Good Essay On The Role Of Toll Like Receptors In Allergy

Introduction

Allergy is an immune system disorder. Allergy or allergic reaction is a hypersensitivity to otherwise innocuous substances present in the environment. The allergic reaction is usually a rapid response; however, the sensitivity to certain allergens can be acquired over a period. It was previously called the type one hypersensitivity. It is characterized by an over activation of leucocytes, called the mast cells and the basophils following activation of immunoglobulin E (IgE) (Frigas, Gleich 1986). This activation of the basophiles and mast cells triggers an inflammatory response.

Pathophysiology of the allergic response

The type 1 hypersensitivity reaction is initiated when an allergen is introduced to the atopic individual, which is then presented by the ‘antigen presenting cell’. This encounter with the allergen then leads to activation of the type 2 helper T lymphocytes (TH2). The TH2 lymphocytes activate the secretion of the cytokine IL-4, interleukin 4, IL-5 and IL-13. The TH2 lymphocytes also interact with the B cells to produce IgE antibodies. A number of cells including the basophiles and the mast cells express IgE specific receptors (Fc receptor, FcRI) on their surface. The cells that have an IgE bound to their surface receptors become sensitized to the allergen. When an allergen is encountered for a second and subsequent time, it can bind to the IgE molecules present on the surface of the basophiles and mast cells. A cross linking between the IgE and the FcRI receptor occurs following binding of the same allergen to the sensitized cells more than one time. A number of histamines and other chemical mediators such as the cytokines, chemokines, interleukins and prostaglandins are secreted from the granules of the mast cells and basophiles followed by the degranulation (Prete 1992). The release of the various chemicals results in effects including, vasodilation, secretion of mucous, contraction of smooth muscles and nerve stimulation. These responses then lead to the development of itchiness, anaphylaxis, rhinorrhea and dyspnea. A localized or systemic response occurs based on the nature of the allergen molecule. Some of the localized allergic reactions include asthma that targets the respiratory system and eczema that is localized to the skin, or the dermis. On the other hand, a classical anaphylaxis is a more system wide reaction. In addition to the acute response to the allergens, delayed or long term responses are possible. The late response occurs due to the migration of other leukocytes, such as neutrophils, eosinophils, macrophages, etc.
It has been demonstrated that a polarized development of helper T 1 or T2 cells can occur that leads to a specific immune response. TH2 cell development is associated with allergy, while TH1 cells are activated to ward off and fight infections(Prete 1992). A theory that has been widely suggested behind the increase in an incidence of allergies is the ‘hygiene hypothesis’. According to the ‘hygiene hypothesis’ exposure of infants to infectious agents’ drives the development of the TH1 cells and away from TH2 cells (Strachan 2000). Environmental and genetic factors play an important role in allergies or hypersensitivity to certain allergens.

Toll like receptor and their signaling.

