Host Defense Against Bacterial Pathogens Biology Essay

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The most important thing of the immune system is the self and non-self recognition .When a pathogen enters the body the immune system gets a signal for an immune response. A part of that is the production of IL-17; this gives a defense mechanism to the body. Phrasing of the question of this research is: What the effects are of IL-17 in host defense against bacterial pathogens.

Bacteria can enter on each place of the body; the immune system will react on this, but disorder in the system can lead to various diseases such as auto-immune disease and infection disease. The immune system is divided in: The innate immune system it is a general system to protect the body; and the adaptive immune system this will protect the body by making anti body's and memory cells.

Interleukin's are essential components of the innate and the adaptive immune system. They are specialized cytokines, and they are produced by activated macrophages and lymphocytes. These cytokines are responsible for the signal between two different cells of the immune system.

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A pro-inflammatory cytokines that are produced by T-cell, are the interleukin's-17. The interleukin-17 is responsible for the induction and maturation of neutrophils, they are very important in the immune system against pathogens. IL-17 plays an important part in mammalian host defense against a wide range of pathogens.

IL-17 gives also a contribution by the arising of inflammations reactions because it introduce the expression of the pro-inflammatory cytokines likes TNF-α, interleukine-1β en interleukine-6 and chemokines.

IL-17 is produced by different T cells, TH 17 cells and NK T cells. The rapid activation of NK T cells to secrete IL-17A might represent an important innate mechanism for the recruitment of neutrophils in response to bacterial infection, in particular at mucosal surfaces. Interleukine-17 has an orchestrating role in the mammalian immune response against bacteria, in particular for neutrophils.

Interleukine-17 maybe also plays a role by chronic infection and auto-immune disease.

Samenvatting

Het immuunsysteem is in staat om lichaamseigen en lichaamsvreemde stoffen (bijvoorbeeld bacteriën) van elkaar te onderscheiden. Wanneer er bacteriën in het lichaam worden aangetroffen, genereert het immuunsysteem acties tegen deze bacteriën, waardoor ze gedood worden. Een onderdeel ervan is de productie van interleukine-17. Deze geeft een verdedigingsmechanisme aan het lichaam. De hoofdvraag bij dit onderzoek is wat de effecten van interleukine-17 op de immuniteit zijn bij het binnendringen van pathogene bacteriën in het lichaam.

Bacteriën kunnen op elke plaats van het lichaam binnendringen. Het immuunsysteem reageert op de bacteriën die het lichaam binnendringen, als het niet goed werkt kan dat tot diverse ziekten leiden, zoals auto-immuunziekten en infectieziekten. Het immuunsysteem bestaat uit twee delen: het aangeboren immuunsysteem en het verworven immuunsysteem. Het aangeboren immuunsysteem werkt heel algemeen om het lichaam te beschermen. Het verworven immuunsysteem reageert specifiek op één ziekteverwekker, onder andere via het vormen van antilichamen en geheugencellen.

Interleukinen zijn essentiële componenten van zowel de aangeboren als de verworven immuunsyteen. Interleukinen zijn gespecialiseerde cytokinen die geproduceerd worden door geactiveerde macrofagen en lymfocyten. Deze cytokinen doen dienst als signalering tussen verschillende cellen van het immuunsysteem. Een pro-inflammatoire cytokine die door

T-cellen worden geproduceerd, zijn de interleukine-17 (synoniem met interleukine-17A). Interleukine-17 zorgen voor de inductie en rijping van neutrofielen, ter indicatie van zijn rol in de acute mechanismen in het immuunsysteem. Ze spelen een belangrijk onderdeel in het immuunsysteem tegen een brede waaier van ziekteverwekkers. Interleukine-17 levert ook een bijdrage bij het ontstaan en in stand houden van ontstekingsreacties doordat het de expressie van de pro-inflammatoire cytokines zoals TNF-α, interleukine-1β en interleukine-6 en chemokines induceert. Interleukine-17 worden door verschillende soorten T cellen evenals TH 17 cellen en NK T cellen geproduceerd, die betrokken zijn in de inductie en effector fase van een variatie van immuunreacties. De snelle activering van NK T cellen om interleukine-17 af te scheiden kan een belangrijk aangeboren mechanisme hebben voor de werving van neutrofielen voor de reactie op bacteriële infectie, in het bijzonder met het slijmvlies oppervlakte. Interleukine-17 hebben een orkestrerende rol in het immuunrespons tegen bacteriën, in het bijzonder voor neutrofielen. Interleukine-17 zouden ook een belangrijke rol spelen bij chronische ontsteking en auto-immuunziekten.

