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PubMed2006

T-cell regulation: with complements from innate immunity.

The complement system was traditionally known as an effector arm of humoral immunity. Today we also recognize it as a main element of the innate immune system. In blood and other body fluids complement is a first line of defence against pathogens, because it becomes fully active within seconds. Active complement fragments attach to the invading pathogen to promote opsonization and lysis, triggering a local inflammatory response. This Review focuses on the evolving role of the complement system in the regulation of T-cell responses, from directing the initiation phase, through driving lineage commitment, to regulating the contraction phase.

Animals↗

PubMed2003

Expression of the GLI2 oncogene and its isoforms in human basal cell carcinoma.

BACKGROUND: Mutations of the patched (Ptc) gene, a developmental regulator implicated in the signalling pathway via sonic hedgehog (Shh) and smoothened (Smo), play an essential pathogenic role in the development of basal cell carcinomas (BCCs). We previously reported the upregulation of Shh signal transducers, including Ptc, Smo and hedgehog-interacting protein, in BCCs. In vertebrates, specific downstream effectors in the Shh signalling pathway include three zinc-finger transcription factors, Gli1, Gli2 and Gli3. Gli1 possesses only an activation domain, while Gli2 and Gli3 contain both activation and repression domains. It remains unclear which of these transcription factors are responsible for the development of BCCs. OBJECTIVES: To examine the expression pattern of Gli2 mRNA by human BCCs in comparison with those by normal human skin and various skin tumours. METHODS: We performed quantitative reverse transcriptase-polymerase chain reaction analyses with a series of samples from BCCs, other skin tumours and normal skin. RESULTS: We found that Gli2 mRNA expression was enhanced in the BCCs we examined, whereas there was no significant increase in other skin tumours or normal skin. Of four spliced Gli2 isoforms designated Gli2alpha, beta, gamma and delta, the expression of Gli2beta mRNA was increased the most in BCCs. CONCLUSIONS: As Gli2beta is an isoform spliced at the first splicing site containing a repression domain and consists of an intact activation domain, its overexpression may lead to the upregulation of the Shh signalling pathway, thereby inducing BCCs.

Aged↗

PubMed2001

Early immunologic events in mucosal and systemic lymphoid tissues after intrarectal inoculation with simian immunodeficiency virus.

The pathogenesis of human immunodeficiency virus transmission via the rectal route remains poorly understood. By use of the simian immunodeficiency virus (SIV)-rhesus macaque model and intrarectal inoculation with pathogenic SIVmac251, a significant increase was found in the percentage of CD11b(+) monocyte lineage cells expressing HLA-DR and/or B7-2 in local and peripheral immune inductive sites, but not in mucosal effector sites, as early as 7 days after inoculation and up to 50 days after inoculation. Moreover, at 21 and 50 days after inoculation, not only the gut but also the lung mucosa were depleted of CD4(+) T cells, which suggests that early loss of CD4(+) T cells may be a common feature of mucosal effector sites. These data suggest that, after intrarectal inoculation with SIV, early activation occurs within the monocyte lineage cell population at immunologic inductive sites, which is followed by a loss of CD4(+) T cells at local and distant mucosal effector sites.

Animals↗

PubMed1998

Human immunodeficiency virus type 1 envelope protein gp120 impairs intracellular antifungal mechanisms in human monocytes.

The key to success of fungal opportunistic pathogens in the immunocompromised host is related to survival inside phagocytic cells, which represent the first line of defense against microorganisms. The contribution of human immunodeficiency virus-1 recombinant envelope protein gp120 on effector functions of peripheral blood monocytes (PBM) against Candida albicans was investigated. gp120 binds CD4 receptors on PBM while not affecting the access of the fungus into the lysosome compartment. However, gp120 reduces the antifungal capacity of PBM. This phenomenon correlates with impaired oxygen-dependent antimicrobial machinery and reduced ability of phagolysosome acidification. The maintenance of phagolysosomal pH at approximately 6.2 restricts antimicrobial properties of the enzyme that work at a low pH, as evidenced by reduced antifungal capability of lysosomal protein extracted from gp120-treated PBM. These findings highlight gp120 perturbation of intracellular antimicrobial mechanisms of phagocytic cells and suggest a new aspect for gp120 in impairing immune functions.

AIDS-Related Opportunistic Infections↗

PubMedDate not supplied

Regulating immunity to malaria.