Toll like receptors (TLR) are a family of receptors that play an important function in natural and adaptive immunity. The TLR are involved in the recognition of pathogen associated molecular patterns (PAMP). The PAMP are recognized from various pathogens including bacteria, fungi or protozoan organisms (Bauer, Hangel, & Yu 2007). The TLR are expressed on the cells that are responsible for the first line of defense mechanism against PAMPs’ including the macrophages, dendritic cells (DC), and mast cells. Activation of the toll like receptors TLRs’ following interaction with their ligand leads to dimerization of the TLR. This dimerization results in recruitment of and the interaction with adapter molecules that bind to their Toll/IL-1 receptor like domain (TIR) domain. The adapter proteins that bind to the TIR domain of the TLR include the Toll/IL-1 receptor containing adapter protein (TIRAP), MyD88, TRIF and TRAM (Gangloff & Guenounou 2004). THE My88 and TRIF are the primary adapter proteins, while the TRAM and the TIRAP are involved in recruiting TRIF and MY88 to their specific TLR. My88 is the primary adapter protein that is recruited by all TLR except TLR3. It is recruited to the TIR domain of the TLR receptor which leads to interaction with IRAK-1 and 4 respectively. IL-1 receptor associated kinase-1 and IL-1 receptor associated kinase -4. IRAK-1 phosphorylates the IRAK-4. The phospho IRAK-1 then associates with the TNF receptor associated factor (TRAF-6). The TRAF6 activation followed by its oligomerization, and subsequent proteasomal degradation leads to activation of the NF-B transcription factor. The activation of the NFB pathway results in transcriptional activation of genes involved in anti-pathogenic reactions and inflammation. There are 13 members of the TLR family identified to date. These receptors can recognize components of bacterial cell wall, double stranded RNA and bacterial DNA molecules (Sabroe, et.al 2002) . While most members of the TLR family are present on the cellular surface including the TLR1,2,4,5,6, and 11; a few are also found inside the cellular organelles and which recognize the nucleic acids for activation (Figure 1, a schematic representation of TLR ligands and adapter proteins in TLR signaling).
Figure 1. A schematic representation of TLR ligands and adapter proteins in TLR signaling.(Bauer, Hangel & Yu 2007)
The different TLR can recognize and bind to specific PAMP molecules resulting in the activation and secretion of specific cytokines. The TLR4 is activated following interaction with Lipopolysaccharide a bacterial cell wall component. The lipid portion of LPS, known as Lipid A is specifically known for stimulation of the immune response. The LPS associates with a few proteins such as LPS binding proteins (LBP) and CD14 and MD2. This complex then binds to the TLR 4 inducing its aggregation and activation. The signaling pathway activated by the TLR-4 can induce the NFB mediated cytokine induction and also induction of IFN- and IL-10(Gangloff & Guenounou 2004). In addition to bacterial LPS, viral envelope proteins of MMTV and RSV virus can activate the signaling of TLR-4. The activation of TLR-4 by the mouse mammary tumor virus (MMTV) results in activation of B cells and bone marrow derived dendritic cells. These dendritic cells then lead to the expression of the receptor protein that allows for viral entry and infection. It has been shown that certain TLR, such as the TLR-2 forms a heterodimer with TLR-1 to recognize triacylated lipopeptides, while the heterodimer of TLR1 and TLR6 can recognize the diacylated lipopeptides only. However, this differential recognition has not been conclusively established as impurities often exist in the biochemically purified bacterial cell wall components (Asai et al., 2005). TLR 7 and 8 recognize the Guanosine or uridine rich Single stranded RNA viruses. Furthermore the receptors also recognize synthetic nucleoside analogues such as imidazoquinolines and activate the secretion of IFN-
FIGURE 2 A detailed representation of TLR-activation and signaling. (courtesy Akira & Takeda 2004.)
TLR are involved in the maturation of the dendritic cells that are responsible for communication between the lymphoid and peripheral tissue and adaptive immunity development. The expression of MHC (major histocompatibility complex), chemokines and chemokine receptors and co-stimulatory molecules such as CD80/CD86 is a function of TLR. The activation of the DC by the TLR allows for DC mediated activation of T cells. This activation of T cells culminates to TH1 type differentiation. It is believed that the TLR activate the TH1 based cell response. The TLR are also expressed by the B and T cells and can also induce activation of CD4+ T cell immunity. A low activation of TLR is associated with increased TH2 and weaker TH1immune cell maturation that causes an increase in allergy response (Montero-Vega& de Martin 2009). It was demonstrated that children of farmers who exhibit a lower incidence of allergies have an increased TLR2 mRNA expression (Prescott 2008). It has also been demonstrated that polymorphism in TLR2 gene resulted in increased allergic susceptibility. The TLR4 has also been demonstrated to play a role in allergy development in epidemiological studies. The gene coding for CD14, a co-receptor for the TLR-4 has been demonstrated to undergo polymorphism, which results in variation in the IgE level associated with allergy. In contrast to these, weaker TLR-3 and TLR-5 signaling was associated with lower risk for allergies in 1 year old babies. This paradoxical observation that a weaker TLR signaling exerts a protective effect on allergic development validates the role of TLR in allergy development; however the theory that a lower TLR signaling predisposes an individual to allergies is an oversimplification (Bellou, Schaub, Ting & Finn 2003).
It has been shown that, in addition to the polarized Th1/Th2 development, regulatory T cells play an important role in regulating hypersensitivity response (Gangloff & Guenounou 2004). An increased number of Treg cells that exert a greater suppressive function can inhibit the allergy responses. TLR are expressed on the surface of Treg cells, and it was demonstrated that the activation of human TLR8 in Treg cells inhibited their function. This effect was independent of dendritic cell activity. It was also demonstrated that the stimulation of the TLR-2 by a synthetic ligand; Pam3Cys resulted in increased proliferation of Treg cells and suppression of Treg activity. It has been shown that following infection TLR activation results in suppression of Treg activity and enabling of an unhampered immune response.

