Molecular Mimicry versus Bystander Activation:Herpetic Stromal Keratitis

S. WICKHAM and D.J.J. CARR*

Department of Ophthalmology, Microbiology, and Immunology, The University of Oklahoma Health Sciences Center, 608 Stanton L Young Blvd.,Oklahoma City, OK 73104, USA

(Accepted 10 April 2004)

Herpes stromal keratitis (HSK) is a significant inflammatory disease of the cornea as a result of herpessimplex virus (HSV) infection often progressing to vision loss if left untreated. However, even withimmunosuppressive compounds and anti-viral drug treatment, HSV continues to be the leading cause ofinfectious corneal blindness in the industrialized world. The inflammatory nature of the disease is theroot of the pathogenic process characterized by irreversible corneal scarring, neovascularization of theavascular cornea, and infiltration of activated leukocytes. Experimental evidence using mice suggestHSK is the result of either molecular mimicry or a bystander activation phenomenon. This review willrevisit the basis of HSK focusing on issues that pertain to the autoimmune component versus collateraldamage as a result of non-specific activation as a means to explain the pathologic manifestations ofthe disease.

Keywords: Herpes simplex virus type 1; CD4þ T lymphocytes; IgG2a; Autoimmunity

HERPES STROMAL KERATITIS

Herpes stromal keratitis (HSK) can be classified into two

distinct presentations: (i) epithelial keratitis characterized

by dendritic and geographic ulcers as a result of

epithelial lesions caused by active viral replication and

(ii) necrotizing stromal keratitis characterized by frank

necrosis, ulceration, and dense infiltration of the stroma

with or without noticeable epithelial damage.[1] There are

approximately 50,000 new cases of HSV corneal infection

per year in the United States with the incidence surfacing

30–40 years of age well after the primary infection.[1,2]

Such observations would suggest the disease is multi-

factorial requiring time to develop. Along these lines,

progression from superficial epithelial infections to

stromal keratitis is not prevented by anti-viral drugs

whereas symptoms of HSK can be alleviated with

immunosuppressive reagents including systemic cortico-

steroids and cyclosporine A.[3] HSK is associated with

chronic reactivation of quiescent virus reappearing in the

cornea from the innervating ganglion[4] (in this case,

trigeminal ganglion) via anterograde transport.[5] Since it

is difficult to characterize the disease at the cellular or

molecular level in the human host, experimental animal

models have been useful with an emphasis employing the

murine model.

EXPLORING HSK IN MICE

In this section, we will summarize those observations

deemed pertinent to the development of HSK. A caveat to

the generalization below is the dependence on certain

HSV-1 strains as well as selective strains of mice in order

to functionally generate HSK especially as it relates to an

autoimmune basis for the disease. Based on the

information at the time of this writing, there would appear

to be three different levels in HSK development that may

or may not be dependent on one another.

Innate Immune Response

During the initial period of HSV-1 epithelial infection (i.e.

48–72 h), the influx of neutrophils is noted in the

underlying corneal stroma[6] associated with the pro-

duction of the pro-inflammatory molecules Interleukin

(IL)-1a and IL-6[7] and the anti-viral cytokine family type

I interferons (IFN).[8] The local production of IL-6 by

ISSN 0891-6934 print/ISSN 1607-842X online q 2004 Taylor & Francis Ltd

DOI: 10.1080/08916930410001713106

*Corresponding author.

Autoimmunity, August 2004 Vol. 37 (5), pp. 393–397

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corneal cells[9] in response to HSV-1-induced IL-1

