Immune Response and Immunopathology

Immune Response and Immunopathology

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Over the past few decades, the field of immunology has witnessed a considerable shift in focus from studying B and T cells and their associated antigen-specific recommending receptors, to pattern recognition receptors (PRRs). These are a group of germline-encoded receptors that are actively involved in innate immunity. PRRs aid in non-self microbial product identification, as well as the identification of “danger” signals as released by the host, which is important in forecasting homeostatic change. Accordingly, PRRs help to identify PAMPs (pathogen-associated molecular r patterns) (Janeway and Medzhitov, 2002), and DAMPs (danger-associated molecular patterns) (Ultaigh et al., 2011). PRRs also play a key role in initiating adaptive immunity. Rheumatoid arthritis (RA) is among the most common autoimmune diseases of public health significance (Pablos and Canete 2013). Epidemiologic and genetic studies have identified the crucial role of interaction between such environmental factors as smoking and adaptive T-cell response in triggering the immunopathogenesis of RA. These interactions lead to a definite systematic antibody response that has been shown to play a crucial role in the synovial inflammatory process. RA is characterised by such clinical manifestations as stiffness, pain, joint destruction, and swelling, and these symptoms are due to chronic inflammation of the synovium, following interactions between such innate immune system cells as dendritic cells, macrophages, among others, and fibroblast-like synoviocytes. The T and B lymphocytes of the adaptive immune system could also be involved (Mogensen, 2009). Complement system proteins, paracrine and autocrine-acting cytokines, immune complexes, and chemokines characterised by homeostatic, anti-inflammatory, and inflammatory properties are also present (Pablos and Cañete, 2013).

Activation of the innate immune cells

The mammalian immune system entails the adaptive arm and the innate non-specific arm. The two effector arms cooperate to offer an all-inclusive defence against various pathogens. By providing an immediate response, the innate immune system endeavours to curtail the systemic spread of various infectious diseases. Before this can happen, it is essential that the receptors affiliated with the innate immune system identify various pathogens.  This happens thanks to the expression of PPRs (pattern recognition receptors) (1). The expression takes place on the cell surface. PPRs play such key roles as the upregulation of cell surface markets and in this way, activate adaptive immunity. They also trigger the expression and release of sytokines, responsible for initiating tissue-resident macrophages, as well as recruiting additional immune cells to sites where infections have occurred. The response is usually replicated in various instances of tissue damage or chronic inflammatory diseases. In this case, PRRs are activated in a sterile inflammatory environment due to the presence of DAMPs (‘damage-associated molecular patterns’ (Tang et al., 2012), which enables them to respond to danger signals.

The PRRs are known to recognise various DAMPs and PAMPs, with the Toll-like receptors (TLRs) being the most recognised class of PRRs (O’Neill, Golenbock and Bowie, 2013). TLRs are type 1 transmembrane receptors and can either be expressed in the endosomal membrane or plasma membrane (Ultaigh et al. 2011). They respond to various forms of ligands such as lipoproteins, nucleic acids, and proteins. The activation of TLRs triggered the downstream signalling pathways of adaptor molecules, thereby resulting in the activation of the nuclear factor (NF) or IRF (interferon regulatory factor) membrane. CLRs (C-type lectin receptors) are yet another form of membrane-bound PRRs and exist as either type 1 or type 2 receptors 96). They play key functions in the regulation of innate immunity and antigen uptake.

Macrophagaes, along with other types of innate immune cells, can be activated in one of several mechanisms. One of the activation mechanisms involves the PRRs, designed in such a manner as to recognised regular and simple non-self molecular structures known as PAMPs (pathogen-associated molecular patterns). Moreover, cells have also been shown to express DAMPs when under duress.  This could happen in case of chronic inflammation, resulting in the expression of such DAMPs as ATP, HSPs (heat shock proteins), uric acid, or gp96(glycoprotein 96) that PRRs can recognise (Jin et al., 2011; Su et al., 2012; Nasi et al., 2014). PRRs occur either as soluble plasma proteins, or they could be membrane-bound.

Patten recognition receptors and chronic inflammatory diseases

A growing body of literature indicates that PRRs play a key role in the innate immunity of various chronic inflammatory diseases, in which inflammation has been shown to influence the chronicity of disease or even worsen the symptoms. Specifically, NLRs (NOD-like receptors) and TLRs have been shown to possess the capability to influence the chronic inflammatory aspect of various arthritides, including psoriatic arthritis, osteoarthritis (OA), gout, and rheumatoid arthritis (RA), among others. The innate immune system plays a crucial role in the initial recognition of various microbial pathogens. The innate system cells, once they come into contact with non-self cells such as dendritic cells and macrophages, through intracellular or membrane-bound PRRs, are activated, and this triggers the production of inflammatory chemokines and cytokines (Pablos and Cañete, 2013). The recruitment of effector molecules and cells affiliated with the innate system takes place locally, and should they fail to overcome the pathogens on their own, this could signify the movement of dendritic cells and macrophages to the local lymphoid tissues. At the local lymphoid tissues, MHC molecules present the naïve T-cells with processed antigens, and this acts as the starting point of an adaptive response that also encompasses a lasting immunological memory.

Opposing anti-inflammatory mediators also assist with the clearance of the organism, thereby brining to an end the inflammatory response. In the case of RA however, the “self” can be either a secondary target or a primary target. As a secondary target, the “self” acts as an innocent bystander and is hence not the main target. However, it can still be converted into the focus of attack. Evidence from studies conducted on RA reveals that the innate immune system is continuously activated as attested to by the persistent expression of cytokines derived from macrophages, including IL-1, TNFα, and IL-6 (Yarilina et al., 2007).

Rheumatoid arthritis affects the synovial joints and involves fibroblast proliferation and infiltration of inflammatory cells. This results in chronic inflammation of the synovial joints, and the subsequent gradual destruction of cartilage and bone (Feldmann, Brennan, and Maini, 1996). The cells located in the RA joint then start to produce such cytokines as IL-1, TNF, and IL-6 at elevated levels. These sytokines facilitate Th17 cell differentiation, in addition to restraining differentiation of the T lymphocytes regulatory cells, thereby escalating the inflammatory environment (Boissier et al., 2012).

Various animal models developed with the aim of exploring the potential role played by TLRs in RA have yielded mixed results.  IL-1Ra−/−(IL-1 receptor antagonist-deficient) mice are susceptible to spontaneous arthritis development. However, crossing these mice with TLR4−/− mice reduces the severity of the disease (Abdollahi-Roodsaz et al., 2008). In contrast, crossing IL-1Ra−/− mice with TLR2−/− mice yields a severe form of arthritis, even as crossing with TLR9−/− mice was not seen to have any impact on arthritis (Abdollahi-Roodsaz et al., 2008).  On the other hand, TLR3 activation reduced disease severity in the mice CIA model, but escalated the severity of arthritis in the rat CIA Models (Yarilina et al., 2007), showing variability in arthritis models.


In sum, innate immunity is crucial in RA pathogenicity. However, the continuous activation of the innate immune system leads to the persistent expression of macrophages-derived sytokines like IL-1, TNFα, and IL-6. This could explain the chronic inflammation of the RA joint. Experimental models point towards the significant role played by innate immune cells in terms of initiating arthritis, thereby triggering auto-antibody production through adaptive immunity development. However, variations in the arthritis model are also evident from various animal models conducted.


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