Hierarchical, imbalanced pro-inflammatory cytokine networks govern the pathogenesis of chronic arthropathies.

BACKGROUND: Chronic inflammatory arthropathies, such as rheumatoid arthritis (RA), spondyloarthritis, including psoriatic arthritis (PsA), ankylosing spondyloarthritis (AS), osteoarthritis (OA), and intervertebral disc degenerative disease (DDD) constitute major public health problems that are anticipated to grow significantly as the human population ages. However, many aspects concerning the molecular mechanisms underlying their onset and progression remain unclear. DESIGN: This narrative review critically analyzes the molecular mechanisms underlying the inflammation-associated pathogenesis of the aforementioned joint diseases. This includes, in particular, the major role played by several key soluble factors (such as cytokines and the associated signaling pathways, designated as "fragile nodes") produced by local cells and recruited to the joints' immune cells, whose elimination by specific drugs has dramatically improved the diseases' symptomatology and outcome in human clinical trials or in rodent arthritis models. HYPOTHESIS AND THE AIM OF THIS REVIEW: We hypothesize that the pathogenesis of chronic inflammatory arthropathies is governed by hierarchical, imbalanced pro-inflammatory cytokine networks (HIPICNs) (comprising a combination of fragile nodes) that are created during the development of both autoimmune (RA, PsA, and AS) and non-autoimmune (OA and DDD) disorders. The main aim of this review is to provide evidence that despite substantial pathobiological differences between these arthropathies, the HIPICNs created are quite common, thus justifying the merging of these disorders mechanistically and suggesting that these common mechanisms exist in the onset and progression of different joint diseases.

Physiologic corticosterone oscillations regulate murine hematopoietic stem/progenitor cell proliferation and CXCL12 expression by bone marrow stromal progenitors.

The role of corticosterone (Cort), the immune system's major stress hormone, in the regulation of hematopoietic stem and progenitor cells (HSPCs) and their dynamic bone marrow (BM) microenvironment is currently unknown. We report that corticotropin-releasing factor receptor 1 (CRFR1) mutant mice with chronically low Cort levels showed aberrant HSPC regulation, having higher HSPC numbers and upregulation of the chemokine CXCL12, phenotypes that were restored by Cort supplementation. Expanded stromal progenitors known to support HSPCs were also observed in these low-Cort-containing mice. A similar phenotype was induced in wild-type (WT) mice by Metyrapone, a Cort synthesis inhibitor. Conversely, high Cort exposure induced HSPC apoptosis, reduced long-term BM repopulation and decreased stromal progenitor cell numbers. We documented circadian oscillations of Cort in WT BM but not in CRFR1 mutant mice, leading to diminished circadian BM CXCL12 fluctuations and increased number of circulating HSPCs in these mice. Finally, low Cort induced expansion of stromal progenitors, CXCL12 expression, HSPC proliferation and BM repopulation capacity, involving Notch1 signaling. This was associated with upregulation of the Notch ligand, Jagged1, in BM myeloid cells. Our results suggest that daily physiologic Cort oscillations are critical for balanced HSPC proliferation and function involving Notch1 signaling and their supportive BM microenvironment.

Neomycin B-arginine conjugate, a novel HIV-1 Tat antagonist: synthesis and anti-HIV activities.

HIV-1 transactivating protein Tat is essential for virus replication and progression of HIV disease. HIV-1 Tat stimulates transactivation by binding to HIV-1 transactivator responsive element (TAR) RNA, and while secreted extracellularly, it acts as an immunosuppressor, an activator of quiescent T-cells for productive HIV-1 infection, and by binding to CXC chemokine receptor type 4 (CXCR4) as a chemokine analogue. Here we present a novel HIV-1 Tat antagonist, a neomycin B-hexaarginine conjugate (NeoR), which inhibits Tat transactivation and antagonizes Tat extracellular activities, such as increased viral production, induction of CXCR4 expression, suppression of CD3-activated proliferation of lymphocytes, and upregulation of the CD8 receptor. Moreover, Tat inhibits binding of fluoresceine isothiocyanate (FITC)-labeled NeoR to human peripheral blood mononuclear cells (PBMC), indicating that Tat and NeoR bind to the same cellular target. This is further substantiated by the finding that NeoR competes with the binding of monoclonal Abs to CXCR4. Furthermore, NeoR suppresses HIV-1 binding to cells. Importantly, NeoR accumulates in the cell nuclei and inhibits the replication of M- and T-tropic HIV-1 laboratory isolates (EC(50) = 0.8-5.3 microM). A putative model structure for the TAR-NeoR complex, which complies with available experimental data, is presented. We conclude that NeoR is a multitarget HIV-1 inhibitor; the structure, and molecular modeling and dynamics, suggest its binding to TAR RNA. NeoR inhibits HIV-1 binding to cells, partially by blocking the CXCR4 HIV-1 coreceptor, and it antagonizes Tat functions. NeoR is therefore an attractive lead compound, capable of interfering with different stages of HIV infection and AIDS pathogenesis.

