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Chapter 26 : Autoimmunity and Disease

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Abstract:

Normally, the presence of self-reactive (autoimmune) cells does not always lead to autoimmune diseases because their numbers are small and are kept in check by peripheral tolerance mechanisms. In this sense, autoimmunity should be distinguished from autoimmune diseases. The biologic effectors that amplify many immunologic reactions that lead to important biologic outcomes of immune recognition, including complement, activated phagocytes, chemokine and cytokine production, and cellular cytotoxicity, are essential components of the pathology of autoimmunity. Systemic lupus erythematosus (SLE) is a complex connective tissue disease with autoimmune characteristics affecting multiple organ systems. Clinical symptoms of SLE are highly variable among patients, ranging from mild skin lesions and arthritis to severe renal dysfunction, cardiomyopathy, and neuropsychiatric manifestations. T cells are thought to play a central role in the initiation and perpetuation of rheumatoid arthritis (RA). Susceptibility to RA is strongly influenced by genetic predisposition. Disease concordance between monozygotic twins is approximately 20% versus 5% in dizygotic twins. Self-reactive lymphocytes are common in normal individuals, and their inappropriate activation and expansion may be responsible for initiating autoimmunity. An ideal therapy for autoimmune diseases would selectively block the lymphocytes that cause autoimmunity without affecting the remainder of the immune system. The newest forms of therapy for autoimmunity are directed at the specific cells or cytokines that contribute to or regulate the aberrant immune response.

Citation: Tse H, Shaw M. 2004. Autoimmunity and Disease, p 625-648. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch26

Key Concept Ranking

Systemic Lupus Erythematosus
0.50923854
Complement System
0.49883205
Tumor Necrosis Factor alpha
0.46319163
0.50923854
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Figures

Image of Figure 26.1
Figure 26.1

Patient with SLE with typical “butterfly” rash.

Citation: Tse H, Shaw M. 2004. Autoimmunity and Disease, p 625-648. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch26
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Image of Figure 26.2
Figure 26.2

Immune-mediated joint damage in RA. A healthy joint. Persistent antigen-antibody immune complexes become lodged on the articular cartilage, leading to local complement activation. Complement split products C3a, C4a, and C5a have chemotactic activity that draws leukocytes such as polymorphonuclear leukocytes (PMNs) to the joint. Proteases and reactive oxygen intermediates released from the PMN cause some joint damage. Macrophages attracted to the joint by complement activation release cytokines that have further chemotactic activity, resulting in the formation of a vascularized granulation tissue called a pannus. Further release of proteases and reactive oxygen and nitrogen intermediates from leukocytes in the pannus causes more severe joint injury.

Citation: Tse H, Shaw M. 2004. Autoimmunity and Disease, p 625-648. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch26
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Image of Figure 26.3
Figure 26.3

Cross section of a neuronal axon, highlighting the myelin sheath formed around the axon by the growth of Schwann cells. Myelin protein in the sheath is one of the principal targets of autoreactive T cells in human MS and mouse EAE.

Citation: Tse H, Shaw M. 2004. Autoimmunity and Disease, p 625-648. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch26
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Image of Figure 26.4
Figure 26.4

Autoimmune attack of the neuromuscular junction in MG. An example of a normal neuromuscular junction. Nerve impulses are transmitted to skeletal muscle as the neurotransmitter (ACh) is released from vesicles in the neuron and binds to receptors (AChR) on the surface of the muscle cell. The early stages of MG are attributable to blockage of AChR on muscle cells by antibodies generated against this receptor. Later stages of disease are marked by antibody- and complement-mediated damage to the neuromuscular junction.

Citation: Tse H, Shaw M. 2004. Autoimmunity and Disease, p 625-648. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch26
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Image of Figure 26.5
Figure 26.5

Normal histology of pancreas, showing an islet of Langerhans that contains the insulin-producing beta cells. IDDM is characterized by intense mononuclear cell infiltration of the islets and destruction of the beta cells. Reprinted from M. A. Atkinson and N. K. Maclaren, (1)62–63, 66–71, with permission.

