Destructive Mechanisms in Autoimmune Diseases Essay

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Destructive Mechanisms in Autoimmune Diseases Essay

Explain the destructive mechanisms in autoimmune diseases. List the guidelines for universal precautions and infection control

  1. It’s important to understand the many terms that are used in connection with conceptual contexts for research. Researchers demonstrate their conceptual clarity through the delineation of a theory, model, or framework on which the study is based. Define and elaborate on each of these three terms. 2. Explain the destructive mechanisms in autoimmune diseases. List the guidelines for universal precautions and infection control.

Autoimmune disease occurs when a specific adaptive immune response is mounted against self antigens. Destructive Mechanisms in Autoimmune Diseases Essay. The normal consequence of an adaptive immune response against a foreign antigen is the clearance of the antigen from the body. Virus-infected cells, for example, are destroyed by cytotoxic T cells, whereas soluble antigens are cleared by formation of immune complexes of antibody and antigen, which are taken up by cells of the mononuclear phagocytic system such as macrophages. When an adaptive immune response develops against self antigens, however, it is usually impossible for immune effector mechanisms to eliminate the antigen completely, and so a sustained response occurs. The consequence is that the effector pathways of immunity cause chronic inflammatory injury to tissues, which may prove lethal. The mechanisms of tissue damage in autoimmune diseases are essentially the same as those that operate in protective immunity and in hypersensitivity diseases. Some common autoimmune diseases are listed in Fig. 13.1.

Autoimmune diseases classified by the mechanism of tissue damage. Autoimmune diseases can be grouped in the same way as hypersensitivity reactions, according to the type of immune response and the mechanism by which it damages tissues. The immunopathological (more…)

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Adaptive immune responses are initiated by the activation of antigen-specific T cells, and it is believed that autoimmunity is initiated in the same way. T-cell responses to self antigens can inflict tissue damage either directly or indirectly. Cytotoxic T-cell responses and inappropriate activation of macrophages by TH1 cells can cause extensive tissue damage, whereas inappropriate T-cell help to self-reactive B cells can initiate harmful autoantibody responses. Autoimmune responses are a natural consequence of the open repertoires of both B-cell and T-cell receptors, which allow them to recognize any pathogen. Although these repertoires are purged of most receptors that bind with high affinity to self antigens encountered during development, they still include receptors of lower affinity reactive to some self antigens. It is not known what triggers autoimmunity, but both environmental and genetic factors, especially MHC genotype, are clearly important. Transient autoimmune responses are common, but it is only when they are sustained and cause lasting tissue damage that they attract medical attention. Destructive Mechanisms in Autoimmune Diseases Essay. In this section, we will examine the nature of autoimmune responses and how autoimmunity leads to tissue damage. In the last section of this chapter, we will examine the mechanisms by which self-tolerance is lost and autoimmune responses are initiated.

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13-1. Specific adaptive immune responses to self antigens can cause autoimmune disease
Early in the study of immunity it was realized that the powerful effector mechanisms used in host defense could, if turned against the host, cause severe tissue damage; Ehrlich termed this horror autotoxicus. Healthy individuals do not mount sustained adaptive immune responses to their own antigens and, although transient responses to damaged self tissues occur, these rarely cause additional tissue damage. But although self-tolerance is the general rule, sustained immune responses to self tissues occur in some individuals, and these autoimmune responses cause the severe tissue damage that Ehrlich predicted.

In certain genetically susceptible strains of experimental animals, autoimmune disease can be induced artificially by injection of ‘self’ tissues from a genetically identical animal mixed with strong adjuvants containing bacteria (see Appendix I, Section A-4). This shows that autoimmunity can be provoked by inducing a specific, adaptive immune response to self antigens and forms the basis for our understanding of how autoimmune disease arises. In humans, autoimmunity usually arises spontaneously; that is, we do not know what events initiate the immune response to self that leads to the autoimmune disease. There is evidence, as we will learn in the last part of this chapter, that some autoimmune disorders, such as rheumatic fever, may be triggered by infectious agents. There is, however, also evidence, particularly from animal models of autoimmunity, that many autoimmune disorders occur through internal dysregulation of the immune system without the participation of infectious agents. Destructive Mechanisms in Autoimmune Diseases Essay.

