Clinical Reviews in Allergy & Immunology

, Volume 42, Issue 2, pp 135–144 | Cite as

The Etiology of Paraneoplastic Autoimmunity

  • Emanual MaverakisEmail author
  • Heidi Goodarzi
  • Lisa N. Wehrli
  • Yoko Ono
  • Miki Shirakawa Garcia


Although they may sometimes appear similar, paraneoplastic autoimmunity has a unique pathogenesis, different from the classical autoimmune diseases not associated with cancer. When distinguished clinically, paraneoplastic autoimmunity is more severe and often presents with a broader range of clinical signs and symptoms. Management of these patients is difficult and is usually centered in part on treatment of the underlying malignancy. Self-antigens recognized in the setting of paraneoplastic autoimmunity can be diverse, and the number of determinants recognized within a single antigen can be numerous. This review uses prototypic examples of paraneoplastic immune-mediated diseases and their associated malignancies to describe the mechanisms by which immune dysregulation can occur in the setting of cancer. Specific diseases covered include paraneoplastic pemphigus, Sweet’s syndrome, pyoderma gangrenosum, thymoma-associated multiorgan autoimmunity, myasthenia gravis, autoimmune hemolytic anemia, immune thrombocytopenia, and the paraneoplastic neurological syndromes. The malignancies discussed include thymoma, non-Hodgkin’s lymphoma, and chronic lymphocytic leukemia, among others. The mechanisms by which cancers induce autoimmunity are broken down into the following categories: disruption of central tolerance, peripheral immune dysregulation, and alteration of self-antigens. For each category, examples of paraneoplastic autoimmune diseases and their associated malignancies are discussed. Finally, mechanisms by which cancer treatment can lead to autoimmunity and examples of polymorphisms that are linked to both cancer and autoimmunity are discussed.


Paraneoplastic pemphigus Myasthenia gravis Autoimmunity Self Non-Hodgkin’s lymphoma CLL Pyoderma gangrenosum Sweet’s syndrome Thymoma Pemphigus vulgaris 



EM holds career awards from the Burroughs Wellcome Fund and the Howard Hughes Medical Institute.


