Pathogen-associated Microbial Patterns Research Articles

Genome-wide characterization of Toll-like receptors in Japanese meagre Argyrosomus japonicus and their response to poly (I:C) injection

Japanese meagre (Argyrosomus japonicus) is well-known for its high nutritional and economic value. In recent years, with the rapid expansion and intensification of aquaculture, Japanese meagre culture has suffered serious economic losses due to infectious diseases. Toll-like receptors (TLRs) can recognize highly conserved structural motif pathogen-associated microbial patterns (PAMPs) and danger-associated molecular patterns (DAMPs), playing a key role in resisting diseases by initiating host innate immune responses. Here, a total of 12 members of the TLR gene family (TLR1, TLR2, TLR2b, TLR3, TLR5M, TLR5S, TLR7, TLR9, TLR13, TLR14, TLR22, and TLR23) were identified in the genome of Japanese meagre. The TLR genes in Japanese meagre were distributed on 10 of 24 chromosomes. The evolutionary analyses showed that 12 different TLR genes were divided into different subfamilies, including the TLR1, TLR3, TLR5, TLR7, and TLR11 subfamilies. The conserved motifs were compared with three other teleost species. The results revealed that the conserved motifs in the same subfamilies were highly consistent. The identity and similarity of the TLR-TIR domain of Japanese meagre demonstrated that the regulatory mechanisms of each of the subfamilies were similar. qRT-PCR assays showed different expression patterns of TLRs in the liver, spleen, head kidney, trunk kidney, brain, and heart of Japanese meagre, but the expression levels in immune tissues were higher. Double-stranded RNA virus (dsRNA) is a common etiological agent of diseases in aquaculture species. Therefore, a synthetic double-stranded RNA called poly (I:C) was used as an injection to understand the immune system function and disease control of Japanese meagre. Following poly (I:C) stimulation, seven of twelve ArgTLR genes, including ArgTLR2, ArgTLR2b, ArgTLR3, ArgTLR7, ArgTLR13, ArgTLR22 and ArgTLR23, were significantly upregulated. In summary, our results not only play a guiding role in disease prevention and control and vaccine development in the future, but also provide basic data for future study of the TLR gene family of Japanese meagre.

Toll-Like Receptors, Infections, and Rheumatoid Arthritis

Toll-like receptors (TLR) that belong to the group of protein recognition receptor (PPR) provide an innate immune response following the sensing of conserved pathogen-associated microbial patterns (PAMPs) and changes in danger-associated molecular patterns (DAMPs) that are generated as a consequence of cellular injury. Analysis of the TLR pathway has moreover offered new insights into the pathogenesis of rheumatoid arthritis (RA). Indeed, a dysfunctional TLR-mediated response characterizes RA patients and participates in establishment of a chronic inflammatory state. Such an inappropriate TLR response has been attributed (i) to the report of important alterations in the microbiota and abnormal responses to infectious agents as part of RA; (ii) to the abnormal presence of TLR-ligands in the serum and synovial fluid of RA patients; (iii) to the overexpression of TLR molecules; (iv) to the production of a large panel of pro-inflammatory cytokines downstream of the TLR pathway; and (v) to genetic variants and epigenetic factors in susceptible RA patients promoting a hyper TLR response. As a consequence, the development of promising therapeutic strategies targeting TLRs for the treatment and prevention of RA is emerging.

The human NAIP-NLRC4-inflammasome senses the Pseudomonas aeruginosa T3SS inner-rod protein.

While NLRC4-dependent sensing of intracellular Gram-negative pathogens such as Salmonella enterica serovar typhimurium is a beneficial host response, NLRC4-dependent sensing of the Pseudomonas aeruginosa type 3 secretion system (T3SS) has been shown to be involved in pathogenicity. In mice, different pathogen-associated microbial patterns are sensed by the combination of the NLRC4-inflammasome with different neuronal apoptosis inhibitory proteins (NAIPs). NAIP2 is involved in sensing PscI, an inner-rod protein of the P. aeruginosa T3SS. Surprisingly, only a single human NAIP (hNAIP) has been found. Moreover, there is no description of hNAIP-NLRC4 inflammasome recognition of T3SS inner-rod proteins in humans. Here, we show that the P. aeruginosa T3SS inner-rod protein PscI and needle protein PscF are both sensed by the hNAIP-NLRC4 inflammasome in human macrophages and PBMCs from healthy donors, allowing caspase-1 and IL-1β maturation and resulting in a robust inflammatory response. TLR4 and TLR2 are involved in redundantly sensing these two T3SS components.

