Skip to main content

Advertisement

Springer Nature Link
Log in

Autoantigen complementarity: a new theory implicating complementary proteins as initiators of autoimmune disease

  • Review
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

Autoimmune diseases affect approximately 1 in 21 persons in the United States. Treatment often requires long-term cytotoxic therapy. How and why these deleterious diseases occur is unclear. A serendipitous finding in our laboratory using serum from patients with autoimmune vasculitis led us to develop the theory of autoantigen complementarity, a novel concept that may elucidate the etiological and pathogenetic mechanisms underlying autoimmune disease in general. The theory proposes that the inciting immunogen that elicits a cascade of immunological events is not the self-antigen (the autoantigen) or its mimic but rather a protein that is complementary in surface structure to the autoantigen; that is, a protein homologous or identical to the amino acid sequence of translated antisense RNA from the noncoding strand of the autoantigen gene. The cascade begins when this complementary protein initiates the production of antibodies that in turn elicit an anti-antibody or anti-idiotypic response. These anti-idiotypic antibodies can now react with the autoantigen. Strikingly, homology search of complementary proteins yields microbial and fungal proteins, thus indicating that invading micro-organisms can deliver the inciting immunogen. Curiously, approximately 50% of our patients transcribe the complementary protein’s antisense RNA. If it transpires that these aberrant RNAs are translated, the complementary protein would be produced by the individual. Here we review published research investigating complementary proteins, anti-idiotypic immune responses, and antisense transcripts, all of which support complementary proteins as initiators of autoimmune disease. In addition, we provide possible microbial and/or fungal organisms that may incite some of the most studied autoimmune diseases. Lastly, we propose mechanisms by which cell-mediated autoimmunity can be triggered by autoantigen complementarity. Based on our data and the contributions of the researchers described in this review, identification of proteins complementary to autoantigens is likely to be informative in most autoimmune diseases. This vein of study is in the early phases; however, we expect “autoantigen complementarity” is an underlying mechanism in many autoimmune diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
€34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Germany)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

ANCA :

Anti-neutrophil cytoplasmic autoantibody

APC :

Antigen-presenting cell

BCR :

B-cell receptor

BP :

Bullous pemphigoid

CDR :

Complementarity-determining region

GBM :

Glomerular basement membrane

GD :

Graves’ disease

HT :

Hashimoto’s thyroiditis

MPO :

Myeloperoxidase

NAT :

Natural antisense transcript

PAT :

Pathologic antisense transcript

PR3 :

Proteinase 3

SLE :

Systemic lupus erythematosus

TCR :

T-cell receptor

T H :

T-helper cell

References

  1. Geld YM van der, Limburg PC, Kallenberg CG (2001) Proteinase 3, Wegener’s autoantigen: from gene to antigen. J Leukoc Biol 69:177–190

    PubMed  Google Scholar 

  2. Falk RJ, Terrell RS, Charles LA, Jennette JC (1990) Anti-neutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro. Proc Natl Acad Sci USA 87:4115–4119

    Google Scholar 

  3. Pendergraft WF, 3rd, Preston GA, Shah RR et al (2004) Autoimmunity is triggered by cPR-3 (105–201), a protein complementary to human autoantigen proteinase-3. Nat Med 10:72–79

    Article  CAS  PubMed  Google Scholar 

  4. Fujinaga M, Chernaia MM, Halenbeck R, Koths K, James MN (1996) The crystal structure of PR3, a neutrophil serine proteinase antigen of Wegener’s granulomatosis antibodies. J Mol Biol 261:267–278

    Article  CAS  PubMed  Google Scholar 

  5. Williams RC Jr, Staud R, Malone CC, Payabyab J, Byres L, Underwood D (1994) Epitopes on proteinase-3 recognized by antibodies from patients with Wegener’s granulomatosis. J Immunol 152:4722–4737

    CAS  PubMed  Google Scholar 

  6. Mekler LB (1969) [Specific selective interaction between amino acid groups of polypeptide chains]. Biofizika 14:581–584

    CAS  PubMed  Google Scholar 

  7. Mekler LB (1973) On the specific mutual interaction of amino acid residues of polypeptide chains and amino acid residues with codons. Oncology 27:286–288

