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A multi-color flow cytometric assay was developed to evaluate TLR responses in different PBMC subsets. Using PBMCs, the TLR ligand concentrations were titrated in the range suggested by the manufacturers and previous studies. After the addition of IL-12, we observed that all the TLR agonists, except type C ODN M362, enhanced substantially the IFN-γ production in isolated NK cells (Fig. The IFN-γ responses of isolated NK cells from one donor stimulated with TLR-ligand alone or with the addition of IL-12 for 24 hours are demonstrated as a representative. In monocytes, mDCs, pDCs, and B cells, the TNF-α responses to TLR ligands were similar when BFA was added immediately prior or half an hour later to TLR agonists (Fig. Next, we sought to validate the assay for cryopreserved cells, since it could be applied to more clinical specimens that were properly cryopreserved. Interestingly, we observed Pam3Cys-hyporesponsiveness in non-purified NK cells of 5 donors (Fig.
Pam3CSK4-induced responses of monocytes, myeloid DCs (mDCs), and NK cells detected in PBMC, and the response of isolated NK cells in 5 donors are demonstrated. At this point we have optimized the conditions of our assay for the evaluation of TLR responses in different subsets of human PBMCs. As described in the previous paragraphs, TLR agonists triggered negligible IFN-γ secretion in freshly isolated NK cells without the addition of co-stimulatory cytokines. Collectively, these results demonstrate that IL-12-preactived NK cells respond to TLR ligands and that the magnitude of this response varies between individuals. In the second part of my project, TLR responses in subsets of PBMCs were examined in people with histories of recurrent HL. TLR ligand-induced TNF-α production in monocytes, myeloid DCs, plasmacytoid DCs, and B cells were compared within the PBMC population of asymptomatic healthy controls (n= 8) and HL subjects (n= 9) (Fig.
In order to exclude the possibility that the observed TLR-hyporesponsiveness is merely due to an enhancement of a subtle defect in the responsiveness to IL-12 alone, we have compared the IFN-γ production of NK cells in controls and HLs after different doses of IL-12 stimulations.
Therefore, our data suggest that the observed poly(I:C)-hyporesponsiveness of purified NK cells from HL subjects might be due to a specific defect in NK cells involving TLR3 signaling. We next examined by flow cytometry the percentage of NK cell subsets within PBMCs of individuals with and without recurrent HL.
Differential NK cell responsiveness to poly (I:C) has been suggested to be associated with the heterogeneity of TLR3 mRNA transcripts [88].
To characterize the functional impact of TLR3 L412F SNP on NK cells, we evaluated the TLR3 expression and response to poly(I:C) in subjects with different genotypes.
To study if there is an association of HL with TLR3 L412F polymorphism, we genotyped subjects with and without histories of recurrent HL for TLR3 L412F by PCR and subsequent melting curve analysis. In previous sections we have compared the TLR responses of people with recurrent HL with TLR functions of HSV-1-seropositive asymptomatic controls. These data suggest that the TLR3 response of NK cells might be important not only in controlling symptomatic HSV-1 reactivations, but also in protecting from primary HSV-1 infections. It is known that HSV-1 proteins interfere with cellular interferon- and TLR- responses, thereby promoting viral replication [90,91,92]. Taken together, these results suggest that NK cells are under most stimulation conditions resistant to HSV-1 infection. Isolated NK cells were infected with GFP-expressing recombinant HSV-1 (MOI=25) after pre-activation with IL-2 and PHA for 24 h. Reduced NK cell percentages and diminished TLR3-induced IFN-γ production were the most prominent findings we observed in subjects with recurrent HL. Degranulations of isolated NK cells from (A) 2 TLR high responders (asymptomatic controls) and (B) 2 TLR low responders (individuals with HL history) are shown. As mentioned in the introduction, NK cells can be divided into CD56dim and CD56bright subsets.
In resting NK cells, the percentage of CD56bright subsets is similar between HL subjects and asymptomatic controls (Fig. Similar to the findings of poly(I:C)-hyporesponsiveness in total NK cells, the diminished R-848 response of CD56bright NK cells derived from HL subjects could be restored when assessed within PBMCs (Fig. These results suggest that soluble factors secreted from accessory cells could restore the reduced R-848-response in CD56bright subsets.
