The Role of Inflammation in Autoimmune Diseases
1. Introduction
The complexity of the role of inflammation in autoimmune diseases is in part due to the multiple and diverse origins of both inflammation and autoimmune diseases. Indeed, the origin of inflammation in an autoimmune disease may be inextricably linked to the etiology of the autoimmune response itself. Inflammation is an integral part of the successful immune response to infections and tissue injury. The immune system has evolved to recognize and respond to pathogens and tissue damage in a way that efficiently clears the pathogen and enhances repair of the damaged tissue. This response and its mediators are not inherently specific for infectious agents and can be induced by a broad array of self antigens. In some instances, failure to resolve an immune response to a self antigen may cause chronic inflammation and ultimately an autoimmune response to that antigen. On the other hand, the inflammation in some autoimmune diseases may be secondary to a primary disturbance of the immune system that is not directly related to recognition of self antigens by the adaptive immune system. This is believed to be the case in systemic lupus erythematosus, where immune complex deposition and activation of the complement cascade cause tissue damage and inflammation. This can cause confusion in the interpretation of the role of inflammation in some autoimmune diseases and may even result in artificial distinctions between autoimmune diseases and diseases of immune dysregulation that are not primarily driven by adaptive immunity to self antigens.
Autoimmune diseases have long been recognized as the prototypic disorders of altered immunity. In 1957, T.H. Bullock and P.M. Medawar defined an autoimmune disease as ‘a disease arising from an abnormal immune response to a normal body part’. A plethora of abnormalities of both the innate and the adaptive immune system have been proposed to underlie autoimmune diseases. While the mechanisms underlying autoimmune diseases are diverse, several lines of investigation have indicated that inappropriately sustained inflammation is a common factor in many of these diseases. Aberrant inflammation causes damage to tissues and enhances presentation of self antigens that can activate the adaptive immune system. This has led to a keen interest in the causes and consequences of inflammation in autoimmune diseases. This is reflected by a growing number of publications that focus on inflammation in autoimmune diseases published each year (figure 1). Nevertheless, the role of inflammation in the pathogenesis of autoimmune diseases is a complex issue.
2. Mechanisms of Inflammation in Autoimmunity
The types of inflammation that cause and effect autoimmune responses in target tissues can be quite varied. For example, the effector mechanism in rheumatoid arthritis is likely to be quite different from that in multiple sclerosis, and indeed from one individual to another with the same disease. In rheumatoid arthritis, there is evidence that the inflammation is a primary autoimmune response, directed against an antigen in the joint tissues. This may be triggered by exogenous agents, but the synovitis and destruction of cartilage and bone appear to be T cell mediated, and the T cells are likely to have recognition of antigen via the T cell receptor, and clonal expansion in the local joint environment. The exact nature of the antigenic trigger and the relevant specificity of T cell responses are as yet undefined, and we are far from understanding the precise events triggering T cell activation in an autoimmune response, but in this case, there is clear similarity to an ongoing T cell response to a defined pathogen, and there is potential for understanding and specific therapy.
One of the most important directions for research in autoimmune disease is to understand the mechanisms by which an immune response against self tissues is engendered. There is considerable evidence that inflammation in the target organ is a crucial component in the pathogenesis of autoimmunity. The role of inflammation in causing tissue damage in autoimmune disease can be direct, through the action of inflammatory cells and mediators on tissue function, and indirect, by potentiating other effector mechanisms such as antibody or cytotoxic T cells.
3. Inflammatory Markers and Autoimmune Disease Diagnosis
An inflammation is a condition where the cause of the respondents to produce inflammation but ends in damage and inception of inflammatory autoimmune disease is still unclear (Lars Klareskog, 2008). The association between the inflammatory process and autoimmune is complex. Inflammation may cause tissue damage and altered self-protein which triggers an immune response against this condition, so the certain result of events that cause autoimmune disease is actually a failure attempt of tissue repair process (Karonline Andersson, 2008). The inflammatory process is mediated by cytokines and chemokines. Cytokines are proteins which serve as mediators and regulators in inflammation and have various functions depending on their group (interferon, interleukin, tumor necrosis factor). On the other hand, chemokines are proteins which play an important role in leukocyte recruitment to the site of inflammation. Cytokines and chemokines have become targets for autoimmune disease therapy because it is believed that inhibition of several cytokines can reduce the progress of tissue damage and overcome symptoms of autoimmune disease (Alan Tyedman, 2007).
