How Body Cope With Pathogenic Microorganisms

The body is always at risk of invasion from harmful microorganisms. To cope with the threat of invasion from a pathogenic microorganism, the body uses the immune system. The immune system is a network of the integrated cell, tissues, and organs that work in synchrony to defend the body against pathogenic microorganisms, destroy malignant self-cells and to get rid of unwanted body debris. From the term immune system, we get the term immunity which translates to the ability and mechanism that is employed by the body to protects itself against non-self-molecules such as pathogens. There are two types of immunities; innate immunity and adaptive immunity. Adaptive immunity refers to immune mechanisms that develop due to first exposure of the body to pathogens. Upon second exposure, the body can recall pathogenic characteristics of the first infection and defend itself against the invading pathogens. Innate immunity, on the other hand, is defenses that act almost immediately (within 24 hours) from the appearance of the pathogen in the body. They are non-specific and target any pathogen.

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The skin forms a key component of the innate immune system. Immune roles of the skin include forming a physical barrier between the body and the external environment, protecting the body from mechanical damage, production of commensals, production of anti-microbial peptides and pure substances such as sebum. Keratinocytes are cells of the skin that primarily form a barrier that protects the body's internal against pathogenic microorganisms. Structurally, the skin is made up structural proteins such as filaggrin and keratin, enzymes such as proteases, lipids, and antimicrobial peptides; these contribute to maintaining the integrity of the physical barrier of the skin. Formation of the skin's physical barrier involves the process of keratinization which where keratinocytes produce excessive keratin and undergo terminal differentiation.

In addition to formation of a physical barrier, the skin also plays an essential immunological role in pathogen detection and evasion Toll-like Receptors (TLRs) are pattern recognition receptors that are involved in host defense mechanism against many microorganisms. TLRs function in the presence of components of microorganism (ligands). In the presence of pathogenic ligands, TLRs activate the expression of different genes leading to either adaptive or innate immune response. Immune cells that are capable of express TLRs are capable of recognizing different microorganism components hence initiating defense host mechanisms. There are different cells in the skin the express TLRs. These include Langer cells in the epidermis, monocytes/macrophages, dendritic cells, T and B lymphocytes, dermal mast cells and keratinocytes. Despite the being the fact they all express TLRs, each cell recognizes a different PRR. As a result of the difference in recognition, the skin cells can play the integral role of immune cutaneous responses which defend the body against microbial pathogens.

Objective

In this paper, we look at immune responses of the keratinocytes, especially HaCaT keratinocytes. The focus of the study is the capacity of these HaCaT to release soluble TLR2 when they are stimulated by suitable ligand; in this case purified microbial component (peptidoglycan and zymosan. The aim is to establish whether the capacity of HaCaT to release sTLR2 is affected by these substances or not. If it is affected, it is in a positive or a negative manner?

Hypothesis

In any research study, it is essential to have a hypothesis; a null hypothesis that is indicative of nothing interesting going on in the area of study and an alternative hypothesis that proposes that something interesting is happening in the area of study. For this research, there are two hypotheses;

Alternative hypothesis: stimulation of HaCaT keratinocytes using zymosan and purifies microbial components affects the capacity of HaCaT keratinocytes to release TLR2 receptors.

Null hypothesis: stimulation of HaCaT keratinocytes using zymosan and purifies microbial components has no effect on the capacity of HaCaT keratinocytes to release TLR2 receptors.

Chapter two

Background Information

Immune system

The body's immune system is characterized by five essential features. First of all, it can discriminate between self or host cells and pathogens or non-self-molecules. Secondly, the system is capable of deciding on how it responds to foreign substances that are trying to invade the body; this is indicative that there is more than one way to deal with a specific pathogen, and the system has a duty to decide on the most effect mechanism. In other cases, the system may choose not to react to any of the invading pathogens or foreign substances such as food or drugs; this is referred to as tolerance. The mechanism that the body uses to achieve protection against specific infection is known as immunity.

To activate immune responses, the system needs to identify and discriminate pathogens from self-cells. This is achieved through pathogen-associated molecular patterns (PAMPs) that are associated with microorganisms. PAMPs are physical or chemical characteristics of microbes that enable them to be identified by the immune system. They can be peptidoglycan layer, cell wall, CPG motifs in nuclear material or double-stranded RNA in viruses. The immune system also identifies damage associated molecular patterns (DAMPs) of self-cells. DAMPs enable immune cells to discriminate between healthy and abnormal host cells. An example of DAMPs is the down-regulation of MHC molecule or the alteration of its expression in the host cell which is an indicator of abnormality in the host cell.