List of abbreviations

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CD Cluster of differentiation

FGF fibroblast growth factor

IL interleukin

K. pneumoniae Klebsiella pneumoniae

MHC Major Histocompatibility complex

NK Natural Killer

TNF Tumor necrosis factor

Contents

Summary 2

Samenvatting 3

List of abbreviations 4

1. How bacteria enters the human body 6

2.1 The immune system 7

2.2 The innate and the adaptive immune system 7

2.3 Auto-immune diseases 9

3. Interleukin 10

3.1 Identification of IL-17 10

3.2 The IL-17 family and its receptors 10

3.4 IL-17 structure 12

3.5 Th17, the cellular source of IL-17 13

3.6 IL-17 in the host defense 13

Conclusion & discussion 15

Appendix 1 17

References 18

1. How bacteria enters the human body

Bacteria can enter the body via skin, mouth, etc. The body consists of many bacteria that some born with these are commensals bacteria.

The antigen recognition is not the body's first line of defense. Simple barriers such as the skin and the epithelial surfaces are the body's first line of defense; they don't have specific or innate protective systems, which limit the entry of potentially invasive organisms. For example fatty acids produced by the skin are toxic to many organisms.

Through the production of antibacterial proteins (colicins), commensal bacteria can limit the pathogen invasion.

The recognition of bacterial components is the body's second line of defense.

There are several ways to recognize the organisms who enter the tissues, for example the old phylogenetically mechanisms the antigen-specific receptors of either B cells or T cells. [1] 

2. Immunity

2.1 The immune system

The function of the immune system is protection of the body against infectious organism (killing pathogens). The immune system is divided in: the adaptive immune system (specific immune system) and the innate system (non-specific immune system).

The origins of all the cells of the immune system are from the bone marrow. The most important thing of the immune system is the self and non-self recognition. Any cell that does not have a marker based on the major histocompatibility complex (MHC) will be attacked, because it is non-self cell. Cells prime the adaptive immune system against the pathogen which results in production of protective antibodies and cytotoxic T cells. The interaction between the innate and the adaptive system leads to control of the pathogen within several days. Disorder in the system can cause serious problems, like when your immune system attacks body's healthy cells by "mistake". This is called autoimmune disease. [2] 

2.2 The innate and the adaptive immune system

When a pathogen enters the body the immune system gets a signal for an immune response. The innate immune system have to be activated first this response is rapid. Then the innate immune system activates the adaptive system, and this will produce antibodies, the production of the antibodies is a specific immune response of the adaptive immune system. The innate immune system is a natural present system someone born with and it is the first line of defense.

There are some of difference between the innate and the adaptive immune system such as:

The action time of the innate system is in hours and action time of the adaptive system is in days.

The cell types of the innate system are macrophages, neutrophils and dentritic cells, and these of the adaptive system are T and B cells.

Receptors of the innate system are fixed in the genome, but in the adaptive system is the rearrangement of gene necessary.

The adaptive system has immunological memory, that means when someone get the same infection for the second time the immune system reacts more rapidly, but the innate system does not have an immunological memory.

The innate system consists of:

Tissue cells: to produce antimicrobial proteins.

Mast cells: to promote an inflammation reaction.

Platelet: is responsible for coagulation and promote inflammation reaction.

Nature killer cells: is for protection against tumor cells and viruses.

