Autoimmunity

An autoimmune response is an attack by the immune system on the host itself. In healthy individuals the immune system is "tolerant" of its host ("self") but attacks foreign ("non-self') constituents such as bacteria and viruses. The ability to distinguish self from non-self is considered to be the determining factor in whether the immune system responds to a suspected challenge. Although it may appear obvious, there is actually considerable debate over what constitutes "self" and "non-self" and what cellular/molecular mechanisms are involved. A fascinating historical perspective on self/non-self recognition has been written by Alan Baxter (see Chapter 3) and includes the often-forgotten point that Mac-farlane Burnet used the phrase "self and not-self' when he first introduced the concept. Possible discriminators between "self' and "non(not)-self" include recognition of infection [1] or identification of danger signals [2]. The outcome of the debate on self/non-self discrimination not withstanding, autoimmunity represents an obvious disruption to the mechanism by which the immune system regulates its activities. Importantly, the responsible effector mechanisms appear to be no different from those used to combat exogenous infective reagents and include soluble products such as antibodies (humoral immunity) as well as direct cell-to-cell contact resulting in specific cell lysis (cell-mediated immunity). No single mechanism has been described that can account for the diversity of autoimmune responses, or the production of autoantibodies. Figure 1.1 outlines

Fig. 1.1 Hypothetical pathway of autoantibody elicitation in human disease and experimental animal models. This model combines features from the most commonly accepted postulated mechanisms for auto-antibody production. Genetically predisposed individuals may be triggered to begin the response by an exogenous agent such as exposure to a drug, chemical toxin, or other environmental influence. The events that follow

(listed in large box) are poorly understood but must involve the emergence of autoreactive lymphoid cells and the presence of autoantigen in a molecular form reactive with autoreactive cells. Once the presentation of autoantigen has activated autoreactive lymphoid cells, the production of autoantibody proceeds essentially as it would for a non-autoimmune antibody response.

Fig. 1.1 Hypothetical pathway of autoantibody elicitation in human disease and experimental animal models. This model combines features from the most commonly accepted postulated mechanisms for auto-antibody production. Genetically predisposed individuals may be triggered to begin the response by an exogenous agent such as exposure to a drug, chemical toxin, or other environmental influence. The events that follow

(listed in large box) are poorly understood but must involve the emergence of autoreactive lymphoid cells and the presence of autoantigen in a molecular form reactive with autoreactive cells. Once the presentation of autoantigen has activated autoreactive lymphoid cells, the production of autoantibody proceeds essentially as it would for a non-autoimmune antibody response.

the common features of hypothetical models of autoantibody elicitation. Most models, particularly those relating to autoimmune disease in animals, include a genetic predisposition. Breeding experiments between inbred strains of mice have shown that the genetic control of autoantibody production is complex, involving multiple genes [3]. Although most of the required genetic elements remain to be characterized, it appears that both acceleration and suppression of autoimmune responses are under genetic control [4-6]. The most frequently observed genetic requirement involves the major histocompatibility complex (MHC) class II genes, which encode proteins responsible for the presentation of processed antigen to CD4+ T cells via the T-cell receptor.

The most perplexing and challenging aspect of autoimmunity and autoanti-body elicitation is the identification of the events involved in the initiation of the response. Although these early events are poorly understood for most autoimmune diseases, it is thought that an exogenous trigger can provide the first step in the initiation of some autoimmune responses. The best evidence for this comes from drug- and chemical-induced autoimmunity, which has been described in both human disease and animal models of autoimmunity [7]. However, even in exogenously induced autoimmunity, many of the events between the administration of a chemical or drug and the appearance of autoantibodies remain to be unveiled. Induction of autoantibodies by exogenous agents can take several weeks to many months. Drug-induced systemic autoimmunity in humans can take prolonged periods of time to develop and can be provoked by a large number of chemically unrelated drugs [7]. The autoantibody response, however, appears quite restricted, targeting histones and histone-DNA complexes, the components of chromatin [8, 9]. Complexes of drug and autoantigen are not the immunogens responsible for the autoantibody response, since the drug is not required for autoantibody interaction with autoantigen. Withdrawal of the drug often leads to cessation of clinical symptoms, clearly implicating the participation of the drug in some mechanism inciting the autoimmune response, although autoantibody may persist for months in the absence of the drug. In several animal models, exposure to chemicals-particularly inorganic forms of heavy metals such as mercury, silver, or gold-can lead to autoantibody expression within weeks [10]. In these murine models the autoantibody response is again restricted, but here the predominant targets are non-chromatin components of the nucleolus [11, 12]. The development of restricted autoanti-body specificities in humans given many different drugs or in mice given heavy metals suggests that it is not the parent molecule that is important but rather the metabolic products of these compounds that lead on the one hand to anti-chromatin autoantibodies and on the other to anti-nucleolar antibodies. In human drug-induced autoimmunity, a common pathway of oxidative metabolism via the ubiquitous neutrophil has been suggested as a means of producing reactive drug metabolites that may perturb immune regulation sufficiently to produce autoimmune disease [13]. Another mechanism that has been proposed is disruption by drug metabolites of positive selection of T cells during their development in the thymus [14-16]. This mechanism has been shown to result in mature CD4+ T cells that are able to respond to self-antigen, leading to T-cell proliferation as well as autoantibody production by B cells [16].

In Figure 1.1 the large boxed area highlights several concepts that form pivotal points in many hypothetical postulates of autoantibody elicitation but about which little is known. How do B and T cells, with receptors for autoantigen, emerge from and escape the regulatory mechanisms that normally keep them in check and then make their way to the secondary lymphoid tissues? Studies involving transgenic mice possessing neo-autoantigens suggest that possible mechanisms include avoidance of apoptotic elimination, escape from tolerance induction, and reversal of an anergic state [17]. Mechanisms of immune tolerance and how their disruption may lead to autoimmunity are discussed by Robert Rubin in Chapter 4.

