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Chapter 7 : Cross-Reactive Antigens of Group A Streptococci

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Abstract:

Cross-reactive antigens are molecules on the group A streptococcus that mimic host molecules and during infection induce an immune response against host tissues. The identification of cross-reactive antigens in group A streptococci is important in the understanding of the pathogenesis of autoimmune sequelae, such as rheumatic fever and glomerulonephritis, which may occur following group A streptococcal infection. Monoclonal antibodies (MAbs) cross-reactive with group A streptococci and human heart tissues were produced from mice immunized with streptococcal cell wall and membrane components and from rheumatic carditis patients. The cross-reactive antibodies were divided into three major subsets based on their cross-reactivity with (i) myosin and other alpha-helical molecules, (ii) DNA, or (iii) N-acetylglucosamine. All three subsets were identified among MAbs from mice immunized with group A streptococcal components, but in the human, the predominant subset reacted with the N-acetyl-glucosamine epitope and myosin and related molecules. This chapter provides more evidence about the identification and analysis of the cross-reactive antigens of the group A streptococcus. It also discusses immune responses to N-acetyl-β-d-glucosamine, dominant epitope of group a polysaccharide, in the pathogenesis of rheumatic heart disease and sydenham chorea in acute rheumatic fever.

Citation: Cunningham M. 2006. Cross-Reactive Antigens of Group A Streptococci, p 74-88. In Fischetti V, Novick R, Ferretti J, Portnoy D, Rood J (ed), Gram-Positive Pathogens, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816513.ch7
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Image of FIGURE 1
FIGURE 1

() Reaction of mouse antistreptococcal MAb with human tissue section of myocardium in indirect immunefluorescence assay. Mouse IgM (20 μg/ml) was unreactive (not shown). MAbs were tested at 20 μg/ml. (From reference 50 with permission from . Copyright 1989, The American Association of Immunologists, Inc.)

Citation: Cunningham M. 2006. Cross-Reactive Antigens of Group A Streptococci, p 74-88. In Fischetti V, Novick R, Ferretti J, Portnoy D, Rood J (ed), Gram-Positive Pathogens, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816513.ch7
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Image of FIGURE 2
FIGURE 2

Subsets of cross-reactive antistreptococcal and antimyosin antibodies. Human and mouse antistreptococcal/antimyosin MAbs have been divided into three subsets based on their reactivity with myosin and -acetyl-glucosamine, the dominant group A carbohydrate epitope; with DNA and the cell nucleus, a property found among mouse MAbs; and with myosin and a family of alpha-helical coiled-coil molecules. (From reference 24 with permission from Indiana University School of Dentistry Press.)

Citation: Cunningham M. 2006. Cross-Reactive Antigens of Group A Streptococci, p 74-88. In Fischetti V, Novick R, Ferretti J, Portnoy D, Rood J (ed), Gram-Positive Pathogens, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816513.ch7
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Image of FIGURE 3
FIGURE 3

The potential mechanism of antibodies in the pathogenesis of rheumatic heart disease. Cross-reactive antibody is shown binding directly to endothelium (top) or binding to basement membrane of the valve (bottom) exposed due to shear stress or damage by antibody and complement.

Citation: Cunningham M. 2006. Cross-Reactive Antigens of Group A Streptococci, p 74-88. In Fischetti V, Novick R, Ferretti J, Portnoy D, Rood J (ed), Gram-Positive Pathogens, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816513.ch7
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Image of FIGURE 4
FIGURE 4

() Reactivity of antistreptococcal/antimyosin MAb 3.B6 with normal human valve endothelium and myocardium. Formalin-fixed human mitral valve (top left) and myocardium (top right) were reacted with MAb 3.B6 at 10 μg/ml. MAb 3.B6 binding was detected using biotin-conjugated antihuman antibodies and alkaline phosphatase-labeled streptavidin followed by fast red substrate. Control sections (bottom) did not react with human IgM at 10 μg/ml. (With permission from the .)

