IMMUNOLOGY - Roit A. - Mir 2000

Chapter 28. Autoimmune Processes and Autoimmune Diseases

■ Autoimmune mechanisms underlie many organ-specific and systemic diseases.

■ Autoimmune disorders can be multiple: the same individual may suffer from several organ-specific or several systemic diseases simultaneously.

■ An important role in The Development of autoimmune diseases belongs to genetic factors, such as the HLA haplotype; likely, multiple genetic factors are involved in any such disease.

■ In EXPERIMENTAL MODELING OF autoimmune phenomena and similar spontaneous disorders in animals, autoimmune mechanisms play a pathogenic role.

■ In humans, autoantibodies can directly exert a pathogenic effect.

■ Systemic autoimmune diseases are frequently associated with The formation of immune complexes.

■ Autoreactive B AND T Cells are present even in healthy individuals, but in disease they undergo Selection by autoantigens and drive autoimmune responses.

■ The cause of autoimmune phenomena may lie in cross-reacting microbial Antigens and disturbances in the cytokine regulatory network.

■ Detecting the presence and levels of autoantibodies has diagnostic and sometimes prognostic significance.

■ Treatment of organ-specific diseases is usually aimed at restoring metabolic balance.

■ Treatment of systemic diseases involves The Use of anti-inflammatory and immunosuppressive agents.

■ Future therapeutic approaches will likely involve targeting autoreactive T cells with antigens or Peptides, utilizing anti-CD4 Antibodies, and possibly T-Cell vaccination.

THE LINK BETWEEN AUTOIMMUNITY AND PATHOLOGY

The Immune System is capable of reacting against a vast array of diverse agents, and since the repertoire of B- and T-cell specificities is generated randomly, it inevitably includes numerous molecules specific for self-components. To prevent autoreactivity, essential mechanisms of self-tolerance operate, allowing the immune system to distinguish between self and non-self antigenic determinants (see Ch. 14). However, as in any biological system, the operation of self-tolerance mechanisms carries a risk of failure. A wide range of diseases is known to feature autoimmune manifestations driven by the Excessive production of autoantibodies and autoreactive T cells.

One classic example of pathology associated with autoantibody production is Hashimoto's thyroiditis. It has been studied in exceptional detail, and many aspects of autoimmune diseases discussed in this chapter are interpreted based on insights gained from this specific condition. Hashimoto's thyroiditis is a Thyroid Gland disorder that most commonly affects middle-aged women, leading to goiter and hypothyroidism. The gland becomes infiltrated (sometimes massively) by inflammatory lymphoid cells, predominantly mononuclear phagocytes, lymphocytes, and plasma cells; moreover, secondary lymphoid follicles typically form within it (Fig. 28.1). Thyroid follicle regeneration frequently occurs in Hashimoto's disease, which distinguishes it from another similar condition—primary Myxedema, associated with analogous immunological abnormalities but accompanied by almost complete destruction and a drastic reduction in the size of The Thyroid Gland.

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Fig. 28.1. Histological changes in Hashimoto's thyroiditis. In a normal thyroid gland (1), acinar epithelial cells (AEC) line the colloid cavity (CC), into which they secrete thyroglobulin, broken down as needed to produce THYROID Hormones (Cap capillaries containing erythrocytes). In Hashimoto's disease (2), The Structure of the thyroid gland is disrupted and almost entirely replaced by other cells (IC), primarily lymphocytes, macrophages, and plasma cells. A secondary lymphoid follicle (LF) with a germinal center (GC) and a mantle (M) of small lymphocytes is visible, alongside small regenerating thyroid follicles (RF). Hematoxylin-eosin stain, x 80.

The serum of patients with Hashimoto's thyroiditis typically contains antibodies against thyroglobulin. At high titers, these can be detected using hemagglutination and precipitation assays. Many patients also possess antibodies to a cytoplasmic (microsomal) antigen located on the apical surface of follicular epithelial cells (Fig. 28.2), which has been identified as thyroid peroxidase, the enzyme responsible for iodinating thyroglobulin.