We next examined whether a fusion protein could have biological effects in vivo. For these experiments, we used a system developed previously, in which tumour cells injected intraperitoneally rapidly and preferentially attach and grow initially on the milky spots, GDC-0980 a series of organized immune aggregates found on the omentum.38 This system offers a convenient way to examine the effects of fusion protein

treatment on tumour growth because fusion protein can be delivered intraperitoneally multiple times and tumour growth can be analysed by examining the dissociated omental cells. For these experiments we used the Colon 38 cell line, a rapidly growing tumour cell line that expresses both MMP2 and MMP9 in vitro (Fig. 6a). The omental tissue normally expresses a relatively small amount of

MMP2 and MMP9 but when Colon 38 tumour is present on the omentum, MMP levels increase (Fig. 6b). Using this tumour model, we examined the ability of the IL-2/MMPcs/IL-2Rα fusion protein to affect tumour growth. Colon 38 cells were injected intraperitoneally, allowed to attach and Vismodegib grow for 1 day, and then treated daily with fusion protein intraperitoneally. At day 7 the animals were killed and the omenta were examined for tumour growth using flow cytometry and by a colony-forming assay (Fig. 6c–e). Figure 6(c) illustrates the gating scheme employed to analyse the tumour population present on the omentum by flow cytometry and panels I, II and III represent plots of single mice from each of the three test groups studied. Figure 6(d) illustrates the compiled flow cytometry data obtained from the individual mice. We found that treatment with the fusion protein can reduce tumour growth in vivo. In the mice that received

tumour and fusion protein treatment (group I), there was a significant decrease (P < 0·01) in the percentage of tumour cells detected on the omenta compared with the mice, which were inoculated with tumour but not treated with fusion protein (group II Fig. 6d). As expected, there was a substantial fraction of cells in the tumour gate in mice that received tumour but were not treated with fusion protein (Fig. 6c panel II) and a very low fraction of cells in the tumour gate of mice that did not receive tumour (Fig. 6c panel III). Similar results were obtained when the presence Selleckchem Cobimetinib of tumour cells was assessed using a colony-forming assay33 in which cells isolated from the omentum were tested for their ability to form colonies in vitro. These compiled data are shown in Fig. 6(e). Again, a significant difference was observed (P = 0·0119) between the fusion-protein-treated mice and the vehicle-treated mice in the number of viable tumour cells present on the omenta. Hence, in both the flow cytometry and the colony-forming assays there was a clear decrease in the tumour burden with fusion protein treatment although it should be noted that the decrease was not evident in all the treated animals.

This study aims to elucidate the role of radiation induces Akt expression in regulatory T cells (Tregs). The surgically removed BCa tissue was collected from 26 patients treated with or without radiotherapy. The frequency of Tregs and apoptotic Tregs in BCa tissue was assessed by

flow cytometry. A cell culture model was employed to investigate the mechanism by which the tumour-infiltrating Tregs survive from radiation. After radiotherapy, the frequency of Treg was increased in the BCa tissue; the apoptotic Tregs were decreased; the expression of Akt was increased in remained Tregs. The results were reproduced in vitro with a cell culture model. The addition of Akt inhibitor blocked the radiation-induced Treg survival in Ku-0059436 mw culture. Akt plays an important

Staurosporine datasheet role in the radiation-induced tumour-infiltrating Treg survival in BCa. The bladder carcinoma (BCa) is the fifth most common cancer, which accounts for 85-90% of the primary carcinomas with increasing incidence worldwide [1, 2]. Although the research on BCa was advanced rapidly in the last decade, the pathogenesis of BCa remains unknown; the prognosis of patients with BCa is unsatisfactory [3]. Regulatory T cells (Tregs) are a subtype of T cells. A majority of Tregs is CD4+ CD25+ Foxp3+ Tregs [4]. Tregs express a set of immune suppressive molecules, such as transforming growth factor (TGF)-β and interleukin (IL)-10, to suppress other effector T cells’ activities [5]. Thus, Tregs are an important cell population in the maintenance of homoeostasis in the body. On the other hand, Tregs also suppress the activities of the antitumour immune cells, such as cytotoxic CD8+ T cells [6]; cancer cells thus get the chance to grow. Some investigators propose to get rid of Tregs from the body, using monoclonal anti-CD25