Citation: Cunningham M. 2006. Cross-Reactive Antigens of Group A Streptococci, p 74-88. In Fischetti V, Novick R, Ferretti J, Portnoy D, Rood J (ed), Gram-Positive Pathogens, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816513.ch7
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FIGURE 5

() Adhesion and extravasation of T lymphocytes into ARF valve in valvulitis. (A, B) Extravasation of CD4 lymphocytes (stained red) (original magnification, ×200 and ×400, respectively). (C) Extravasation of CD8 lymphocytes (stained red) into the valve through the valvular endothelium (magnification, ×200). An IgG isotype control MAb (IgG) did not react with the same valve (not shown) (magnification, ×400). (With permission from reference 117, the , University of Chicago.)

Citation: Cunningham M. 2006. Cross-Reactive Antigens of Group A Streptococci, p 74-88. In Fischetti V, Novick R, Ferretti J, Portnoy D, Rood J (ed), Gram-Positive Pathogens, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816513.ch7
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Image of FIGURE 6
FIGURE 6

Sequence alignment of streptococcal M6 protein and human cardiac tropomyosin in a region exhibiting significant homology. Lowercase letters a to g directly above the sequence designate the position of these amino acids within the seven-residue periodicity in both segments. Lowercase letters at the top of the figure designate identities at external locations in the heptad repeat. Double dots indicate identities and single dots indicate conservative substitutions. Within this segment of the streptococcal M6 molecule, 31% homology is observed with tropomyosin. Because both molecules are alpha-helical coiled-coil proteins, they contain the seven-residue repeat pattern in which positions a and d are usually hydrophobic. Similar homologies are seen between M proteins and myosin heavy chains and any of the three laminin chains. (From reference 50 with permission from . Copyright 1989, The American Association of Immunologists, Inc.)

Citation: Cunningham M. 2006. Cross-Reactive Antigens of Group A Streptococci, p 74-88. In Fischetti V, Novick R, Ferretti J, Portnoy D, Rood J (ed), Gram-Positive Pathogens, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816513.ch7
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Image of FIGURE 7
FIGURE 7

Antimyosin antibody cross-reactive sites in M5 protein A-, B-, and C-repeat regions of the molecule. Arrows point to sites determined to induce human cardiac myosin cross-reactive antibody ( ). The asterisk marks the location of peptide NT4 containing several repeats of an epitope in cardiac myosins that causes myocarditis in MRL/++ and BALB/c mouse strains ( ). Site QKSKQ is the epitope determined to react with antimyosin antibody in ARF sera ( ). (From reference 4a, copyright ©2000, by Oxford University Press, Inc. Used by permission of Oxford University Press, Inc.)

Citation: Cunningham M. 2006. Cross-Reactive Antigens of Group A Streptococci, p 74-88. In Fischetti V, Novick R, Ferretti J, Portnoy D, Rood J (ed), Gram-Positive Pathogens, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816513.ch7
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Image of FIGURE 8
FIGURE 8

Reactivity of the antistreptococcal M5 peptide sera in the Western immunoblot of human cardiac myosin. The 200-kDa protein band of the purified human cardiac myosin, shown in the stained (S) portion of the Western blot, reacted most strongly with antipeptide sera from mice immunized with M5 peptides NT3–7, B2B3B, and C1A, C1B, C2C3, and C3. Sera were tested at a 1:1000 dilution. A control antimyosin MAb, CCM-52 (a gift from Dr. William Clark, Cardiovascular Research Institute, Michael Reese Hospital and Medical Center, Chicago, Ill.), reacted with the 200-kDa band present in our purified preparation of human cardiac myosin heavy chain. Purification of the human cardiac myosin heavy chain to homogeneity has been previously described by Dell et al. ( ). The Western blot confirms the data seen in the enzyme-linked immunosorbent assay with human cardiac myosin. (From reference with permission.)