Phagocytes: these are monocyte, macrophages (this eat the bacteria and give it to the adaptive immune system), and granulocyte. The first function is to clear of bacteria and death cells, and the second function is to present antigen to the adaptive immune system. [3] 4

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Adaptive immune system has two classes of response: cell-mediated response and the antibody response. Antibody response is the first class response of the adaptive system and it is responsible for the activation of B-cells to secret antibodies, these antibodies are proteins called immunoglobulin. In the blood the antibodies circulate and bind to antigen. The antibody- antigen binding will block the binding of pathogens on the host cell receptor. The second class response of the adaptive system is cell-mediated response. This response is responsible for the activation of T-cells, when they are activated they will react directly against strange antigen that is presented on the surface of the host cell. In some cases signal molecules will be produced by T-cells that will activate macrophages, these macrophages are able to destroy the microbes. Then the adaptive system makes memory cells for the second time of the same infection. That means that the body is immune to an infection, and can kill the germs but without symptoms. [5] 

Figure 1: The innate and the adaptive system

2.3 Auto-immune diseases

Auto-immune diseases are multi-factorial processes involving deregulation of multiple components of the immune system include the innate and the adaptive immune system

The interaction of multiple components of the immune system is necessary for clinically manifest autoimmune disease.

Strong innate immune responses carry a limited risk to stimulate an autoimmune disease as long as they are short-lived. Such innate signals are necessary for pathogen clearance preventing infectious disease and immunopathology. Long-term activation of the innate immune system can break peripheral tolerance or ignorance.

Auto immune diseases occur when body's healthy cells miss some receptors that are needed to be recognized as body's-own cells/substances. Missing these receptors will activate the two major parts of the immune system, which will cause the B and T lymphocytes to remove these cells. [6] 7

3. Interleukin

Interleukins (IL) are specialized cytokines to identify the influences of the functions of lymphocytes. These proteins act as the primary signalling response between cells of the immune system and are produced by diversity of cells, including lymphocytes, phagocytes, and endothelial cells. [8] 

Interleukins are essential mechanism of both adaptive and innate responses in mammals. The term 'interleukin' is to illustrate cytokines, generally produced by leukocytes, which take action on leukocytes in a specific way. [9] 

3.1 Identification of IL-17

Interleukine-17 (synonymous with IL-17A) was discovered in 1995/96 as a proinflammatory cytokine formed by T cells. IL-17 was shown to make neutrophil stimulation and maturation, an indication of its function in the acute mechanisms in host defense. This outcome indicated very early the relationship between IL-17 and neutrophil biology. It was discovered under the name of CTLA-8, a gene product without clear function. [10] 

IL-17 is a prototype molecule for a total family of IL-17 cytokines. Now believed, to be formed mainly by a specific separation of CD4 cells, named Th-17 cells. IL-17 is to be found at the line of innate and acquired immunity. There is growing evidence that the IL-17 signaling might be helpful in a diversity of diseases including asthma, multiple sclerosis and rheumatoid arthritis. [11] 

3.2 The IL-17 family and its receptors

IL-17 is the founding member of the IL-17 family, which includes IL-17A-F. Th17 cells have been first discovered in the mouse with the production of IL-17A, and they also produced a list of other proinflammatory cytokines including IL-17F, IL-22, TNF, IL-6. The primary receptor for IL-17 named IL-17R was described in 1995/96 when IL-17 was discovered. [12] 

IL-17 family

IL-17 was identified primarily as a rodent complementary DNA transcript named cytotoxic T-lymphocyte-associated antigen 8. IL-17 is now the prototypic member of a family of cytokines that also includes IL-17B, IL-17C, IL- 17D and IL-17F, which were discovered utilizing homology-based cloning (Table 1). IL-17E (now renamed IL-25) was identified separately but is no longer regarded as a member of the IL-17 family because of its functional role as an eosinophil-promoting cytokine. [13] 

IL-17 receptors

Like the IL-17 cytokine family, IL-17 receptors form a unique family including IL-17 receptor R A-E. IL-17 stimulates a receptor compound consisting of IL-17 RA and IL-17 RC. IL-17 RA, which also the founding member is of this family, is a type I transmembrane protein consisting of a 293 amino acid extracellular domain, a 21 amino acid transmembrane domain and a 521 amino acid cytoplasmic tail. Besides IL-17 RA and IL-17 RC, three additional

IL-17 receptors have been established; these are IL-17 RB, IL-17 RD and IL- 17 RE but their particular functional characteristics remain to be identified. [14] 