  1. 1.
    Amagai M, Nishikawa T, Nousari HC, Anhalt GJ, Hashimoto T (1998) Antibodies against desmoglein 3 (pemphigus vulgaris antigen) are present in sera from patients with paraneoplastic pemphigus and cause acantholysis in vivo in neonatal mice. J Clin Invest 102:775–782PubMedCrossRefGoogle Scholar
  2. 2.
    Futei Y, Amagai M, Hashimoto T, Nishikawa T (2003) Conformational epitope mapping and IgG subclass distribution of desmoglein 3 in paraneoplastic pemphigus. J Am Acad Dermatol 49:1023–1028PubMedCrossRefGoogle Scholar
  3. 3.
    Lehmann PV, Forsthuber T, Miller A, Sercarz EE (1992) Spreading of T-cell autoimmunity to cryptic determinants of an autoantigen. Nature 358:155–157PubMedCrossRefGoogle Scholar
  4. 4.
    Bowen GM et al (2000) Lichenoid dermatitis in paraneoplastic pemphigus: a pathogenic trigger of epitope spreading? Arch Dermatol 136:652–656PubMedCrossRefGoogle Scholar
  5. 5.
    Wang L, Bu D, Yang Y, Chen X, Zhu X (2004) Castleman’s tumours and production of autoantibody in paraneoplastic pemphigus. Lancet 363:525–531PubMedCrossRefGoogle Scholar
  6. 6.
    Anhalt GJ et al (1990) Paraneoplastic pemphigus. An autoimmune mucocutaneous disease associated with neoplasia. N Engl J Med 323:1729–1735PubMedCrossRefGoogle Scholar
  7. 7.
    Sehgal VN, Srivastava G (2009) Paraneoplastic pemphigus/paraneoplastic autoimmune multiorgan syndrome. Int J Dermatol 48:162–169PubMedCrossRefGoogle Scholar
  8. 8.
    Ehst BD, Minzer-Conzetti K, Swerdlin A, Devere TS (2010) Cutaneous manifestations of internal malignancy. Curr Probl Surg 47:384–445PubMedCrossRefGoogle Scholar
  9. 9.
    Martinez De Pablo MI et al (2005) Paraneoplastic pemphigus associated with non-Hodgkin B-cell lymphoma and good response to prednisone. Acta Derm Venereol 85:233–235PubMedGoogle Scholar
  10. 10.
    Mimouni D et al (2002) Paraneoplastic pemphigus in children and adolescents. Br J Dermatol 147:725–732PubMedCrossRefGoogle Scholar
  11. 11.
    Billet SE, Grando SA, Pittelkow MR (2006) Paraneoplastic autoimmune multiorgan syndrome: review of the literature and support for a cytotoxic role in pathogenesis. Autoimmunity 39:617–630PubMedCrossRefGoogle Scholar
  12. 12.
    Buck T, Gonzalez LM, Lambert WC, Schwartz RA (2008) Sweet’s syndrome with hematologic disorders: a review and reappraisal. Int J Dermatol 47:775–782PubMedCrossRefGoogle Scholar
  13. 13.
    Zappasodi P, Forno C, Corso A, Lazzarino M (2006) Mucocutaneous paraneoplastic syndromes in hematologic malignancies. Int J Dermatol 45:14–22PubMedCrossRefGoogle Scholar
  14. 14.
    Sands J, Tuscano JM (2010) Geoepidemiology and autoimmune manifestations of lymphoproliferative disorders. Autoimmun Rev 9:A335–A341PubMedCrossRefGoogle Scholar
  15. 15.
    Perry HO, Brunsting LA (1957) Pyoderma gangrenosum; a clinical study of nineteen cases. AMA Arch Derm 75:380–386PubMedCrossRefGoogle Scholar
  16. 16.
    Bernstein CN, Blanchard JF, Rawsthorne P, Yu N (2001) The prevalence of extraintestinal diseases in inflammatory bowel disease: a population-based study. Am J Gastroenterol 96:1116–1122PubMedCrossRefGoogle Scholar
  17. 17.
    Tan MH, Gordon M, Lebwohl O, George J, Lebwohl MG (2001) Improvement of Pyoderma gangrenosum and psoriasis associated with Crohn disease with anti-tumor necrosis factor alpha monoclonal antibody. Arch Dermatol 137:930–933PubMedGoogle Scholar
  18. 18.
    Veloso FT, Carvalho J, Magro F (1996) Immune-related systemic manifestations of inflammatory bowel disease. A prospective study of 792 patients. J Clin Gastroenterol 23:29–34PubMedCrossRefGoogle Scholar
  19. 19.
    Brunsting LA, Goeckerman WH, O’Leary PA (1930) Pyoderma (echthyma) gangrenosum—clinical and experimental observations in five cases occurring in adults. Arch Dermatol Syph 22:655–680CrossRefGoogle Scholar
  20. 20.
    Bennett ML et al (2000) Pyoderma gangrenosum. A comparison of typical and atypical forms with an emphasis on time to remission. Case review of 86 patients from 2 institutions. Medicine (Baltimore) 79:37–46CrossRefGoogle Scholar
  21. 21.
    Duguid CM, O’Loughlin S, Otridge B, Powell FC (1993) Paraneoplastic pyoderma gangrenosum. Australas J Dermatol 34:17–22PubMedCrossRefGoogle Scholar