    CAS  PubMed  Google Scholar 

  8. Blalock JE, Smith EM (1984) Hydropathic anti-complementarity of amino acids based on the genetic code. Biochem Biophys Res Commun 121:203–207

    CAS  PubMed  Google Scholar 

  9. Blalock JE (1990) Complementarity of peptides specified by ‘sense’ and ‘antisense’ strands of DNA. Trends Biotechnol 8:140–144

    Article  CAS  PubMed  Google Scholar 

  10. Heal JR, Roberts GW, Raynes JG, Bhakoo A, Miller AD (2002) Specific interactions between sense and complementary peptides: the basis for the proteomic code. Chembiochemistry 3:136–151

    Article  CAS  Google Scholar 

  11. Tropsha A, Kizer JS, Chaiken IM (1992) Making sense from antisense: a review of experimental data and developing ideas on sense-antisense peptide recognition. J Mol Recognit 5:43–54

    CAS  PubMed  Google Scholar 

  12. Ward PA (2004) The dark side of C5a in sepsis. Nat Rev Immunol 4:133–142

    Article  CAS  PubMed  Google Scholar 

  13. Fujita E, Farkas I, Campbell W, Baranyi L, Okada H, Okada N (2004) Inactivation of C5a anaphylatoxin by a peptide that is complementary to a region of C5a. J Immunol 172:6382–6387

    CAS  PubMed  Google Scholar 

  14. Bost KL, Blalock JE (1989) Complementary peptides as interactive sites for protein binding. Viral Immunol 2:229–238

    CAS  PubMed  Google Scholar 

  15. Fassina G, Cassani G, Gnocchi P, Fornasiero MC, Isetta AM (1995) Inhibition of interleukin-2/p55 receptor subunit interaction by complementary peptides. Arch Biochem Biophys 318:37–45

    Article  CAS  PubMed  Google Scholar 

  16. Fassina G, Melli M (1994) Identification of interactive sites of proteins and protein receptors by computer-assisted searches for complementary peptide sequences. Immunomethods 5:114–120

    Article  CAS  PubMed  Google Scholar 

  17. Bost KL, Blalock JE (1989) Production of anti-idiotypic antibodies by immunization with a pair of complementary peptides. J Mol Recognit 1:179–183

    CAS  PubMed  Google Scholar 

  18. Araga S, Blalock JE (1994) Use of complementary peptides and their antibodies in B-cell-mediated autoimmune disease: prevention of experimental autoimmune myasthenia gravis with a peptide vaccine. Immunomethods 5:130–135

    Article  CAS  PubMed  Google Scholar 

  19. Jerne NK (1974) Towards a network theory of the immune system. Ann Immunol (Paris) 125C:373–389

    Google Scholar 

  20. Jerne NK, Roland J, Cazenave PA (1982) Recurrent idiotopes and internal images. EMBO J 1:243–247

    CAS  PubMed  Google Scholar 

  21. Weathington NM, Blalock JE (2003) Rational design of peptide vaccines for autoimmune disease: harnessing molecular recognition to fix a broken network. Expert Rev Vaccines 2:61–73

    CAS  PubMed  Google Scholar 

  22. Araga S, LeBoeuf RD, Blalock JE (1993) Prevention of experimental autoimmune myasthenia gravis by manipulation of the immune network with a complementary peptide for the acetylcholine receptor. Proc Natl Acad Sci USA 90:8747–8751

    Google Scholar 

  23. Elias D, Maron R, Cohen IR, Schechter Y (1984) Mouse antibodies to the insulin receptor developing spontaneously as anti-idiotypes. II. Effects on glucose homeostasis and the insulin receptor. J Biol Chem 259:6416–6419

    CAS  PubMed  Google Scholar 

  24. Shechter Y, Maron R, Elias D, Cohen IR (1982) Autoantibodies to insulin receptor spontaneously develop as anti-idiotypes in mice immunized with insulin. Science 216:542–545

    CAS  PubMed  Google Scholar 

  25. Shechter Y, Elias D, Maron R, Cohen IR (1984) Mouse antibodies to the insulin receptor developing spontaneously as anti-idiotypes. I. Characterization of the antibodies. J Biol Chem 259:6411–6415