production has been found to significantly contribute

towards the influx of neutrophils either alone or as a result

of CXCL1/2 or CCL3 expression.[10] Immunopathological

consequences of neutrophil residence in the cornea during

acute HSV-1 infection is exemplified by a study in which

severe combined immunodeficient (SCID) mice recon-

stituted with CD4þ T cells and depleted of neutrophils

display significantly less incidence and severity of

HSK.[11] Implied in this last observation is the dependence

on the presence of CD4þ T lymphocytes for the

development of HSK, an observation made a quarter

century earlier[12] that constitutes another level in the

initiation of HSK that will be discussed later. Following

the influx of polymorphonuclear neutrophils (PMNs),

macrophages[13] and natural killer (NK) cells[14] traffic to

the cornea as well. Both cell types may contribute to HSK

development either directly[15] or through the secretion of

soluble factors that are instrumental in the progression of

HSK.[16] Following the initial wave of leukocyte

infiltration, a second onslaught occurs starting around

day 10 post infection constituted by PMNs and CD4þ

T lymphocytes (virus strain dependent). It is this second

wave that is most influenced by the local production

of IFN-g. Local levels of IFN-g have been shown to

up-regulate the expression of platelet endothelial

cell adhesion molecule 1 and intercellular adhesion

molecule 1 that facilitate neutrophil infiltration.[17]

Additional factors[18] also are critical in the development

of HSK during this second wave of infiltrating cells that

may be more related to the adaptive immune response

including IL-2.[19] As mentioned earlier, type I IFNs

generated during the initial phase of acute corneal

infection may contribute towards manifestations associ-

ated with keratitis as a result of bystander activation of

T cells at the level of dendritic cells.[20,21] In fact, HSV-1

replication resulting in double-stranded RNA synthesis, a

known inducer of type I IFN,[22] is required to elicit

HSK.[23] Corneal Langerhans cells could serve as the local

dendritic cell depot exposed to type I IFN as they migrate

centripetally following HSV-1 infection.[24]

Another means by which the innate immune response

contributes towards the development of HSK resides with

the local production of IL-1 and a seemingly unrelated

event, angiogenesis. Transgenic mice that over express the

IL-1 receptor antagonist (IL-1Ra) are found to be highly

resistant to HSK presenting with marked reduction in

neovascularization and low levels of IL-6 and CXCL1/2 in

the cornea compared to wild type controls.[25] The

reduction in inflammation is also associated with fewer

infiltrating PMNs. PMNs are a rich source of matrix

metalloproteinase-9 and vascular endothelial growth

factor that would contribute towards the development of

neovascularization during ocular HSV-1 infection.[26,27]

Although the results would appear to implicate PMNs as

the principle player in HSK, the issue is certainly more

complicated than what is presented. For example, HSV

DNA contains CpG motifs that are reportedly

angiogenic[28] and immunostimulatory.[29] Coupled with

the observation that transgenic mice over expressing the

IL-1Ra retain significantly more virus than wild type or

IL-1Ra knockout mice[25] and yet, show reduced corneal

angiogenesis suggest while contributory, additional

factors in addition to angiogenesis and the innate immune

response are involved in establishing HSK in mice. It is

perhaps the process of neovascularization that provides an

environment conducive for the subsequent adaptive

immune events to transpire through accessibility to

normally avascular tissue that ultimately initiates HSK.

Adaptive Immune Response

As indicated from an early study[12] that was later

substantiated,[30] CD4þ T cells are required for the

development of HSK. As the CD4þ T cells percolate into

the cornea following activation in the draining lymph

nodes, re-exposure to antigen within the cornea is likely at

the level of Langerhans cells[31] or resident keratocytes[32]

both of which express MHC class II and the co-stimula-

tory molecule, CD80. The importance of co-stimulatory

molecules to the progression of HSK was demonstrated

by blocking CD80 expression in vivo and showing

a significant reduction in the incidence of HSK.[31] In a

similar fashion, another study demonstrated the import-

ance of the interaction of the co-stimulatory molecules

CD137/CD137L in ocular tissue pathology in that when

this association is prevented, a marked reduction in

corneal inflammation results corresponding with a

reduction in infiltrating leukocytes and lack of HSK

development.[33] It was noted that the level of CXCL10

mRNA in the cornea was dramatically reduced in HSV-1-

infected mice deficient in CD137 expression.[33] Blocking

CXCL10 expression using anti-CXCL10 antibody during

the initial phase of acute corneal HSV-1 infection has also

been reported to significantly reduce subsequent inflam-

matory processes including leukocyte infiltration, chemo-

kine expression, and edematous cornea development[34]

suggesting that local levels of CXCL10 may be a major

contributing factor towards the development of HSK.