  22. 22.
    Oka M et al (2000) Interleukin-8 overexpression is present in pyoderma gangrenosum ulcers and leads to ulcer formation in human skin xenografts. Lab Invest 80:595–604PubMedGoogle Scholar
  23. 23.
    Oka M (2007) Pyoderma gangrenosum and interleukin 8. Br J Dermatol 157:1279–1281PubMedCrossRefGoogle Scholar
  24. 24.
    Tanaka N, Fujioka A, Tajima S, Ishibashi A, Hirose S (2000) Elafin is induced in epidermis in skin disorders with dermal neutrophilic infiltration: interleukin-1 beta and tumour necrosis factor-alpha stimulate its secretion in vitro. Br J Dermatol 143:728–732PubMedCrossRefGoogle Scholar
  25. 25.
    Saito S et al (2006) CD30+ anaplastic large cell lymphoma complicated by pyoderma gangrenosum with increased levels of serum cytokines. Eur J Haematol 77:251–254PubMedCrossRefGoogle Scholar
  26. 26.
    Kawakami T, Yamazaki M, Soma Y (2009) Reduction of interleukin-6, interleukin-8, and anti-phosphatidylserine-prothrombin complex antibody by granulocyte and monocyte adsorption apheresis in a patient with pyoderma gangrenosum and ulcerative colitis. Am J Gastroenterol 104:2363–2364PubMedCrossRefGoogle Scholar
  27. 27.
    Bister V, Makitalo L, Jeskanen L, Saarialho-Kere U (2007) Expression of MMP-9, MMP-10 and TNF-alpha and lack of epithelial MMP-1 and MMP-26 characterize pyoderma gangrenosum. J Cutan Pathol 34:889–898PubMedCrossRefGoogle Scholar
  28. 28.
    Brooklyn TN et al (2006) Infliximab for the treatment of pyoderma gangrenosum: a randomised, double blind, placebo controlled trial. Gut 55:505–509PubMedCrossRefGoogle Scholar
  29. 29.
    Mittal S, Milner BJ, Vickers MA (2005) Pyoderma gangrenosum as a cause of splenomegaly and association with a T-cell clone. Clin Lab Haematol 27:402–404PubMedCrossRefGoogle Scholar
  30. 30.
    Brooklyn TN, Williams AM, Dunnill MG, Probert CS (2007) T-cell receptor repertoire in pyoderma gangrenosum: evidence for clonal expansions and trafficking. Br J Dermatol 157:960–966PubMedCrossRefGoogle Scholar
  31. 31.
    Su WP, Schroeter AL, Perry HO, Powell FC (1986) Histopathologic and immunopathologic study of pyoderma gangrenosum. J Cutan Pathol 13:323–330PubMedCrossRefGoogle Scholar
  32. 32.
    Gapin L et al (1998) Quantitative analysis of the T cell repertoire selected by a single peptide-major histocompatibility complex. J Exp Med 187:1871–1883PubMedCrossRefGoogle Scholar
  33. 33.
    Maverakis E et al (2003) Autoreactive T cells can be protected from tolerance induction through competition by flanking determinants for access to class II MHC. Proc Natl Acad Sci USA 100:5342–5347PubMedCrossRefGoogle Scholar
  34. 34.
    Sercarz EE, Maverakis E (2003) Mhc-guided processing: binding of large antigen fragments. Nat Rev Immunol 3:621–629PubMedCrossRefGoogle Scholar
  35. 35.
    Maverakis E, Beech JT, Schneider S, Sercarz EE (2008) Presentation of a determinant by MHC class II can be prevented through competitive capture by a flanking determinant on a multideterminant peptide. J Autoimmun 31:59–65PubMedCrossRefGoogle Scholar
  36. 36.
    Gammon G, Sercarz E (1989) How some T cells escape tolerance induction. Nature 342:183–185PubMedCrossRefGoogle Scholar
  37. 37.
    Engels EA, Pfeiffer RM (2003) Malignant thymoma in the United States: demographic patterns in incidence and associations with subsequent malignancies. Int J Cancer 105:546–551PubMedCrossRefGoogle Scholar
  38. 38.
    Melms A et al (2006) Thymus and myasthenia gravis: antigen processing in the human thymus and the consequences for the generation of autoreactive T cells. Acta Neurol Scand Suppl 183:12–13PubMedCrossRefGoogle Scholar
  39. 39.
    Wadhera A et al (2007) Thymoma-associated multiorgan autoimmunity: A graft-versus-host-like disease. J Am Acad Dermatol 57(4):683–689PubMedCrossRefGoogle Scholar
  40. 40.
    Nagvekar N et al (1998) A pathogenetic role for the thymoma in myasthenia gravis. Autosensitization of IL-4- producing T cell clones recognizing extracellular acetylcholine receptor epitopes presented by minority class II isotypes. J Clin Invest 101:2268–2277PubMedCrossRefGoogle Scholar
  41. 41.