antibodies to promote the therapeutic effect of cancer Adenosine triphosphate [7]. How the increase in tumour-infiltrating Tregs occurs is unclear. Protein kinase B is also known as Akt. Akt is a serine/threonine protein kinase that plays an important role in a number of cellular processes such as glucose metabolism, cell proliferation, apoptosis, transcription and cell migration. Cumulative reports indicate that Akt plays an important role in cancer cell survival [8]. Direct inhibition of the serine/threonine kinase Akt provides another avenue to pharmacologically suppress tumour cells’ activity [9]. Yet, whether the expression of Akt in cancer tissue has any association with Treg survival is unclear. Thus, we collected surgically removed BCa tissue and found an increase in Akt expression in the tumour-infiltrating Tregs, which greatly promoted the Treg’s survival. Reagents.  The fluorescently labelled antibodies were purchased from BD Bioscience (Shanghai, China). Monoclonal antibodies of Foxp3, CD4, CD25, Akt, CD3 and CD28 were purchased from Santa Cruz Biotech (Santz Cruz, CA, USA).

In addition, as our study suggests, IL-15 is unlikely to be the only stimulus that determines the extent of NK-cell expansion. We found that stimulation with IL-15 had a profound impact on NK cells, but that the kinetics and the extent of activation were readily enhanced by addition of other cytokines. Addition of SCF accelerated the IL-15 induced downregulation of c-kit, whereas the combination of IL-7 and IL-15 downregulated

CD127 even more profoundly than IL-15 alone (data not shown). Hence, SCF, Cabozantinib cost IL-2, IL-7 and perhaps multiple other stimuli present in the plasma of transplanted patient may modulate the effect of IL-15 and conceal the direct relationship between IL-15 and the extent of NK-cell expansion. Our data show that the “aberrant” NK-cell phenotypes as well as the reversed CD56bright/CD56dim observed after HSCT 27–30, 32, 33 can be attributed

ZD1839 to activation and subsequent expansion of CD56bright. Because we found no correlation between the number of ptCD56bright and CD56dim, we find it unlikely that the bulk of ptCD56bright are NK cells maturing toward CD56dim. Moreover, we observed that patients with high numbers of ptCD56bright could have low numbers of CD56dim for a prolonged period of time and that the number of ptCD56bright could remain high for as long as 6 months in patients with slow T-cell recovery (data not shown). Obviously, our data do not exclude that part of ptCD56bright mature into CD56dim nor suggest that CD56bright circulating in peripheral blood and lymph nodes cannot be the precursors of from CD56dim. They do show, however, that the level of expression of c-kit and CD127, two receptors often used as markers to define distinct NK-cell lineages 37, 38 or different NK-cell subsets 4, 9, 12, 15, 17, 19 may simply reflect the cytokine level of the environment they have been isolated from and that caution should be taken to interpret low c-kit- or CD127-levels as proof of maturation of CD56bright toward CD56dim. Patients (eleven AML, five ALL, six CML, one CLL, two MDS, two HL and two NHL) received PBSC from related (n=14) or unrelated (n=15) donors after standard intensity (n=24)

or reduced intensity conditioning (n=5) combined with ATG if the donor was unrelated. Twenty-three patients received grafts depleted by Alemtuzumab in vitro followed by T-cell add-back on day+1 as described previously 53. GvHD prophylaxis was by Cyclosporine combined with Methotrexate or with Mycophenolate Mophetil after reduced intensity conditioning. Sequential analysis of mixed chimerism 54 showed that all hematological lineages were of donor-origin except for T cells that could be of mixed origin during the first 6 months. Sixteen healthy individuals donating blood at our Blood Transfusion Center served as normal controls. Our institutional ethics committee approved the research and patients gave informed consent.