The optimal outcome of a malaria infection is that parasitized cells are killed and degraded without inducing significant pathology. Since much of the pathology of malaria infection can be immune-mediated, this implies that immune responses have to be carefully regulated. The mechanisms by which anti-malarial immune responses are believed to be regulated were discussed at the recent Malaria Immunology Workshop (Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA; February 2005). Potential regulatory mechanisms include regulatory T cells, which have been shown to significantly modify cellular immune responses to various protozoan infections, including leishmania and malaria; neutralising antibodies to pro-inflammatory malarial toxins such as glycosylphosphatidylinositol and haemozoin; and self-regulating networks of effector molecules. Innate and adaptive immune responses are further moderated by the broader immunological environment, which is influenced by both the genetic background of the host and by co-infection with other pathogens. A detailed understanding of the interplay between these different immunoregulatory processes may facilitate the rationale design of vaccines and novel therapeutics.

Animals↗

PubMed2005

The intracellular fate of Salmonella depends on the recruitment of kinesin.

Salmonella enterica causes a variety of diseases, including gastroenteritis and typhoid fever. The success of this pathogen depends on its capacity to proliferate within host cells in a membrane-bound compartment. We found that the Salmonella-containing vacuole recruited the plus-end-directed motor kinesin. Bacterial effector proteins translocated into the host cell by a type III secretion system antagonistically regulated this event. Among these effectors, SifA targeted SKIP, a host protein that down-regulated the recruitment of kinesin on the bacterial vacuole and, in turn, controlled vacuolar membrane dynamics.

Adaptor Proteins, Signal Transducing↗

PubMed1985

Role of resident macrophages, peripheral neutrophils, and translymphatic absorption in bacterial clearance from the peritoneal cavity.

Microbial pathogens within the peritoneal cavity are thought to encounter three categories of host defense mechanisms: (i) removal mechanisms, which occur via diaphragmatic lymphatic absorption; (ii) killing mechanisms, in which host phagocytes act as effector cells; and (iii) sequestration mechanisms due to fibrin trapping and the formation of adhesions between visceral surfaces. We sought to define and quantitate the relative role of the first two components in an experimental rat model of Escherichia coli peritonitis in which fibrinous adhesions do not form. Intraperitoneal challenge with greater than or equal to 2 X 10(8) CFU of viable E. coli led to an initial decline in bacterial numbers followed by ongoing proliferation and greater than 50% mortality. With inocula of less than or equal to 5 X 10(7) CFU, elimination of bacteria occurred after moderate initial proliferation, and no mortality ensued. Nonviable, radiolabeled E. coli organisms were utilized to examine bacterial clearance via translymphatic absorption and phagocytosis. Both processes were extremely rapid, serving to eliminate free bacteria rapidly within the peritoneal cavity. Although macrophages and polymorphonuclear leukocytes within the peritoneal cavity demonstrated similar phagocytic capacities, the predominance of macrophages at the time of the initial bacterial insult led to the conclusion that these cells, in addition to translymphatic absorption, represent the first line of host defenses, acting to eliminate bacteria in the incipient stages of infection.

Animals↗

PubMed1998

Signal transduction pathways involved in enterohemorrhagic Escherichia coli-induced alterations in T84 epithelial permeability.

Enterohemorrhagic Escherichia coli (EHEC) infection is associated with watery diarrhea and can lead to complications, including hemorrhagic colitis and the hemolytic-uremic syndrome. The mechanisms by which these organisms produce diarrheal disease remain to be elucidated. Changes in T84 epithelial cell electrophysiology were examined following EHEC infection. T84 cell monolayers infected with EHEC O157:H7 displayed a time-dependent decrease in transepithelial resistance. Increases in the transepithelial flux of both [3H]mannitol and 51Cr-EDTA accompanied the EHEC-induced decreases in T84 resistance. Altered barrier function induced by EHEC occurred at the level of the tight junction since immunofluorescent staining of the tight-junction-associated protein ZO-1 was disrupted when examined by confocal microscopy. Decreased resistance induced by EHEC involved a protein kinase C (PKC)-dependent pathway as the highly specific PKC inhibitor, CGP41251, abrogated the EHEC-induced drop in resistance. PKC activity was also increased in T84 cells infected with EHEC. Calmodulin and myosin light chain kinase played a role in EHEC-induced resistance changes as inhibition of these effector molecules partially reversed the effects of EHEC on barrier function. These studies demonstrate that intracellular signal transduction pathways activated following EHEC infection link the increases in T84 epithelial permeability induced by this pathogen.

Calmodulin↗

PubMed1997

Activation of NF-kappaB in intestinal epithelial cells by enteropathogenic Escherichia coli.