Inflammatory markers are objective parameters used to assess the existence, type, and activity of an inflammatory process. In some patients with autoimmune disease, it is hard to determine whether it’s disease activity, infection, or an inflammatory process which is caused by a side effect of therapy. By assessing disease activity and the inflammatory process, physicians can help determine the next therapy and predict the outcome of a certain autoimmune disease. Inflammatory markers aren’t only used in assessing inflammatory autoimmune disease but also inflammation in healthy tissue or diseases that aren’t caused by an inflammatory process.
4. Therapeutic Approaches Targeting Inflammation
Ongoing inflammation is another key process that often leads to tissue damage in autoimmune diseases. Studies of the inflammatory process have identified various cytokines (hormone-like proteins) that are produced by immune cells and have effects on cell activation, proliferation, and effector function. Some of these cytokines have been directly implicated in the pathogenesis of particular autoimmune diseases. These provide further potential targets for the development of cytokine inhibitors or specific anti-inflammatory drugs. An example is rheumatoid arthritis, where there has been much success in the treatment of joint inflammation and destruction by inhibiting the effect of pro-inflammatory cytokines, particularly TNF and interleukin-1.
Since autoimmune diseases involve an immune response that is directed against particular components of a person’s own body, a general way to prevent the development or spread of autoimmune diseases is to inhibit immune responses. Glucocorticoids and cytotoxic drugs are examples of non-specific therapies that have been useful in suppressing the symptoms and progression of a wide variety of autoimmune diseases. Although these drugs can have serious side effects, especially with prolonged use, advances in our understanding of the immune process provide hope for the development of more specific immunosuppressive agents with less toxicity. For example, the migration of autoreactive T cells into target organs is a key event in many autoimmune diseases. This process is dependent on T cell expression of specific adhesion molecules and their receptors on endothelial cells in the microvasculature of the target organ. Studies have shown that in animal models of certain autoimmune diseases, disease development can be inhibited by blocking the interaction of T cell adhesion molecules with their ligands on endothelial cells. This can be achieved using specific adhesion molecule antagonists or certain drugs that have indirect effects on T cell adhesion.
Clearly, our improved understanding of the complex role of inflammation in autoimmune diseases has already suggested several potential targets for therapeutic intervention. The ideal therapy would block the initiation of the autoimmune process and spread of the disease, be safe for prolonged use, be relatively inexpensive, and effective for all patients with a specific disease regardless of their genetic or environmental circumstances. From what we know now, this ideal therapy does not exist. However, progress is being made in the development of specific anti-inflammatory and anti-invasive therapies based on the pathogenesis of different autoimmune diseases. A few of these are described here.
5. Conclusion
The importance of inflammation in enhancing tissue-specific autoimmune diseases means that strategies targeting various inflammatory mediators may be useful therapies. Current therapies already target TNF-alpha and IL-1. However, due to the multitude of proinflammatory molecules involved, targeting a single mediator may not be effective, and knowledge of specific mechanisms of inflammation in specific diseases is required for tailored, effective treatments.
The inflammation that occurs in autoimmune diseases has adverse effects. Circulating inflammatory molecules or immune cells gain access to the CNS and PNS and induce neuroinflammation, leading to tissue damage and the clinical manifestations observed in multiple sclerosis, Parkinson’s disease. Clinical trials of anti-inflammatory treatments in rheumatic diseases show that reduction of inflammation reduces signs and symptoms of disease in disease models and humans, further emphasizing a pathogenic role for inflammation.
Various proteins, adhesion molecules, and proinflammatory cytokines and chemokines have been implicated in the pathogenesis of a number of autoimmune diseases. This is why it has been postulated that T cell involvement is crucial, with various activated T helper subsets (Th1, Th2, Th17) contributing to inflammation in different ways. However, it is now known that B cells are equally important in presenting autoantigens and producing pathogenic autoantibodies or by affecting T cell responses.