    Moschella SL (1967) Pyoderma gangrenosum. A patient successfully treated with intralesional injections of steroid. Arch Dermatol 95:121–123PubMedCrossRefGoogle Scholar
  42. 42.
    Jennings JL (1983) Pyoderma gangrenosum: successful treatment with intralesional steroids. J Am Acad Dermatol 9:575–580PubMedCrossRefGoogle Scholar
  43. 43.
    Mrowietz U, Christophers E (1991) Clearing of pyoderma gangrenosum by intralesional cyclosporin A. Br J Dermatol 125:499PubMedCrossRefGoogle Scholar
  44. 44.
    Rosenow EC 3rd, Hurley BT (1984) Disorders of the thymus. A review. Arch Intern Med 144:763–770PubMedCrossRefGoogle Scholar
  45. 45.
    Lara PN Jr (2000) Malignant thymoma: current status and future directions. Cancer Treat Rev 26:127–131PubMedCrossRefGoogle Scholar
  46. 46.
    Good RA (1954) Agammaglobulinaemia: a provocative experiment of nature. Bull Univ Minn Hosp 26:1–19Google Scholar
  47. 47.
    Fujimoto W et al (2002) Paraneoplastic pemphigus associated with Castleman’s disease and asymptomatic bronchiolitis obliterans. Eur J Dermatol 12:355–359PubMedGoogle Scholar
  48. 48.
    Wang J et al (2005) Autoantibody production from a thymoma and a follicular dendritic cell sarcoma associated with paraneoplastic pemphigus. Br J Dermatol 153:558–564PubMedCrossRefGoogle Scholar
  49. 49.
    Wang J et al (2005) Paraneoplastic pemphigus associated with Castleman tumor: a commonly reported subtype of paraneoplastic pemphigus in China. Arch Dermatol 141:1285–1293PubMedCrossRefGoogle Scholar
  50. 50.
    Nikolskaia OV, Nousari CH, Anhalt GJ (2003) Paraneoplastic pemphigus in association with Castleman’s disease. Br J Dermatol 149:1143–1151PubMedCrossRefGoogle Scholar
  51. 51.
    Kim WY, Kim H, Jeon YK, Kim CW (2010) Follicular dendritic cell sarcoma with immature T-cell proliferation. Hum Pathol 41:129–133PubMedCrossRefGoogle Scholar
  52. 52.
    Harding FA, McArthur JG, Gross JA, Raulet DH, Allison JP (1992) CD28-mediated signalling co-stimulates murine T cells and prevents induction of anergy in T-cell clones. Nature 356:607–609PubMedCrossRefGoogle Scholar
  53. 53.
    Thompson ED, Enriquez HL, Fu YX, Engelhard VH (2010) Tumor masses support naive T cell infiltration, activation, and differentiation into effectors. J Exp Med 207:1791–1804PubMedCrossRefGoogle Scholar
  54. 54.
    Hamblin TJ (2006) Autoimmune complications of chronic lymphocytic leukemia. Semin Oncol 33:230–239PubMedCrossRefGoogle Scholar
  55. 55.
    Dearden C (2008) Disease-specific complications of chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program, pp 450–456Google Scholar
  56. 56.
    Tomic J et al (2006) Sensitization of IL-2 signaling through TLR-7 enhances B lymphoma cell immunogenicity. J Immunol 176:3830–3839PubMedGoogle Scholar
  57. 57.
    Jablonska E et al (2005) TNF family molecules in the serum of patients with B-cell chronic lymphocytic leukemia (B-CLL). Leuk Lymphoma 46:1307–1312PubMedCrossRefGoogle Scholar
  58. 58.
    Hall AM, Vickers MA, McLeod E, Barker RN (2005) Rh autoantigen presentation to helper T cells in chronic lymphocytic leukemia by malignant B cells. Blood 105:2007–2015PubMedCrossRefGoogle Scholar
  59. 59.
    Gorgun G, Holderried TA, Zahrieh D, Neuberg D, Gribben JG (2005) Chronic lymphocytic leukemia cells induce changes in gene expression of CD4 and CD8 T cells. J Clin Invest 115:1797–1805PubMedCrossRefGoogle Scholar
  60. 60.
    Ramsay AG et al (2008) Chronic lymphocytic leukemia T cells show impaired immunological synapse formation that can be reversed with an immunomodulating drug. J Clin Invest 118:2427–2437PubMedGoogle Scholar
  61. 61.
    Abu-Shakra M, Buskila D, Ehrenfeld M, Conrad K, Shoenfeld Y (2001) Cancer and autoimmunity: autoimmune and rheumatic features in patients with malignancies. Ann Rheum Dis 60:433–441PubMedCrossRefGoogle Scholar
  62. 62.
    Cines DB, Bussel JB, Liebman HA, Luning Prak ET (2009) The ITP syndrome: pathogenic and clinical diversity. Blood 113:6511–6521PubMedCrossRefGoogle Scholar
  63. 63.
    Beyer M et al (2005) Reduced frequencies and suppressive function of CD4 + CD25hi regulatory T cells in patients with chronic lymphocytic leukemia after therapy with fludarabine. Blood 106:2018–2025PubMedCrossRefGoogle Scholar
