Host Tissue Destruction Research Articles

CD4+ invariant natural killer T cells protect from murine GVHD lethality through expansion of donor CD4+CD25+FoxP3+ regulatory T cells

AbstractDysregulated donor T cells lead to destruction of host tissues resulting in graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT). We investigated the impact of highly purified (>95%) donor CD4+ invariant natural killer T (iNKT) cells on GVHD in a murine model of allogeneic HCT. We found that low doses of adoptively transferred donor CD4+ iNKT cells protect from GVHD morbidity and mortality through an expansion of donor CD4+CD25+FoxP3+ regulatory T cells (Tregs). These Tregs express high levels of the Ikaros transcription factor Helios and expand from the Treg pool of the donor graft. Furthermore, CD4+ iNKT cells preserve T-cell–mediated graft-versus-tumor effects. Our studies reveal new aspects of the cellular interplay between iNKT cells and Tregs in the context of tolerance induction after allogeneic HCT and set the stage for clinical translation.

Generic determinants of Streptococcus colonization and infection

Bacteria within the genus Streptococcus have evolved to become exquisitely adapted to the colonization of humans and other animals. These bacteria predominantly live in harmony with their hosts, but all have capacity to cause disease should prevailing conditions allow. Streptococci express a myriad of colonization and virulence attributes that promote their survival at a variety of ecological sites. Many of these factors are surface-expressed adhesins that exhibit conservation at structural or functional levels across the genus. This reflects the importance of adherence interactions with a multitude of host substrata, such as epithelia or extracellular matrix components, to streptococcal survival. Other important factors are more restricted in their distribution, often conferring pathogenic capabilities associated with immune evasion or host tissue destruction. Evidence suggests that dissemination of these streptococcal attributes has frequently been driven by the movement of genetic material via lateral gene transfer, reflecting ecological pressures. Such recombination events have simultaneously facilitated extensive diversification, resulting in distinct tropisms at the species- or strain- level. These generic determinants offer significant potential as targets for combating streptococcal disease. However, this will depend upon better understanding of their mechanistic basis, and refined mapping of their distribution by epidemiological and metagenomic studies.

Pore-forming toxins from pathogenic amoebae

Some amoeboid protozoans are facultative or obligate parasites in humans and bear an enormous cytotoxic potential that can result in severe destruction of host tissues and fatal diseases. Pathogenic amoebae produce soluble pore-forming polypeptides that bind to prokaryotic and eukaryotic target cell membranes and generate pores upon insertion and oligomerization. This review summerizes the current knowledge of such small protein toxins from amoebae, compares them with related proteins from other species, focuses on their three-dimensional structures, and gives insights into divergent activation mechanisms. The potential use of pore-forming toxins in biotechnology will be briefly outlined.

Lipids rule: resetting lipid metabolism restores T cell function in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a devastating autoimmune disease characterized by chronic inflammation and systemic destruction of host organs or tissue. A key feature of SLE is T cell dysfunction characterized by hyperresponsive antigen receptor signaling. In this issue of the JCI, McDonald and colleagues provide evidence that homeostasis of a subset of lipids, the glycosphingolipids (GSLs), is severely perturbed in the membranes of T cells from SLE patients. Furthermore, normalization of GSLs restored TCR signaling and ameliorated T cell dysfunction. These data suggest that targeting host metabolism may be an effective means of reinforcing self-tolerance and attenuating autoimmunity.

Selected wildlife trematodiasis.

Trematodes may affect their hosts in a variety of ways: destruction of host tissue and mechanical irritation. Trematodes may bring about a change in the normal blood parameters (anemia, leukocytosis, lymphocytosis, eosinophilia). Wildlife infected with trematodes may show no signs or symptoms of disease or only slight disturbances. The host may show morbidity or the infection may result in death. This chapter presents a review of the characteristic processes of pathology demonstrated by the action of trematodes in selected groups of mammals.