The initial response to infection is recruitment of acute inflammatory cells to the involved site. Interleukin (IL)-8 is the prototypical effector molecule for this process. Transcription of the IL-8 gene is primarily governed by the nuclear transcription factor (NF)-kappaB. Intestinal epithelial cells produce IL-8 in response to infection by enteric pathogens yet remain quiescent in a milieu where they are literally bathed in normal bacterial flora. We therefore sought to investigate NF-kappaB activation in response to enteropathogenic Escherichia coli (EPEC), nonpathogenic E. coli, and bacterial lipopolysaccharide in an intestinal epithelial cell (T84) model and to determine whether EPEC-induced activation of NF-kappaB factor is causally linked to IL-8 production. We report herein that NF-kappaB is activated by EPEC, yet such a response is not extended to nonpathogenic organisms or purified E. coli lipopolysaccharide. Transcription factor decoys significantly diminished IL-8 production in response to EPEC, demonstrating a causal relationship. Furthermore, deletion of specific EPEC virulence genes abrogates the NF-kappaB-activating property of this pathogen, suggesting that specific bacterial factors are crucial for inducing this response. These studies show for the first time that infection of intestinal epithelial cells with EPEC activates NF-kappaB, which in turn initiates IL-8 transcription, and highlight the differential response of these cells to bacterial pathogens vs. nonpathogens.

Base Sequence↗

PubMed2002

Correlation of tissue distribution, developmental phenotype, and intestinal homing receptor expression of antigen-specific B cells during the murine anti-rotavirus immune response.

The intestinal homing receptor, alpha(4)beta(7), helps target lymphocytes to Peyer's patches (PP) and intestinal lamina propria (ILP). We have previously shown that protective immunity to rotavirus (RV), an intestinal pathogen, resides in memory B cells expressing alpha(4)beta(7). In this study, using a novel FACS assay, we have directly studied the phenotype of B cells that express surface RV-specific Ig during the in vivo RV immune response. During primary infection, RV-specific B cells first appear as large IgD(-)B220(low)alpha(4)beta(7)(-)and alpha(4)beta(7)(+) cells (presumptive extrafollicular, Ab-secreting B cells), and then as large and small IgD(-)B220(high)alpha(4)beta(7)(-)cells (presumptive germinal center B cells). The appearance of B cells with the phenotype of large IgD(-)B220(low)alpha(4)beta(7)(+) cells in PP and most notably in mesenteric lymph nodes coincides with the emergence of RV-specific Ab-secreting cells (ASC) in the ILP. Thus, these B lymphocytes are good candidates for the migratory population giving rise to the RV-specific ASC in the ILP. RV-specific long-term memory B cells preferentially accumulate in PP and express alpha(4)beta(7). Nine months after infection most RV-specific IgA ASC are found in PP and ILP and at lower frequency in bone marrow and spleen. This study is the first to follow changes in tissue-specific homing receptor expression during Ag-specific B cell development in response to a natural host, tissue-specific pathogen. These results show that alpha(4)beta(7) is tightly regulated during the Ag-specific B cell response to RV and is expressed concurrently with the specific migration of memory and effector B cells to intestinal tissues.

Animals↗

PubMed1997

[Susceptibility to infection].

Recurrent infections in individual patients prompt concern regarding an underlying immunodeficiency. It is often difficult to make a distinction between "normal" and abnormally frequent occurrence of infections. Infectious diseases are the result of a series of complicated interactions between host factors, pathogen properties and epidemiological circumstances. This paper reviews the role of non-specific and antigen-specific host factors relevant to the management of a patient with suspected immunodeficiency. The most important effector mechanisms of immune defence are outlined and the consequences of their failure with respect to specific infections are discussed. Analysis of the clinical presentation, pathophysiology and microorganisms involved offers clues as to which part of the immune system is failing in an individual patient. Based on this, further tests will confirm or exclude an underlying immunodeficiency. The paper concludes with an overview of relevant therapeutic and prophylactic options.

Complement Activation↗

PubMed1998

Immunopathology of herpetic stromal keratitis: discordance in CD4+ T cell function between euthymic host and reconstituted SCID recipients.