One intriguing aspect in HSK presentation relates to

the timing of expression. Typically following acute

infection of the cornea, replicating infectious virus is only

detected 7–9 days post infection with no detectable lytic

gene (e.g. ICP27) by day 14 post infection.[35]

Paradoxically, HSK does not typically peak until day 14

after infection in mice[36] suggesting the pathology

associated with stromal keratitis may be indirectly related

to HSV-1 infection. The possibility exists that viral

peptides presented by Langerhans cells within the cornea

could elicit the necessary stimulus to initiate the

inflammatory cascade. Alternatively, tissue-associated

antibody–antigen complexes that result in complement

activation might lead to direct tissue pathology and

recruitment of inflammatory cells. However, in the

absence of B cells, lesions consistent with HSK develop

in HSV-1 infected mice excluding antibody as a major

S. WICKHAM AND D.J.J. CARR394

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component in the pathogenic process.[37] Another

consideration lies with HSV-1 DNA itself. Recently

reported to be immunostimulatory promoting a strong

TH1 response,[29] HSV-1 DNA has been found in the

epithelial cells of the conjunctiva and eyelids of mice out

to at least 37 days post infection.[38] Therefore, within the

context of the mouse model, viral DNA could serve as a

potent stimulus in HSK development through the

activation of dendritic cells and macrophages that serve

to amplify the inflammatory process including bystander

activation of infiltrating T lymphocytes or presentation of

cryptic corneal self-antigen.[29] Although data to support

bystander activation as a mechanism to explain HSK has

been demonstrated,[39] current evidence suggest bystan-

der activated T cells decrease during viral infection as a

result of insufficient triggering of the T cell receptor to its

cognate antigen.[40]

Molecular Mimicry

The mouse genotype largely determines the suscepti-

bility or resistance to the development of HSK.[41] This

relationship proved useful in developing a model to

study the proposed induction of autoimmunity as a

basis to explain HSK. Specifically, congenic mouse

strains C.AL-20 and C.B-17 were successfully used to

show susceptible C.AL-20 mice that developed HSK

possessed an epitope within the Igh locus (i.e. IgG2ab)

that cross reacts with corneal antigen.[42] T cell clones

that recognize the locus were also found to recognize

HSV-1 UL-6 protein suggesting T cells were the

primary instigator in this autoreactive phenomenon

depending on the quantity of infectious virus used to

inoculate the mice.[43,44] Although the results are

convincing, the realistic application of this outcome to

the human condition remains suspect. Along these lines,

the results are found only using one strain of virus, a

less virulent strain compared to those strains (e.g. RE,

strain F, and strain McKrae) that truly promote HSK

and establish a latent infection in the mouse model.

Furthermore, another group reported HSV-1 primed T

cells from the resistant strain of mouse (C.B-17) could

induce HSK in SCID mice infected with HSV

suggesting that the environment within the cornea

rather than the T cells themselves were critical in

initiating the inflammatory process.[45] Finally, T cell

clones derived from CD4þ or CD8þ T cells infiltrating

the cornea of HSK patients have not been found to

recognize HSV-1 UL6.[46,47]

Describing molecular mimicry as a means to explain the

development of HSK following HSV-1 infection should

not be dismissed based on the conflicting data illustrated

above. Rather, the model emphasizes that under certain

conditions, epitopes of selective viral proteins can cross-

react with self-antigen leading to the activation of T cells

that have not undergone appropriate thymic education due

to the cryptic nature of the proteins that exist in the eye.

Other studies have also provided data in support of

immune activation to self as a result of cross-reactivity to

HSV-1 glycoproteins.[48,49] In one instance, the molecular

basis for cross-reactivity between HSV-1 glycoprotein

D and the human acetylcholine receptor alpha chain was

reported and supported by serological tests.[50 – 52]

It seems apparent that self-reactive lymphocytes

exists under selective conditions and therefore, could

contribute towards the pathogenesis manifested by

patients exhibiting HSK.