    CAS  PubMed  Google Scholar 

  26. Erlanger BF, Cleveland WL, Wassermann NH et al (1986) Auto-anti-idiotype: a basis for autoimmunity and a strategy for anti-receptor antibodies. Immunol Rev 94:23–37

    CAS  PubMed  Google Scholar 

  27. Hill BL, Erlanger BF (1988) Monoclonal antibodies to the thyrotropin receptor raised by an autoantiidiotypic protocol and their relationship to monoclonal autoantibodies from Graves’ patients. Endocrinology 122:2840–2850

    CAS  PubMed  Google Scholar 

  28. Erlanger BF (1989) Auto-anti-idiotypy, autoimmunity and some thoughts on the structure of internal images. Int Rev Immunol 5:131–137

    CAS  PubMed  Google Scholar 

  29. Shoenfeld Y (1994) Idiotypic induction of autoimmunity: a new aspect of the idiotypic network. FASEB J 8:1296–1301

    CAS  PubMed  Google Scholar 

  30. Shoenfeld Y (2004) The idiotypic network in autoimmunity: antibodies that bind antibodies that bind antibodies. Nat Med 10:17–18

    Article  CAS  PubMed  Google Scholar 

  31. Shoenfeld Y, Rauova L, Gilburd B et al (2002) Efficacy of IVIG affinity-purified anti-double-stranded DNA anti-idiotypic antibodies in the treatment of an experimental murine model of systemic lupus erythematosus. Int Immunol 14:1303–1311

    Article  CAS  PubMed  Google Scholar 

  32. Arbuckle MR, McClain MT, Rubertone MV et al (2003) Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med 349:1526–1533

    Article  CAS  PubMed  Google Scholar 

  33. Routsias JG, Touloupi E, Dotsika E et al (2002) Unmasking the anti-La/SSB response in sera from patients with Sjogren’s syndrome by specific blocking of anti-idiotypic antibodies to La/SSB antigenic determinants. Mol Med 8:293–305

    CAS  PubMed  Google Scholar 

  34. Routsias JG, Dotsika E, Touloupi E et al (2003) Idiotype-anti-idiotype circuit in non-autoimmune mice after immunization with the epitope and complementary epitope 289–308aa of La/SSB: implications for the maintenance and perpetuation of the anti-La/SSB response. J Autoimmunol 21:17–26

    Article  CAS  Google Scholar 

  35. Papamattheou MG, Routsias JG, Karagouni EE et al (2004) T cell help is required to induce idiotypic-anti-idiotypic autoantibody network after immunization with complementary epitope 289–308aa of La/SSB autoantigen in non-autoimmune mice. Clin Exp Immunol 135:416–426

    Article  CAS  PubMed  Google Scholar 

  36. Ruiz PJ, Wolkowicz R, Waisman A et al (1998) Idiotypic immunization induces immunity to mutated p53 and tumor rejection. Nat Med 4:710–712

    Article  CAS  PubMed  Google Scholar 

  37. Erez-Alon N, Herkel J, Wolkowicz R et al (1998) Immunity to p53 induced by an idiotypic network of anti-p53 antibodies: generation of sequence-specific anti-DNA antibodies and protection from tumor metastasis. Cancer Res 58:5447–5452

    CAS  PubMed  Google Scholar 

  38. Herkel J, Erez-Alon N, Mimran A et al (2000) Systemic lupus erythematosus in mice, spontaneous and induced, is associated with autoimmunity to the C-terminal domain of p53 that recognizes damaged DNA. Eur J Immunol 30:977–984

    Article  CAS  PubMed  Google Scholar 

  39. Herkel J, Mimran A, Erez N et al (2001) Autoimmunity to the p53 protein is a feature of systemic lupus erythematosus (SLE) related to anti-DNA antibodies. J Autoimmunol 17:63–69

    Article  CAS  Google Scholar 

  40. Herkel J, Modrow JP, Bamberger S et al (2002) Prevalence of autoantibodies to the p53 protein in autoimmune hepatitis. Autoimmunity 35:493–496

    Article  CAS  PubMed  Google Scholar 

  41. Lehner B, Williams G, Campbell RD, Sanderson CM (2002) Antisense transcripts in the human genome. Trends Genet 18:63–65