Matrix Metalloproteinase-8 Levels in Peri-implant Sulcus Fluid Adjacent to Titanium and Zirconium Nitride Surfaces

During host interaction against oral biofilm, matrix metalloproteinase-8 (MMP-8) is activated, leading to collagenolytic destruction of host tissues. In periimplantitis patients, the active form of MMP-8 is elevated in peri-implant sulcus fluid (PISF). In this study, MMP-8 in PISF from titanium abutments and those coated with zirconium nitride (ZrN) was compared in vivo in a split-mouth design in 60 patients at 6 weeks, 6 months, and 12 months after prosthetic restoration. At each time point, MMP-8 values in PISF differed significantly between titanium and ZrN abutment surfaces. For example, mean MMP-8 values reached 10 to 12 ng/mL in titanium and only 6.6 to 7.5 ng/mL with ZrN. Similarly, the 75th percentile MMP-8 concentrations were 12 to 15 ng/mL and 8 to 9 ng/mL for titanium and ZrN, respectively. Based on this finding, ZrN-coated abutments seem to exert a beneficial effect regarding collagenolytic tissue destruction driven by MMP-8 in situ.

Effect of Porphyromonas gingivalis outer membrane vesicles on gingipain-mediated detachment of cultured oral epithelial cells and immune responses

Porphyromonas gingivalis is a major etiological agent of periodontal diseases and the outer membrane vesicles (OMVs) contain virulence factors such as LPS and gingipains. In this study, we investigated the potential role of the OMVs in host immune response and tissue destruction during P. gingivalis infection. Firstly, we found that sera from periodontitis patients had significantly stronger reactivity against an OMV-producing wild type strain than the isogenic OMV-depleted strain. OMVs were found to be highly antigenic, as absorption of patient sera with OMVs greatly reduced reactivity with whole cells of P. gingivalis. LC-MS/MS analysis of OMVs revealed multiple forms of gingipains and several gingipain-related proteins. Western blots of OMVs using patient sera revealed a conserved immunoreactive antigen profile resembling the profile of OMV antigens that were recognized by gingipain antiserum, suggesting a potential role of OMV-associated gingipains in triggering antibody-mediated immune responses to P. gingivalis infection. When OMVs were added to a monolayer of an oral squamous epithelial cell line, OMVs caused cell detachment, which was inhibited by preincubating OMVs with anti-gingipain antiserum. These data suggest that gingipain-laden OMVs may contribute to tissue destruction in periodontal diseases by serving as a vehicle for the antigens and active proteases.

Experimental amoebic liver abscess in hamsters caused by trophozoites of a Brazilian strain of Entamoeba dispar

It has been claimed that amoebic molecules such as amoebapore, galactose/N-acetyl galactosamine inhibitable lectin, and cysteine proteases are responsible for host tissue destruction and are present in both pathogenic Entamoeba histolytica and non-pathogenic Entamoeba dispar. Some reports have provided evidence that after infection with E. dispar, pathological changes may occur in some humans. The aim of this study was to evaluate E. dispar pathogenicity by comparing it to the pathogenicity of E. histolytica through liver abscesses induced in hamsters. Syrian golden hamsters were challenged by intrahepatic inoculation with the 03C E. dispar strain or with two strains of E. histolytica (HM1:IMSS and EGG) to compare their virulence grades. As control groups, we used bacterial flora and Pavlova's modified medium. Lesions were verified at 1, 3 and 6 days after inoculation. Multiplex Polymerase Chain Reaction was performed to characterize each strain using EdP1/EdP2 and EhP1/EhP2 primers. The EGG and HM1:IMSS E. histolytica strains and 03C E. dispar were able to cause liver lesions. The EGG strain caused extensive hepatic abscesses, and trophozoites were found in the lesions throughout the three periods of study. The HM1:IMSS strain caused smaller abscesses when compared to EGG lesions; however, trophozoites were observed at 1 and 3 days after inoculation. The 03C E. dispar strain caused intermediate abscesses when compared to the others; trophozoites were observed in all periods analyzed. The EGG strain caused progressive evolution of the injury, which differed from the HM1:IMSS and 03C strains. These results strongly suggest that the 03C E. dispar strain is pathogenic in the experimental hamster model. Additional studies are necessary to identify potential factors that regulate the manifestation of virulence of this strain and others.