Citation: Tse H, Shaw M. 2004. Autoimmunity and Disease, p 625-648. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch26
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Image of Figure 26.6
Figure 26.6

Thyroid destruction in the HT. A normal thyroid. Thyroid in HT, showing intense mononuclear cell infiltrate. Diagram of a thyroid acinar cell showing the synthesis of thyroid hormones (T) and (T). Synthesis of T and T is stimulated by TSH released by the pituitary gland, which binds to a specific receptor (TSHR) on the acinar cell. Synthesis of T and T involves the modification of tyrosine amino acids (Tyr) of the protein thyroglobulin (TG) by covalent addition of iodine (I). This occurs by the action of the enzyme iodine peroxidase (IPO), and results in the formation of monoiodotyrosine (MIT) and diiodotyrosine (DIT). Further activity of the IPO enzyme causes a condensation reaction that combines MIT and DIT to form the hormones T and T. The TSHR, IPO, and TG proteins are all targets of autoimmune responses during advanced HT, although the initial loss of thyroid activity is probably due to blockage of the TSHR by anti-TSHR antibodies. (A and B) Courtesy of Edward C. Klatt.

Citation: Tse H, Shaw M. 2004. Autoimmunity and Disease, p 625-648. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch26
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Image of Figure 26.7
Figure 26.7

GD is an autoimmune disease that results in overstimulation of the thyroid, not in its destruction. Normal regulation of the production of thyroid hormones. Production of T and T is stimulated by TSH. Buildup of T and T has a feedback-inhibitory effect on the synthesis of TSH. In GD, stimulatory anti-TSHR antibody binds to the TSHR, stimulating production of T and T. While T and T negatively inhibit TSH production, the synthesis of T and T continues to be stimulated by the autoantibody in a completely unregulated fashion.

Citation: Tse H, Shaw M. 2004. Autoimmunity and Disease, p 625-648. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch26
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Image of Figure 26.8
Figure 26.8

New Zealand Black/White progeny (BWF) mice are used as an experimental model of human SLE. BWF1 mice have many of the characteristics of human SLE. The data are from E. D. Dubois et al., 285–289, 1966.

Citation: Tse H, Shaw M. 2004. Autoimmunity and Disease, p 625-648. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch26
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Image of Figure 26.9
Figure 26.9

NOD mice are naturally prone to develop IDDM. This disease is T cell mediated, since it can be prevented by either removal of a mouse's thymus at birth or ablation of the mouse's T cells with a CD3-specific monoclonal antibody .

Citation: Tse H, Shaw M. 2004. Autoimmunity and Disease, p 625-648. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch26
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Image of Figure 26.10
Figure 26.10

EAE is an animal model of the human disease MS. EAE can be induced by vaccinating mice with MBP, expanding the MBP-specific lymphocytes in culture, and then introducing them into an isogenic mouse. EAE follows a remitting/relapsing course similar to that observed in some humans with MS. Panel B is reproduced with permission from C. Kim and H. Y. Tse, 129–136, 1993.

Citation: Tse H, Shaw M. 2004. Autoimmunity and Disease, p 625-648. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch26
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Image of Figure 26.11
Figure 26.11

MBP-specific T cells in mice with EAE home to the brain, where they mediate destruction of the myelin sheath. The time course of lymphocyte homing to brain tissue correlates well with the onset of disease symptoms (bar at top of graph). Modified with permission from Y. Naparstek et al., 418–423, 1983.

Citation: Tse H, Shaw M. 2004. Autoimmunity and Disease, p 625-648. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch26
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Image of Figure 26.12
Figure 26.12

Vaccinating mice with CII induces autoimmune arthritis. This arthritis is mediated in large part by CD4 T cells, since destruction of these cells with an anti-CD4 monoclonal antibody both reduces the incidence of disease and slows its onset. From G. E. Ranges et al., 1105–1110, 1985, with permission.