SUMMARY

HSK is a complex multi-factorial condition most likely

influenced by the duration and magnitude of the local

immune response to the viral insult. Bystander activation

within the unique environment of the eye as a result

of prolonged or repeated exposure (in the case

of spontaneous or incomplete reactivation of latent

HSV-1[53]) to antigen may insure the clonal expansion of

relatively low-affinity, self-reactive T cells that under a

single exposure to virus would not normally survive.

Factored within this equation are the recently described

CD4þCD25þ Treg cells that influence the adaptive

immune response to acute HSV-1 infection.[54] Although

the function of these cells is enhanced during HSV-1

infection in the periphery limiting the host response,[54] it

is unclear as to their role following ocular infection or

reactivation with HSV-1. Therefore, it will be intriguing to

determine if a relationship exists between Treg cell

function and HSK development. Moreover, therapeutic

applications that dampen the host immune response may

be useful in treating HSK. Experimentally, the application

of plasmid DNA encoding IL-10 or antisense oligonucleo-

tides specific for TNF-a have proven effective in

suppressing HSK in mice.[55,56]

References

[1] Liesegand, T.J. (1999) “Classification of herpes simplex viruskeratitis and anterior uveitis”, Cornea 18, 127–143.

[2] Liesegand, T.J. (1989) “Epidemiology of ocular herpes simplex.Natural history in Rochester, MN 1950 through 1982”, Arch.Ophthalmol. 107, 1160–1165.

[3] Heiligenhaus, A. and Steuhl, K.P. (1999) “Treatment of HSV-1stromal keratitis with topical cyclosporine A: a pilot study”,Graefe’s Arch. Clin. Exp. Ophthalmol. 237, 435–438.

[4] Wagner, E.K. and Bloom, D.C. (1997) “Experimental investigationof herpes simplex virus latency”, Clin. Microbiol. Rev. 10,419–443.

[5] Garner, J.A. and LaVail, J.H. (1999) “Differential anterogradetransport of HSV type 1 viral strains in the murine pathway”,J. Neurovirol. 5, 140–150.

[6] Tumpey, T.M., Chen, S.-H., Oakes, J.E. and Lausch, R.N. (1996)“Neutrophil-mediated suppression of virus replication after herpessimplex virus type 1 infection of the murine cornea”, J. Virol. 70,898–904.

[7] Staats, H.F. and Lausch, R.N. (1993) “Cytokine expression in vivoduring murine herpetic stromal keratitis”, J. Immunol. 151,277–283.

[8] Daigle, J. and Carr, D.J.J. (1998) “Androstenediol antagonizesherpes simplex virus type 1-induced encephalitis through theaugmentation of type I IFN production”, J. Immunol. 160,3060–3066.

MOLECULAR MIMICRY VS. BYSTANDER ACTIVATION 395

Aut

oim

mun

ity D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

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y U

nive

rsity

of

Cal

ifor

nia

Irvi

ne o

n 10

/26/

14Fo

r pe

rson

al u

se o

nly.

[9] Lausch, R.N., Chen, S.-H., Tumpey, T.M., Su, Y.-H. and Oakes, J.E.(1996) “Early cytokine synthesis in the excised mouse cornea”,J. Interferon Cytokine Res. 16, 35–40.

[10] Fenton, R.R., Molesworth-Kenyon, S., Oakes, J.E. and Lausch, R.N.(2002) “Linkage of IL-6 with neutrophil chemoattractantexpression in virus-induced ocular inflammation”, Investig.Ophthalmol. Vis. Sci. 43, 7373–7743.

[11] Thomas, J., Gangappa, S., Kanangat, S. and Rouse, B.T. (1997)“On the essential involvement of neutrophils in the immunopatho-logic disease. Herpetic stromal keratitis”, J. Immunol. 158,1383–1391.