PAMPs and DAMPs are recognized by pattern recognition receptors (PRR) of immune cells. These structures are expressed in the surface, cytoplasm, endospore of immune cells; especially those involved in the innate response. They can also be secreted as soluble factors. There are several types of PRRs; Toll-like receptor (TLR), RIG-1 receptors, NOD-like receptors and endocytic receptors such as C-type lectin, formylmethionine receptors, glucan receptors and opsonin receptors. The focus of this study is the Toll-like receptors

Toll-like receptors

To understand the functionality of keratinocytes and TLRs in immune responses, it is essential to have a deeper look at them. TLRs are glycoproteins that transverse the cell membranes and are structurally made up of ectodomains of motifs that are rich in leucine. The structure of these receptors is made up of a transmembrane domain and a cytoplasmic tail domain that resembles the receptor for interleukin-1. The cytoplasmic tail plays a role in initiating a cascade of various signals. Some of these signal cascades include the nuclear factor kappa-B activation; an essential factor in transcription that enhances the expression of immune response genes such as those encoding for cytokines, chemokine, adhesion and co-stimulatory molecules. In human beings, there are ten types of TLRs that have been identified; TLR 1 up to 10. These TLRs are unique physiologically as they each one of them recognizes a different PAMP. The receptors can work in a synergetic manner to help in recognition of invading pathogens. For instance, TLR2 can for a heterodimer with TLR1 or TLR6 to enable recognition of tri-acyl lipopeptides or diacyl lipoproteins. TLR2 are used to recognize the murein or the peptidoglycan layer of bacterial and fungal components. TLR3 recognizes foreign nucleic acid from pathogens such as double-stranded RNA found in viruses during their replication cycle. TLR4 works with CD14 to recognize lipopolysaccharide in gram negative. TLR 5, on the other hand, recognizes bacterial flagella while TLR 7 and 8 recognize single-stranded RNA and are also responsible for imidazoquinoline compounds such an imiquimod and resiquimod. Recognition of hypomethylated CPG motifs in double-stranded DNA resulting from replication process.Toll-like receptor 2 (TLR2)

TLR2 also known as CD282 (cluster of differentiation 282), is a membrane protein receptor that is expressed by various cells on their surface and distinguishes foreign molecules resulting to the passage of the correct signal to the immune system for immune response activation. It is encoded by the TLR2 gene in humans and plays an essential role in pathogen recognition and activation of innate immunity. It recognizes PAMPs from infectious agents and mediates cytokines production which is essential for the development of effective immunity. TLR2 gene is expressed mainly in the peripheral blood white blood cells and controls the response of the host to gram-positive bacteria and yeast via stimulation of NF-kB (nuclear factor kappa-light-chain-enhancer of activated B cells). Moreover, it also regulates CYP1A1 expression; a key enzyme in the detoxification of carcinogenic polycyclic aromatic hydrocarbons.

TLR2 recognizes a wide range of bacterial, fungal, viral and various substances of endogenous origin. Recognition results in uptake of the bound material through phagocytosis or internalization by phagosomes and also cellular activation. This also results in activation of non-specific defense cells such as the polymorphonuclear cell (PMNs), dendritic cells, macrophages, B1a and MZ B cells from the first antibody and also initiate the formation of a specific antibody. Cytokines are also involved in this process. The cytokines that are involved include various interleukins (IL1-a, IL1-b, IL-6, IL-8, and Il-12) and tumor necrosis factor-alpha (TNF-a).

Before the discovery of TLRs, most of their molecules were classified as modules. In the most experimental model, an immune deviation is observed in the direction due to cytokine pattern that corresponds to Th1 characteristics rather than Th2 characteristics. At that time, conjugates were being developed as vaccines even without proper knowledge of the mechanism of action of TLR2. The functionality of this TLR2 is impaired by various polymorphism that reduce their survival rates especially in infection with gram-positive bacteria

Expression of TLR2 occurs on microglia, monocytes, macrophages, dendritic cells, polymorphonuclear leukocytes, B cells such as MZ B, B2 and B1a and T cells such as Treg. There are also scenarios where TLR2 can be found as heterodimers; for instance, a combination of TLR2 with TLR1 or TLR6. They are also expressed by epithelia of air passages, pulmonary alveoli, renal tubules and the Bowman's capsule in renal corpuscles. Skin cells such as keratinocytes are also key expressers of TLR2 together with sebaceous glands where TLR2 induces the formation of bactericidal sebum.

There are several ligands that bind to TLR2 and induce immune responses. These agonistic ligands are listed below.

- Agonistic Ligand Organism

- Lipopolysaccharide Leptospirosis and Porphyromonas gingivalis

- MALP-2and MALP 404 Mycoplasma, Chlamydophila pneumonia

- Lipoteichoic acid Gram positive bacteria

- OspABorrelia burgdorferi (Lyme disease)

- PorinNeiseria meningitides, Haemophilus influenzaeLcrVYersinia

- Antigen mixtures Propionibacterium acnes, apergillus fumigatus, candida albicansGPl anchor Trypanosoma cruziLipomannan Mycobacterium tuberculosis

- LipophosphatidylserineSchistosoma mansoniLiphosphoglycan (LPG) Leishmania major

- ZymonasSacchromyces cerevisiae (yeast), MalaseeziaGlycophosphatidylinositol (GPl) Plasmodium falciparum

- Hsp 60 Herpes simplez virus, Varicella zoster virus, cytomegalovirus (CMV)

- HammagglutininMeasles

Interaction with the above ligands is through the formation of dimeric complexes with TLR1 or TLR6 on the cell membrane. All the above ligands are an example of agonistic PAMPs for the rec...