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Massive thymic deletion results in systemic autoimmunity through elimination of CD4+ CD25+ T regulatory cells.

Shih FF, Mandik-Nayak L, Wipke BT, Allen PM - J. Exp. Med. (2004)

Bottom Line: Extensive thymic deletion resulted in lymphopenia and elimination of CD4+ CD25+ regulatory T cells (Tregs), but spared some CD4+ T cells expressing endogenous TCR, which oligoclonally expanded in the periphery.Thus, our studies demonstrated that central tolerance can paradoxically result in systemic autoimmunity through differential susceptibility of Tregs and autoreactive T cells to thymic deletion.Therefore, too little or too much negative selection to a self-antigen can result in systemic autoimmunity and disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.

ABSTRACT
Incomplete deletion of KRN T cells that recognize the ubiquitously expressed self-antigen glucose-6-phosphate-isomerase (GPI) initiates an anti-GPI autoimmune cascade in K/BxN mice resulting in a humorally mediated arthritis. Transgenic (Tg) expression of a KRN T cell receptor (TCR) agonist under the major histocompatibility complex class II promoter resulted in thymic deletion with loss of anti-GPI T and B cell responses and attenuated arthritis course. However, double Tg mice succumbed to systemic autoimmunity with multiorgan inflammation and autoantibody production. Extensive thymic deletion resulted in lymphopenia and elimination of CD4+ CD25+ regulatory T cells (Tregs), but spared some CD4+ T cells expressing endogenous TCR, which oligoclonally expanded in the periphery. Disease was transferred by these T cells and prevented by cotransfer of CD4+ CD25+ Tregs. Moreover, we extended our findings to another TCR system (anti-hen egg lysozyme [HEL] TCR/HEL mice) where similarly extensive thymic deletion also resulted in disease. Thus, our studies demonstrated that central tolerance can paradoxically result in systemic autoimmunity through differential susceptibility of Tregs and autoreactive T cells to thymic deletion. Therefore, too little or too much negative selection to a self-antigen can result in systemic autoimmunity and disease.

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KRN/G7mTg7k/g7 mice displayed inflammation in multiple organs. We examined 10 KRN/G7mTg7k/g7 mice (7 aged 8–12 wk, 2 aged 16–20 wk, 1 aged 4 wk), 8 KRN mice (7 aged 8–12 wk, 1 aged 4 wk), and 2 G7mTg7k/g7 mice (both 8–10 wk) for histological evidence of autoimmunity. Paraffin sections of liver (A and D), kidneys (B and E), lungs (C and F), heart (G and I), and colon (H and J) from 2-mo-old KRN/G7mTg7k/g7 (A–C, G, and H) and KRNk/g7 (D–F, I, and J) mice are stained with hematoxylin and eosin. *, crypt abscesses. ×100. Bar, 100 μM.
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fig3: KRN/G7mTg7k/g7 mice displayed inflammation in multiple organs. We examined 10 KRN/G7mTg7k/g7 mice (7 aged 8–12 wk, 2 aged 16–20 wk, 1 aged 4 wk), 8 KRN mice (7 aged 8–12 wk, 1 aged 4 wk), and 2 G7mTg7k/g7 mice (both 8–10 wk) for histological evidence of autoimmunity. Paraffin sections of liver (A and D), kidneys (B and E), lungs (C and F), heart (G and I), and colon (H and J) from 2-mo-old KRN/G7mTg7k/g7 (A–C, G, and H) and KRNk/g7 (D–F, I, and J) mice are stained with hematoxylin and eosin. *, crypt abscesses. ×100. Bar, 100 μM.

Mentions: A survey of multiple organs from 4–20-wk-old KRN/G7mTg7k/g7 mice revealed involvement of the liver, kidneys, lungs, heart, pancreatic islets, salivary glands, thyroid, and gastrointestinal (GI) tract. No histologic inflammation was seen in the muscle, skin, brain, ovaries, and testes. Two patterns of inflammatory infiltrates were observed. The first was well-organized perivascular infiltrates comprised of T and B cells, as well as neutrophils, seen in the liver, kidneys, lungs, pancreatic islets, and salivary glands (Fig. 3, A–C, and unpublished data). In the more affected organs, the infiltrates eroded through the vessel walls with resultant vasculitis occluding the lumen. The organ parenchyma was relatively spared as there was no hepatocellular necrosis or glomerulonephritis. These perivascular lesions were observed in all the KRN/G7mTg7k/g7 mice as early as 4 wk of age, albeit to a lesser degree.