CBL-interacting protein kinase 6 negatively regulates immune response to Pseudomonas syringae in Arabidopsis.

Cytosolic calcium ion (Ca2+) is an essential mediator of the plant innate immune response. Here, we report that a calcium-regulated protein kinase Calcineurin B-like protein (CBL)-interacting protein kinase 6 (CIPK6) functions as a negative regulator of immunity against the bacterial pathogen Pseudomonas syringae in Arabidopsis thaliana. Arabidopsis lines with compromised expression of CIPK6 exhibited enhanced disease resistance to the bacterial pathogen and to P. syringae harboring certain but not all avirulent effectors, while restoration of CIPK6 expression resulted in abolition of resistance. Plants overexpressing CIPK6 were more susceptible to P. syringae. Enhanced resistance in the absence of CIPK6 was accompanied by increased accumulation of salicylic acid and elevated expression of defense marker genes. Salicylic acid accumulation was essential for improved immunity in the absence of CIPK6. CIPK6 negatively regulated the oxidative burst associated with perception of pathogen-associated microbial patterns (PAMPs) and bacterial effectors. Accelerated and enhanced activation of the mitogen-activated protein kinase cascade in response to bacterial and fungal elicitors was observed in the absence of CIPK6. The results of this study suggested that CIPK6 negatively regulates effector-triggered and PAMP-triggered immunity in Arabidopsis.

Lack of broad functional differences in immunity in fully vaccinated vs. unvaccinated children.

Concerns have been raised that with an increase in the number of vaccines administered early in life, immune development could be altered, leading to either increased or decreased immune reactivity. We investigated the impact of vaccination on immune status, contrasting the immune response to general, nonantigen-specific stimuli in a cohort of entirely unvaccinated vs. fully vaccinated children at 3-5 y of age. Innate immunity was assessed by quantifying bulk and cell-type-specific cytokine production in response to stimulation with pathogen associated microbial patterns. Adaptive immune status was characterized by assessing lymphocyte proliferation and cytokine production in response to generic T cell stimuli. Our investigations failed to reveal a broadly evident alteration of either innate or adaptive immunity in vaccinated children. Equivalently robust innate and adaptive responses to pathogen associated microbial patterns and generic T cell stimulants were observed in both groups. Although our sample size was small, our data suggest that standard childhood vaccinations do not lead to long-lasting gross alterations of the immune system.

Moving nitrogen to the centre of plant defence against pathogens.

Plants require nitrogen (N) for growth, development and defence against abiotic and biotic stresses. The extensive use of artificial N fertilizers has played an important role in the Green Revolution. N assimilation can involve a reductase series ( NO3- → NO2- → NH4+ ) followed by transamination to form amino acids. Given its widespread use, the agricultural impact of N nutrition on disease development has been extensively examined. When a pathogen first comes into contact with a host, it is usually nutrient starved such that rapid assimilation of host nutrients is essential for successful pathogenesis. Equally, the host may reallocate its nutrients to defence responses or away from the site of attempted infection. Exogenous application of N fertilizer can, therefore, shift the balance in favour of the host or pathogen. In line with this, increasing N has been reported either to increase or to decrease plant resistance to pathogens, which reflects differences in the infection strategies of discrete pathogens. Beyond considering only N content, the use of NO3- or NH4+ fertilizers affects the outcome of plant-pathogen interactions. NO3- feeding augments hypersensitive response- (HR) mediated resistance, while ammonium nutrition can compromise defence. Metabolically, NO3- enhances production of polyamines such as spermine and spermidine, which are established defence signals, with NH4+ nutrition leading to increased γ-aminobutyric acid (GABA) levels which may be a nutrient source for the pathogen. Within the defensive N economy, the roles of nitric oxide must also be considered. This is mostly generated from NO2- by nitrate reductase and is elicited by both pathogen-associated microbial patterns and gene-for-gene-mediated defences. Nitric oxide (NO) production and associated defences are therefore NO3- dependent and are compromised by NH4+ . This review demonstrates how N content and form plays an essential role in defensive primary and secondary metabolism and NO-mediated events.

Innate affairs of allergens

Activation of receptors of the innate immune system is a critical step in the initiation of immune responses. It has been shown that dominant allergens have properties that could allow them to interact with toll-like and C-type lectin receptors to favour Th2-biased responses and many bind lipids and glycans that could associate with ligands to mimic pathogen-associated microbial patterns. In accord with the proposed allergen-specific innate interactions it has been shown that the immune responses to different allergens and antigens from the same source are not necessarily coordinately regulated.