Over-expression of the functional interleukin-11 alpha receptor in the development of B-cell chronic lymphocytic leukemia.

Several cytokines have been found to play a role in the pathogenesis of B-CLL. In the present study using reverse-transcriptase polymerase chain reaction (RT-PCR), FACS analysis and immunofluorescence we have shown the constitutive expression of IL-11 and IL-11R alpha in B-chronic lymphocytic leukemia (B-CLL). The expression level of IL-11R alpha in B-CLL cells is much higher than in PBL of normal donors. Recombinant human IL-11 (rhIL-11) activates B-CLL cells, leading to morphologic alterations of the cells and increase in cell number and size. Short-term cultivation in the presence of rhIL-11 did not lead to quantitative changes in the ratio of the living vs apoptotic and dead cells. However, in contrast to rhIL-6, pretreatment with rhIL-11, did not cause B-CLL cells to be resistant to the action of dexamethasone. These data suggest an essential role for the IL-11/IL11 R alpha system in the pathogenesis of the malignant B-CLL cells.

Helminths, human immunodeficiency virus and tuberculosis.

Helminth infections affect over a quarter of the world's population, especially in the developing countries. These long-lasting parasitic infections cause widespread immune activation and dysregulation, a dominant Th2 cytokine immune profile and an immune hyporesponsiveness state. Considering these profound immune changes and the similar geographic distributions of helminthic infections, HIV and tuberculosis (TB), we suggest that helminthic infections play a major role in the pathogenesis of AIDS and TB. They apparently make the host more susceptible to infection by HIV and Mycobacterium tuberculosis, and impair his/her ability to generate protective immunity against both infections. The implication of these ideas is that without eradication of helminth infections and/or modulation of the immune changes that they cause, HIV and TB vaccines may fail to confer protection against their respective infections in helminth-endemic areas.

Immune activation correlates better than HIV plasma viral load with CD4 T-cell decline during HIV infection.

This study addressed the role of T-cell immune activation in determining HIV-1 plasma viral load and CD4+ T-cell blood levels during HIV-1 infection. A decrease of blood CD4 levels and CD4/CD8 ratios and an increase of CD8 levels in both treated (n = 35) and untreated (n = 19) HIV-positive individuals were more strongly correlated to immune activation (log percentage of HLA-DR+CD3+ cells; R = -0.78, R = -0.77, and R = 0.58, respectively; p <.0001) than to CD4 T-cell proliferation (log percentage of Ki-67+CD4+ cells; R = -0.57 [p <.0001], R = -0.48 [p <.001], and R = 0.37 [p <.01], respectively) or to viral load (R = -0.36 [p <.01], R = -0.23 [p =.09], R = 0.13 [p =.35], respectively). Because almost half of the Ki-67+CD4+ cells were also positive for CTLA-4 (a marker for activated nonproliferating cells), the correlation of CD4 levels to Ki-67 expression is only partially related to cell proliferation and more likely represents mainly immune activation of the cells without proliferation. Taken together, these results suggest that immune activation is the major determinant of CD4 decline and should therefore be considered central for the monitoring of HIV infection and its outcome after antiviral treatment.

Increased CCR5 and CXCR4 expression in Ethiopians living in Israel: environmental and constitutive factors.

HIV coreceptors play a major role in determining susceptibility and HIV cell tropism. The present work studied whether the high expression of these coreceptors found on lymphocytes and monocytes of Ethiopian immigrants to Israel (ETH) is the result of environmental and/or constitutive genetic factors. The study of 26 ETH shortly after their arrival to Israel (new ETH), 22 ETH in Israel over 7 years (old ETH), and 20 Caucasian Israelis (non-ETH) enabled us to address this issue. The new ETH had elevated levels of activated HLA-DR+CD4+ and CD38+CD8+ cells in comparison with both old ETH and non-ETH groups (P < 0.01), most probably related to chronic helminthic infections. Surface CCR5 expression, i.e., the percentage of CCR5+ cells and the number of CCR5 molecules/cell, was higher (2- to 3- and 8- to 31-fold, respectively) in activated than in nonactivated CD4+ cells, in all groups. However, CCR5 expression, in both activated and nonactivated CD4+ cells, was higher in both ETH groups than in the non-ETH group. CXCR4 expression was higher in nonactivated CD4+ cells in all groups and was also higher in both ETH groups, in both activated and nonactivated CD4+ cells, than in the non-ETH group. These findings suggest that constitutive factors, in addition to immune activation caused by environmental factors, account for the elevated expression of CCR5 and CXCR4 on CD4+ cells of ETH. This increased HIV coreceptor expression may make ETH more susceptible to HIV infection and may account in part for the rapid spread of AIDS in Ethiopia and the rest of Africa as well.