Toll-like receptors: A double edge sword

Innate immunity is the first line of host defense and represents inherited resistance to infection. Innate immunity works through toll-like receptors (TLRs), which recognize the conserved molecular patterns on pathogenic bacteria known as pathogen-associated molecular patterns (PAMPs). The periodontium is a unique environment in which oral microorganisms are in constant contact with the host immune system. The TLRs present on gingival epithelial cells are continuously stimulated, resulting in production of cytokines and defensins that help to maintain oral health. If the epithelial barrier is breached, allowing invasion of bacteria into the underlying connective tissue, the TLRs on other resident and non-resident cells of the periodontium become activated. This leads to an exaggerated release of pro-inflammatory cytokines and other biological mediators, which may cause host tissue destruction. Clinical Relevance to Interdisciplinary Dentistry Protecting periodontium during and after the restoration is very important. since, periodontal tissues are in continuous contact with oral microorganisms and through that to the host immune system. The TLRs present on gingival epithelial cells are continuously stimulated, resulting in production of cytokines that help to maintain oral health. If the epithelial barrier is breached, during the restorative procedures or due to impinging restorations, allowing invasion of bacteria into the underlying connective tissue, which may cause host tissue destruction.

Autoimmune Disorders: An Overview of Molecular and Cellular Basis in Today’s Perspective

Autoimmunity arises when immune responses mounted in the host are directed against self-components. Autoimmune diseases are pathophysiological states that result from a loss of self-tolerance and the consequent immune destruction of host tissues. Autoimmunity is mediated by a variety of molecular and cellular events, and responses. The development of an is a very complex process in which recognition of selfantigens by lymphocytes is centrally involved in pathologic organ damage. Autoimmune disease is inherited as a complex trait, with multiple loci controlling various aspects of disease susceptibility. More recently, some of these susceptibility genes have been identified. Certain environmental influences, such as cigarette smoke, ultraviolet light, or infectious agents, may interplay with this genetic predisposition to initiate the disease process. Silica exposure and its role in systemic lupus erythematosus (SLE) have been identified in studies of occupational exposure, and experimental studies have explored potential mechanisms related to immune dysregulation. Some autoimmune responses emerge following infection by a pathogen, whose protein(s) hold structural similarities to regions on proteins of the host. Thus, antibodies evoked against a pathogen might cross-react with a self-protein and act as autoantibodies, and the concerned autoantigen then provides a source for persistent stimulation. Evidence is emerging that activation of autoimmune B cells and T cells can be influenced by innate immune receptors, such as Toll-like receptors, which primarily recognize pathogen-derived molecular structures but may cross-react with host molecules. Proteins to which the immune system is generally self-tolerant might, if altered, elicit autoimmune responses. Potential involvement of chaperones in the induction of pathogenesis has also been explored. The contributions of microRNA to pathogenesis of autoimmune diseases like SLE are beginning to be uncovered and may provide us a new arena for exploration of mechanisms responsible for initiation and pathogenesis of autoimmune diseases.

Glycobiology Aspects of the Periodontal Pathogen Tannerella forsythia.