Suppression of PAMPs, Pathogen-Associated Microbial Patterns, Induced Cytokine Synthesis of PBMC, Human Blood Mononuclear Cells, by Immunoglobulin Preparation

The applications of immunoglobulin preparation for intravenous injection (IVIg) for various intractable diseases are increasing. The two major clinical indications for IVIg are the replacement therapy and the anti-inflammation therapy for a variety of acute and chronic autoimmune diseases. One of the proposed mechanisms of IVIg activity is the modulation of cytokine expression and function; therefore, we analyzed the effect of IVIg on pathogen-associated molecular pattern (PAMP)-induced cytokine production by peripheral blood mononuclear cells (PBMCs). The production of tumor necrosis factor-α (TNF-α) as a result of stimulation with lipopolysaccharide (LPS), polyinosinic-polycytidylic acid sodium salt (Poly I:C), or Pam3CysSerLys4 (Pam3) was significantly inhibited by sulfonated-IVIg (S-IVIg), or by F(ab')2. Assessed by one-color microarray analysis, the expressions of 229 genes were inhibited to 1/200 or less by F(ab')2. On the other hand, the expressions of 159 genes were increased by more than 100-fold by F(ab')2. According to these results, it was suggested that IVIg inhibits inflammatory PAMPs-induced cytokine production by PBMCs, due to the modulation of varieties of gene expression.

1111 Innate Immune Sensing of a Bacterial Protein in the Endoplasmic Reticulum by Inositol-Requiring Enzyme 1 (Ire1α)

Background & Aims: Micro-RNAs (miRNAs) are short, non-coding RNAs that regulate gene expression post transcriptionally. Several studies have demonstrated distinct miRNA profiles in a wide range of human disorders including inflammatory bowel disease and colon cancer. Surprisingly little is known about miRNA responses in immune cells that are challenged with relevant proinflammatory stimuli, i.e. cytokines or pathogen-associated microbial patterns. With this study we thus aim to generate a prototypic picture of inflammatory miRNA networks in monocytes as a relevant immune cell population and to understand functional consequences of selected regulated miRNAs on inflammatory signalling pathways. Methods: Levels of 330 miRNAs upon stimulation with a panel of pro-inflammatory components such as microbial pattern molecules (flagellin, diacylated lipopeptide lipopolysaccharide, muramyl dipeptide), infection with Listeria monocytogenes and TNF-alpha as pro-inflammatory control in primary human monocytes were qunatified using real time PCR. Selected miRNAs were verified in parallel in LPMNCs and biopsies from IBD patients. Transfection of premiRs and antago-miRs in THP1 monocytic cells were employed in order to understand functional consequences of miRNA regulation. Results: We identified distinct miRNA response clusters pointing to unique and shared mechanisms for different proinflammatory stimuli even in a single cell type. Additionally, we identified potential target genes of three selected miRNAs miR-129-5p, miR-146a and miR-378 which were part of PAMP-specific response clusters by transfecting THP1 monocytes with the corresponding preor antimiRNAs . The miRNAs induced distinct transcriptomal signatures, e.g. overexpression of miRNA129-5p, which was selectively upregulated by the NOD2-elicitor MDP, led to an upregulation of DEFB1, IRAK1, FBXW7 and IKK-gamma (Nemo). Interestingly, regulation of several overlap miRNAs shared between stimuli could also be detected in samples from IBD patients. Conclusions: Our findings on co-regulated clusters of miRNAs support the hypothesis that miRNAs act in functional groups. This study indicates that miRNAs play an important role in fine-tuning inflammatory mechanisms. Investigation in the field of miRNA responses in intestinal inflammation will help to understand their effects on gene expression and may close the regulatory gap between mRNA and protein expression in inflammatory diseases.