Figure 2: Until now are six IL-17 family cytokines (IL-17A-IL-17F) and five members of the IL-17 receptor family (IL-17RA-IL-17RE) been identified. The various receptor complexes through which each ligand induce signalling are shown. The receptor for IL-17D and the ligand for IL-17RD and IL-17RA-IL-17RD are unknown. [15] 

3.4 IL-17 structure

IL-17 is a homodimeric glycoprotein consisting of 155 amino acids and has a molecular weight of 35 kDa. Between the accurate members of the IL-17 family, IL-17F has the greatest degree of structural and functional homology with IL-17. Since IL-17 and IL-17F are both homodimers, it is not unexpected that there is now evidence that mouse and human CD4 cells can produce an IL-17-IL-17F heterodimer also with similar proinflammatory properties. Mouse and rat in addition to bovine and swine IL-17 are structurally the same to the human IL-17, in particular concerning the structure of the cysteine residues forming the canonical pseudo-knot fold. The molecular structure of IL-17 is among several mammalian species compatible with IL-17, having a crucial role in the mammalian immune system. [16] 

3.5 Th17, the cellular source of IL-17

The most recent step was the discovery in 2006 of the cell source of IL-17. IFN-γ was identified as a maker of Th1 cells and IL-4 of Th2 cells. The source of IL-17 was different and these cells were named Th17. In the mouse, this new division was identified by the expression of the inhibitory effect of IFN-γ on IL-17 production in mouse models of autoimmune diseases. [17] 

3.6 IL-17 in the host defense

Even though the documentation of the involvement of IL-17 in human host defense is still incomplete, experimental studies in mice provide broad and convincing evidence that IL-17 plays an important part in mammalian host defense against a wide range of pathogens. For example, it has been reported that patients with a deficiency of the IL-12p40 subunit, leading to a combined absence of IL-12 and IL-23, or with a deficiency of IL-12 R b1, leading to IL-12 and IL-23 signaling impairments, are indeed more susceptible to mycobacterial disease and infections with nontyphoidal Salmonellae. These results also provide support for an involvement of IL-17 because the lack of IL-23 is likely to lead to a fewer release of IL-17 protein and an insufficient differentiation and maturation of Th-17 cells. Animal models of infection with Gram-negative and Gram-positive bacteria, in addition to Mycoplasma pneumoniae and certain protozoa, do indicate that IL-17 contributes to host defense against these microbes through its promoting effects on neutrophil recruitment and activation and the subsequent improved the clearance of the pathogens. In addition, IL-17 up regulates the expression of antimicrobial molecules, such as b-defensins, in the lung, skin and gut. [18] 

IL-17 in antibacterial host defense

The protective effects of IL-17 in host defense against bacterial pathogens was first verified by Kolls and colleagues in studies that compared the vulnerability of IL-17 receptor-deficient and control mice to K. pneumoniae. After intranasal infection, IL-17 receptor-deficient mice have increased numbers of recoverable bacteria in the lung, increased bacterial dissemination into the spleen, and reduced overall survival. The increased vulnerability of IL-17 receptor-deficient mice to K. pneumoniae was directly associated with delayed neutrophil recruitment and reduced expression levels of granulocyte colony-stimulating factor and macrophage-inflammatory protein-2 in the lungs within the first 12-24 hr after infection. [19] 

Even though TH1 and TH2 cells give protection against intracellular microbes and nematodes, respectively, TH17 cells have been implicated in the defense against certain bacteria and fungi. In addition to their helpful roles in the control of pathogens, TH subset effector responses can also induce pathology. In mice the importance of IL-17 in conferring protection against pulmonary bacterial infections was verified after intranasal challenge with Klebsiella pneumoniae. In the lack of functional IL-17RA signaling, infected animals displayed increased bacterial spreading and mortality when compared with their wild-type counterparts. The role of TH17 cells in this model was supported by Happel et al, who showed increased vulnerability to disease in IL-23p19- and IL-23p40- deficient mice but decreased bacterial load after administration of IL-17A. [20] 

Figure 3: Beneficial and detrimental roles for TH17 effector cytokines in the course of pulmonary immune responses. Bacterial and fungal infections in the lung trigger generation of TH1 cells, TH17 cells, gd T cells, and NK T cells, which secrete a panel of proinflammatory cytokines. IL-17A and related cytokines play an important role in inducing mobilization and activation of neutrophils, which contribute to pathogen clearance.