    Article  CAS  PubMed  Google Scholar 

  42. Berns K, Hijmans EM, Mullenders J et al (2004) A large-scale RNAi screen in human cells identifies new components of the p53 pathway. Nature 428:431–437

    Article  CAS  PubMed  Google Scholar 

  43. Labrador M, Mongelard F, Plata-Rengifo P, Baxter EM, Corces VG, Gerasimova TI (2001) Protein encoding by both DNA strands. Nature 409:1000

    Article  CAS  PubMed  Google Scholar 

  44. Lavorgna G, Dahary D, Lehner B, Sorek R, Sanderson CM, Casari G (2004) In search of antisense. Trends Biochem Sci 29:88–94

    Article  CAS  PubMed  Google Scholar 

  45. Kohm AP, Fuller KG, Miller SD (2003) Mimicking the way to autoimmunity: an evolving theory of sequence and structural homology. Trends Microbiol 11:101–105

    Article  CAS  PubMed  Google Scholar 

  46. Zhao ZS, Granucci F, Yeh L, Schaffer PA, Cantor H (1998) Molecular mimicry by herpes simplex virus-type 1: autoimmune disease after viral infection. Science 279:1344–1347

    Article  CAS  PubMed  Google Scholar 

  47. Katz-Levy Y, Neville KL, Girvin AM et al (1999) Endogenous presentation of self myelin epitopes by CNS-resident APCs in Theiler’s virus-infected mice. J Clin Invest 104:599–610

    CAS  PubMed  Google Scholar 

  48. Olson JK, Croxford JL, Calenoff MA, Dal Canto MC, Miller SD (2001) A virus-induced molecular mimicry model of multiple sclerosis. J Clin Invest 108:311–318

    Article  CAS  PubMed  Google Scholar 

  49. Hemmer B, Fleckenstein BT, Vergelli M et al (1997) Identification of high potency microbial and self ligands for a human autoreactive class II-restricted T cell clone. J Exp Med 185:1651–1659

    Article  CAS  PubMed  Google Scholar 

  50. Davies DJ, Moran JE, Niall JF, Ryan GB (1982) Segmental necrotising glomerulonephritis with antineutrophil antibody: possible arbovirus aetiology? BMJ 285:606–610

    CAS  PubMed  Google Scholar 

  51. Falk RJ, Hogan S, Carey TS, Jennette JC (1990) Clinical course of anti-neutrophil cytoplasmic autoantibody-associated glomerulonephritis and systemic vasculitis. The Glomerular Disease Collaborative Network. Ann Intern Med 113:656–663

    CAS  PubMed  Google Scholar 

  52. Stegeman CA, Tervaert JW, Sluiter WJ, Manson WL, de Jong PE, Kallenberg CG (1994) Association of chronic nasal carriage of Staphylococcus aureus and higher relapse rates in Wegener granulomatosis. Ann Intern Med 120:12–17

    CAS  PubMed  Google Scholar 

  53. Pudifin DJ, Duursma J, Gathiram V, Jackson TF (1994) Invasive amoebiasis is associated with the development of anti-neutrophil cytoplasmic antibody. Clin Exp Immunol 97:48–51

    CAS  PubMed  Google Scholar 

  54. Falk RJ Jennette JC (1988) Anti-neutrophil cytoplasmic autoantibodies with specificity for myloperoxidase in patients with systemic vasculitis and idiopathic necrotizing and crescentic glomerulonephritis. N Engl J Med 318:1651–1657

    CAS  PubMed  Google Scholar 

  55. Xiao H, Heeringa P, Hu P et al (2002) Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice. J Clin Invest 110:955–963

    Article  CAS  PubMed  Google Scholar 

  56. Falk RJ, Jennette JC (2002) ANCA are pathogenic-oh yes they are! J Am Soc Nephrol 13:1977–1979

    Google Scholar 

  57. Tomizawa K, Mine E, Fujii A et al (1998) A panel set for epitope analysis of myeloperoxidase (MPO)-specific antineutrophil cytoplasmic antibody MPO-ANCA using recombinant hexamer histidine-tagged MPO deletion mutants. J Clin Immunol 18:142–152