Chronic immune activation associated with intestinal helminth infections results in impaired signal transduction and anergy.

Helminthic parasites cause widespread, persistent infections in humans. The immigration of Ethiopians to Israel (a group denoted here by "Eth."), many of them infested with helminths and in a chronic immune-activation state, enabled us to investigate the effects of such immune activation on immune responses. We studied the immune profile and immune functions of 190 Eth. and Israeli non-Eth. (Isr.) highly, partially, or non-immune-activated individuals. Immune cells from highly immune-activated individuals were defective in several signaling responses, all of which were restored gradually following anti-helminthic treatment. These cells showed poor transmembrane signaling, as seen by the phosphorylation of various tyrosine kinases and of the MAPK kinases, ERK1/2 and p38; deficient degradation of phosphorylated IkappaBalpha; increased expression of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), which appears to block proliferative responses in these cells; decreased beta-chemokine secretion by CD8(+) cells after stimulation; and reduced proliferation to recall antigen stimulation. Highly immune-activated individuals also showed decreased delayed-type skin hypersensitivity responses to recall antigen before deworming. These findings support the notion that chronic helminthic infections cause persistent immune activation that results in hyporesponsiveness and anergy. Such impaired immune functions may diminish the capacity of these individuals to cope with infections and to generate cellular protective immunity after vaccination.

Increased CCR5 expression with decreased beta chemokine secretion in Ethiopians: relevance to AIDS in Africa.

OBJECTIVE: This study was undertaken to determine the contribution of HIV co-receptors and beta chemokine secretion to the increased susceptibility for human immunodeficiency virus (HIV) infection of peripheral blood mononuclear cells (PBMC) obtained from HIV-seronegative Ethiopian immigrants in Israel (ETH). STUDY DESIGN: Immune activation markers and HIV co-receptor expression on lymphocytes and monocytes, and beta chemokine secretion by CD8+ cells, were compared between ETH and non-Ethiopian Israeli (IS) HIV-negative individuals. RESULTS: The percentage of lymphocytes and monocytes expressing CCR5 was 1.6 and 3.0 times higher in ETH (n = 83) than in IS (n = 45), respectively (P < .001), whereas RANTES and MIP-1alpha secretion was 0.5 and 0.7 times lower (P < .01 and P < .05). The percentage of CCR5-expressing cells and RANTES secretion were inversely correlated (r = -0.7; P < .002). No differences were found in the proportion of CXCR4-expressing cells. No correlation between CCR5 expression and cell activation profile in the whole ETH population was found. However, in highly activated individuals (HLA-DR/CD3 > 7%), a significant decrease in CCR5 expression was observed. CONCLUSIONS: An increased proportion of CCR5-expressing cells with decreased beta chemokine secretion observed in ETH may account for the increased susceptibility to HIV infection of cells obtained from this group. These findings may partly explain the higher susceptibility for HIV infection in Africa and thus the rapid spread of acquired immunodeficiency syndrome (AIDS) in that continent.

Chemokines and chemokine receptors: role in HIV infection.

Our understanding of the host factors that determine susceptibility and progression of HIV infection has been very limited. In particular, it has been not clear why some people remain uninfected being repeatedly exposed to HIV-1, and others who have been infected by HIV, remain clinically asymptomatic for long periods of time. Recently it has been demonstrated that mutated forms of a number of chemokine receptors that act as coreceptors for HIV-1 entry may account for some of these phenomena. Furthermore, chemokines such as RANTES and others, being the natural ligands for chemokine receptors, have been shown to be effective inhibitors of HIV-1 infection. In this review we discuss some of the genetic, immunological, virological and epidemiological data relevant to the very important role chemokines and chemokine receptors play in HIV pathogenesis with special reference to the increased susceptibility of the African host to HIV infection.

Infection by different HIV-1 subtypes (B and C) results in a similar immune activation profile despite distinct immune backgrounds.