Methods:  We retrospectively reviewed the serology of BBV in a longitudinal fashion in the haemodialysis-dependent population treated in the TENT of Australia from 2000 to 2009 inclusive. HBV, HCV, HIV and HTLV serology on commencement of dialysis and at exit or January 2010, whichever was earlier, as well as demographic details were collected. Patients with a change in serological status had all serology reviewed. Results:  Four-hundred and forty patients were included in the analysis. Of these, 84.3% were Indigenous and 55.4% female, with a median age of 50 (IQR 43–59) years at the commencement of haemodialysis. Evidence of past HBV infection was

documented in 42.7% and 8.9% were hepatitis B surface AZD1152HQPA antigen-positive. Positive serology for HTLV was documented in 2.2%, 1.6% were hepatitis C antibody-positive Selleckchem NU7441 and no individual was HIV-positive. Three patients had a definite change in their HBV serology over time; this equates to an absolute seroconversion

risk of 0.1 per 100 person years or 0.0006 per dialysis episode. Conclusions:  In this cohort, there was a high rate of past and current hepatitis B infection but low rates of seroconversion while on haemodialysis. “
“NAGAHARA YASUKO, SATO YUKA, SUZUKI YASUHIRO, KATO NORITOSHI, KATSUNO TAKAYUKI, OZAKI TAKENORI, KOSUGI TOMOKI, SATO WAICHI, TSUBOI NAOTAKE, MIZUNO MASASHI, MARUYAMA SHOICHI, ITO YASUHIKO, MATSUO SEIICHI Department of Nephrology, Nagoya University Graduate School of Medicine Introduction: Atypical Hemolytic Uremic syndrome (aHUS) is a rare thrombotic microangiopathy that results from dysregulation of the complement system. We describe an adult

patient, with L-gulonolactone oxidase plasma-exchange refractory aHUS and renal failure, who was successfully treated with eculizumab. Case report: Our patient was a 35-years-old male. Hypertension was pointed out in health examination 3 months before hospitalization. He visited the previous hospital because of presenting of low grade fever, general fatigue, and facial edema, and was hospitalized immediately. His laboratory evaluation revealed acute renal failure (S-Cr 3.75 mg/dl), anemia (Hb 11.3 g/dl), thrombocytopenia (6.8 × 104/μl), elevated LDH, and schistocytes on peripheral blood smear. ADAMTS13 activity level was 111%. He had a diagnosis of aHUS. From the next day of hospitalization, daily plasma exchange (PE) and steroid therapy ware performed. After several days of PE, his platelet count improved to normal range. However, when the frequency of PE wes reduced, he developed a worsening thrombocytopenia, and presented low grade fever, general fatigue, and purpura again. Then, he was transferred to our hospital to be treated with eculizumab.

There is a growing body of literature on the symptom management of patients with ESKD. Patients need clear information about the potential effects dialysis and non-dialysis pathways on symptom burden and how this can change BVD-523 manufacturer with time. Standardization of tools used to collate information about symptoms can assist in the provision of information to patients. We recommend the Patient Outcome Scale symptom module (Renal Version) tool (accessible via the kcl.ac.uk website) for assessing symptom burden. Patients with end-stage kidney disease (ESKD)

whether or not on renal replacement therapy (RRT) have considerable prevalence of symptoms. Indeed this group is among the most heavily burdened of any disease group.[1-3] A large, systematic review of prevalence studies of symptoms,[4] experienced by dialysis patients showed a significant burden of symptoms.

A subsequent study by the same group found a similar prevalence of symptoms in patients being managed conservatively.[5] A summary of the results of those studies appears below in Table 1. In addition to individual symptoms, it is important to note that patients may experience multiple symptoms simultaneously. These may be from multiple sources, some from the renal failure (e.g. pruritus and restless legs), from comorbidities (e.g. diabetic peripheral neuropathy, RXDX-106 datasheet diabetes-related gastroparesis, angina) or be related to dialysis therapies (intradialytic hypotension, cramping, sleep disturbance from automated peritoneal dialysis alarms). Also, the interaction

of individual symptoms may exacerbate other problems. For example, the simultaneous presence of nocturnal Thalidomide uraemic pruritus, restless legs syndrome and pain secondary to arthritis, may result in significantly disturbed sleeping, in turn leading to daytime somnolence and enhanced fatigue. Symptoms experienced by patients with ESKD are consistently underassessed and inadequately managed. In addition to the experience of the individual symptom itself, some symptoms (e.g. uraemic pruritus) have been shown to be associated with reduced quality of life and a shortened life expectancy.[6] Symptom burden is likely to alter and increase over time for patients choosing either a dialysis or non-dialysis pathway and therefore needs to be regularly reassessed. In the experience of the St George’s Hospital Renal Unit, New South Wales, in approximately one-fifth patients, symptoms are not improved by initiation of dialysis. In the Renal Supportive Care clinic at this unit, two-thirds of the patients who attend are on dialysis and one-third are following the Renal Supportive Care pathway, showing also the symptom burden of those dialysing. Anecdotally, some patients may have very few symptoms, regardless of management choice and stage of disease.