Monocytes were stimulated with other cells of PBMC for 4 hours with medium only (Med) or with different concentrations of Pam3Cys for 4 hours. It has been reported that DCs recognizes HSV via TLR9 and TLR2, which forms hetero-dimmers with TLR1 or TLR6 [6]. To further characterize the impact of TLR1 I602S on the course of gastric cancer, we evaluated the association of TLR1 SNP genotype with the percentage of patients who had distant metastasis when gastric cancer was diagnosed. Now, HSV is reportedly set to launch a new Maloo variant that could smash the previous Maloo R8’s record. In addition to the engine, the Maloo GTS would also pick up the rest of the performance upgrades offered on the GTS sedan.
Unfortunately, only 150 examples are destined to be built before production of its donor car, the Holden Commodore, comes to an end in 2017. A 36-year-old female presented to the Emergency Treatment Center (ETC) of the University of Iowa Hospitals and Clinics (UIHC) with one day of right eye pain, photophobia and decreased vision.
The following day, her symptoms did not resolve and was therefore referred to the UIHC Cornea service for further evaluation.
During the first ten days of treatment, all subjective symptoms resolved with the exception of mild blurring of vision. She returned for routine follow-up one month after discontinuation of topical corticosteroids. HSV keratitis can present with involvement of the corneal epithelium, stroma, or endothelium, with or without associated inflammation of the anterior chamber (Table 1).[1-4] Pathophysiologic manifestations may be related to the presence of live virus, immunological reactions to viral antigen, or secondary to previous herpetic injury ("metaherpetic"), particularly the loss of corneal sensation. The diagnosis of HSV keratitis is primarily clinical, although additional tests may be useful in providing confirmation, but never exclusion.[1-4] The Tzanck (Giemsa) smear of multinucleated epithelial cells is a quick test with high specificity but low sensitivity. HSV epithelial keratitis invariably involves active viral proliferation.[1-4] The classic epithelial dendrite is the most common presentation of epithelial disease (Figure 1).
HSV stromal keratitis is associated with the highest and most severe morbidity of any ocular herpetic disease.[1-4] Although this condition frequently follows previous HSV epithelial keratitis, it can be the initial presentation of ocular herpetic disease. HSV disciform (endothelial) keratitis is a cell-mediated immune reaction to corneal endothelial tissue that presents with diffuse stromal edema.[1-4] In approximately half of cases, there is no prior history of HSV epithelial keratitis.
HSV keratouveitis may occur as a separate entity or in association with herpetic epithelial, stromal, or endothelial disease.[1-4] It may be granulomatous or non-granulomatous and may, in some cases, be associated with live virus (Figure 6).
Metaherpetic manifestations of HSV keratitis include neurotrophic keratopathy and microbial (i.e.
Although HSV epithelial keratitis is self-limited in most cases, the rationale for aggressive antiviral therapy is to prevent corneal nerve damage and potential future immunologic disease.[1] Prior to the advent of antiviral therapy, simple epithelial debridement was the treatment of choice.
The most common mistake in the management of HSV keratitis is premature termination of topical steroid therapy. In our clinics, the taper for stromal keratitis and keratouveitis is only one-third complete when it has been reduced to prednisolone acetate 1.0% once daily. Our preferred steroid use and taper regimens are based upon whether or not the patient is a steroid-responder. The introduction of oral antiviral prophylaxis constituted a major advance in the management of chronic herpetic eye disease.


There are no uniformly accepted guidelines governing the use of antiviral prophylaxis in conjunction with topical corticosteroid use in situations where live viral manifestations are not present. Late surgical intervention is indicated for management of intractable corneal pain or visual impairment associated with herpetic disease. Stromal keratitis- Acute: mid-deep stromal infiltrate with intact epithelium and minimal necrosis. In order to decrease the influence of cytokines secreted by bystander cells and at the same time measure the TLR response that is closest to in vivo biology, we added BFA to the whole PBMC population along with TLR ligands in some experiments.
The frequency of IFN-γ positive cells was compared to samples treated with IL-12 alone (Fig.