We compared the immune activation profile of 46 HIV-negative and 75 HIV-positive Israelis infected with HIV-1 subtype B, with 85 HIV-negative and 102 HIV-positive Ethiopian immigrants to Israel, who were infected with HIV subtype C. The HIV-negative Ethiopians had exceedingly high blood levels of eosinophils, immunoglobulin E (IgE), and p75s tumor-necrosis factor receptors (p75sTNFR); secretion of interleukin-4 (IL-4) and IL-10 by peripheral blood mononuclear cells (PBMC); proportion of human leukocyte antigen (HLA)-DR+ cells within CD3+, CD4+, and CD8+ T-cell subsets; and proportion of CD45RO+ CD4+ cells; while having significantly lower secretion of interferon-gamma (IFN-gamma) by PBMC and percentage of CD45RA+ CD4+ and CD28+ CD8+ cells. HIV infection in both populations was associated with reduced IL-2, IL-4, IL-10, and IL-12 secretion, number of CD28+ and CD45RA+ CD8+ cells, and increased number of HLA-DR+-CD3+, CD4+, and CD8+ cells, and CD45RO+ CD8+ cells. Thus, infection with HIV-1 subtypes B and C of studied Israelis and Ethiopians, respectively, results in a similar immune activation profile at all stages of the infection when living in the same environment, despite the striking different immune profile observed in the HIV-negative Israeli and Ethiopian populations. Together with our previous observations, this indicates that HIV subtype is not a major determinant in the natural course of HIV infection.

Decreased CD4 and increased CD8 counts with T cell activation is associated with chronic helminth infection.

We have previously reported the presence of marked immune dysregulation with a dominant Th2 profile, in a population of Ethiopian immigrants (ETH) in Israel heavily infected with helminths. In order to characterize better this immune dysregulation we studied by flow cytometry the expression of several activation markers on peripheral T cell populations, and lymphocyte apoptosis, in blood samples obtained from 63 'new' ETH (recently arrived), 18 'old' ETH (> 5 years since immigration) and 34 non-Ethiopian Israelis. The main findings in the 'new' ETH group in comparison with the non-Ethiopian controls were: (i) decreased CD4 and increased CD8 lymphocyte counts; (ii) elevated levels of activated T cells (CD3, CD4 and CD8) expressing HLA-DR; (iii) decreased levels of 'naive' CD4+ cells (CD45RA+), with increased levels of 'memory' CD4+ cells (CD45RO+); (iv) decreased numbers of CD28+ CD8+ lymphocytes; (v) marked increase in lymphocyte apoptosis. These T cell alterations and activation profile remained unchanged in 10 'new' ETH in whom the helminth infections persisted for 6-11 months. In contrast, in 18 'old' ETH, without helminth infections, the T cell activation profile was within the normal range. These findings suggest that chronic helminth infections may have a profound effect on the immune system of the host that disappears after eradication of these infections and adjustment to the new environment. It should therefore be taken into consideration for every immunomodulation therapy and especially in vaccine design and trials, in regions endemic for helminth infections.

Soluble tumor necrosis factor (sTNF) receptors: a possible prognostic marker for bone marrow transplantation-related complications.

Involvement of tumor necrosis factor (TNF) in bone marrow transplantation (BMT)-associated complications has been documented. Biological response to TNF requires interaction with specific cell membrane receptors. Extracellular domains of these receptors are released into body fluids as soluble molecules, and participate in the bioactivity of TNF. Serum levels of p55 and p75 soluble tumor necrosis factor receptors (sTNFR) were determined in 34 patients with different diseases who underwent BMT. Sequential studies initiated 10 days before BMT and continued up to 110 days post-transplantation showed that p55 and p75 sTNFR levels were elevated significantly in patients who subsequently developed major transplant-related complications (TRC). Moreover, both sTNFR levels were increased 2- to 3-fold over control values during post-BMT febrile periods in those patients who at a later stage suffered major TRC. These results indicate that the serum level of sTNFR may be used as a prognostic marker for major TRC in BMT.

Immune dysregulation in Ethiopian immigrants in Israel: relevance to helminth infections?

The infectious disease background and particularly the helminth infections that are endemic in Africa could have profound effects on the host immune system. Studies that we have performed on an Ethiopian HIV- immigrant population that has recently reached Israel, lend support to this notion. They have indeed revealed a very high prevalence of helminth and several other infections with an extreme immune dysregulation, consisting of: (i) highly elevated plasma IgE, IgG, placental isoferritin, p75 soluble TNF receptor (sTNFR) levels and very high blood eosinophilia; (ii) increased secretion from phytohaemagglutinin (PHA)-simulated peripheral blood mononuclear cells (PBMC) of the cytokines IL-2, IL-4, IL-10 and p75 sTNFR, and decreased secretion of interferon-gamma (IFN-gamma) and IL-6; (iii) increased and decreased surface expression of p75 TNFR and IL-6 receptor on lymphocytes, respectively. The causal relationship between this immune dysregulation and the infectious background is highly suggestive, and could have far-reaching implications in the resistance to other infections.