Furthermore, FISH is not a stand-alone technique in the diagnostic setting, as culture is still used for antibiotic susceptibility testing. While traditionally the probes for FISH were based on single this website stranded DNA, another set of probes increasingly used in diagnostics are based on a polyamide ‘peptide’ backbone (Egholm et al., 1993; Bjarnsholt et al., 2008). PNA FISH probes abide by Watson/Crick

pairing but possess unique hybridization characteristics because of their uncharged chemical backbone, including rapid and stronger binding to complementary targets compared with traditional DNA probes. PNA probes can also be used with unfixed biological samples; however, only a limited number of probes are currently available, restricting the use of PNA FISH for the present. CLSM and FISH emphasize that demonstrating biofilm spatial organization is extremely important to: (1) identify whether the bacteria present are aggregated, (2) indicate a polymicrobial nature of a biofilm, (3) indicate the extent of biofilm on a surface that CFU may vastly underestimate, and (4) to show biofilm EPS that may comprise a greater

part of the biofilm than cells alone. On nonbiological, flat surfaces, biofilm spatial organization can best be measured by various parameters using image analysis software. The most common program is comstat that yields a number of spatial parameters including thickness, biovolume, check details and roughness (Heydorn et al., 2000). Quantification of biofilm spatial organization is harder Methocarbamol however in clinical specimens that usually have a complicated and convoluted surface geometry, and currently is largely descriptive

or qualitative in these samples – that is, data showing cells or clusters per unit area without a good method to quantify spatial dimensions. As comstat thresholding does not work well on tissue backgrounds, quantifying the biofilm involves a manual rendering of biofilm images in other software to resolve bacteria and laborious cell counting, particularly if NA probes are used because they stain host cell nuclei as well as bacterial DNA (Nistico et al., 2011). Resolving biofilm spatial organization is also made more difficult because of the spatial scales involved. For example to be able to resolve individual bacteria in an image, the field of view needs to be on the order of 100 μm2, while the specimen might be on the order of cm2 (1 million fields) for tissue or even 100s of cm2 (over 100 million fields) for large orthopedic implants making microscopic data from a small proportion of the sample often the only practical method to demonstrate biofilm in situ. Finally, because biofilms may also be extremely localized, it is difficult to quantify by averaging several images on the surface, because heterogeneity leads to extensive sample variability.

Overall, our results show that miR-155 has a pro-inflammatory role in microglia and is necessary for the progression of the immune response through the modulation of SOCS-1, suggesting that, in a chronic inflammatory context, miR-155 inhibition can have a neuroprotective effect. HDAC inhibitor Inflammation is believed to play an important role in several central nervous system (CNS) diseases of both acute and chronic nature. Local inflammatory reactions are early events following neuronal death as a consequence of stroke, infection

and traumatic brain injury,1 but can also be a response to the accumulation of misfolded or aggregated proteins in neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease and multiple sclerosis.2 As resident immune cells of the CNS, microglia cells are responsible for monitoring the CNS environment and sensing potential threats, through pattern recognition receptors, Napabucasin in vivo such as Toll-like receptors (TLRs), capable of binding highly conserved structural motifs present in different families of pathogens.3 Upon recognition of a specific pathogen-associated pattern, microglia change to an activated state and initiate both innate

and adaptive immune responses, by producing an array of pro-inflammatory cytokines, free radicals and nitric oxide, while simultaneously initiating the recruitment of other immune-related cells. Although microglia-mediated immune responses have the major purpose of promoting pathogen clearance and tissue regeneration, the resulting inflammatory state, if left unchecked, can aggravate neuronal injury. It is now believed that neuroinflammation Ribonucleotide reductase is an important contributor to neurodegeneration in various CNS diseases, such as Alzheimer’s disease4 and multiple sclerosis.5 Neurons are particularly susceptible to oxidative damage and to certain inflammatory mediators, which are either themselves neurotoxic or attract leucocytes with cytotoxic properties.6,7 This hypothesis has been supported by several studies showing that

inhibiting microglia activation or blocking cytokine expression, cytokine receptor activation and the production of oxidative species contributes to neuronal survival in different models of brain injury.8–10 Compelling evidence now links small endogenous RNA molecules, known as microRNAs (miRNAs), to the regulation of many biological processes such as development, cellular differentiation and disease. These small RNA molecules exert their function by modulating mRNA half-life or inhibiting its translation via co-operative binding to the 3′ untranslated region (UTR) of target genes. Recently, miRNAs were shown to be directly involved in the control of both innate and adaptive immune responses, by directly interfering with TLR-mediated signal transduction mechanisms11 and the ensuing cytokine response.