Since NK cells are critical components of HSV-1 infections, we further examined specific TLR ligand-induced responses in isolated NK cells in detail. It has been reported that IL-12 has synergistic effects with TLR agonists and can promote IFN-γ production in NK cells [57]. Each dot represents a result measured at the same time point on date 1 or date 2, and different symbols indicate NK cell responses to different TLR ligands. Representative FACS graphs of IFN-γ-producing NK cells in response to different TLR agonists in one control and one HL subject are shown.
Interestingly, people with HL showed significantly lower frequencies of NK cells in the lymphocyte population (median, HL vs.
In order to find out if the ability to respond to poly(I:C) stimulation is correlated with the level of TLR3 in resting NK cells, we evaluated the amount of TLR3 via flow cytometry. Of the 51 HL subjects and 53 controls genotyped in this study, we found a trend of higher mutant allele frequency in people with HL (38.2% vs.
During the course of our studies we identified 6 individuals without HL histories, who were HSV-1 seronegative. Therefore, the reduced TLR3 response observed in NK cells of HL subjects is less likely to be due to the suppressive effect of direct HSV-1 infection. Infected NK cells were examined via fluorescence microscope (upper panel) and flow cytometry (lower panel). To address the possibility that other NK cell effector functions in HL subjects were also impaired, we studied the cytotoxic potential of isolated NK cells in 2 HL subjects whose NK cells showed hyporesponsiveness to poly(I:C) stimulations, and compared the results with those of 2 asymptomatic healthy controls whose NK cells were highly responsive to all TLR agonists. In the HL group, addition of monocytes, DCs, and supernatant from R-848-activated PBMCs increased the level of CD56bright cell response to R-848. NK cells (CD56dim and CD56bright subsets) analyzed within PBMCs of both the asymptomatic controls and the HL group produced substantial amount of IFN-γ in response to HSV-1 lysate (Fig.
Remarkably, patients carrying the variant TLR1 602S allele showed increased frequency of gastric cancer metastasis at the time of diagnosis, as compared to wild type-allele carriers (P = 0.04, Table 6). According to Carsguide, HSV is planning a new Maloo GTS model, which would feature General Motors Company’s [NYSE:GM] LSA V-8 found in HSV’s GTS sedan as well as the Chevrolet Camaro ZL1. These include extra engine and transmission cooling, a high-strength differential and tailshaft, Magnetic Ride suspension, a launch control system, 20-inch wheels and AP Racing brakes with six-piston, forged aluminum calipers.
Pictured above is the current Maloo R8, which features GM's LS3 V-8 and is rated at 435 hp and 405 lb-ft of torque. Slit lamp photo demonstrating classic epithelial dendrites in our patient after fluorescein staining.
Most cases (> 90%) are unilateral, but bilateral cases may occur, especially in atopic or immunocompromised patients. It represents areas of epithelial breakdown due to cell destruction by proliferating virus and is best demonstrated after fluorescein staining under cobalt blue lighting.
The vast majority of cases are an immune stromal keratitis (ISK), which involves the antibody-complement cascade against retained viral antigens in the stroma. Accordingly, acute-onset, unilateral corneal edema should be considered to be due to herpetic eye disease unless proven otherwise. A guiding principle is that prior to the onset of immune-mediated disease, control and elimination of epithelial manifestations is the highest priority. Our experience is that the optimal initial frequency is hourly for NSK, every two hours for ISK, and every three hours for disciform keratitis. In such cases, there is almost invariably a reappearance of corneal inflammation that is mislabeled as "recurrent" disease, when, in fact, it is actually a "pseudo-recurrence" that is merely a continuation of the same immunological reaction that has now become clinically apparent due to therapeutic withdrawal. Due to the very high benefit-to-risk ratio associated with oral antiviral therapy, it is our preference to use these medications in every instance in which topical corticosteroids are utilized.