Citation: Tse H, Shaw M. 2004. Autoimmunity and Disease, p 625-648. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch26
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Image of Figure 26.13
Figure 26.13

The immunosuppressants cyclosporin A (CsA) and FK506 inhibit the activation of T lymphocytes. T-cell activation requires nuclear translocation of several including NF-κB and NF-AT. To enter the nucleus, NF-AT must first be dephosphorylated by the phosphatase calcineurin. CsA and FK506 prevent T-cell activation by preventing calcineurin from dephosphorylating NF-AT.

Citation: Tse H, Shaw M. 2004. Autoimmunity and Disease, p 625-648. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch26
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Image of Figure 26.14
Figure 26.14

Cytokine therapies for autoimmune disease. IFN-γ serves to activate macrophages and is a component of many autoimmune reactions. IFN-γ action can be blocked by either anti-IFN antibodies or a soluble that binds to the cytokine before the latter can bind a cell-surface IFN-γ receptor (IFN-R).

Citation: Tse H, Shaw M. 2004. Autoimmunity and Disease, p 625-648. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch26
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Image of Figure 26.15
Figure 26.15

T-cell activation can be prevented by interfering with the CD28 and CTLA-4 costimulatory proteins of T cells. Normal T-cell activation requires the delivery of one signal to the T cell via the TCR (green) binding to MHC-peptide complexes (either MHC class I or class II; class II is depicted) on an APC (the green curved shape is CD4 or CD8) and the delivery of a second signal to the T cell via an interaction between CD28 (pink) on the T cell with the B7 protein (blue) on the APC. After activation, the T cell increases its expression of the CTLA-4 protein (red). A subsequent interaction of CTLA-4 on the T cell with B7 on an APC (middle panel) turns off T-cell activation and leads to apoptosis of the T cell (bottom panel), thus ending the immune response. The requirement of T-cell activation for the “second signal” can be used in therapy development. A soluble fusion protein of immunoglobulin and CTLA-4 (CTLA4-Ig) can bind to B7 on the APC and prevent B7 from binding to the T-cell CD28 protein. The T cell thus receives an incomplete signal and enters a state of unresponsiveness called . The role of CTLA-4 in terminating T-cell activation is also being studied as a possible therapy. An antibody to CTLA-4 can bind to CTLA-4 on activated self-reactive T cells, causing the T cell to inactivate and undergo apoptosis.

Citation: Tse H, Shaw M. 2004. Autoimmunity and Disease, p 625-648. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch26
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Image of Figure 26.16
Figure 26.16

Altered peptide ligands are modified antigenic peptides that can exhibit antagonistic properties on T cells, inducing T-cell anergy instead of activation. These peptides offer promise as clone-specific reagents for preventing T-cell activation. The figure shows the HLA-DR4-presented peptide M12p54-68 derived from protein. Amino acid substitutions at some positions resulted in T-cell antagonism. The size of each arrow corresponds to the relative percentage of substitutions at each position that resulted in antagonism. Of the antagonistic peptides, some of them cause antagonism along with partial activation (enlarged cell size, increased cytokine production without T-cell proliferation). Modified with permission from Y. Z. Chen et al., 3783–3790, 1996. Original figure in : copyright 1996 The American Association of Immunologists, Inc.

Citation: Tse H, Shaw M. 2004. Autoimmunity and Disease, p 625-648. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch26
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Image of Figure 26.17
Figure 26.17

Diagram of a strategy to engineer self-reactive lymphocytes to perform regulatory functions. MBP-specific T cells from a mouse with EAE are isolated and transfected with a genetic construct directing overexpression of the regulatory cytokine IL-10. When reintroduced into the EAE mouse, these lymphocytes home to the area of autoimmune inflammation, where they exert negative regulatory effects on non-engineered self-reactive T cells.

