We hypothesized that one mechanism of immune dysfunction in the setting of Zn2+ deficiency is impaired phagocytosis by macrophages.MethodsRAW 264.7 murine macrophages were incubated for three hours with E. coli cell walls labeled with Vybrant and pHrodo fluorescent reporters. Co‐incubation occurred in the presence or absence of two intracellular Zn2+ chelators (high affinity TPEN 10μM, low affinity BAPTA 10μM) and one extracellular zinc chelator (DTPA 10 μM). Confirmatory experiments were performed with mouse peritoneal macrophages.ResultsIntracellular zinc chelators caused reduced phagocytosis vs control (TPEN: 28% ± 8; BAPTA 54% ± 14%, p < 0.02, N = 5). In contrast, chelation of extracellular zinc with DTPA had no effect.ConclusionFree cytoplasmic Zn2+ is required for effective internalization of extracellular bacterial particles by both cultured and primary murine macrophages. Under acute conditions, intracellular stores are sufficient to optimize function.

Expression of interleukin-10 in isolated CD8+ T cells and monocytes from growth factor-mobilized peripheral blood stem cell products: a mechanism of immune dysfunction.

Previous reports showed the abnormal activation of immune cells in growth factor-mobilized peripheral blood stem cell (PBSC) products, which might be responsible for depressed T cell responsiveness to mitogens compared with normal peripheral blood mononuclear cells (PBMC). In the present study, the mRNA expression levels of interleukin (IL)-2, IL-4, IL-10, and interferon-gamma (IFN-gamma) were significantly higher in CD4+ and CD8+ T cells from mobilized PBSC products compared with CD4+ and CD8+ cells from normal peripheral blood (PB). The mRNA expression levels of IL-4 and IL-10 were significantly higher in CD8+ compared with CD4+ cells from PBSC products. However, the expression of IL-2 and IFN-gamma mRNA transcripts was similar in the CD4+ and CD8+ T cells from PBSC products. The levels of IL-10, IL-8, and tumor necrosis factor (TNF)-alpha mRNA were also significantly higher in monocytes isolated from PBSC products compared with monocytes isolated from normal PB. Expression of IL-10-specific mRNA in monocytes also was significantly higher than the levels observed in CD8+ cells from PBSC products. We suggest that both CD4+ and CD8+ cells in the PBSC products are highly activated. However, their response to phytohemagglutinin (PHA) mitogenesis is depressed in part because of IL-10 expression by CD8+ cells and monocytes in addition to the higher levels of monocyte-dependent T cell inhibitory activity. These data demonstrate that aberrant IL-10 expression in the CD8+ T cells and monocytes present in PBSC products may represent a possible mechanism of immune dysfunction in patients after high-dose chemotherapy (HDT) and peripheral blood stem cell transplantation (PBSCT).