CD45 regulates retention, motility, and numbers of hematopoietic progenitors, and affects osteoclast remodeling of metaphyseal trabecules

The CD45 phosphatase is uniquely expressed by all leukocytes, but its role in regulating hematopoietic progenitors is poorly understood. We show that enhanced CD45 expression on bone marrow (BM) leukocytes correlates with increased cell motility in response to stress signals. Moreover, immature CD45 knockout (KO) cells showed defective motility, including reduced homing (both steady state and in response to stromal-derived factor 1) and reduced granulocyte colony-stimulating factor mobilization. These defects were associated with increased cell adhesion mediated by reduced matrix metalloproteinase 9 secretion and imbalanced Src kinase activity. Poor mobilization of CD45KO progenitors by the receptor activator of nuclear factor κB ligand, and impaired modulation of the endosteal components osteopontin and stem cell factor, suggested defective osteoclast function. Indeed, CD45KO osteoclasts exhibited impaired bone remodeling and abnormal morphology, which we attributed to defective cell fusion and Src function. This led to irregular distribution of metaphyseal bone trabecules, a region enriched with stem cell niches. Consequently, CD45KO mice had less primitive cells in the BM and increased numbers of these cells in the spleen, yet with reduced homing and repopulation potential. Uncoupling environmental and intrinsic defects in chimeric mice, we demonstrated that CD45 regulates progenitor movement and retention by influencing both the hematopoietic and nonhematopoietic compartments

Increased TNF-alpha and sTNFR2 levels are associated with high-grade anal squamous intraepithelial lesions in HIV-positive patients with low CD4 level

Compared with HIV-negative individuals, HIV-positive individuals have a higher prevalence of anogenital human papillomavirus (HPV) infection, the causative agent of anogenital cancer. TNF-alpha is a major proinflammatory cytokine. sTNFR2 is the soluble form of one of its receptors and is strongly expressed on stimulated lymphocytes. To further understand the role of TNF-alpha, sTNFR2 and other cytokines in the pathogenesis in HPV-related neoplasia, the profiles of serum cytokines in high-risk patients were analyzed for association with anal lesion status. Patients were categorized into 4 groups based on HIV status (HIV-negative vs. HIV-positive with a CD4+ level < 200/uL) and anal lesion status [no lesion, low-grade anal squamous intraepithelial lesion (LSIL) vs. high-grade squamous intraepithelial lesion (HSIL)] based on high resolution anoscopy-guided biopsy. Following adjustment for multiplicity, HIV-negative men with HSIL had lower levels of sTNFR2 than HIV-positive men with low CD4 level and HSIL (p=0.02). HIV-positive men with HSIL had higher levels of TNF-alpha than HIV-negative men with HSIL (p < 0.001), as well as HIV-positive men with no lesion or LSIL (p=0.03). The levels of other factors, including IL-1beta, IL-2, IL-4, IL-8, IFN-gamma, GM-CSF, sTNFR1 and DR5, were not significantly different between groups. Although the sample size was small, these results suggest that systemic activation of TNF-alpha/sTNFR2 in HIV-positive patients with a low CD4 level may promote the development of HSIL and possibly anal cancer

Helminth-Associated Systemic Immune Activation and HIV Co-receptor Expression: Response to Albendazole/Praziquantel Treatment

Background: It has been hypothesized that helminth infections increase HIV susceptibility by enhancing systemic immune activation and hence contribute to elevated HIV-1 transmission in sub-Saharan Africa. Objective: To study systemic immune activation and HIV-1 co-receptor expression in relation to different helminth infections and in response to helminth treatment. Methods: HIV-negative adults with (n = 189) or without (n = 57) different helminth infections, as diagnosed by Kato-Katz, were enrolled in Mbeya, Tanzania. Blinded to helminth infection status, T cell differentiation (CD45RO, CD27),activation (HLA-DR, CD38) and CCR5 expression was determined at baseline and 3 months after Albendazole/Praziquantel treatment. Plasma cytokine levels were compared using a cytometric bead array. Results: Trichuris and Ascaris infections were linked to increased frequencies of "activated'' CD4 and/or CD8 T cells (p< 0.05),whereas Hookworm infection was associated with a trend towards decreased HLA-DR+ CD8 T cell frequencies (p = 0.222). In Trichuris infected subjects, there was a linear correlation between HLA-DR+ CD4 T cell frequencies and the cytokines IL-1 beta and IL-10 (p<0.05). Helminth treatment with Albendazole and Praziquantel significantly decreased eosinophilia for S. mansoni and Hookworm infections (p<0.005) but not for Trichuris infection and only moderately modulated T cell activation. CCR5 surface density on memory CD4 T cells was increased by 1.2-fold during Trichuris infection (p-value: 0.053) and reduced after treatment (p = 0.003). Conclusions: Increased expression of T cell activation markers was associated with Trichuris and Ascaris infections with relatively little effect of helminth treatment

Serum Concentrations of TNF α and Its Soluble Receptors in Patients with Adrenal Tumors Treated by Surgery