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13-2. Autoimmune diseases can be classified into clusters that are typically either organ-specific or systemic
The classification of disease is an uncertain science, especially in the absence of a precise understanding of causative mechanisms. This is well illustrated by the difficulty in classifying the autoimmune diseases. It is useful to distinguish two major patterns of autoimmune disease, the diseases in which the expression of autoimmunity is restricted to specific organs of the body, known as ‘organ-specific’ autoimmune diseases, and those in which many tissues of the body are affected, the ‘systemic’ autoimmune diseases. Examples of organ-specific autoimmune diseases are Hashimoto’s thyroiditis and Graves’ disease, each predominantly affecting the thyroid gland, and type I insulin-dependent diabetes mellitus (IDDM), which affects the pancreatic islets. Examples of systemic autoimmune disease are systemic lupus erythematosus (SLE) and primary Sjögren’s syndrome, in which tissues as diverse as the skin, kidneys, and brain may all be affected. (Insulin-Dependent Diabetes Mellitus and Systemic Lupus Erythematosus, in Case Studies in Immunology, see Preface for details) Destructive Mechanisms in Autoimmune Diseases Essay.

The autoantigens recognized in these two categories of disease are themselves respectively organ-specific and systemic. Thus, Graves’ disease is characterized by the production of antibodies to the thyroid-stimulating hormone (TSH) receptor in the thyroid gland; Hashimoto’s thyroiditis by antibodies to thyroid peroxidase; and type I diabetes by anti-insulin antibodies. By contrast, SLE is characterized by the presence of antibodies to antigens that are ubiquitous and abundant in every cell of the body, such as anti-chromatin antibodies and antibodies to proteins of the pre-mRNA splicing machinery—the spliceosome complex—within the cell.

It is likely that the organ-specific and systemic autoimmune diseases have somewhat different etiologies, which provides a biological basis for their division into two broad categories. Evidence for the validity of this classification also comes from observations that different autoimmune diseases cluster within individuals and within families. The organ-specific autoimmune diseases frequently occur together in many combinations; for example, autoimmune thyroid disease and the autoimmune depigmenting disease vitiligo are often found in the same person. Similarly, SLE and primary Sjögren’s syndrome can coexist within a single individual or among different members of a family.

These clusters of autoimmune diseases provide the most useful classification into different subtypes, each of which may turn out to have a distinct mechanism.Destructive Mechanisms in Autoimmune Diseases Essay. A working classification of autoimmune diseases based on clustering is given in Fig. 13.2. It can be seen that the strict separation of diseases into ‘organ-specific’ and ‘systemic’ categories breaks down to some extent. Not all autoimmune diseases can be usefully classified in this manner. Autoimmune hemolytic anemia, for example, sometimes occurs as a solitary entity and could be classified as an organ-specific disease. In other circumstances it may occur in conjunction with SLE as part of a systemic autoimmune disease.

Some common autoimmune diseases classified according to their ‘organ-specific’ or ‘systemic’ nature. Diseases that tend to occur in clusters are grouped in single boxes. Clustering is defined as more than one disease affecting (more…)

Although anyone can, in principle, develop an autoimmune disease, it seems that some individuals are more at risk than others of developing particular diseases. We will first consider those factors that contribute to susceptibility.

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13-3. Susceptibility to autoimmune disease is controlled by environmental and genetic factors, especially MHC genes
The best evidence in humans for susceptibility genes for autoimmunity comes from family studies, especially studies of twins. A semiquantitative technique for measuring what proportion of the susceptibility to a particular disease arises from genetic factors is to compare the incidence of disease in monozygotic and dizygotic twins. If a disease shows a high concordance in all twins, it could be caused by shared genetic or environmental factors. This is because both monozygotic and dizygotic twins tend to be brought up in shared environmental conditions. If the high concordance is restricted to monozygotic rather than dizygotic twins, however, then genetic factors are likely to be more important than environmental factors.