Role of Toll like receptor in allergic contact dermatitis (ACD)

ACD is an allergic condition of the skin in which the cutaneous immune system responds to otherwise harmless chemicals and cause itching, rashes, redness and inflammation. The Toll like receptors, 2 and 4 signaling pahways is involved in this hypersensitivity response. It has been demonstrated that in individuals with ACD, exposure to the chemical allergen results in the presentation of antigenic stimulus and delivery of so called ‘danger signals’. The exposure to allergens results in activation of Danger associated molecular patterns (DAMP), which are endogenous proteins ligands to the TLR-4, including fibronectin, -defensin, and hyaluran and which activate TLR-4(Peiser, et. al 2012). The activation of TLR-4 results in the production of IL-6, TNF-, IFN-, etc. that are required for the recruitment and migration of epidermal cells and possibly of dermal dendritic cells(McFadden, et. al 2013). This release of cytokines is believed to be an important step that results in the delivery of antigens to lymph nodes and activation of a Th1 cells. A positive feedback loop results following activation of Th1 cells that induce activation of the TLR ligands, DAMPs. This creates an overactive immune response associated with the ACD.

TLR ligands in therapy

Unmethylated CpG containing bacterial dinucleotides are natural ligands for the TLR-9. It has been demonstrated that stimulation of TLR-9 leads to stimulation of the TH1 cells, which inhibits the allergy inducing TH2 cell development. The use of CpG motif containing synthetic oligonucleotides can be used as potent treatment strategy for asthma and other allergies (Horner et al., 2001). The synthetic ligands for TLR-7 and 8 including imidazoquinoline resiquimod has been demonstrated to be potent candidates to revert the Th2 induction, which results in greater allergy response (Jurk et al., 2002)
Figure 3. Targeting TLR in allergy. (Courtesy ww.abcam.com)

Summary and Future directions

The drastic increase in allergy rate is caused by the interplay of genetic and environmental factors in susceptible individuals. A popular hypothesis associated with high allergy incidence is the ‘hygiene hypothesis’. According to this hypothesis, an reduction of exposure to microbes causes an increase in allergy. A polarized development of TH1 and TH2 cells is associated with TH1 based immune response and TH2 based allergic response. The Toll like receptors (TLR) are associated with initiating TH1 response and play an important role in the antimicrobial defense of the host. However, TLR4 activation followed by their interaction with regulatory T cells and dendritic cells is also responsible for TH2 mediated alloergic response. An interplay in genetic and environmental factors are associated with the development of an impairment in TLR signaling and development of allergic sensitivity. The future research would involve around the role of impaired TLR functioning in allergy development. The variation in the normal ontogeny of TLR function in patients susceptible to allergies and development of a therapeutic strategy targeted toward TLR in allergies would be the relevant future direction for TLR and allergy.

References

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