    Article  CAS  PubMed  Google Scholar 

  58. Fujii A, Tomizawa K, Arimura Y et al (2000) Epitope analysis of myeloperoxidase (MPO) specific anti-neutrophil cytoplasmic autoantibodies (ANCA) in MPO-ANCA-associated glomerulonephritis. Clin Nephrol 53:242–252

    CAS  PubMed  Google Scholar 

  59. Cooper GS, Dooley MA, Treadwell EL, St Clair EW, Gilkeson GS (2002) Risk factors for development of systemic lupus erythematosus: allergies, infections, and family history. J Clin Epidemiol 55:982–989

    Article  PubMed  Google Scholar 

  60. Toker E, Yavuz S, Direskeneli H (2004) Anti-Ro/SSA and anti-La/SSB autoantibodies in the tear fluid of patients with Sjogren’s syndrome. Br J Ophthalmol 88:384–387

    Google Scholar 

  61. Fournier B, Descamps V, Bouscarat F, Crickx B, Belaich S (1996) Bullous pemphigoid induced by vaccination. Br J Dermatol 135:153–154

    Article  CAS  PubMed  Google Scholar 

  62. Baykal C, Okan G, Sarica R (2001) Childhood bullous pemphigoid developed after the first vaccination. J Am Acad Dermatol 44:348–350

    Article  CAS  PubMed  Google Scholar 

  63. Erbagci Z (2002) Childhood bullous pemphigoid following hepatitis B immunization. J Dermatol 29:781–785

    PubMed  Google Scholar 

  64. Mutasim DF (2003) Autoimmune bullous dermatoses in the elderly: diagnosis and management. Drugs Aging 20:663–681

    PubMed  Google Scholar 

  65. Di Zenzo G, Grosso F, Terracina M et al (2004) Characterization of the anti-BP180 autoantibody reactivity profile and epitope mapping in bullous pemphigoid patients. J Invest Dermatol 122:103–110

    PubMed  Google Scholar 

  66. Shimanovich I, Skrobek C, Rose C et al (2002) Pemphigoid gestationis with predominant involvement of oral mucous membranes and IgA autoantibodies targeting the C-terminus of BP180. J Am Acad Dermatol 47:780–784

    Article  PubMed  Google Scholar 

  67. Ionescu-Drinea M, Serbanescu G, Nicolau C, Voiculescu V (1973) Association of myasthenic and neuritic symptoms following administration of antitetanic serum. Rev Roum Neurol 10:239–243

    CAS  PubMed  Google Scholar 

  68. Giovanardi Rossi P, Nanni AG, Gambi D, Borromei A (1976) [Juvenile myasthenia gravis of possible post-vaccinal inoculation: study of 2 cases]. Riv Neurol 46:265–296

    PubMed  Google Scholar 

  69. Tzartos SJ, Kokla A, Walgrave SL, Conti-Tronconi BM (1988) Localization of the main immunogenic region of human muscle acetylcholine receptor to residues 67–76 of the alpha subunit. Proc Natl Acad Sci USA 85:2899–2903

    Google Scholar 

  70. Brocke S, Brautbar C, Steinman L et al (1988) In vitro proliferative responses and antibody titers specific to human acetylcholine receptor synthetic peptides in patients with myasthenia gravis and relation to HLA class II genes. J Clin Invest 82:1894–1900

    CAS  PubMed  Google Scholar 

  71. Brocke S, Dayan M, Rothbard J, Fuchs S, Mozes E (1990) The autoimmune response of different mouse strains to T-cell epitopes of the human acetylcholine receptor alpha subunit. Immunology 69:495–500

    CAS  PubMed  Google Scholar 

  72. Katz-Levy Y, Paas-Rozner M, Kirshner S et al (1997) A peptide composed of tandem analogs of two myasthenogenic T cell epitopes interferes with specific autoimmune responses. Proc Natl Acad Sci USA 94:3200–3205

    Google Scholar 

  73. Paas-Rozner M, Dayan M, Paas Y et al (2000) Oral administration of a dual analog of two myasthenogenic T cell epitopes down-regulates experimental autoimmune myasthenia gravis in mice. Proc Natl Acad Sci USA 97:2168–2173