For painful eyes without visual potential, a Gunderson flap will reduce chronic inflammation and eliminate pain. Full dose oral antiviral followed by prophylactic oral antiviral (for 1 year up to indefinitely). For detecting the APCs, PBMCs were first gated according to the forward and sideward scatters (Fig. The double negative population was then gated on BDCA1 (marker for mDC) and BDCA2 (marker for pDC). Instead of adding BFA 30-60 minutes after TLR stimulation in the antigen-presenting cell panel, BFA was added with TLR ligands at the beginning of incubation for 4 hours. Interestingly, when BFA was added together with TLR stimulators, the responses of NK cells to TLR ligands were much lower (Fig. Isolated NK cells also produced substantial amounts of IFN-γ in response to these TLR agonists (Fig.
Monocytes and myeloid DCs (mDCs) detected in the PBMC of these 5 donors, however, showed enhanced TNF-α production to Pam3Cys stimulations (Fig.
Representative FACS graphs of TLR-triggered IFN-γ responses in CD56bright NK subset are shown in Fig.
Similarly, IFN-γ responses triggered by TLR1-8 agonists in NK cells and CD8+T cells were also evaluated in the 2 groups. The background production of TNF-α in unstimulated sample of the APC panel had been subtracted. Percentages of IFN-γ-positive cells are marked in the right upper corner of each graph. The authors also showed that 293T cells transfected with L412F had lower surface expression compared to wild type [89]. Of note, 5 of the seronegative donors were TLR3 wild type, with the other one being TLR3 L412F heterozygote.
Cytotoxic response was detected by degranulation as assessed by CD107a surface expression after co-incubations of IL-12-preactivated NK cells with the NK-target K562 cells (Fig.
Co-incubation experiments of NK cells with monocytes, DCs, or supernatant of R-848-activated PBMCs were performed to determine the co-stimulatory factor. Therefore, we wanted to further analyze if the IFN-γ response of NK cells to HSV-1 is impaired in HL subjects.
Mann-Whitney U test was performed to compare the responses between the homozygous people and the combination of individuals with wild type and heterozygous alleles.
Therefore, the TLR1 I602S SNP impairing the IFN-γ responses of NK cells and CD8+T cells might play a role in the susceptibility to gastric cancer. Of note, the TLR1 I602S heterozygotes, who did not show elevated risks for primary gastric cancer, also exhibited higher frequencies of metatstasis in comparison to wild type patients. That was enough to take the record from the Dodge Ram SRT-10, which in 2004 hit 154.59 mph.


In chronic cases, demonstration of decreased sensation by Cochet-Bonnet aesthesiometry can be helpful in differentiating true recurrent dendritic keratitis from pseudo-dendritic keratitis, especially that related to recurrent epithelial erosions.
The presence of keratouveitis mandates a thorough funduscopic examination to exclude concomitant acute retinal necrosis. However, once immune-mediated disease has been established, management of stromal or endothelial manifestations, with their potential for irreversible visual impairment, has higher priority than control of epithelial disease. However, corneal toxicity related to the topical antivirals available in the United States led to a preference on the part of many specialists to rely exclusively on equally effective systemic therapy.
If concomitant epithelial disease is present, full systemic antiviral dosing is also required since steroid therapy exacerbates this condition. For eyes with post-herpetic scarring and good visual potential, the surgical procedure is based upon the corneal pathology. Moreover, the optimal concentrations of poly(I:C) and CpG oligonucleotide were determined as the ones to induce the maximal cytokine production of myeloid DCs and plasmacytoid DCs, respectively.
Furthermore, IFN-γ secretion in NK and T cells represents an important effector function in antiviral defences.
The response to poly(I:C) of NK cells in the PBMC increased almost 2-fold following IL-12 priming. Because antigen-presenting cells can provide signals to NK cells and T cells via soluble factors or cell contact [86,87], we investigated the NK cell response to TLR ligands in both purified and un-separated populations. Box-whisker plot represents median, minimum, and maximum frequencies of IFN-γ positive cells from 18 donors. No statistically significant difference in the frequency of cytokine-producing cells was found. The data suggest that NK cell hyporesponsiveness to poly(I:C) could be restored by accessory cells in the PBMCs.
The percentage of GFP-positive, and therefore infected, NK cells is given in the upper right corner. Interestingly, besides the stimulating effect of monocytes and DCs, the addition of R-848-activated supernatant alone could largely increase the IFN-γ response of CD56bright NK cells in HL subjects (Fig. 19B, IL-15 could increase the R-848-responsiveness of CD56bright NK cells in these individuals. Supernatants of HSV-1-uninfected and -infected NK cells were collected for detection of IFN-γ.
