Immunological mechanisms as pathologic processes

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The assumption is generally made that the immune response is protective. To appreciate the concept of immunologic mechanisms as pathologic processes, the paradigm of the immune system as a beneficial event has to be shifted completely.

There are some situations where the actual lesion is a relatively localized interaction between cell-cell and cell-organism. Perhaps the classic example is that of the most commonly recognized form of Mycobacterium tuberculosis infection, where a relatively minute area with only one or two bacilli is identifiable in the tissue lesions. However, it is the tissue response to these localized interactions that is so extensive and is what is in fact recognized as the disease. To continue the example: the extensive granuloma formation is itself what is destructive and spreading into surrounding tissues, and it is this reaction that is recognized as the immunopathology.

In these instances, where the disease itself can be regarded as immunopathologic, the initiating agent may no longer be identified, but nonetheless the ongoing processes are frequently destructive and may be life-threatening. Perhaps the hallmark of such processes is in fact that they readily become self-perpetuating, i.e. the immunologic cascade has been initiated and continues to generate further tissue damage way beyond the original insult.

Immunopathology in this context is thus very closely linked to the classic four patterns of tissue injury (hypersensitivity reactions) that have been described in the literature. Like these four reactions, there are often extrinsic antigens which cause the disease process, but autologous antigens often play either a primary or perpetuating role.

Although type I anaphylactic reactions have their own distinctive features, they are rapidly developing immunologic reactions which occur in minutes and long-standing changes such as tissue destruction are usually not a feature. These are the forms of tissue injury where IgE synthesis is the key component, and the immunopathologic process is recognized when there is perpetuation of the process with basophils and mast cells predominating.

In many cytotoxic reactions, such as transfusion and hemolysis, the clinical emphasis is usually placed upon the circulating components, but the immunopathologic event itself is the synthesis of antibody which destroys a self component present on the surface of the target cell. This component may be either autologous or extrinsic, such as when drugs are coupled to red cells. The immunologic events which follow include complement activation and target cell lysis.

Variants of the cytotoxic form of immunopathology include where the antibody is against a receptor, blocking ligand-receptor interaction. This may have the same consequences as lysis of target (i.e.

nonfunction), even though the receptor-bearing cell remains alive. Perhaps the best characterized example of this type of immunopathologic event is the synthesis of antibodies to the acetylcholine receptor, which is the cause of impaired neuromuscular transmission and hence muscle weakness in myasthenia gravis.

The other well-established variant is when antibodies are directed against connective tissue components such as basement membrane. The disease which is perhaps the best-known example of an immunopathologic process, where the primary injury is not known but the mcchanism is immunologically mediated, is Goodpasture's syndrome. Antibasement membrane antibodies bind directly and block function to give linear glomerular deposits and also involve the alveolar wall interface with lung capillaries. That the lesion is immunopathologic has been confirmed by remission induction using plasmapheresis.

Immune complex formation leads to several different types of immunopathology. At a basic level, the question is really not why immune complexes constitute such an important component in immunopathologic processes, but rather what are the factors that make these particular immune complex patterns pathologic, whereas most immune complex formation is by definition a successful form of host defense.

Immune complex formation can be localized in an Arthus reaction) or systemic. The tissue hallmark is commonly a vasculitis, and this vasculitis may occur in many different sites: arthritis, endocarditis, glomerulonephritis and alveolitis are all possible. The nature of the complex varies, depending on whether the antigen is endogenous or exogenous, and on whether the immunopathologic event is the formation of a complex per se, as in lupus erythematosus, or of a complex of antigen, antibody and antiantibody, as seen in rheumatoid arthritis.

The immunopathogenetic mechanism in immune complex disease starts as an acute local inflammatory reaction in response to the presence of the complex, but the key event is probably complement activation and fixation. Serum complement levels fall due to 'consumption' by complexes and neutrophils are attracted to the site. The natural history of the disease varies, but is again commonly persistent and chronic.

The granulomatous form of immunopathology has already been mentioned. These cell-mediated events are often a reflection of a classic delayed-type hypersensitivity and are the most obvious example of how a response can itself become the disease. Leprosy, with destructive paucibacillary disease, may be even more dramatic than tuberculosis, with nerve damage due to the aggressive nature of the immunopatho-logy. There is a cascade effect in which lymphocytes play a role. Necrosis occurs as a frequent concomitant of granulomas, and is a key immunopathologic change, since by definition it is a destructive rather than reparative event.

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