Infection of the mouse cornea with herpes simplex virus (HSV) results in an immunopathologic disease of the eye termed herpetic stromal keratitis (HSK), in which the principal orchestrator is the CD4+ T cell. The mouse genotype largely determines susceptibility or resistance to HSK. BALB/c mice (H2dIgh-1a) are susceptible, while its congenic C.B-17 strain (H2dIgh-1b), which differs only in the Ig heavy chain locus, is resistant to HSK. As the magnitude and duration of viral replication as well as anti-HSV immune responses were similar in both strains, it was determined whether resistance was due to failure of CD4+ T cells to organize the immunopathologic reaction. Adoptive transfer of HSV-primed or naive CD4+ T cells from resistant C.B-17 strain into HSV-infected SCID mice resulted in HSK lesions indistinguishable from those caused by similar transfers of BALB/c CD4+ T cells. Similar results were obtained with transfers of whole T cell populations as well as with unfractionated splenocytes from the resistant mice. These results show that while intact C.B-17 mice exhibit resistance to HSK, they possess potentially pathogenic CD4+ T cells in their repertoire. The data suggest that the HSV-infected SCID mouse provides a proinflammatory microenvironment that overrides regulatory controls and/or cause activation of quiescent cells into aggressive effector T cells that orchestrate HSK.

Adoptive Transfer↗

PubMed1999

Candida albicans pathogenicity: a proteomic perspective.

Candida albicans is an opportunistic fungus which causes both superficial infections and life-threatening systemic candidiasis in immunocompromised hosts such as AIDS patients, people with cancer, or other immunosuppressed individuals. Virulence factors for this fungus include the ability to adhere to host tissues, production of tissue damaging secreted enzymes, and changes in morphological form that may enhance tissue penetration and avoidance of immune surveillance. Treatment of candidiasis patients is hampered by a limited choice of antifungal agents and the appearance of clinical isolates resistant to azole drugs. Proteome analysis involves the separation and isolation of proteins by two-dimensional gel electrophoresis and their identification and characterization by mass spectrometry. The systematic application of this methodology to C. albicans is in its infancy, but is progressing rapidly. Comparing protein profiles between avirulent and virulent C. albicans strains, between drug-sensitive and -resistant strains, or between different morphological forms, could identify key control and effector proteins. There are difficulties, however, associated with the display of low abundance and cell envelope-associated proteins and the choice of conditions for obtaining suitable C. albicans cells. This article describes the potential of applying proteome analysis to C. albicans in order to better understand pathogenicity and identify new antifungal targets.

Candida albicans↗

PubMed2005

Permanent effector phenotype of neuroantigen-specific T cells acquired in the central nervous system during experimental allergic encephalomyelitis.

Experimental autoimmune encephalomyelitis (EAE) is regarded as an animal model of the human autoimmune disease multiple sclerosis (MS). Autoreactive T cells are present in the peripheral T cell repertoire of healthy mice and mediate clinical autoimmune disease only after activation by immunization or pathogens and migrate into the central nervous system (CNS). Because it is not known whether autoreactive T cells are regulated differentially once entering the CNS we investigated cytokine regulation in T cells from peripheral lymphatic organs and from the inflamed CNS ex vivo obtained from SJL mice after inducing relapsing-remitting EAE with PLP peptide 139-151. We show here that during acute EAE, an interleukin-2 (IL-2) biased T cell response exists in the spleen, while an interferon-gamma (IFN-gamma) biased T cell response prevails in the CNS of mice with acute EAE. The IFN-gamma biased phenotype was stable with optimized costimulation and even after in vitro stimulation with IL-2. After adoptive transfer into naïve syngeneic mice these T cells were only partially reversed to an IL-2 biased phenotype. These findings of our work suggest that a permanent effector phenotype of neuroantigen-specific T cells is finally acquired in the CNS in EAE.

Animals↗

PubMed2006

Spx is a global effector impacting stress tolerance and biofilm formation in Staphylococcus aureus.

In Bacillus subtilis, Spx was recently characterized as a novel type of global regulator whose activity is regulated by the redox status of the cells. In the present study, we demonstrate that inactivation of Spx in the important pathogen Staphylococcus aureus renders the cells hypersensitive to a wide range of stress conditions including high and low temperature, high osmolarity, and hydrogen peroxide. Moreover, growth was restricted under nonstress conditions. Two-dimensional gel electrophoresis revealed that the proteome of the spx mutant differs substantially from the proteome of wild-type cells, supporting the finding that Spx is also a global regulator in S. aureus. More specifically, we demonstrated that Spx is required for transcription of trxB, encoding thioredoxin reductase, under all growth conditions examined. As trxB is essential in S. aureus, we speculate that the severely reduced trxB transcription could account for some of the growth defects of the spx mutant. Inactivation of spx also enhanced biofilm formation. S. aureus biofilm formation is associated with the production of the polysaccharide intercellular adhesin encoded by the ica operon. Interestingly, our data indicate that the augmented capacity of the spx mutant to form biofilms is due to Spx modulating the expression of icaR, encoding a repressor of the structural ica genes (icaABCD). In summary, we conclude that Spx fulfills an important role for growth, general stress protection, and biofilm formation in S. aureus.