    Google Scholar 

  74. Hellmark T, Burkhardt H, Wieslander J (1999) Goodpasture disease. Characterization of a single conformational epitope as the target of pathogenic autoantibodies. J Biol Chem 274:25862–25868

    Article  CAS  PubMed  Google Scholar 

  75. Hellmark T, Segelmark M, Unger C, Burkhardt H, Saus J, Wieslander J (1999) Identification of a clinically relevant immunodominant region of collagen IV in Goodpasture disease. Kidney Int 55:936–944

    Article  CAS  PubMed  Google Scholar 

  76. Stassi G, De Maria R (2002) Autoimmune thyroid disease: new models of cell death in autoimmunity. Nat Rev Immunol 2:195–204

    Article  CAS  PubMed  Google Scholar 

  77. Bresson D, Pugniere M, Roquet F et al (2004) Directed mutagenesis in region 713–720 of human thyroperoxidase assigns 713KFPED717 residues as being involved in the B domain of the discontinuous immunodominant region recognized by human autoantibodies. J Biol Chem 279:39058–39067

    Article  CAS  PubMed  Google Scholar 

  78. Myers MA, Fenalti G, Gray R et al (2003) A diabetes-related epitope of GAD65: a major diabetes-related conformational epitope on GAD65. Ann N Y Acad Sci 1005:250–252

    Article  CAS  PubMed  Google Scholar 

  79. Nepom GT, Lippolis JD, White FM et al (2001) Identification and modulation of a naturally processed T cell epitope from the diabetes-associated autoantigen human glutamic acid decarboxylase 65 (hGAD65). Proc Natl Acad Sci USA 98:1763–1768

    Google Scholar 

  80. Nakamura A, Yuasa T, Ujike A et al (2000) Fcgamma receptor IIB-deficient mice develop Goodpasture’s syndrome upon immunization with type IV collagen: a novel murine model for autoimmune glomerular basement membrane disease. J Exp Med 191:899–906

    Article  CAS  PubMed  Google Scholar 

  81. Takai T, Ono M, Hikida M, Ohmori H, Ravetch JV (1996) Augmented humoral and anaphylactic responses in Fc gamma RII-deficient mice. Nature 379:346–349

    Article  CAS  PubMed  Google Scholar 

  82. Yajima K, Nakamura A, Sugahara A, Takai T (2003) FcgammaRIIB deficiency with Fas mutation is sufficient for the development of systemic autoimmune disease. Eur J Immunol 33:1020–1029

    Article  CAS  PubMed  Google Scholar 

  83. Kalluri R, Danoff TM, Okada H, Neilson EG (1997) Susceptibility to anti-glomerular basement membrane disease and Goodpasture syndrome is linked to MHC class II genes and the emergence of T cell-mediated immunity in mice. J Clin Invest 100:2263–2275

    CAS  PubMed  Google Scholar 

  84. Pfister H, Ollert M, Froehlich LF et al (2004) Anti-neutrophil cytoplasmic autoantibodies (ANCA) against the murine homolog of proteinase 3 (Wegener’s autoantigen) are pathogenic in vivo. Blood (in press)

  85. Dembic Z, Schenck K, Bogen B (2000) Dendritic cells purified from myeloma are primed with tumor-specific antigen (idiotype) and activate CD4+ T cells. Proc Natl Acad Sci USA 97:2697–2702

    Google Scholar 

  86. Bogen B, Malissen B, Haas W (1986) Idiotope-specific T cell clones that recognize syngeneic immunoglobulin fragments in the context of class II molecules. Eur J Immunol 16:1373–1378

    CAS  PubMed  Google Scholar 

  87. Weiss S, Bogen B (1989) B-lymphoma cells process and present their endogenous immunoglobulin to major histocompatibility complex-restricted T cells. Proc Natl Acad Sci USA 86:282–286

    Google Scholar 

  88. Weiss S, Bogen B (1991) MHC class II-restricted presentation of intracellular antigen. Cell 64:767–776

    CAS  PubMed  Google Scholar 

  89. Ludviksson BR, Sneller MC, Chua KS et al (1998) Active Wegener’s granulomatosis is associated with HLA-DR+ CD4+ T cells exhibiting an unbalanced Th1-type T cell cytokine pattern: reversal with IL-10. J Immunol 160:3602–3609