Citation: Tse H, Shaw M. 2004. Autoimmunity and Disease, p 625-648. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch26
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References

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1. Anderton, S. M.,, and D. C. Wraith. 2002. Selection and fine-tuning of the autoimmune T-cell repertoire. Nat. Rev. Immunol. 2:487498.
2. Bendelac, A.,, M. Bonneville,, and J. F. Kearney. 2001. Autoreactivity by design: innate B and T lymphocytes. Nat. Rev. Immunol. 1:177186.
3. Bowness, P. 2002. HLA B27 in health and disease: a double-edged sword? Rheumatology (Oxford) 41:857868.
4. Boyton, R. J.,, and D. M. Altmann. 2002. Transgenic models of autoimmune disease. Clin. Exp. Immunol. 127:411.
5. Brabb, T.,, P. von Dassow,, N. Ordonez,, B. Schnabel,, B. Duke,, and J. Goverman. 2000. In situ tolerance within the central nervous system as a mechanism for preventing autoimmunity. J. Exp. Med. 192:871880.
6. Cohen, I. R. 2001. T-cell vaccination for autoimmune disease: a panorama. Vaccine 12:706710.
7. Daikh, D. I., and Wofsy, D. 2001. Treatment of autoimmunity by inhibition of T cell costimulation. Adv. Exp. Med. Biol. 490:113117.
8. Elenkov, I. J.,, and G. P. Chrousos. 2002. Stress hormones, proinflammatory and antiinflammatory cytokines, and autoimmunity. Ann. N. Y. Acad. Sci. 966:290303.
9. Hemmer, B.,, S. Cepok,, S. Nessler,, and N. Sommer. 2002. Pathogenesis of multiple sclerosis: an update on immunology. Curr. Opin. Neurol. 15:227231.
10. Kuchroo, V. K.,, A. C. Anderson,, H. Waldner,, M. Munder,, E. Bettelli,, and L. B. Nicholson. 2002. T cell response in experimental autoimmune encephalomyelitis (EAE): role of self and cross-reactive antigens in shaping, tuning, and regulating the autopathogenic T cell repertoire. Annu. Rev. Immunol. 20: 101123.
11. Liblau, R. S.,, F. S. Wong,, L. T. Mars,, and P. Santamaria. 2002. Autoreactive CD8 T cells in organ-specific autoimmunity: emerging targets for therapeutic intervention. Immunity 17:16.
12. Nabozny, G. H.,, J. M. Baisch,, S. Cheng,, D. Cosgrove,, M. M. Griffiths,, H. S. Luthra,, and C. S. David. 1996. HLA-DQ8 transgenic mice are highly susceptible to collagen-induced arthritis: a novel model for human polyarthritis. J. Exp. Med. 183:2737.
13. O’Shea, J. J.,, A. Ma,, and P. Lipsky. 2002. Cytokines and autoimmunity. Nat. Rev. Immunol. 2:3745.
14. Rosmalen, J. G.,, W. van Ewijk,, and P. J. Leenen. 2002. T-cell education in autoimmune diabetes: teachers and students. Trends Immunol. 23:4046.
15. Smith, J. B.,, and M. K. Haynes. 2002. Rheumatoid arthritis—a molecular understanding. Ann. Intern. Med. 136:908922.
16. Townsend, S. E.,, C. W. Bennett,, and C. C. Goodnow. 1999. Growing up on the streets: why B cell development differs from T cell development. Immunol. Today 20:217220.

Tables

Generic image for table
Table 26.1

A 2 × 2 contingency table to calculate relative disease risk

Citation: Tse H, Shaw M. 2004. Autoimmunity and Disease, p 625-648. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch26
Generic image for table
Table 26.2

Relative risk of some autoimmune diseases

Citation: Tse H, Shaw M. 2004. Autoimmunity and Disease, p 625-648. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch26

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