1113 Caveolin 1 Stimulates Intestinal Epithelial Restitution by Activating CA2+ Signaling and is Regulated by Cellular Polyamines

Background & Aims: Micro-RNAs (miRNAs) are short, non-coding RNAs that regulate gene expression post transcriptionally. Several studies have demonstrated distinct miRNA profiles in a wide range of human disorders including inflammatory bowel disease and colon cancer. Surprisingly little is known about miRNA responses in immune cells that are challenged with relevant proinflammatory stimuli, i.e. cytokines or pathogen-associated microbial patterns. With this study we thus aim to generate a prototypic picture of inflammatory miRNA networks in monocytes as a relevant immune cell population and to understand functional consequences of selected regulated miRNAs on inflammatory signalling pathways. Methods: Levels of 330 miRNAs upon stimulation with a panel of pro-inflammatory components such as microbial pattern molecules (flagellin, diacylated lipopeptide lipopolysaccharide, muramyl dipeptide), infection with Listeria monocytogenes and TNF-alpha as pro-inflammatory control in primary human monocytes were qunatified using real time PCR. Selected miRNAs were verified in parallel in LPMNCs and biopsies from IBD patients. Transfection of premiRs and antago-miRs in THP1 monocytic cells were employed in order to understand functional consequences of miRNA regulation. Results: We identified distinct miRNA response clusters pointing to unique and shared mechanisms for different proinflammatory stimuli even in a single cell type. Additionally, we identified potential target genes of three selected miRNAs miR-129-5p, miR-146a and miR-378 which were part of PAMP-specific response clusters by transfecting THP1 monocytes with the corresponding preor antimiRNAs . The miRNAs induced distinct transcriptomal signatures, e.g. overexpression of miRNA129-5p, which was selectively upregulated by the NOD2-elicitor MDP, led to an upregulation of DEFB1, IRAK1, FBXW7 and IKK-gamma (Nemo). Interestingly, regulation of several "overlap" miRNAs shared between stimuli could also be detected in samples from IBD patients. Conclusions: Our findings on co-regulated clusters of miRNAs support the hypothesis that miRNAs act in functional groups. This study indicates that miRNAs play an important role in fine-tuning inflammatory mechanisms. Investigation in the field of miRNA responses in intestinal inflammation will help to understand their effects on gene expression and may close the regulatory gap between mRNA and protein expression in inflammatory diseases.

1112 Characterization of Duox2 as a Candidate Glutathione Peroxidase-Deficiency-Associated- Colitis, Gdac1, Gene in Mice

Background & Aims: Micro-RNAs (miRNAs) are short, non-coding RNAs that regulate gene expression post transcriptionally. Several studies have demonstrated distinct miRNA profiles in a wide range of human disorders including inflammatory bowel disease and colon cancer. Surprisingly little is known about miRNA responses in immune cells that are challenged with relevant proinflammatory stimuli, i.e. cytokines or pathogen-associated microbial patterns. With this study we thus aim to generate a prototypic picture of inflammatory miRNA networks in monocytes as a relevant immune cell population and to understand functional consequences of selected regulated miRNAs on inflammatory signalling pathways. Methods: Levels of 330 miRNAs upon stimulation with a panel of pro-inflammatory components such as microbial pattern molecules (flagellin, diacylated lipopeptide lipopolysaccharide, muramyl dipeptide), infection with Listeria monocytogenes and TNF-alpha as pro-inflammatory control in primary human monocytes were qunatified using real time PCR. Selected miRNAs were verified in parallel in LPMNCs and biopsies from IBD patients. Transfection of premiRs and antago-miRs in THP1 monocytic cells were employed in order to understand functional consequences of miRNA regulation. Results: We identified distinct miRNA response clusters pointing to unique and shared mechanisms for different proinflammatory stimuli even in a single cell type. Additionally, we identified potential target genes of three selected miRNAs miR-129-5p, miR-146a and miR-378 which were part of PAMP-specific response clusters by transfecting THP1 monocytes with the corresponding preor antimiRNAs . The miRNAs induced distinct transcriptomal signatures, e.g. overexpression of miRNA129-5p, which was selectively upregulated by the NOD2-elicitor MDP, led to an upregulation of DEFB1, IRAK1, FBXW7 and IKK-gamma (Nemo). Interestingly, regulation of several "overlap" miRNAs shared between stimuli could also be detected in samples from IBD patients. Conclusions: Our findings on co-regulated clusters of miRNAs support the hypothesis that miRNAs act in functional groups. This study indicates that miRNAs play an important role in fine-tuning inflammatory mechanisms. Investigation in the field of miRNA responses in intestinal inflammation will help to understand their effects on gene expression and may close the regulatory gap between mRNA and protein expression in inflammatory diseases.