[12] Metcalf, J.F., Hamilton, D.S. and Reichert, R.W. (1976)“Herpetic keratitis in athymic (nude) mice”, Infect. Immun. 26,1164–1171.

[13] Zisman, B., Hirsch, M.S. and Allison, A.C. (1970) “Selectiveeffects of anti-macrophage serum, silica, and anti-lymphocyteserum in pathogenesis of herpes virus infection of young adultmice”, J. Immunol. 104, 1155–1159.

[14] Habu, S., Akanatsu, K.I., Tamaoki, N. and Okumura, K. (1984)“In vivo significance of NK cell on resistance against virus (HSV-1)infection in mice”, J. Immunol. 133, 2743–2747.

[15] Bauer, K., Mrzyk, S., Van Rooijen, N., Steuhl, K.-P. andHeiligenhaus, A. (2001) “Incidence and severity of herpetic stromalkeratitis: impaired by the depletion of lymph node macrophages”,Exp. Eye Res. 72, 261–269.

[16] Hendricks, R.L., Tumpey, T.M. and Finnegan, A. (1992) “IFN-gand IL-2 are protective in the skin but pathologic in the corneas ofHSV-1-infected mice”, J. Immunol. 149, 3023–3028.

[17] Tang, Q. and Hendricks, R.L. (1996) “Interferon-g regulates plateletendothelial cell adhesion molecule 1 expression and neutrophilinfiltration into herpes simplex virus-infected mouse corneas”,J. Exp. Med. 184, 1435–1447.

[18] Bouley, D.M., Kanangat, S., Wire, W. and Rouse, B.T. (1995)“Characterization of herpes simplex virus type-1 infection andherpetic stromal keratitis development in IFN-g knockout mice”,J. Immunol. 155, 3964–3971.

[19] Tang, Q., Chen, W. and Hendricks, R.L. (1997) “Proinflammatoryfunctions of IL-2 in herpes simplex virus corneal infection”,J. Immunol. 158, 1275–1283.

[20] Tough, D.F., Borrow, P. and Sprent, J. (1996) “Induction ofbystander T cell proliferation by viruses and type I interferonin vivo”, Science 272, 1947–1950.

[21] LeBon, A., Etchart, N., Rossmann, C., Ashton, M., Hou, S.,Gewert, D., Borrow, P. and Tough, D.F. (2003) “Cross-priming ofCD8þ T cells stimulated by virus-induced type I interferon”, Nat.Immunol. 4, 1009–1015.

[22] Samuel, C.E. (1991) “Antiviral actions of interferon. Interferon-regulated cellular proteins and their surprisingly selective antiviralactivities”, Virology 183, 1–11.

[23] Babu, J.S., Thomas, J., Kanangat, S., Morrison, L.A., Knipe, D.M.and Rouse, B.T. (1996) “Viral replication is required for inductionof ocular immunopathology by herpes simplex virus”, J. Virol. 70,101–107.

[24] Hendricks, R.L., Janowicz, M. and Tumpey, T.M. (1992)“Critical role of corneal Langerhans cells in the CD4 2 butnot CD8-mediated immunopathology in herpes simplexvirus-1-infected mouse corneas”, J. Immunol. 148, 2522–2529.

[25] Biswas, P.S., Banerjee, K., Kim, B. and Rouse, B.T. (2004) “Micetransgenic for IL-1 receptor antagonist protein are resistant toherpetic stromal keratitis: possible role for IL-1 in herpetic stromalkeratitis pathogenesis”, J. Immunol. 172, 3736–3744.

[26] Lee, S., Zheng, M., Kim, B. and Rouse, B.T. (2002) “Role of matrixmetalloproteinase-9 in angiogenesis caused by ocular infection withherpes simplex virus”, J. Clin. Investig. 110, 1105–1111.

[27] Zheng, M., Deshpande, S., Lee, S., Ferrara, N. and Rouse, B.T.(2001) “Contribution of vascular endothelial growth factor in theneovascularization process during the pathogenesis of herpeticstromal keratitis”, J. Virol. 75, 9828–9835.