Studies with twins have been undertaken for several human diseases in which autoimmunity is important, including type I IDDM, rheumatoid arthritis, multiple sclerosis, and SLE. Destructive Mechanisms in Autoimmune Diseases Essay. In each case, around 20% of pairs of monozygotic twins show disease concordance, compared with fewer than 5% of dizygotic twins. A similar technique is to compare the frequency of a disease such as diabetes in the siblings of patients who have diabetes with the frequency of that disease in the general population. The ratio of these two frequencies gives a measure of the heritability of the disease, although shared environmental factors within families could also be at least partly responsible for an increased frequency.

Results from both twin and family studies show an important role for both inherited and environmental factors in the induction of autoimmune disease. In addition to this evidence from humans, certain inbred mouse strains have an almost uniform susceptibility to particular spontaneous or experimentally induced autoimmune diseases, whereas other strains do not. These findings have led to an extensive search for genes that determine susceptibility to autoimmune disease.

So far, susceptibility to autoimmune disease has been most consistently associated with MHC genotype. Human autoimmune diseases that show associations with HLA type are shown in Fig. 13.3. For most of these diseases, susceptibility is linked most strongly with MHC class II alleles, but in some cases there are strong associations with particular MHC class I alleles. Destructive Mechanisms in Autoimmune Diseases Essay.

Associations of HLA serotype and sex with susceptibility to autoimmune disease. The ‘relative risk’ for an HLA allele in an autoimmune disease is calculated by comparing the observed number of patients carrying the HLA allele with the (more…)

The association of MHC genotype with disease is assessed initially by comparing the frequency of different alleles in patients with their frequency in the normal population. For IDDM, this approach originally demonstrated an association with HLA-DR3 and HLA-DR4 alleles identified by serotyping (Fig. 13.4). Such studies also showed that the MHC class II allele HLA-DR2 has a dominant protective effect; individuals carrying HLA-DR2, even in association with one of the susceptibility alleles, rarely develop diabetes. Another way of determining whether MHC genes are important in autoimmune disease is to study the families of affected patients; it has been shown that two siblings affected with the same autoimmune disease are far more likely than expected to share the same MHC haplotypes (Fig. 13.5). Destructive Mechanisms in Autoimmune Diseases Essay.

Population studies show association of susceptibility to IDDM with HLA genotype. The HLA genotypes (determined by serotyping) of diabetic patients (bottom panel) are not representative of those found in the population (top panel). Almost all diabetic (more…)

Figure 13.5. Family studies show strong linkage of susceptibility to IDDM with HLA genotype.
Figure 13.5
Family studies show strong linkage of susceptibility to IDDM with HLA genotype. In families in which two or more siblings have IDDM, it is possible to compare the HLA genotypes of affected siblings. Affected siblings share two HLA haplotypes much more (more…)

As HLA genotyping has become more exact through the sequencing of HLA alleles, disease associations that were originally discovered through HLA serotyping using antibodies have been defined more precisely. For example, the association between IDDM and the DR3 and DR4 alleles is now known to be due to their tight genetic linkage to DQβ alleles that confer susceptibility to disease. Indeed, disease susceptibility is most closely associated with polymorphisms at a particular position in the DQβ amino acid sequence. The most abundant DQβ amino acid sequence has an aspartic acid at position 57 that is able to form a salt bridge across the end of the peptidebinding cleft of the DQ molecule. Destructive Mechanisms in Autoimmune Diseases Essay. By contrast, the diabetic patients in Caucasoid populations mostly have valine, serine, or alanine at that position and thus make DQ molecules that lack this salt bridge (Fig. 13.6). The nonobese diabetic (NOD) strain of mice, which develops spontaneous diabetes, also has a serine at that position in the homologous MHC class II molecule, known as I-Ag7.