1110 Microbial Pattern Recognition Causes Distinct Functional Micro-RNA Signatures in Human Monocytes

Background & Aims: Micro-RNAs (miRNAs) are short, non-coding RNAs that regulate gene expression post transcriptionally. Several studies have demonstrated distinct miRNA profiles in a wide range of human disorders including inflammatory bowel disease and colon cancer. Surprisingly little is known about miRNA responses in immune cells that are challenged with relevant proinflammatory stimuli, i.e. cytokines or pathogen-associated microbial patterns. With this study we thus aim to generate a prototypic picture of inflammatory miRNA networks in monocytes as a relevant immune cell population and to understand functional consequences of selected regulated miRNAs on inflammatory signalling pathways. Methods: Levels of 330 miRNAs upon stimulation with a panel of pro-inflammatory components such as microbial pattern molecules (flagellin, diacylated lipopeptide lipopolysaccharide, muramyl dipeptide), infection with Listeria monocytogenes and TNF-alpha as pro-inflammatory control in primary human monocytes were qunatified using real time PCR. Selected miRNAs were verified in parallel in LPMNCs and biopsies from IBD patients. Transfection of premiRs and antago-miRs in THP1 monocytic cells were employed in order to understand functional consequences of miRNA regulation. Results: We identified distinct miRNA response clusters pointing to unique and shared mechanisms for different proinflammatory stimuli even in a single cell type. Additionally, we identified potential target genes of three selected miRNAs miR-129-5p, miR-146a and miR-378 which were part of PAMP-specific response clusters by transfecting THP1 monocytes with the corresponding preor antimiRNAs . The miRNAs induced distinct transcriptomal signatures, e.g. overexpression of miRNA129-5p, which was selectively upregulated by the NOD2-elicitor MDP, led to an upregulation of DEFB1, IRAK1, FBXW7 and IKK-gamma (Nemo). Interestingly, regulation of several overlap miRNAs shared between stimuli could also be detected in samples from IBD patients. Conclusions: Our findings on co-regulated clusters of miRNAs support the hypothesis that miRNAs act in functional groups. This study indicates that miRNAs play an important role in fine-tuning inflammatory mechanisms. Investigation in the field of miRNA responses in intestinal inflammation will help to understand their effects on gene expression and may close the regulatory gap between mRNA and protein expression in inflammatory diseases.

Toll-like receptor and its roles in myocardial ischemic/reperfusion injury

SummaryThe innate immune system, mediated via toll-like receptors (TLRs), represents the first line of defensive mechanisms that protects hosts from invading microbial pathogens. TLRs are a family of pattern recognition receptors (PRRs), and are pathologically activated by a set of pathogen-associated microbial patterns (PAMPs) and damage-associated molecular patterns (DAMPs). TLRs deliver signals via a specific intracellular signaling pathway involving distinctive adaptor proteins and protein kinases, and ultimately initiate transcriptional factors resulting in inflammatory responses. TLR4 is a paramount type of TLRs, located in the heart, and plays an important role in mediating myocardial ischemic reperfusion (I/R) injury. Loss-of-function experiments and animal models using genetic techniques have found that the MyD88-independent and the MyD88-dependent pathways together participate in the pathological process of myocardial I/R injury. Some other distinctive signaling pathways, such as the PI3K/AKt and AMPK/ERK pathways, interacting with the TLR4 signaling pathway, were also found to be causes of myocardial I/R injury. These different pathways activate a series of downstream transcriptional factors, produced a great quantity of inflammatory cytokines, such as IL, TNF, and initiate inflammatory response. This results in cardiac injury and dysfunction, such as myocardial stunning, no reflow phenomenon, reperfusion arrhythmias and lethal reperfusion injury, and other related complication such as ventricular remodeling. In the future, blockades aimed at blocking the signaling pathway could benefit developments in pharmacology.

Anti-fungal Cell Wall β-glucan Antibody in Animal Sera

beta-Glucan is a major component of the cell walls and pathogen-associated microbial patterns of fungi. We previously reported the presence of an antibody which reacts to beta-glucan, anti-beta-glucan (BG) antibody, in human sera. In livestock and domestic pets, the antibody's response to fungal cell wall beta-glucan is little understood. In this study, we examined the existence and reactivity of anti-BG antibody in various animal species. We demonstrated the presence of the anti-BG antibody in each animal's serum. Individual differences in the titer existed. The antibody was highly reactive to Candida solubilized cell wall beta-glucan (CSBG) while reacting little to grifolan (GRN) from Grifola frondosa. This suggested that the anti-BG antibody interacted with fungal cell wall beta-glucan and participated in the immune-response to pathogenic fungi.