Glycobiology is important for the periodontal pathogen Tannerella forsythia, affecting the bacterium’s cellular integrity, its life-style, and virulence potential. The bacterium possesses a unique Gram-negative cell envelope with a glycosylated surface (S-) layer as outermost decoration that is proposed to be anchored via a rough lipopolysaccharide. The S-layer glycan has the structure 4‑MeO-b-ManpNAcCONH2-(1→3)-[Pse5Am7Gc-(2→4)-]-b-ManpNAcA-(1→4)-[4-MeO-a-Galp-(1→2)-]-a-Fucp-(1→4)-[-a-Xylp-(1→3)-]-b-GlcpA-(1→3)-[-b-Digp-(1→2)-]-a-Galp and is linked to distinct serine and threonine residues within the D(S/T)(A/I/L/M/T/V) amino acid motif. Also several other Tannerella proteins are modified with the S‑layer oligosaccharide, indicating the presence of a general O‑glycosylation system. Protein O‑glycosylation impacts the life-style of T. forsythia since truncated S-layer glycans present in a defined mutant favor biofilm formation. While the S‑layer has also been shown to be a virulence factor and to delay the bacterium's recognition by the innate immune system of the host, the contribution of glycosylation to modulating host immunity is currently unraveling. Recently, it was shown that Tannerella surface glycosylation has a role in restraining the Th17-mediated neutrophil infiltration in the gingival tissues. Related to its asaccharolytic physiology, T. forsythia expresses a robust enzymatic repertoire, including several glycosidases, such as sialidases, which are linked to specific growth requirements and are involved in triggering host tissue destruction. This review compiles the current knowledge on the glycobiology of T. forsythia.

Lifestyle transitions in plant pathogenic Colletotrichum fungi deciphered by genome and transcriptome analyses.

Colletotrichum species are fungal pathogens that devastate crop plants worldwide. Host infection involves the differentiation of specialized cell types that are associated with penetration, growth inside living host cells (biotrophy) and tissue destruction (necrotrophy). We report here genome and transcriptome analyses of Colletotrichum higginsianum infecting Arabidopsis thaliana and Colletotrichum graminicola infecting maize. Comparative genomics showed that both fungi have large sets of pathogenicity-related genes, but families of genes encoding secreted effectors, pectin-degrading enzymes, secondary metabolism enzymes, transporters and peptidases are expanded in C. higginsianum. Genome-wide expression profiling revealed that these genes are transcribed in successive waves that are linked to pathogenic transitions: effectors and secondary metabolism enzymes are induced before penetration and during biotrophy, whereas most hydrolases and transporters are upregulated later, at the switch to necrotrophy. Our findings show that preinvasion perception of plant-derived signals substantially reprograms fungal gene expression and indicate previously unknown functions for particular fungal cell types.

Inhibition of Human Neutrophil Elastase by α1-Antitrypsin Functionalized Colloidal Microcarriers

Layer-by-layer (LbL)-coated microcarriers offer a good opportunity as transport systems for active agents into specific cells and tissues. The assembling of oppositely charged polyelectrolytes enables a modular construction of the carriers and therefore an optimized integration and application of drug molecules. Here, we report the multilayer incorporation and transport of α(1)-antitrypsin (AT) by colloidal microcarriers. AT is an anti-inflammatory agent and shows inhibitory effects toward its pro-inflammatory antagonist, human neutrophil elastase (HNE). The highly proteolytic enzyme HNE is released by polymorphonuclear leukocytes (PMNs) during inflammatory processes and can cause host tissue destruction and pain. The high potential of this study is based on a simultaneous intra- and extracellular application of AT-functionalized LbL carriers. Carrier application in PMNs results in significant HNE inhibition within 21 h. Microcarriers phagocytosed by PMNs were time dependently decomposed inside phagolysosomes, which enables the step-by-step release of AT. Here, AT inactivates HNE before being released, which avoids a further HNE concentration increase in the extracellular space and, subsequently, reduces the risk of further tissue destruction. Additionally, AT surface-functionalized microcarriers allow the inhibition of already released HNE in the extracellular space. Finally, this study demonstrates the successful application of LbL carriers for a concurrent extra- and intracellular HNE inhibition aiming the rebalancing of protease and antiprotease concentrations and the subsequent termination of chronic inflammations.