In the presence of polarizing cytokines, this APC-independent activation regimen generated effector T cells producing equivalent amounts Palbociclib research buy of IFN-γ and IL-17, irrespective of the naive T-cell donor age (Fig. 2B). When T-cell activation was titrated to include lower doses of anti-CD3 in the absence of polarizing cytokines, 2-week-old T cells produced even higher amounts of IFN-γ and slightly elevated levels of IL-17 (Supporting Information Fig. 1). These findings highlight that T cells are generally capable of differentiating into encephalitogenic Th1 and Th17 cells at the age of 2 weeks, suggesting that an immaturity of peripheral T cells is unlikely to explain EAE resistance

in 2-week-old mice. Activation and proinflammatory differentiation of CD4+ T cells depends on recognition of Ag provided by Ag-presenting cells, such as DCs, monocytes, and B cells [13]. Accordingly, we next investigated whether the insufficiency of young mice to generate encephalitogenic T cells may relate to an age-dependent alteration Kinase Inhibitor Library mw within the APC compartment. Similar to the investigations on T cells, we first

determined that the overall frequency of DCs, monocytes, and B cells in 2-week-old mice was comparable with that in adult mice (Fig. 2C–E and Table 1). Recent findings suggest that subclasses of DCs and myeloid cells may differ in their capacity to activate T cells, with subtypes rather suppressing than promoting proinflammatory T-cell differentiation. In this regard, further phenotyping of DCs revealed that at an age of 2 weeks, mice contained a higher frequency of CD11cintPDCA+Siglec-H+ plasmacytoid DCs, which can promote development of Treg cells and inhibit CNS autoimmune disease [14]. In contrast, the frequency of CD11b+ myeloid DCs with a strong

capacity to generate Th1 and Th17 cell responses, but also to reactivate encephalitogenic T cells in the inflamed CNS [15] was reduced (Fig. 2C and Table 1). Along the same lines, the frequency of CD115+Gr-1+ myeloid-derived suppressor cells, which can impair expansion and homeostasis of proinflammatory T cells [16] and development of EAE [17] was elevated in 2-week-old mice (Fig. 2D and Table 1). Taken together, within the compartment of APCs of myeloid origin young mice contained a markedly higher Sodium butyrate percentage of phenotypes with the potential to suppress autoimmune T-cell responses. Proinflammatory differentiation of CD4+ T cells requires two signals [18]. The first signal is Ag recognition in the context of MHC II via their T-cell receptor, the second mandatory interaction consists of ligation of co-stimulatory molecules. In order to investigate whether APC from 2-week-old mice may differ in quantity or quality of these signals, myeloid CD11b+ APCs as well as B cells from 2- or 8-week-old mice were evaluated for surface expression of MHC II and the co-stimulatory molecules CD40, CD80, and CD86.

NAD(P)H oxidase-derived ROS may act as intercellular

regulators of the redox-sensitive transcription factors HIF-1α and Nrf2, and their target genes including NQO1, γ-glutamylcysteine synthetase, and HO-1 [94]. In aortic endothelial cells, advanced glycation end products evoke ROS generation and activate Nrf2-dependent expression of HO-1 and NQO1, providing evidence of adaptive Nrf-2-mediated protection against oxidative stress in diabetes [33]. Increased ROS production by the mitochondria, xanthine oxidase, and uncoupled eNOS may also activate these transcription factors leading to upregulation www.selleckchem.com/products/NVP-AUY922.html of antioxidant enzymes; however, with age the responsiveness of redox-sensitive transcription factors wanes in the aorta and carotid arteries [93,94]. Together, these findings suggest that an age-related decline in the ability to activate endogenous antioxidant mechanisms contributes to increased endothelial inflammation and apoptosis in large arteries. Future work will be needed to determine whether or not the function of endogenous antioxidant defense mechanisms declines in the microvascular endothelium with advancing age. The impact of an age-related decline in endogenous antioxidant mechanisms on angiogenesis, endothelium-dependent vasodilation, and microvascular permeability remains to be assessed in the microvasculature. In contrast to O2•−,