Figure 13.6. Amino acid changes in the sequence of an MHC class II protein correlate with susceptibility to and protection from diabetes.
Figure 13.6
Amino acid changes in the sequence of an MHC class II protein correlate with susceptibility to and protection from diabetes. The HLA-DQβ1 chain contains an aspartic acid (Asp) at position 57 in most people; in Caucasoid populations, patients with IDDM (more…)

The association of MHC genotype with autoimmune disease is not surprising, because autoimmune responses involve T cells, and the ability of T cells to respond to a particular antigen depends on MHC genotype. Thus the associations can be explained by a simple model in which susceptibility to an autoimmune disease is determined by differences in the ability of different allelic variants of MHC molecules to present autoantigenic peptides to autoreactive T cells. This would be consistent with what we know of T-cell involvement in particular diseases. In diabetes, for example, there are associations with both MHC class I and MHC class II alleles and this is consistent with the finding that both CD8 and CD4 T cells, which respond to antigens presented by MHC class I and MHC class II molecules, respectively, mediate the autoimmune response. Destructive Mechanisms in Autoimmune Diseases Essay.

An alternative hypothesis for the association between MHC genotype and susceptibility to autoimmune diseases emphasizes the role of MHC alleles in shaping the T-cell receptor repertoire (see Chapter 7). This hypothesis proposes that self peptides associated with certain MHC molecules may drive the positive selection of developing thymocytes that are specific for particular autoantigens. Such autoantigenic peptides might be expressed at too low a level or bind too poorly to self MHC molecules to drive negative selection in the thymus, but be present at a sufficient level or bind strongly enough to drive positive selection. This hypothesis is supported by observations that I-Ag7, the disease-associated MHC class II molecule in the diabetes-prone NOD mice, binds many peptides very poorly and may therefore be less effective in driving intrathymic negative selection of T cells that bind self peptides.

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However, MHC genotype alone does not determine genetic susceptibility to disease. Identical twins, sharing all of their genes, are far more likely to develop the same autoimmune disease than MHC-identical siblings, demonstrating that genetic factors other than the MHC also affect whether an individual develops disease. Recent studies of the genetics of autoimmune diabetes in humans and mice have shown that there are several independently segregating disease susceptibility loci in addition to the MHC.

There is also evidence that variation in the level of a potential autoantigen within the thymus can influence disease development. In the case of human insulin, which can act as an autoantigen in type I IDDM, the level of transcription of the insulin gene shows genetic variation between individuals; this is associated with a polymorphic minisatellite sequence located upstream of the gene. Gene variants that are transcribed at a high level in the thymus tend to protect against the development of diabetes, whereas variants transcribed at a lower level are associated with disease susceptibility. Destructive Mechanisms in Autoimmune Diseases Essay. This is because the expression of high levels of insulin in the thymus may cause the deletion of T cells specific for the insulin peptides (see Section 7-24).

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13-4. The genes that have been associated with the development of systemic lupus erythematosus provide important clues to the etiology of the disease
The major serological abnormality in SLE is the presence of autoantibodies to ubiquitous and abundant intracellular antigens, such as chromatin. How is tolerance broken to such all-pervasive self antigens? A number of genes have been implicated in the etiology of SLE in humans and mice (Fig. 13.7). These can be classified into three categories on the basis of their physiological function. The first comprises genes whose products are active in the body’s mechanisms for disposing of dead and dying cells, which could provide a source of autoantigens. Genetic knockout in mice (see Appendix I, Section A-47) of four genes in this category has produced animal models of SLE. One of these genes codes for the complement protein C1q, which, together with other complement proteins, is involved in the effective clearance of immune complexes and apoptotic cells. A second gene in this category encodes serum amyloid P component, which binds chromatin and may mask it from the immune system. Its deletion results in the development of antibodies against chromatin and development of glomerulonephritis caused by deposition of immune complexes of these antibodies in the kidney. Third, deletion of DNase I, an enzyme that digests extracellular chromatin, results in the development of anti-chromatin antibodies and glomerulonephritis. Fourth, a similar phenotype has been seen in mice in which the secretory portion of the immunoglobulin μ chain is deleted, and which thus lack secreted IgM, which may have an important role in the clearance of effete cells. However, the majority of cases of spontaneous SLE are likely to be influenced by far more complex genetic factors than these single-gene defects. Destructive Mechanisms in Autoimmune Diseases Essay.