The peripheral blood levels of TNF α and its soluble receptors were studied in 39 patients with malignant and benign adrenal tumors treated by adrenalectomy. The concentrations of TNF α were significantly elevated in patients with malignant tumors of the adrenal cortex and in patients with Conn’s syndrome compared to control. In patients with non-functioning adenomas and pheochromocytomas, TNF α levels were similar to those detected in the control. In subjects with myelolipomas, the serum concentration of TNF α was lower compared to the control. After adrenalectomy, the levels of TNF α were decreased in patients with malignant tumors and in patients with Conn’s syndrome, nonfunctioniong adenomas and pheochromocytomas compared to the concentration before surgery. The serum concentrations of soluble receptors of TNF α did not differ among different patient groups and compared to the control. After adrenalectomy, the blood concentrations of TNF α R1 and TNF α R2 were decreased in patients with Conn’s syndrome. However, to confirm practicality of the evaluation of TNF α and its soluble receptors in differential diagnosis in patients with adrenal tumors, a larger study group is needed

Downregulation of MIP-1α/CCL3 with praziquantel treatment in Schistosoma haematobium and HIV-1 co-infected individuals in a rural community in Zimbabwe

The results of our study show that the MIP-1alpha/CCL3 levels were positively associated with S. haematobium egg counts at baseline but not with HIV-1 infection status. MIP-1alpha/CCL3 levels were significantly reduced at three months post treatment with praziquantel. We therefore conclude that MIP-1alpha/CCL3 is produced during infection with S haematobium. S. haematobium infection is associated with increased MIP-1alpha/CCL3 levels in an egg intensity-dependent manner and treatment of S. haematobium is associated with a reduction in MIP-1alpha/CCL3

Necator americanus and Helminth Co-Infections: Further Down-Modulation of Hookworm-Specific Type 1 Immune Responses

Parasitic infections in humans are common in tropical regions and under bad housing and sanitation conditions multiple parasitic infections are the rule rather than the exception. For helminth infections, which are thought to affect almost a quarter of the world's population, most common combinations include soil-transmitted helminths, such as hookworm, roundworm, and whipworm, as well as extra-intestinal infections by schistosomes. In order to develop and test a hookworm vaccine in endemic areas, the understanding of the impact of multiple helminth infections (co-infection) on the immune response against hookworm in infected individuals is crucial. The authors report in their article, that several parameters of the cellular (T cell markers, cytokines, chemokines) and humoral immune response (e.g. IgG4 and IgE antibodies) against hookworm are significantly affected or modulated in individuals co-infected with hookworm, roundworm and/or schistosomes. These results imply that the immune response against components of a hookworm vaccine might be altered by previous contact with other helminth species in endemic areas

Circulating Mesenchymal Stem Cells Microparticles in Patients with Cerebrovascular Disease

Preclinical and clinical studies have shown that the application of CD105+ mesenchymal stem cells (MSCs) is feasible and may lead to recovery after stroke. In addition, circulating microparticles are reportedly functional in various disease conditions. We tested the levels of circulating CD105+ microparticles in patients with acute ischemic stroke. The expression of CD105 (a surface marker of MSCs) and CXCR4 (a CXC chemokine receptor for MSC homing) on circulating microparticles was evaluated by flow cytometry of samples from 111 patients and 50 healthy subjects. The percentage of apoptotic CD105 microparticles was determined based on annexin V (AV) expression. The relationship between serum levels of CD105+/AV− microparticles, stromal cells derived factor-1α (SDF-1α), and the extensiveness of cerebral infarcts was also evaluated. CD105+/AV− microparticles were higher in stroke patients than control subjects. Correlation analysis showed that the levels of CD105+/AV− microparticles increased as the baseline stroke severity increased. Multivariate testing showed that the initial severity of stroke was independently associated with circulating CD105+/AV− microparticles (OR, 1.103 for 1 point increase in the NIHSS score on admission; 95% CI, 1.032–1.178) after adjusting for other variables. The levels of CD105+/CXCR4+/AV− microparticles were also increased in patients with severe disability (r = 0.192, p = 0.046 for NIHSS score on admission), but were decreased with time after stroke onset (r = −0.204, p = 0.036). Risk factor profiles were not associated with the levels of circulating microparticles or SDF-1α. In conclusion, our data showed that stroke triggers the mobilization of MSC-derived microparticles, especially in patients with extensive ischemic stroke

The Hookworm Tissue Inhibitor of Metalloproteases (Ac-TMP-1) Modifies Dendritic Cell Function and Induces Generation of CD4 and CD8 Suppressor T Cells

Hookworm infection is a major cause of disease burden for humans. Recent studies have described hookworm-related immunosuppression in endemic populations and animal models. A Tissue Inhibitor of Metalloproteases (Ac-TMP-1) has been identified as one of the most abundant proteins released by the adult parasite. We investigated the effect of recombinant Ac-TMP-1 on dendritic cell (DC) and T cell function. Splenic T cells from C57BL/6 mice injected with Ac-TMP-1 showed reduced proliferation to restimulation with anti CD3 or bystander antigens such as OVA. Incubation of bone marrow-derived DCs with Ac-TMP-1 decreased MHC Class I and, especially, Class II expression but increased CD86 and IL-10 expression. Co-incubation of splenic T cells with DCs pulsed with Ac-TMP-1 induced their differentiation into CD4+ and, particularly, CD8+ CD25+Foxp3+ T cells that expressed IL-10. These cells were able to suppress proliferation of naïve and activated CD4+ T cells by TGF-Β-dependent (CD4+ suppressors) or independent (CD8+ suppressors) mechanisms. Priming of DCs with non-hookworm antigens, such as OVA, did not result in the generation of suppressor T cells. These data indicate that Ac-TMP-1 initiates the development of a regulatory response through modifications in DC function and generation of suppressor T cells. This is the first report to propose a role of suppressor CD8+ T cells in gastrointestinal helminthic infections