H2O2 is not a free radical (i.e., unpaired electrons on an open shell configuration), making it less reactive, more stable and longer lasting [2]. These properties and the ability of H2O2 to diffuse across cell membranes allow it to play an important Protein Tyrosine Kinase inhibitor signaling role. H2O2 is primarily produced by the dismutation of O2•− by SOD, but can also be formed by the spontaneous dismutation of O2•−, or directly by the action of enzymes such as xanthine oxidase, glucose oxidase [7], and NADPH oxidase [17,51,72,76]. H2O2 is found in both physiological and pathophysiological states. In aging, H2O2 production is increased [13,48]

possibly due to age-related increases in mitochondrial H2O2 generation [79–81] and eNOS dependent O2•− generation [4]. H2O2 does not inactivate NO• and in conditions TCL of oxidant stress, H2O2 may act as a compensatory mechanism to maintain NO• bioavailability. H2O2 has been shown to cause a potent dose-dependent increase in NO• production [9], upregulate eNOS expression [8,19], and to enhance eNOS function by promoting eNOS phosphorylation and eNOS dephosphorylation at Thr-495 [90]. Recently, Martin-Garrido et al. [50] demonstrated that H2O2 enhances vascular relaxation to NO by stabilizing sGCβ1 mRNA through HuR, increasing the expression of sGCβ1 and thus increasing cGMP formation. However, Gerassimou et al. [27] showed that higher concentrations of H2O2 downregulated sGCα1 mRNA indicating that the levels of H2O2 may dictate its action.

All baboons developed increased plaque, gingival inflammation and bleeding, pocket depths and attachment loss following placement of the ligatures. By MP, both prostaglandin

learn more E2 (PGE2) and bactericidal permeability inducing factor (BPI) were greater than baseline, while increased levels of interleukin (IL)-6 occurred in the experimental animals by the time of delivery. IL-8, MCP-1 and LBP all decreased from baseline through the ligation phase of the study. Stratification of the animals by baseline clinical presentation demonstrated that PGE2, LBP, IL-8 and MCP-1 levels were altered throughout the ligation interval, irrespective of baseline clinical values. IL-6, IL-8 and LBP were significantly lower in the subset of animals that demonstrated the least clinical response to ligation, indicative of progressing periodontal disease. PGE2, macrophage chemotactic protein (MCP)-1, regulated upon activation, normal T cell expressed and secreted (RANTES) and LBP were decreased in the most diseased subset of animals at delivery. Systemic antibody responses to Fusobacterium nucleatum, Porphyromonas gingivalis, Actinobacillus actinomycetemcomitans and Campylobacter rectus were associated most frequently with variations in inflammatory mediator levels.

These results provide a profile of systemic inflammatory mediators during ligature-induced periodontitis in pregnant baboons. The relationship of the oral clinical parameters to systemic inflammatory responses selleck chemicals llc Anti-infection Compound Library cell line is consistent with a contribution to adverse pregnancy outcomes in a subset of the animals. Historically, adaptive immunity has been the focus of immunological investigations related to infectious diseases, due to the specificity of adaptive immunity and the opportunity to create and evaluate vaccine strategies to individual

pathogens. However, during the initial contact with a primary infection, the host protective armamentarium is focused upon inflammation and innate immunity. Fundamentally, the innate immune system prevents entry of microorganisms into tissues or, once they have gained entry, eliminates them prior to the occurrence of disease. Thus, the immune system is an interactive network of cellular and molecular processes that are responsible for recognizing and eradicating pathogens and other noxious molecules. The acute phase response (APR) represents an early and highly complex reaction to remove noxious challenge and restore homeostasis. This process is accomplished by substantial increases in the plasma levels of acute phase proteins that can modulate immune cell function and neutralize the noxious components challenging the systemic circulation [1,2]. C-reactive protein (CRP) is a classic member of this family and one of the soluble pathogen-associated molecular pattern (PAMP) recognition receptors.