1.6.2 Acute inflammation mediated by cytotoxic antibodies

Type II, or antibody-dependent cytotoxic hypersensitivity occurs when antibody binds to either self antigen or foreign antigen on cells, and leads to phagocytosis, killer cell activity or complement-mediated lysis.

Both type II and type III hypersensitivity are caused by IgG and IgM antibodies. The main distinction is that type II reactions involved antibodies directed to antigens on the surface of specific cells or tissues, whereas type III reactions involve antibodies against widely distributed soluble antigens in the serum. Thus, damage caused by type II reactions is localized to a particular tissue or cell type, whereas damage caused by type III reactions affects those organs where antigen-antibody complexes are deposited.

These hypersensitivity reactions are related to normal immune responses seen against microorganisms and larger multicellular parasites. Indeed, in mounting a reaction to a pathogen, exaggerated immune reactions may sometimes be as damaging to the host as the effects of the pathogen itself. In such cases the bordeline between a normal, useful immune response and hypersensitivity is blurred. Hypersensitivity reactions may also occur in many other conditions involving immune reactions, particularly autoimmunity and transplantation.

In type II hypersensitivity, antibody directed against cell surface or tissue antigens forms immune complex which interacts with complement and a variety of effector cells to bring about damage to the target cells. Antibodies can link the target cells to effectors cells, such as macrophages, neutrophils, eosinophils and generally, K cells, by means of Fc receptors on these effector cells. This is so-called antibody-dependent cell-mediated cytotoxicity (ADCC). Alternatively, the antibodies after binding to tissue antigens can interact with complement by activating C1 of the classical pathway. This results in the deposition of the C5b678(9) membrane attack complex and following lysis of antibody-sensitized cells.

Both the complement fragments and IgG can act as opsonins bound to host tissues or to microorganisms, and phagocytes take up the opsonized particles. By enhancing the lysosomal activity of phagocytes, and potentiating their capacity to produce reactive oxygen intermediates, the opsonins increase the phagocytes' capacity to destroy pathogen, but also increase their ability to produce immunopathological damage in hypersensitivity reactions. For example, neutrophils from the synovial fluid of patients with rhematoid arthritis produce more superoxide when stimulated than neutrophils from the blood. This is thought to be related to their activation, in the rheumatoid joint, by mediators which include immune complexes and complement fragments.

The accumulation of inflammatory cells (neutrophils), with release of neutrophil lysosomal enzymes and generation of toxic oxygen intermediates, together with complement-mediated tissue lysis, leads to destruction of tissues as in the glomerular and pulmonary basement membrane damage in Goodpasture's syndrome or in the autoimmune haemolytic anemia and immune-mediated thrombocytopenia of systemic lupus erythematosus.

There are three main subtypes of cytotoxic hypersensitivity:

1. Type II reactions between members of the same species. They are caused by isoimmunization and include transfusion reactions after transfusion of blood incompatible in the AB0 system, haemolytic disease of the newborn due to rhesus incompatibility and/or transplantation reaction provoked by antibodies in the recipient directed against surface transplantation antigens on the graft.

2. Autoimmune type II hypersensitivity reactions are evoked by antibodies in the host directed against his own cell or tissue antigens (autoantibodies). As an example may serve autoimmune haemolytic anaemia caused by autoantibodies to the patient's own red cells; Hashimoto's thyroiditis with autoantibodies against thyroid peroxidase surface antigen; idiopathic thrombocytopenic purpura manifest by platelet destruction evoked by anti-platelet antibodies; Goodpasture's syndrome in which complement-mediated damage to basement membrane due to specific autoantibodies is observed.

   Many diseases are caused by autoantibodies against hormone receptors. Recently, they are also known as type V hypersensitivity reactions. Autoantibodies directed against receptors can have the function of agonist resulting in stimulatory hypersensitivity and/or of antagonist leading to the blockade of signal transmited through the receptor occupied by such an autoantibody. The example of stimulary hypersitivity is thyrotoxicosis where pathological stimulation of TSH receptor occurs, whereas to the blocking hypersensitivity belong primary myxoedema (blockade of TSH receptor) or myasthenia gravis (blockade of acetylcholine receptor).

3. Type II drug reactions are very complicated. Drugs may become coupled to body components and thereby undergo conversion from a hapten to a full antigen which may sensitive certain individuals. If, during this response, IgE antibodies are produced, anaphylactic reactions can result. In some circumstances, cell-mediated hypersensitivity may by induced. In other cases where coupling to serum proteins occurs, the possibility of type III immune complex-mediated reactions may arise. Finally, the drug antigenic complex with a molecule on the surface of host cells may evoke the production of antibodies which are cytotoxic for the cell-drug complex. Examples of this mechanism have been seen in the haemolytic anaemia sometimes associated with continued administration of chlorpromazine or phenacetin, in the agranulocytosis asociated with the taking of amidopyrine or of quinidine, and now classic situation of thrombocytopenic purpura which may be produced by a sedative edormid. When the drug is withdrawn, the hypersensitivy is no longer evident.