[28] Zheng, M., Klinman, D.M., Gierynska, M. and Rouse, B.T. (2002)“DNA containing CpG motifs induces angiogenesis”, Proc. NatlAcad. Sci. USA. 99, 8944–8949.

[29] Lundberg, P., Welander, P., Han, X. and Cantin, E. (2003) “Herpessimplex virus type 1 DNA is immunostimulatory in vitro andin vivo”, J. Virol. 77, 11158–11169.

[30] Mercadal, C.M., Bouley, D.M., DeStephano, D. and Rouse, B.T.(1993) “Herpetic stromal keratitis in the reconstituted scid mousemodel”, J. Virol. 67, 3404–3408.

[31] Chen, H. and Hendricks, R.L. (1998) “B7 costimulatoryrequirements of T cells at an inflammatory site”, J. Immunol.160, 5045–5052.

[32] Seo, S.K., Gebhardt, B.M., Lim, H.Y., Kang, S.W., Higaki, S.,Varnell, E.D., Hill, J.M., Kaufman, H.E. and Kwon, B.S. (2001)“Murine keratocytes function as antigen-presenting cells”, Eur.J. Immunol. 31, 3318–3328.

[33] Seo, S.K., Park, H.Y., Choi, J.H., Kim, W.Y., Kim, Y.H.,Jung, H.W., Kwon, B.S., Lee, H.W. and Kwon, B.S. (2003)“Blocking 4-1BB/4-1BB ligand interactions prevents herpeticstromal keratitis”, J. Immunol. 171, 576–583.

[34] Carr, D.J.J., Chodosh, J., Ash, J. and Lane, T.E. (2003) “Effect ofanti-CXCL10 monoclonal antibody on herpes simplex virus type 1keratitis and retinal infection”, J. Virol. 77, 10037–10046.

[35] Halford, W.P., Gebhardt, B.M. and Carr, D.J.J. (1996) “Persistentcytokine expression in trigeminal ganglion latently infected withherpes simplex virus type 1”, J. Virol. 157, 3542–3549.

[36] Streilein, J.W., Dana, M.R. and Ksander, B.R. (1997) “Immunitycausing blindness: five different paths to herpes stromal keratitis”,Immunol. Today 18, 443–449.

[37] Deshpande, S.P., Zheng, M., Daheshia, M. and Rouse, B.T. (2000)“Pathogenesis of herpes simplex virus-induced ocular immuno-inflammatory lesions in B-cell-defienct mice”, J. Virol. 74,3517–3524.

[38] Maggs, D.J., Chang, E., Nasisse, M.P. and Mitchell, W.J.(1998) “Persistence of herpes simplex virus type 1 DNA inchronic conjunctival and eyelid lesions of mice”, J. Virol. 72,9166–9172.

[39] Gangappa, S., Babu, J.S., Thomas, J., Daheshia, M. andRouse, B.T. (1998) “Virus-induced immunoinflammatory lesionsin the absence of viral antigen recognition”, J. Immunol. 161,4289–4300.

[40] Welsh, R.M., McNally, J.M., Brehm, M.A. and Selin, L.K. (2000)“Consequences of cross-reactive and bystander CTL responsesduring viral infections”, Virology 270, 4–8.

[41] Foster, D.S., Tsai, Y., Monroe, J.G., Campbell, R.C., Destari, M.,Knipe, D. and Greene, M.I. (1986) “Genetic studies on murinesusceptibility to herpes simplex keratitis”, Clin. Immunol.Immunopathol. 40, 313–325.

[42] Avery, A.C., Zhao, Z.-S., Rodriguez, A., Bikoff, E.K., Soheilian, M.,Foster, C.S. and Cantor, H. (1995) “Resistance to herpes stromalkeratitis conferred by an IgG2a-derived peptide”, Nature 376,431–434.

[43] Zhao, Z.-S., Granucci, F., Yeh, L., Schaffer, P.A. and Cantor, H.(1998) “Molecular mimicry by herpes simplex virus-type 1:autoimmune disease after viral infection”, Science 279,1344–1347.