  64. 64.
    Dearden C et al (2008) The prognostic significance of a positive direct antiglobulin test in chronic lymphocytic leukemia: a beneficial effect of the combination of fludarabine and cyclophosphamide on the incidence of hemolytic anemia. Blood 111:1820–1826PubMedCrossRefGoogle Scholar
  65. 65.
    Citores MJ et al (2010) CD154 expression triggered by purine analogues in vitro: correlation with treatment response and autoimmune events in chronic lymphocytic leukemia. Exp Hematol 38:165–173PubMedCrossRefGoogle Scholar
  66. 66.
    Gooptu C et al (2001) Paraneoplastic pemphigus: an association with fludarabine? Br J Dermatol 144:1255–1261PubMedCrossRefGoogle Scholar
  67. 67.
    Hodi FS et al (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711–723PubMedCrossRefGoogle Scholar
  68. 68.
    Di Bernardo MC et al (2008) A genome-wide association study identifies six susceptibility loci for chronic lymphocytic leukemia. Nat Genet 40:1204–1210PubMedCrossRefGoogle Scholar
  69. 69.
    Shaffer AL et al (2008) IRF4 addiction in multiple myeloma. Nature 454:226–231PubMedCrossRefGoogle Scholar
  70. 70.
    Biswas PS et al (2010) Phosphorylation of IRF4 by ROCK2 regulates IL-17 and IL-21 production and the development of autoimmunity in mice. J Clin Invest 120:3280–3295PubMedCrossRefGoogle Scholar
  71. 71.
    Novak AJ et al (2009) Genetic variation in B-cell-activating factor is associated with an increased risk of developing B-cell non-Hodgkin lymphoma. Cancer Res 69:4217–4224PubMedCrossRefGoogle Scholar
  72. 72.
    Juszczynski P et al (2002) Human leukocyte antigens class II and tumor necrosis factor genetic polymorphisms are independent predictors of non-Hodgkin lymphoma outcome. Blood 100:3037–3040PubMedCrossRefGoogle Scholar
  73. 73.
    Chu VT et al (2009) Systemic activation of the immune system induces aberrant BAFF and APRIL expression in B cells in patients with systemic lupus erythematosus. Arthritis Rheum 60:2083–2093PubMedCrossRefGoogle Scholar
  74. 74.
    Zhang W et al (2010) B-cell activating factor and v-Myc myelocytomatosis viral oncogene homolog (c-Myc) influence progression of chronic lymphocytic leukemia. Proc Natl Acad Sci USA 107:18956–18960PubMedCrossRefGoogle Scholar
  75. 75.
    Lang B, Vincent A (1996) Autoimmunity to ion-channels and other proteins in paraneoplastic disorders. Curr Opin Immunol 8:865–871PubMedCrossRefGoogle Scholar
  76. 76.
    Ehrenfeld M, Abu-Shakra M, Buskila D, Shoenfeld Y (2001) The dual association between lymphoma and autoimmunity. Blood Cell Mol Diseases 27:750–756CrossRefGoogle Scholar
  77. 77.
    Dalmau J et al (2007) Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma. Ann Neurol 61:25–36PubMedCrossRefGoogle Scholar
  78. 78.
    Butler MH et al (2000) Autoimmunity to gephyrin in Stiff–Man syndrome. Neuron 26:307–312PubMedCrossRefGoogle Scholar
  79. 79.
    Polans AS et al (1995) Recoverin, a photoreceptor-specific calcium-binding protein, is expressed by the tumor of a patient with cancer-associated retinopathy. Proc Natl Acad Sci USA 92:9176–9180PubMedCrossRefGoogle Scholar
  80. 80.
    Buckanovich RJ, Yang YYL, Darnell RB (1996) The onconeural antigen Nova-1 is a neuron-specific RNA-Binding protein, the activity of which is inhibited by paraneoplastic antibodies. J Neurosci 16:1114–1122PubMedGoogle Scholar
  81. 81.
    Lennon VA et al (1995) Calcium-channel antibodies in the Lambert–Eaton syndrome and other paraneoplastic syndromes. N Engl J Med 332:1467–1474PubMedCrossRefGoogle Scholar
  82. 82.
    Yu Z et al (2001) CRMP-5 neuronal autoantibody: marker of lung cancer and thymoma-related autoimmunity. Ann Neurol 49:146–154PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC (outside the USA)  2011

Authors and Affiliations

  • Emanual Maverakis
    • 1
    • 2
    Email author
  • Heidi Goodarzi
    • 1
  • Lisa N. Wehrli
    • 1
  • Yoko Ono
    • 1
  • Miki Shirakawa Garcia
    • 1
  1. 1.Department of DermatologyUniversity of California Davis, School of MedicineSacramentoUSA
  2. 2.Department of Veteran Affairs Northern California Health Care SystemSacramentoUSA

Personalised recommendations