Molecular identification of autoantigens, their presence in macromolecular complexes, the occurrence of autoantibodies to different components of the same complex, and the appearance of somatic mutations in the variable regions of autoantibodies have suggested that it is the autoantigen that drives the autoimmune response [18]. It remains unclear how autoantigens, particularly intra-cellular autoantigens, are made available to autoreactive lymphoid cells, and what molecular forms of these complex macromolecular structures interact with autoreactive lymphoid cells. One mechanism that has been proposed as a means by which autoantigens might be made available to the immune system is apoptotic cell death. The impetus for this hypothesis is the finding that many autoantigens undergo proteolytic cleavage during apoptotic cell death and that apoptotic bodies (debris from dying cells) contain multiple autoantigens [19]. Processing and presentation of such material by antigen-presenting cells (APCs) has been suggested as a means of providing antigen to autoreactive T cells [20]. However, uptake of apoptotic cellular material does not lead to the activation of APCs [21-24], which is necessary if APCs are to activate T cells. Inability of apoptotic material to activate APCs may stem from the observation that apopto-sis is a descriptor for programmed cell death (PCD), which is a physiological process. This contrasts sharply with necrotic cell death, which is a non-physiological process that produces cellular material that activates APCs [25]. Also of note is that necrotic cell death induced by mercury leads to proteolytic cleavage of the autoantigen fibrillarin [26]. Immunization with the N-terminal fragment of such cleavage leads to autoantibodies against fibrillarin that possess some of the characteristics of the anti-fibrillarin response elicited by mercury alone [26]. In contrast the antibody response elicited by immunization with full-length fi-brillarin does not mimic the mercury-induced response, suggesting that processing and presentation of fragmented autoantigens may allow loss of self/non-self discrimination. Examination of the molecular forms of autoantigens during and after cell death and their roles in activating both APCs and T cells will be fruitful areas of future research. An overview of the two major forms of cell death and the evidence supporting their role in autoimmunity are discussed by Carlos Casiano and Fabio Pacheco in Chapter 6. How autoantigen might become modified to generate novel, non-tolerized structures and the role that pro-

teolytic cleavage during cell death might have on such a process are analyzed by Antony Rosen and colleagues in Chapter 7.

Roles in autoantibody production have been argued for pathways that either are or are not dependent on the presence of T cells. A T cell-dependent response is shown in Figure 1.1, with an APC supplying processed antigen to CD4+ Tcells. An essential element in any model of autoantibody elicitation is the emergence of antibody-secreting B cells, which recognize material derived from the host [27]. As indicated in Figure 1.1 the interaction between Tand B cells involves both soluble (e.g., interleukin) and membrane-bound receptor-co-receptor interactions [28]. The effect of the presence, or absence, of these molecular interactions on autoimmunity is discussed by Barbara Schraml and Stanford Peng in Chapter 5. The antibody secreted by a B cell is directed against a single region (or epitope) on an antigen. An autoantibody response can target a number of epitopes on any one antigen, clearly showing that multiple autoreactive B-cell clones are activated during an autoimmune response. In the systemic autoimmune diseases, many autoantigens are complexes of nucleic acid and/or protein, and an autoimmune response may target several of the components of a complex [29]. It is unknown whether the autoantibody responses to the components of a complex arise simultaneously, sequentially, independently, or through interrelated mechanisms. For a detailed analysis of the T- and B-cell response against a self-antigen, see Chapter 19 by James McCluskey and colleagues.

In only a few diseases have autoantibodies been shown to be the causative agents of pathogenesis (e.g., anti-acetylcholine receptor autoantibodies in myasthenia gravis, anti-thyroid-stimulating hormone receptor autoantibodies in Graves' disease) [30, 31]. It is noteworthy not only that these diseases are organ specific but also that their autoantigens are extracellular or on the surface of cell membranes and therefore easily targeted by the immune system. In some individuals the largest organ, the skin, can suffer insult from several blistering conditions now known to be autoimmune diseases characterized by autoantibodies against products of keratinocytes [32]. The autoantigens involved are cell adhesion molecules that are important in maintaining the integrity of the skin by cell-cell contact between the various cell layers in the epidermis and at the dermal-epidermal junction. In the non-organ-specific autoimmune disease systemic lupus erythematosus (SLE), anti-double-stranded DNA (dsDNA) autoantibodies have been shown to participate in pathogenic events by way of complexing with their cognate antigen to cause immune complex-mediated inflammation [33, 34]. These examples show that in both the organ-specific and systemic autoimmune diseases, in vivo disposition of autoantibody in tissues and organs has clinical significance inasmuch as it indicates sites of inflammation, which may contribute to the pathological process. Moreover, detection of autoantibody deposits in the organ-specific autoimmune diseases has particular significance because some organ-specific autoantibodies have been found to be the direct mediators of pathological lesions. In most autoimmune diseases, however, it has not been determined whether autoantibodies cause or contribute to disease or are merely a secondary consequence of the underlying clinical condition.

How To Bolster Your Immune System

How To Bolster Your Immune System

All Natural Immune Boosters Proven To Fight Infection, Disease And More. Discover A Natural, Safe Effective Way To Boost Your Immune System Using Ingredients From Your Kitchen Cupboard. The only common sense, no holds barred guide to hit the market today no gimmicks, no pills, just old fashioned common sense remedies to cure colds, influenza, viral infections and more.

Get My Free Audio Book


Post a comment