Monocytes derived from subjects homozygous for 602S were found to have decreased TNF-α production in response to Pam3Cys, due to impaired receptor trafficking [40].
In accordance with the functional data, the frequency of TLR1 602S allele was not higher in HL subjects.
The information about the presence of H pylori was unavailable in this gastric cancer cohort. There was, however, patchy anterior stromal inflammation in the visual axis that did not resemble the characteristic post-dendritic "footprints" and was felt to represent early immune stromal keratitis (Figure 2).
On examination, the epithelium was intact but there was mild patchy anterior stromal haze in the same distribution in the visual axis as before. Bacterial and fungal cultures, along with confocal microscopy, can be used to rule out other etiologies of microbial keratitis. Our preference is to use acyclovir 400 mg PO five times daily or valacyclovir 1000 mg PO three times daily. Phototherapeutic keratectomy may be utilized as a keratoplasty-sparing intervention for superficial corneal scarring. CD3+ cells derived from the lymphocyte gate are T cells, and CD3-CD56+ population are NK cells, which were further divided into CD56bright (<10% of total NK cells) and dim subsets. R-848, a ligand for TLR7 and 8, triggered the biggest TNF-α production in every cell population. The TLR9 agonist ODN M362 (invivoGen), however, did not trigger IFN-γ response in isolated NK cells either in the presence or absence of IL-12 (data not shown). Frequencies of IFN-γ-producing cells in response to TLR-ligands were compared between NK cell subsets in Fig. The IL-12-enhancecd increase of CD107a levels was not lower in the 2 HL subjects (low responders) as compared with the 2 controls (high responders) (Fig.
In order to rule out indirect TLR responses mediated by accessory cells within PBMCs, NK cells were further isolated.
We did not detect any significant association of the allele frequencies with gastric cancer (Table 4). Treatment was initiated with topical prednisolone acetate 1.0% QID, while maintaining antiviral and prophylactic antibiotic coverage. There are unsubstantiated concerns that this procedure may be associated with activation of immunological stromal keratitis; in any case, perioperative use of full antiviral therapy followed by a prolonged prophylactic course obviates this issue.
Cells negative for both CD14 and CD19 were further divided into BDCA-1+ cells and BDCA-2+ cells, and were defined as myeloid DCs and plasmacytoid DCs, respectively. And consistently, ODN M362, a type C oligonucleotide containing unmethylated CpG motif, showed the specific ability to stimulate TNF-α secretion in pDCs and B cells.
Mann-Whitney U test showed no significant difference of TLR responses of PBMC subsets between the two groups.
11G), indicating that there is no obvious general defect in the ability of NK cells from HL subjects to produce IFN-γ.
There was no peripheral stromal vascularization, perineuritis, endothelial or anterior chamber inflammation.
Although most practitioners prefer a short course of therapy, we treat our patients for a total of 14 to 21 days to ensure complete eradication of replicating organisms.
For deeper stromal scarring, penetrating or deep anterior lamellar keratoplasty are the procedures of choice. Therefore, TLR-ligand induced TNF-α production was determined as the final read-out of the APC panel of the assay. However, in accordance with a previous study [57], further addition of the TLR3 agonist did not increase the IL-12-induced cytotoxicity in both groups (shown as a representative histogram in Fig. We therefore compared the TLR1 genotype frequency between patients with cardia- and non-cardia gastric cancers (Table. After successful treatment, therapy can be discontinued without tapering, unless long-term prophylaxis is used (see below; antiviral prophylaxis). The prognosis for graft survival has improved dramatically over the last quarter century since the introduction of oral antiviral prophylaxis. This can be attributed to reduced recurrence of herpetic epithelial keratitis, a condition that is frequently associated with acute endothelial rejection episodes. Neither ISK nor NIK is self-limited and failure to provide appropriate pharmaceutical intervention will result in progressive corneal scarring and visual impairment.
In the unusual situation of corneal endothelial decompensation due to neglected or recalcitrant endothelial keratitis, endothelial keratoplasty can be performed if stromal disease has not been present.



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