Bacterial and Salivary Biomarkers Predict the Gingival Inflammatory Profile

The aim of this human investigation is to explore the relationship of gingivitis with salivary biomarkers, periodontal pathogens, and interleukin (IL)-1 polymorphism after a transient inflammatory burden. Thirty healthy human participants were randomized by IL-1 genotype status to control for potential influences of this particular single nucleotide polymorphism on the inflammatory profile. Oral hygiene practices ceased for 21 days to induce gingivitis (induction), after which home care was reinstated until 35 days (resolution). Clinical parameters included plaque (PI) and gingival (GI) indices and papillary bleeding score (PBS). Levels and proportions of 40 subgingival bacteria were determined using checkerboard DNA-DNA hybridization. Saliva was analyzed using a multiplex protein array for 30 biomarkers associated with host defense, inflammation, tissue destruction, and angiogenesis. Mean PI, GI, and PBS values were significantly increased during induction and decreased during resolution as measured at 35 days (P <0.01), although no differences were observed between IL-1 groups. Participants were stratified as either "high" or "low" responders based on inflammatory response (high: GI >1.5; low: GI ≤1.5). Baseline levels of salivary IL-6 and IL-8 demonstrated the highest ability to discriminate between high and low responders (area under the curve [AUC] of 0.81 and 0.72, respectively). Salivary biomarkers, matrix metalloproteinases (MMPs), and bacterial biofilm were combined to generate receiver operating characteristic curves. High levels of IL-6 and MMP-1 at baseline demonstrated the strongest ability to predict high responders (AUC of 0.89; odds ratio of 17.0; 95% confidence interval, 1.7 to 171.7). In this proof-of-concept investigation, we identified specific biomarker and microbial signatures that are associated with gingival inflammation (ClinicalTrials.gov number NCT00980525).

Inhibition of Cathepsin S Reduces Allogeneic T Cell Priming but Not Graft-versus-Host Disease Against Minor Histocompatibility Antigens

Cathepsin (Cathepsin) S, L, and B proteases mediate antigen presentation on major histocompatibility complex (MHC) class II by degrading the invariant chain Ii, which blocks peptide loading. The ability of the Cathepsin S inhibitor LHVS (morpholinurea-leucine-homophenylalanine-vinylsulfone phenyl) to impede antigen presentation has led its development as a therapy for autoimmune diseases. There is substantial evidence that donor T cell recognition of host minor histocompatibility antigens (miHA) and subsequent destruction of host tissue mediates graft-versus-host disease (GVHD). We hypothesized that enzymes involved in antigen presentation may play a role in the development of GVHD. Using the C57BL/6 → BALB.B minor mismatch acute GVHD (aGVHD) model, we found that the cathepsin S activity of spleens from allogenetically transplanted mice were significantly increased 1 week after transplantation compared with syngeneic mice. Although LHVS decreased T cell priming responses against both single OVA antigen and miHA invitro, LHVS did not reduce the severity of aGVHD. In fact, LHVS exacerbated a CD4(+)-T cell-dependent model of GVHD similar to chronic GVHD. This suggests that cytokines rather than T cells may mediate much of the damage in the aGVHD model and that therapeutics based on inhibition of antigen presentation for GVHD must be approached with caution.

HLA-Associated Hemorrhagic Fever with Renal Syndrome Disease Progression in Slovenian Patients

Major histocompatibility complex (MHC) class I and class II genes regulate the balance between appropriate aggressive responses and invading pathogens while minimizing the destruction of host tissue. Several studies have shown that in hemorrhagic fever with renal syndrome (HFRS) patients, the disease outcome is determined by a complex interaction between the virus and immunopathologic and human genetic factors. In Slovenia, the severity of the disease caused by Puumala virus (PUUV) is significantly lower than that of HFRS due to Dobrava virus (DOBV). We have determined 23 different HLA-B and 12 different HLA-DRB1 types in Slovenian HFRS patients. Comparison of HLA frequencies between healthy individuals and HFRS patients showed no strong association with the susceptibility for hantaviral infection. Significant associations were recognized when the patient group was separated according to the virus responsible for the infection. DOBV-infected patients have a significantly higher frequency of HLA-B*35 than PUUV-infected patients. For HLA class II genes, the biggest difference between the PUUV- and DOBV-infected groups of patients was in HLA-DRB1*13, where this phenotype was more frequent in PUUV-infected patients, especially in the severe form of the disease. HLA-B*07 could play a protective role in PUUV-caused HFRS in the Slovenian population. Our study shows diverse associations of HLA molecules with DOBV- and PUUV-induced HFRS, and therefore, we presume that different hantaviruses are presented differently through the same HLA molecules and that this might lead to either a more severe or a milder form of the disease. In line with this idea, we have noticed that HLA-B*35 might be a genetic risk factor for DOBV infection in the Slovenian population.