Citation: Cunningham M. 2006. Cross-Reactive Antigens of Group A Streptococci, p 74-88. In Fischetti V, Novick R, Ferretti J, Portnoy D, Rood J (ed), Gram-Positive Pathogens, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816513.ch7
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Image of FIGURE 9
FIGURE 9

Sequence homology between human cardiac myosin and peptide NT4, which causes myocarditis ( ). The homologous sequence repeats four times in the streptococcal M5 protein and in NT4 and once in cardiac myosin. Repeated sequences in M proteins that mimic cardiac myosin may be important in inducing inflammatory heart disease. (Adapted from reference with permission from . Copyright 1989, The American Association of Immunologists, Inc.)

Citation: Cunningham M. 2006. Cross-Reactive Antigens of Group A Streptococci, p 74-88. In Fischetti V, Novick R, Ferretti J, Portnoy D, Rood J (ed), Gram-Positive Pathogens, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816513.ch7
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Image of FIGURE 10
FIGURE 10

Proposed immunopathogenesis of poststreptococcal heart disease. Initially, B and T cells are activated by specific streptococcal antigens and superantigens, leading to strong responses against streptococcal and host antigens. The development of pathogenic clones of B and T lymphocytes is important in development of the disease. The antibodies against the group A carbohydrate, which is cross-reactive with the valve surface, bind to the valve surface endothelium (endocardium) and lead to damage and/or upregulation of cell adhesion molecules such as VCAM-1 on activated surface endothelium of the valve. M protein-reactive T cells enter the valve through the surface endothelium by binding to cell adhesion molecules such as VCAM-1 and extravasate into the valve ( ). The formation of scar tissue in the valve, followed by neovascularization, allows the disease to continue in the valve. The specificity of the T cells entering the valve has been shown to be M protein ( ). (Reproduced from reference with permission from .)

Citation: Cunningham M. 2006. Cross-Reactive Antigens of Group A Streptococci, p 74-88. In Fischetti V, Novick R, Ferretti J, Portnoy D, Rood J (ed), Gram-Positive Pathogens, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816513.ch7
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Image of FIGURE 11
FIGURE 11

Proposed events leading to Sydenham chorea. Antibodies against the group A streptococcal carbohydrate and brain ganglioside react with the surface of neuronal cells and trigger the cell signaling event, leading to up-regulation of calcium/calmodulin-dependent protein kinase II and eventually dopamine release, which leads to the choreic movement disorder.

Citation: Cunningham M. 2006. Cross-Reactive Antigens of Group A Streptococci, p 74-88. In Fischetti V, Novick R, Ferretti J, Portnoy D, Rood J (ed), Gram-Positive Pathogens, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816513.ch7
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References

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Tables

Generic image for table
TABLE 1

M5 protein sequences that produce myocarditis in mice

NT4 produced myocarditis in BALB/c ( ) and MRL/++ mice ( ); the other peptides shown produced myocarditis in BALB/c mice. (From with permission from Lippincott-Williams and Wilkins.)

Citation: Cunningham M. 2006. Cross-Reactive Antigens of Group A Streptococci, p 74-88. In Fischetti V, Novick R, Ferretti J, Portnoy D, Rood J (ed), Gram-Positive Pathogens, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816513.ch7
Generic image for table
TABLE 2

Summary of myosin or heart cross-reactive T-cell epitopes of streptococcal M5 protein

From reference .

Amino terminal TVTRGTIS sequence (peptide 1–25) was taken from the M5 amino acid sequence published by Manjula et al. ( ) and deviates from the M5 sequence published by Miller et al. ( ) at positions 1 and 8. Sequences for peptides 81–96 and 163–177 were taken from the PepM5 sequence as reported by Manjula et al. ( ). These two sequences are given as 67–89 and 174–188, respectively, in the sequence reported by Miller et al. ( ). All other sequences shown are from the M5 gene sequence reported by Miller et al. ( ).

PBL, peripheral blood lymphocytes; ARF, acute rheumatic fever.

BALB/c mice immunized with purified human cardiac myosin and the recovered lymph node lymphocytes were stimulated with each of the peptides in tritiated thymidine uptake assays.

Citation: Cunningham M. 2006. Cross-Reactive Antigens of Group A Streptococci, p 74-88. In Fischetti V, Novick R, Ferretti J, Portnoy D, Rood J (ed), Gram-Positive Pathogens, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816513.ch7

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