[44] Panoutsakopoulou, V., Sanchirico, M.E., Huster, K.M., Jansson, M.,Granucci, F., Shim, D.J., Wucherpfennig, K.W. and Cantor, H.(2001) “Analysis of the relationship between viral infection andautoimmune disease”, Immunity 15, 137–147.

[45] Thomas, J. and Rouse, B.T. (1998) “Immunopathology of herpeticstromal keratitis: discordance in CD4þ T cell function betweeneuthymic host and reconstituted SCID recipients”, J. Immunol. 160,3965–3970.

[46] Koelle, D.M., Reymond, S.N., Chen, H., Kwok, W.W.,McClurkan, C., Gyaltsong, T., Petersdorf, E.W., Rotkis, W., Talley,A.R. and Harrison, D.A. (2000) “Tegument-specific, virus-reactiveCD4 T cells localize to the cornea in herpes simplex virus interstialkeratitis in humans”, J. Virol. 74, 10930–10938.

[47] Verjans, G.M., Remeijer, L., Mooy, C.M. and Osterhaus, A.D.(2000) “Herpes simplex virus-specific T cells infiltrate the cornea ofpatients with herpetic stromal keratitis: no evidence for autoreactivecells”, Investig. Ophthalmol. Vis. Sci. 41, 2607–2612.

[48] Tsuchiya, N., Williams, Jr, R.G. and Hutt-Fletcher, L.M. (1990)“Rheumatoid factors may bear the internal image of the Fcg-binding protein of herpes simplex virus type 1”, J. Immunol. 144,4742–4748.

[49] Huemer, H.P., Wang, Y., Garred, P., Koistinen, V. and Oppermann, S.(1993) “Herpes simplex virus glycoprotein C: molecular mimicry ofcomplement regulatory proteins by a viral protein”, Immunology 79,639–647.

[50] Schwimmbeck, P.L., Dyrberg, T., Drachman, D.B. and Oldstone,M.B.A. (1989) “Molecular mimicry and myasthenia gravis. Anautoantigenic site of the acetylcholine receptor alpha-subunit hasbiologic activity and reacts immunochemically with herpes simplexcirus”, J. Clin. Investig. 84, 1174–1180.

S. WICKHAM AND D.J.J. CARR396

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of

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/26/

14Fo

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[51] Dyrberg, T., Petersen, J.S. and Oldstone, M.B.A. (1990)“Immunological cross-reactivity between mimicking epitopes ona virus protein and a human autoantigen depends on a single aminoacid residue”, Clin. Immunol. Immunopathol. 54, 290–297.

[52] Gebhardt, B.M. (2000) “Evidence for antigenic cross-reactivitybetween herpesvirus and the acetylcholine receptor”,J. Neuroimmunol. 105, 145–153.

[53] Feldman, L.T., Ellison, A.R., Voytek, C.C., Yang, L., Krause, P. andMargolis, T.P. (2002) “Spontaneous molecular reactivation ofherpes simplex virus type 1 latency in mice”, Proc. Natl Acad. Sci.USA. 99, 978–983.

[54] Suvas, S., Kumaraguru, U., Pack, C.D., Lee, S. and Rouse, B.T.(2003) “CD4þCD25þ T cells regulate virus-specific primary andmemory CD8þ T cell responses”, J. Exp. Med. 198, 889–901.

[55] Daheshia, M., Kuklin, N., Kanangat, S., Manickan, E. and Rouse,B.T. (1997) “Suppression of ongoing ocular inflammatory diseaseby topical administration of plasmid DNA encoding rIL-10”,J. Immunol. 159, 1945–1952.

[56] Wasmuth, S., Bauer, D., Yang, Y., Steuhl, K.-P. and Heiligenhaus, A.(2003) “Topical treatment with antisense oligonucleotides targetingtumor necrosis factor-a in herpetic stromal keratitis”, Investig.Ophthalmol. Vis. Sci. 44, 5228–5234.

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