Cesium cessation? An advantage of pathogen reduction treatments

Cesium cessation? An advantage of pathogen reduction treatments

Gingipains produced by Porphyromonas gingivalis ATCC49417 degrade human-β-defensin 3 and affect peptide's antibacterial activity in vitro

Porphyromonas gingivalis, one of the major pathogen associated with periodontitis, is a highly proteolytic bacterial species. Production of proteases is a common microbial virulence factor that enables the destruction of host tissues and evasion from host defense mechanisms. Antimicrobial peptides are important effector molecules of the innate immune system with a broad range of antimicrobial and immunoregulatory activities. We and others have previously demonstrated that P. gingivalis is relatively resistant to the bactericidal activity of the human β-defensin 3 (hBD3). In this study, ability of proteases released by the pathogenic strain of P. gingivalis ATCC 49417 to degrade hBD3 and to affect the antibacterial properties of the peptide was assessed. P. gingivalis culture supernatants (CS) were found to degrade hBD3 in a concentration- and time-dependent manner. Such degradation was mainly due to the activity of Arg and Lys-gingipains, as pretreatment of CS with inhibitors selective for this class of proteases abolished CS ability to degrade hBD3. Importantly, preincubation of hBD3 with CS reduced peptide's antibacterial activity against a susceptible strain of Staphylococcus aureus, while the presence of gingipain inhibitors in the bactericidal assay increased P. gingivalis susceptibility to hBD3. Altogether these results suggest that gingipains may have a role in the resistance of P. gingivalis ATCC 49417 to hBD3.

Contribution of dendritic cell/T cell interactions to triggering and maintaining autoimmunity

Under healthy conditions, there is a balance between tolerance to self-tissue constituents and immunity against foreign antigens. Autoimmunity diseases (AD) take place when that equilibrium is disrupted and the immune response is directed to self-antigens, leading to injury or destruction of host tissues. The mechanisms conducing to the loss of immune tolerance remain largely unknown. The recent appearance of biological therapies has contributed to significant reduction in morbidity. However, currently available therapies are associated with important side effects and work only as palliative treatments. Dendritic cells (DCs) have emerged as key players in developing and maintaining adaptive immunity due to their capacity to prime and modulate T cell function. Therefore, because DCs work as central modulators of immune tolerance, it is likely that alterations in their function can lead to the onset of autoimmune-inflammatory diseases. By modulating DC function, novel pathways in antigen-specific tolerance could be established. In this article, the possible contribution of altered DC-T cell interactions to the onset of autoimmunity are discussed. In addition, we expand on the notion that some of the functions of these cells could be relevant targets for intervening therapies aimed to restore the balance or even prevent the loss of tolerance.

Toll-like receptors and their dual role in periodontitis: a review

Innate immunity is the first line of host defense and represents inherited resistance to infection. Innate immunity works through toll-like receptors (TLRs), which recognize the conserved molecular patterns on pathogenic bacteria known as pathogen-associated molecular patterns. The periodontium is a unique environment in which oral microorganisms are in constant contact with the host immune system. The TLRs present on gingival epithelial cells are continuously stimulated, resulting in production of cytokines and defensins that help to maintain oral health. If the epithelial barrier is breached, allowing invasion of bacteria into the underlying connective tissue, the TLRs on other resident and non-resident cells of the periodontium become activated. This leads to an exaggerated release of pro-inflammatory cytokines and other biological mediators, which may cause host tissue destruction. The present review examines the role of TLRs and their signaling in periodontal health and disease.