    CAS  PubMed  Google Scholar 

  90. Balding CE, Howie AJ, Drake-Lee AB, Savage CO (2001) Th2 dominance in nasal mucosa in patients with Wegener’s granulomatosis. Clin Exp Immunol 125:332–339

    Article  CAS  PubMed  Google Scholar 

  91. Sanders JS, Stegeman CA, Kallenberg CG (2003) The Th1 and Th2 paradigm in ANCA-associated vasculitis. Kidney Blood Press Res 26:215–220

    Article  CAS  PubMed  Google Scholar 

  92. Billetta R, Filaci G, Zanetti M (1995) Major histocompatibility complex class I-restricted presentation of influenza virus nucleoprotein peptide by B lymphoma cells harboring an antibody gene antigenized with the virus peptide. Eur J Immunol 25:776–783

    CAS  PubMed  Google Scholar 

  93. Vandenbark AA, Morgan E, Bartholomew R et al (2001) TCR peptide therapy in human autoimmune diseases. Neurochem Res 26:713–730

    Article  CAS  PubMed  Google Scholar 

  94. Mitra-Kaushik S, Shaila MS, Karande A, Nayak R (2002) Idiotype and anti-idiotype specific T cell responses on transplantation with hybridomas reactive to viral hemagglutinin and human tumor antigen. Immunol Lett 80:81–87

    Article  CAS  PubMed  Google Scholar 

  95. Chakrabarti D, Ghosh SK (1992) Induction of syngeneic cytotoxic T lymphocytes against a B cell tumor. I. Role of idiotypic immunoglobulin. Cell Immunol 142:54–66

    CAS  PubMed  Google Scholar 

  96. Chakrabarti D, Ghosh SK (1992) Induction of syngeneic cytotoxic T lymphocytes against a B cell tumor. III. MHC class I-restricted CTL recognizes the processed form (s) of idiotype. Cell Immunol 144:455–464

    Article  CAS  PubMed  Google Scholar 

  97. Mitra-Kaushik S, Shaila MS, Karande AK, Nayak R (2001) Idiotype and antigen-specific T cell responses in mice on immunization with antigen, antibody, and anti-idiotypic antibody. Cell Immunol 209:109–119

    Article  CAS  PubMed  Google Scholar 

  98. Nayak R, Mitra-Kaushik S, Shaila MS (2001) Perpetuation of immunological memory: a relay hypothesis. Immunology 102:387–395

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank the collaborators involved in those studies described here and those that are ongoing in our laboratory, including Alex Tropsha, Ph.D., Ruchir Shah, Thomas Hellmark, Ph.D., Marten Segelmark, M.D., Ph.D., Jorgen Wieslander, Ph.D., Anna Sediva, M.D., Ph.D., and Charles Carter, Ph.D. We also thank the many investigators referenced in this review that contributed to advancements in the field of complementary proteins, the idiotypic network, antisense transcripts, and autoimmunity.

Author information

Authors and Affiliations

  1. Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7155, USA

    William F. Pendergraft III, Barrak M. Pressler, J. Charles Jennette, Ronald J. Falk & Gloria A. Preston

  2. Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7155, USA

    William F. Pendergraft III, Barrak M. Pressler, Ronald J. Falk & Gloria A. Preston

  3. Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7155, USA

    J. Charles Jennette, Ronald J. Falk & Gloria A. Preston

Authors
  1. William F. Pendergraft III
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Barrak M. Pressler
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. J. Charles Jennette
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Ronald J. Falk
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Gloria A. Preston
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Gloria A. Preston.

Additional information

This review is based on information from our own laboratory and that of others obtained by a recent Medline search with “complementary peptide/protein,” “antisense transcript,” and “autoimmunity” with or without “epitope” as keywords

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pendergraft, W.F., Pressler, B.M., Jennette, J.C. et al. Autoantigen complementarity: a new theory implicating complementary proteins as initiators of autoimmune disease. J Mol Med 83, 12–25 (2005). https://doi.org/10.1007/s00109-004-0615-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-004-0615-3

Keywords