TLR3 Ligand Polyinosinic:Polycytidylic Acid Induces IL-17A and IL-21 Synthesis in Human Th Cells

TLR3 and TLR9 recognize the pathogen-associated microbial patterns dsRNA and unmethylated DNA, respectively. The recent discovery that these receptors also recognize endogenous ligands from necrotic material has drawn increased attention to their involvement in autoimmunity. Th cell cytokines IL-17A and IL-21 have been assigned with pivotal roles in the regulation of such autoimmune diseases. IL-17A is the hallmark cytokine of the recently discovered proinflammatory Th cell subset T(H)17. By contrast, the expression of IL-21 does not seem to be limited to a single distinct Th cell subset. We investigated the expression of IL-17A and IL-21 in human CD4+ T cells in response to stimulation with the TLR3 ligand polyinosinic:polycytidylic acid (poly(I:C)) and the TLR9 ligand CpG. We discovered that poly(I:C) induced synthesis of both IL-17A and IL-21. Moreover, we found that poly(I:C) was able to drive the differentiation of naive Th cells into an IL-21 but not into an IL-17A-producing phenotype and did this without affecting the levels of transcription factors T-bet, GATA-3, or retinoic acid receptor-related orphan receptor C. Finally, we found that the IL-21-producing cells that were differentiated in response to poly(I:C) expressed the chemokine receptor CXCR3, which is important in the recruitment of T cells into inflamed joints in rheumatoid arthritis. This is the first report to show that the TLR3 ligand poly(I:C) can directly induce the synthesis of IL-17A and IL-21 and drive differentiation of human naive CD4+ T cells.

Phagocytosis of Amyloid-β and Inflammation: Two Faces of Innate Immunity in Alzheimer's Disease

Innate immunity provides the first line of defense by recognizing pathogen-associated microbial patterns and inducing key co-stimulatory molecules and cytokines, which activate the mechanisms of the adaptive immune response. Innate immune cells perform phagocytosis, which can clear pathogens and tissue waste products but may also contribute to tissue injury due to harmful side effects of inflammation. Genetic studies of APOE4, cytokine polymorphisms and overexpression of inflammatory genes suggest that chronic inflammation may have adverse effects in patients with sporadic Alzheimer's disease. However, a vaccine against amyloid-beta induced beneficial clearance of amyloid-beta deposits, possibly through Fc receptor-mediated stimulation of microglial and macrophage uptake. A reconciliation of these two pathogenetic mechanisms is crucial to future progress in immune diagnosis and effective therapy. This may be possible by extending our recent observations suggesting that phagocytosis of amyloid-beta by macrophages is excellent in normal subjects but is deficient in most AD patients. Thus increased proinflammatory cytokine levels and activated microglia and macrophages in patients may be compensatory for defective clearance of amyloid-beta. Consequently, therapeutic interventions that increase phagocytosis of amyloid-beta might decrease brain inflammation as well as reduce inflammation-induced neurodegeneration. Finally, peripheral blood leukocytes are a superior model system for investigation of innate immune dysfunction in Alzheimer's disease.

Novel genetic markers in inflammatory bowel disease

Genetic factors play a significant role in determining inflammatory bowel disease (IBD) susceptibility. Epidemiologic data support genetic contribution to the pathogenesis of IBD, which include familial aggregation, twin studies, racial and ethnic differences in disease prevalence. Linkage studies have identified several susceptibility genes contained in different genomic regions named IBD1 to IBD9. Nucleotide oligomerization domain (NOD2) and human leukocyte antigen (HLA) genes are the most extensively studied genetic regions (IBD1 and IBD3 respectively) in IBD. Mutations of the NOD2 gene are associated with Crohn's disease (CD) and several HLA genes are associated with ulcerative colitis (UC) and CD. Toll like receptors (TLRs) have an important role in the innate immune response against infections by mediating recognition of pathogen-associated microbial patterns. Studying single-nucleotide polymorphisms (SNPs) in molecules involved in bacterial recognition seems to be essential to define genetic backgrounds at risk of IBD. Recently, numerous new genes have been identified to be involved in the genetic susceptibility to IBD: NOD1/Caspase-activation recruitment domains 4 (CARD4), Chemokine ligand 20 (CCL20), IL-11, and IL-18 among others. The characterization of these novel genes potentially will lead to the identification of therapeutic agents and clinical assessment of phenotype and prognosis in patients with IBD.