Bacterial Proteins↗

PubMed2004

Amplifying cancer vaccine responses by modifying pathogenic gene programs in tumor cells.

Immunosuppressive factors, such as vascular endothelial growth factor, transforming growth factor-beta, prostaglandin E2, interleukin (IL)-10, and IL-6, are made frequently by cancer cells. These factors, along with others, can inhibit the development and function of tumor-reactive effector T cells and the clinical results of cancer vaccines. Production of these factors by tumor cells is associated with disease progression and may represent an active immune surveillance escape mechanism. However, a number of factors appear to be made directly in response to signaling molecules, such as RAS, AKT, and signal transducer and activator of transcription 3, which are activated as a result of genetic events that occur during oncogenesis. Methods to overcome the negative effects of immunosuppressive factors, which are "hard wired" into gene programs of cancer cells, might then improve the results of cancer vaccines. For example, specific blocking antibodies, which recognize such factors, or kinase inhibitors, which block the signaling pathways that lead to their production, could potentially be used as vaccine adjuvants. The effects of immunosuppressive factors may also be "turned off" by cytokines with tumor suppressor properties. The enhanced clinical and immunological effects of melanoma vaccines observed after the administration of high doses of interferon-alpha2b provide a "proof of principle" in human patients, that agents which counter the gene programs of cancer cells, causing them to intrinsically resist tumor-reactive T cells, may improve significantly the efficacy of cancer vaccines.

Adjuvants, Immunologic↗

PubMed2001

Measles virus induced immunosuppression: targets and effector mechanisms.

A profound, transient suppression of immune functions during and after the acute infection is the major cause of more than one million cases of infant deaths associated with measles worldwide. Concommittant with the generation of an efficient measles virus (MV) specific immunity, immune responses towards other pathogens are strongly impaired and provide the basis for the establishment and severe course of opportunistic infections. The molecular basis for MV-induced immunosuppression has not been resolved as yet. Similar to other immunosuppressive viruses, MV is lymphotropic and viral nucleic acid and proteins are detectable in peripheral blood mononuclear cells (PBMC). It is considered central to MV-induced immunosuppression that PBMC isolated from patients largely fail to proliferate in response to antigen specific and polyclonal stimulation. The low abundancy of MV-infected PBMC suggests that MV-induced immunosuppression is not directly caused by infection-mediated cell loss or fusion, but rather by indirect mechanisms such as deregulation of cytokines or surface contact-mediated signaling which may lead to apoptosis or impair the proliferative response of uninfected PBMC. Evidence for a role of any of these mechanisms was obtained in vitro, however, much has still to be learned about the tropism of MV and its interactions with particular host cells such as dendritic cells in vivo.

Animals↗

PubMed2026

The complement system in inflammatory bowel disease: from early observations to emerging frontiers.

PURPOSE OF REVIEW: The complement system is one of the most evolutionarily conserved arms of innate immunity and has re-emerged as an important regulator of intestinal inflammation in inflammatory bowel disease (IBD). Early observations from the mid-1970 s such as complement deposition in diseased bowel tissue and elevated serum complement levels in patients with ulcerative colitis and Crohn's disease have evolved into a nuanced understanding of how individual complement components can exert both protective and pathogenic effects in IBD. This review highlights recent advances in complement biology and examines how complement shapes intestinal immune responses, particularly in the setting of ongoing inflammation. RECENT FINDINGS: The complement system consists of more than 60 proteins that act as rapid first responders to infection. Although traditionally considered primarily liver-derived circulating effectors, recent work has demonstrated local synthesis and activation of key complement components at mucosal sites, including the colon. In parallel, genome-wide association studies have identified variants in complement genes associated with severe IBD complications. Collectively, these findings reveal a dichotomous role for complement in IBD, whereby excessive activation promotes inflammation, while impaired function compromises host defense and worsens disease outcomes. SUMMARY: Complement-targeted therapies have been effective in other diseases but have not yet translated to IBD. A deeper understanding of context-dependent protective versus pathogenic complement functions will be essential for developing future therapeutic strategies.

Humans↗