Massive thymic deletion results in systemic autoimmunity through elimination of CD4+ CD25+ T regulatory cells.

Shih FF, Mandik-Nayak L, Wipke BT, Allen PM - J. Exp. Med. (2004)

KRN/G7mTg7k/g7 mice displayed inflammation in multiple organs. We examined 10 KRN/G7mTg7k/g7 mice (7 aged 8–12 wk, 2 aged 16–20 wk, 1 aged 4 wk), 8 KRN mice (7 aged 8–12 wk, 1 aged 4 wk), and 2 G7mTg7k/g7 mice (both 8–10 wk) for histological evidence of autoimmunity. Paraffin sections of liver (A and D), kidneys (B and E), lungs (C and F), heart (G and I), and colon (H and J) from 2-mo-old KRN/G7mTg7k/g7 (A–C, G, and H) and KRNk/g7 (D–F, I, and J) mice are stained with hematoxylin and eosin. *, crypt abscesses. ×100. Bar, 100 μM.
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Related In: Results  -  Collection

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fig3: KRN/G7mTg7k/g7 mice displayed inflammation in multiple organs. We examined 10 KRN/G7mTg7k/g7 mice (7 aged 8–12 wk, 2 aged 16–20 wk, 1 aged 4 wk), 8 KRN mice (7 aged 8–12 wk, 1 aged 4 wk), and 2 G7mTg7k/g7 mice (both 8–10 wk) for histological evidence of autoimmunity. Paraffin sections of liver (A and D), kidneys (B and E), lungs (C and F), heart (G and I), and colon (H and J) from 2-mo-old KRN/G7mTg7k/g7 (A–C, G, and H) and KRNk/g7 (D–F, I, and J) mice are stained with hematoxylin and eosin. *, crypt abscesses. ×100. Bar, 100 μM.
Mentions: A survey of multiple organs from 4–20-wk-old KRN/G7mTg7k/g7 mice revealed involvement of the liver, kidneys, lungs, heart, pancreatic islets, salivary glands, thyroid, and gastrointestinal (GI) tract. No histologic inflammation was seen in the muscle, skin, brain, ovaries, and testes. Two patterns of inflammatory infiltrates were observed. The first was well-organized perivascular infiltrates comprised of T and B cells, as well as neutrophils, seen in the liver, kidneys, lungs, pancreatic islets, and salivary glands (Fig. 3, A–C, and unpublished data). In the more affected organs, the infiltrates eroded through the vessel walls with resultant vasculitis occluding the lumen. The organ parenchyma was relatively spared as there was no hepatocellular necrosis or glomerulonephritis. These perivascular lesions were observed in all the KRN/G7mTg7k/g7 mice as early as 4 wk of age, albeit to a lesser degree.

Bottom Line: Extensive thymic deletion resulted in lymphopenia and elimination of CD4+ CD25+ regulatory T cells (Tregs), but spared some CD4+ T cells expressing endogenous TCR, which oligoclonally expanded in the periphery.Thus, our studies demonstrated that central tolerance can paradoxically result in systemic autoimmunity through differential susceptibility of Tregs and autoreactive T cells to thymic deletion.Therefore, too little or too much negative selection to a self-antigen can result in systemic autoimmunity and disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.

ABSTRACT
Incomplete deletion of KRN T cells that recognize the ubiquitously expressed self-antigen glucose-6-phosphate-isomerase (GPI) initiates an anti-GPI autoimmune cascade in K/BxN mice resulting in a humorally mediated arthritis. Transgenic (Tg) expression of a KRN T cell receptor (TCR) agonist under the major histocompatibility complex class II promoter resulted in thymic deletion with loss of anti-GPI T and B cell responses and attenuated arthritis course. However, double Tg mice succumbed to systemic autoimmunity with multiorgan inflammation and autoantibody production. Extensive thymic deletion resulted in lymphopenia and elimination of CD4+ CD25+ regulatory T cells (Tregs), but spared some CD4+ T cells expressing endogenous TCR, which oligoclonally expanded in the periphery. Disease was transferred by these T cells and prevented by cotransfer of CD4+ CD25+ Tregs. Moreover, we extended our findings to another TCR system (anti-hen egg lysozyme [HEL] TCR/HEL mice) where similarly extensive thymic deletion also resulted in disease. Thus, our studies demonstrated that central tolerance can paradoxically result in systemic autoimmunity through differential susceptibility of Tregs and autoreactive T cells to thymic deletion. Therefore, too little or too much negative selection to a self-antigen can result in systemic autoimmunity and disease.

Show MeSH
Related in: MedlinePlus