Autoimmunity Can Develop Spontaneously in Animals

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A number of autoimmune diseases that develop spontaneously in animals exhibit important clinical and pathologic similarities to certain autoimmune diseases in humans. Certain inbred mouse strains have been particularly valuable models for illuminating the immunologic defects involved in the development of autoimmunity.

New Zealand Black (NZB) mice and F1 hybrids of NZB and New Zealand White (NZW) mice spontaneously develop autoimmune diseases that closely resemble systemic lupus ery-thematosus. NZB mice spontaneously develop autoimmune hemolytic anemia between 2 and 4 months of age, at which time various auto-antibodies can be detected, including antibodies to erythrocytes, nuclear proteins, DNA, and T lymphocytes. F1 hybrid animals develop glomerulonephritis from immune-complex deposits in the kidney and die prematurely by 18 months. As in human SLE, the incidence of autoimmunity in the (NZB X NZW)F1 hybrids is greater in females.

An accelerated and severe form of systemic autoimmune disease resembling systemic lupus erythematosus develops in a mouse strain called MRL/lpr/lpr. These mice are homozygous for a gene called lpr, which has been identified as a defective fas gene. The fas-gene product is a cell-surface protein belonging to the TNF family of cysteine-rich membrane receptors (see Figure 12-6d). When the normal Fas protein interacts with its ligand, it transduces a signal that leads to apoptotic death of the Fas-bearing cells. This mechanism may operate in destruction of target cells by some CTLs (see Figure 14-9). Fas is known also to be essential in the death of hyperactivated peripheral CD4+ cells. Normally, when mature peripheral T cells become activated, they are induced to express both Fas antigen and Fas ligand, When Fas-bearing cells come into contact with a neighboring activated cell bearing Fas ligand, the Fas-bearing cell is induced to die. It is also possible that Fas ligand can engage Fas from the same cell, inducing a cellular suicide. In the absence of Fas, mature peripheral T cells do not die, and these activated cells continue to proliferate and produce cytokines that result in grossly enlarged lymph nodes and spleen. Defects in fas expression similar to that found in the lpr mouse are observed in humans, and these can have severe consequences. However there is no link between fas expression and SLE in humans, which suggests that the lpr mouse may not be a true model for SLE.

Another important animal model is the nonobese diabetic (NOD) mouse, which spontaneously develops a form of diabetes that resembles human insulin-dependent dia-

betes mellitus (IDDM). Like the human disease, the NOD mouse disease begins with lymphocytic infiltration into the islets of the pancreas. Also, as in IDDM, there is a strong association between certain MHC alleles and the development of diabetes in these mice. Experiments have shown that T cells from diabetic mice can transfer diabetes to nondiabetic recipients. For example, when the immune system of normal mice is destroyed by lethal doses of x-rays and then is reconstituted with an injection of bone-marrow cells from NOD mice, the reconstituted mice develop diabetes. Conversely, when the immune system of still healthy NOD mice is destroyed by x-irradiation and then reconstituted with normal bone-marrow cells, the NOD mice do not develop diabetes. Various studies have demonstrated a pivotal role for CD4+ T cells in the NOD mouse, and recent evidence implicates the Th1 subset in disease development.

Several other spontaneous autoimmune diseases have been discovered in animals that have served as models for similar human diseases. Among these are Obese-strain chickens, which develop both humoral and cell-mediated reactivity to thyroglobulin resembling that seen in Hashimoto's thyroiditis.

Lymph-node cells

Lymph-node cells

Hashimotos Lymph Nodes

EAE rat (most die; some recover)

FIGURE 20-7

Normal rat

MBP-specific T-cell clones

Experimental autoimmune encephalomyelitis (EAE) can be induced in rats by injecting them with myelin basic protein (MBP) in complete Freud's adjuvant (CFA). MBP-specific T-cell clones can be generated by culturing lymph-node cells from EAE rats with MBP. When these T cells are injected into normal animals, most develop EAE and die, although a few recover.

EAE rat (most die; some recover)

FIGURE 20-7

Normal rat

MBP-specific T-cell clones

Experimental autoimmune encephalomyelitis (EAE) can be induced in rats by injecting them with myelin basic protein (MBP) in complete Freud's adjuvant (CFA). MBP-specific T-cell clones can be generated by culturing lymph-node cells from EAE rats with MBP. When these T cells are injected into normal animals, most develop EAE and die, although a few recover.

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