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Chapter: Essential Clinical Immunology: Immunological Aspects of Renal Disease

Mechanisms of Immune Injury to the Kidneys

Cells of both innate and adaptive immu-nity mediate human defense against microbes.



Cells of both innate and adaptive immu-nity mediate human defense against microbes. The principal components of innate immunity are composed of physical and chemical barriers (e.g., epithelial cells and antimicrobial substances produced by the cells), phagocytic cells (neutrophils and macrophages), natural killer cells, comple-ment systems, and cytokines. These repre-sent the first line of defense against micro-bial agents. In contrast, adaptive immunity is represented by B and T lymphocytes. These cells are initially stimulated by expo-sure to offending agents. Subsequent expo-sure to similar agents cause specific cells to mount a defense in increasing magnitude.

Adaptive immunity is distinguished as having the ability to “remember” specific molecules and therefore provide specific immunity. Both types of immunity work in tandem to provide comprehensive defense against offending microbes.


Diseases caused by immune responses are often called hypersensitivity diseases. These are classified according to the type of immune responses and the effector mecha-nisms that are responsible for cell and tis-sue injury.

Immediate hypersensitivity or type I disease is mediated by immunoglobulin E (IgE), which is produced in response to an allergen. After exposure to a spe-cific allergen, TH2 cells specific for the allergen are activated. IgE antibodies are then produced, which subsequently bind to the Fc receptor of mast cells and basophils. This binding releases biogenic amines (histamine), neutral serine prote-ases, lipid mediators, and cytokines. Bio-genic amines and lipid mediators cause vascular leakage, vasodilation, and air-way bronchoconstriction. Serine prote-ases cause tissue damage. Cytokines are implicated in late phase reaction. Certain drugs, especially methicillin, nonsteroi-dal agents, rifampin, sulfa, cimetidine, cephalosporins, and 5-aminosalicylates, can cause allergic interstitial nephritis. Affected patients present with acute renal failure three to five days after intake of the offending drug. Fever, rash, hematu-ria, proteinuria, and eosinophiluria are typical findings. On kidney biopsy, tubu-lointerstitial inflammation is prominent with occasional demonstration of eosino-phils. The glomeruli appear spared of any inflammatory effects. Treatment consists of withholding the offending drug and use of steroids.

Antibody-mediated or type II disease is caused by antibodies against fixed cell and tissue antigens. Although most cases demonstrate the presence of autoantibod-ies, some antibodies can be produced by a foreign antigen that is immunologically cross-reactive to human tissue. Three mechanisms have been described to explain this phenomenon. First, antibodies may opsonize cells or activate the complement system that eventually produces comple-ment proteins that assist in opsonization of cells. Macrophages bind to Fc receptors of antibodies or complement protein receptors to cause endocytosis and destruction of the offending antigen. This appears to be the main mechanism in hemolytic anemia and autoimmune thrombocytopenic purpura. Second, antibodies bound in target tissues recruit neutrophils and macrophages by binding to Fc receptors or by activating complement. Activated neutrophils and macrophages release intracellular enzymes and reactive oxygen radicals that cause tissue injury. Examples of glomerular dis-ease that can be explained by this pathway include Goodpasture’s syndrome and anti-neutrophil cytoplasmic antibody (ANCA) mediated disease. Third, antibodies may bind to normal cellular receptors and inter-fere with their function to cause disease. However, no actual tissue injury is dem-onstrated. Graves’ disease represents this mechanism where the TSH receptor is tar-geted by the anti-TSH-receptor antibody. This mechanism causes hyperthyroidism. No glomerular disease has been associated with this mechanism (see Table 17.1).


Immune-complex-mediated, or type III, disease is caused by deposition of antibod-ies bound to self- or foreign antigens into target tissues. Although the glomerulus is a common target for immune complexes, other organ systems are involved, which suggests the systemic nature of this dis-ease. A classic example is the serum dis-ease or serum sickness, which was origi-nally described by Clemens von Pirquet in 1911. During his time, diphtheria infec-tions were treated with passive immuniza-tion using serum from horses immunized with diphtheria toxin. He noted that joint inflammation (arthritis), rash, and fever occurred in patients injected with the anti-toxin-containing horse serum. On further investigation, similar symptoms were seen in patients injected with horse serum with-out the antitoxin. The symptoms usually occurred at least one week after the first injection and more rapidly on subsequent injections. He concluded that the host had developed antibodies to the horse serum, and deposition of antibody–serum protein complexes (immune complexes) to differ-ent tissues of the host caused the symp-toms described earlier. In experimental animals like the rabbit, injection of a large dose of a foreign protein antigen leads to the formation of antibodies against the antigen (see Figure 17.3). Subsequent for-mation of antibody–antigen complexes leads to enhanced phagocytosis and clear-ance of the antigen by the macrophages in the liver and the kidney. With subse-quent injection of the antigen, more of the immune complexes are formed and may be deposited in the vascular bed, renal glomeruli, and synovia. These activate the complement, which leads to recruitment of inflammatory cells (predominantly neutrophils) to cause injury to the affected tissues. Clinical and pathological manifes-tations are vasculitis, glomerulonephri-tis, and arthritis. Clinical symptoms are short-lived and resolve with discontinua-tion of the injection. As will be noted in later discussion, the majority of immune-related disease falls into this category.


T-cell-mediated, or type IV, hyper-sensitivity diseases involve activation of CD4+ T cells of the TH1 subset and CD8+ T cells. Both types of T cells release interferon-γ and activate macrophages, which can release tumor necrosis factor (TNF), interleukin-I (IL-1), and other chemokines that are involved the inflammatory processes. In delayed-type hypersensitivity (DTH), tissue injury is mediated by hydrolytic enzymes, reactive oxygen intermediates, and nitric oxide.

There is also up-regulation of adhesion molecules and class II molecules in vascular endothelial cells. Chronic DTH processes cause fibrosis because of continuous secretion of cytokines and growth factors. In some instances, CD8+ cytolytic T cells (CTL) directly kill target cells bearing class I MHC cells.


T-cell-mediated renal diseases are best exemplified in kidney allograft rejection. In acute allograft rejection, T cells react to alloantigens, including MHC molecules, which reside on the vascular endothelial and renal parenchymal cells. Microvas-cular endothelitis is an early finding in acute rejection. Later involvement of the medium-sized arteries signifies severe rejection. Experimental evidence that points to the involvement of CD8+ CTL in allograft rejection include the presence of RNAs encoding CTL-specific genes (e.g., perforin and granzyme B), presence of cel-lular infiltrates enriched with CTL popu-lation, and ability to adoptively transfer alloreactive CD8+ CTL cells. CD4+ T cells mediate rejection by secreting cytokines and inducing DTH-like reactions in the allograft. Adoptive transfer of alloreactive CD4+ T cells in experimental animals has been known to cause rejection of the allo-graft as well. In chronic allograft rejection, histopathological findings are compatible with by-products of a chronic inflamma-tory state (interstitial fibrosis, vascular occlusion, and glomerulosclerosis) (Abbas and Lichtman 2005).


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