In line with the expected effector function of IL-17A, the increased vulnerability of IL-17RA-deficient mice to bacterial infection correlated with decreased chemokine production and dysfunctional neutrophil recruitment to the site of infection. [21] 

Conclusion & discussion

Bacteria can enter the body via skin, mouth, etc. Simple barriers such as the skin and the epithelial surfaces are the body's first line of defense; they don't have specific or innate protective systems, which limit the entry of potentially invasive organisms. The recognition of bacterial components is the body's second line of defense.

The most important thing of the immune system is the self and non-self recognition. The immune system is divided in: the adaptive immune system and the innate system. The innate immune system activates the adaptive system, and this will produce antibodies. The innate immune system is a natural present system someone born with and it is the first line of defense. Adaptive immune system has two classes of response: cell-mediated response and the antibody response. The antibody- antigen binding will block the binding of pathogens on the host cell receptor. The second class response of the adaptive system is cell-mediated response. This response is responsible for the activation of T-cells.

The progressively more research on IL-17 biology during the past 15 years has provided compelling verification that IL-17 has an orchestrating role in the mammalian immune response against bacteria, in particular for neutrophils. IL-17 might also be pathogenically important in chronic inflammatory and autoimmune disorders.

Contrasting the relatively well-studied IL-17 and IL-17F, the possible role of other IL-17 family members in host defense against bacterial infections remains mostly unknown.

Many studies over the last decade have given IL-17 a unique function in the location of the inflammatory response. This cytokine is produced mainly by T cells rather than by macrophages or other cells of the innate immune system and thus it is believed to play an important role in the inflammatory events triggered by the adaptive or memory immune system

Th17 cells play important roles in host defense against infection with extracellular bacterial pathogens by recruiting acute inflammatory cells into local sites of infection. As a result, the discovery that Th17 cells provide protection against extracellular bacterial fills a deficit in immunity to a role of pathogens not previously covered by the Th1 or Th2 lineages and furthers understanding of the host defense. In addition to host defense, plenty experimental evidence supports a pathological role for Th17 cells during numerous systemic and organ-specific autoimmune diseases. Accumulating evidence demonstrates that Th17 cells also provide protective effects during infection with more traditional intracellular pathogens.

The anecdote of IL-17 and Th17 separation is a new stimulation of the role of some T cells to chronic inflammation and extra-cellular matrix destruction. A list of diseases has been associated with IL-17 but the final demonstration of its contribution to disease pathogenesis is still missing. Tools are now getting organized to test these concepts in the hospital.

In conclusion, IL-17 is produced by different types of T cells, as well as TH17 cells and NK T cells that are involved in the induction and effector phase of a variety of immune responses. The rapid activation of NK T cells to secrete IL-17 might represent an important innate mechanism for the recruitment of neutrophils in response to bacterial infection, in particular at mucosal surfaces. Depending on the timing, the tissue, and the local microenvironment, IL-17-secreting cells appear to play both positive and damaging roles in lung immunity and disease. Future studies on humans will shed more light on the more specific immunological and pathogenic role of IL-17 in higher primates are required.

Appendix 1

Intracellular IL-17 signaling. (a) Act-1-dependent: after ligand activation of the IL-17 receptor R complex (i.e. IL-17 RA and IL-17 RC), the adaptor protein nuclear factor-kB activator 1 (Act-1) forms a complex with the similar expression to fibroblast growth factor (FGF) genes and IL-17 receptors (SEFIR) domain of IL-17 R complex. Subsequently, intracellular signaling molecules (e.g. TRAF3, TRAF6 and TAK1) are activated leading to the involvement of transcription factors such as NF-kB, C/EBP-b and C/EBP-g. As a consequence, secretion of neutrophil-mobilizing cytokines is induced. (b) Act-1-independent: it involves Janus kinase (JAK)1 and phosphatidylinositol3- kinase (PI3K) followed by subsequent inactivation of glycogen synthase kinase (GSK)-3b, gene activation and cytokine secretion