Cytotoxic Reactions (Type Ii Hypersensitivity)

CYTOTOXIC REACTIONS (TYPE II HYPERSENSITIVITY)

This second type of hypersensitivity involves, in its most common forms, complement-fixing antibodies (IgM or IgG) directed against cellular or tissue antigens. The clinical ex-pression of type II hypersensitivity reaction depends largely on the distribution of the anti-gens recognized by the responsible antibodies.

A. Autoimmune Hemolytic Anemia and Other Autoimmune Cytopenias

Autoimmune hemolytic anemia, autoimmune thrombocytopenia, and autoimmune neu-tropenia  are clear examples of type II (cytotoxic) hypersensitivity reactions in which the antigens are unique to cellular ele-ments of the blood. Autoimmune hemolytic anemia is the best understood of these conditions.

Patients with autoimmune hemolytic anemia synthesize antibodies directed to their own red cells. Those antibodies may cause hemolysis by two main mechanisms:

1.           If the antibodies are of the IgM isotype, complement is activated up to C9, and the red cells can be directly hemolysed (intravascular hemolysis).

2.           If, for a variety of reasons, the antibodies (usually IgG) fail to activate the full complement cascade, the red cells will be opsonized with antibody (and possibly C3b) and are taken up and destroyed by phagocytic cells expressing FcγR and C3b receptors (extravascular hemolysis).

Intravascular hemolysis is associated with release of free hemoglobin into the circu-lation (hemoglobinemia), which eventually is excreted in the urine (hemoglobinuria). Mas-sive hemoglobinuria can induce acute tubular damage and kidney failure, which is usually reversible. In contrast, extravascular hemolysis is usually associated with increased levels of bilirubin, derived from cellular catabolism of hemoglobin. All hemolytic reactions usu-ally lead to the mobilization of erythrocyte precursors from the bone marrow to compen-sate for the acute loss. This is reflected by reticulocytosis and, in severe cases, by ery-throblastosis .

B. Goodpasture’s Syndrome

The classical example of a type II hypersensitivity reaction in which the antibodies are di-rected against tissue antigens is Goodpasture’s syndrome. The pathogenesis of Goodpas-ture’s syndrome involves the spontaneous emergence of basement membrane autoantibod-ies that bind to antigens of the glomerular and alveolar basement membranes. Those antibodies are predominantly of the IgG isotype. Using fluorescein-conjugated antisera, the deposition of IgG and complement in patients with Goodpasture’s syndrome usually fol-lows a linear, very regular pattern, corresponding to the outline of the glomerular or alve-olar basement membranes.

Two types of observations support the pathogenic role of anti–basement membrane antibodies:

1.           Elution studies yield immunoglobulin-rich preparations that, when injected into primates, can induce a disease similar to human Goodpasture’s syndrome.

2.           Goodpasture’s syndrome recurs in patients who receive a kidney transplant, and the transplanted kidney shows identical patterns of IgG and complement deposi-tion along the glomerular basement membrane.

Once antigen-antibody complexes are formed in the kidney glomeruli or in the lungs, complement will be activated and, as a result, C5a and C3a will be generated. These com-plement components are chemotactic for polymorphonuclear (PMN) leukocytes; C5a also increases vascular permeability directly or indirectly (by inducing the degranulation of ba-sophils and mast cells) . Furthermore, C5a can upregulate the expression of cell adhesion molecules of the CD11b/CD18 family  in PMN leukocytes and monocytes, promoting their interaction with ICAM-1 expressed by endothelial cells, thus facilitating the migration of inflammatory cells into the extravascular space. In the ex-travascular space PMN leukocytes will recognize the Fc regions of basement mem-brane–bound antibodies, as well as C3b bound to the corresponding immune complexes, and will release their enzymatic contents, which include a variety of metalloproteinases in-cluding collagenases and plasminogen activator. Plasminogen activator converts plasminogen into plasmin, which in tum can split complement components and generate bioactive fragments, enhancing the inflammatory reaction. Collagenases and other metallo-proteinases cause tissue damage (i.e., destruction of the basement membrane), that eventu-ally may compromise the function of the affected organ.

The pathological sequence of events after the reaction of anti–basement membrane antibodies with their corresponding antigens is indistinguishable from the reactions trig-gered by the deposition of soluble immune complexes or by the reaction of circulating an-tibodies with antigens passively fixed to a tissue, considered as type III hypersensitivity re-actions.

C. Nephrotoxic (Masugi) Nephritis

This experimental model of immunologically mediated nephritis, named after the scientist who developed it, is induced by injection of heterologous anti–basement membrane anti-bodies into healthy animals. Those antibodies combine with basement membrane antigens, particularly at the glomerular level, and trigger the development of glomerulonephritis.

This experimental model has been extremely useful to demonstrate the pathogenic importance of complement activation and of neutrophil accumulation. For example, if in- stead of complete antibodies, one injects Fab or F(ab’ )2 fragments generated from anti–basement membrane antibodies that do not activate complement, the accumulation of neutrophils in the glomeruli fails to take place, and tissue damage will be minimal to nonex-istent. Similar protection against the development of glomerulonephritis is observed when animals are rendered C3 deficient by injection of cobra venom factor prior to the adminis-tration of anti–basement membrane antibodies, or when those antibodies are administered to animals rendered neutropenic by administration of cytotoxic drugs or of antineutrophil antibodies.