Syphilis pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Aysha Anwar, M.B.B.S[2]; Nate Michalak, B.A.

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Syphilis is caused by a spirochete, Treponema pallidum. It has an average incubation period of 3 - 12 weeks. However, it may vary according to the size of innoculum. Spirochete penetrates intact mucous membrane or microscopic dermal abrasions and rapidly enters systemic circulation with the central nervous system being invaded during the early phase of infection. The histopathological hallmark findings are endarteritis and plasma cell-rich infiltrates reflecting a delayed-type of hypersensitivity reaction to the spirochete.[1][2][3][4][5][6][7]


The pathogenesis of syphilis may be described in the following steps:[1][2][3][4][5][6][7][8][9][10][11]


Treponema pallidum is usually transmitted via direct contact with the infected lesion (sexual contact) or blood transfusion (rare).


The incubation period varies with the size of innoculum (9-90 days).



Immune response

Different stages of syphilis results from the interaction between the antigen and the host immune response.[1][2]

Acute response

  • The initial infection in primary syphilis is limited due to Th1 response and lack of the antibody response.
  • It is speculated that there is a shift from Th1 to Th2 response during secondary syphilis.



There is no known genetic association of syphilis. However, neurosyphilis may be associated with the gene polymorphism for IL-10 production with increased levels seen in the patients with neurosyphilis.[11]

Associated conditions

Syphilis is associated with increased transmission of HIV. The underlying mechanism may be related to the accumulation of dendritic cells containing CCR5 co-receptors at the site of infection, the same receptor entity binding the HIV.[9]

Microscopic pathology

On microscopic histopathological analysis, characteristic findings of syphilis depends on the stage of the disease:

Primary syphilis

  • Mononuclear leukocytic infiltration, macrophages, and lymphocytes
  • Swelling and proliferation of small blood vessels

Secondary syphilis

  • Swelling and dilatation of blood vessels in the dermis
  • Epidermal hyperplasia and neutrophilic infiltration
  • Inflammatory cell infiltrate, predominantly plasma cell

Tertiary syphilis


  1. 1.0 1.1 1.2 Carlson JA, Dabiri G, Cribier B, Sell S (2011). "The immunopathobiology of syphilis: the manifestations and course of syphilis are determined by the level of delayed-type hypersensitivity". Am J Dermatopathol. 33 (5): 433–60. doi:10.1097/DAD.0b013e3181e8b587. PMC 3690623. PMID 21694502.
  2. 2.0 2.1 2.2 Fitzgerald TJ (1992). "The Th1/Th2-like switch in syphilitic infection: is it detrimental?". Infect Immun. 60 (9): 3475–9. PMC 257347. PMID 1386838.
  3. 3.0 3.1 Singh AE, Romanowski B (1999). "Syphilis: review with emphasis on clinical, epidemiologic, and some biologic features". Clin Microbiol Rev. 12 (2): 187–209. PMC 88914. PMID 10194456.
  4. 4.0 4.1 Engelkens HJ, ten Kate FJ, Vuzevski VD, van der Sluis JJ, Stolz E (1991). "Primary and secondary syphilis: a histopathological study". Int J STD AIDS. 2 (4): 280–4. PMID 1911961.
  5. 5.0 5.1 Thomas DD, Navab M, Haake DA, Fogelman AM, Miller JN, Lovett MA (1988). "Treponema pallidum invades intercellular junctions of endothelial cell monolayers". Proc Natl Acad Sci U S A. 85 (10): 3608–12. PMC 280263. PMID 3285346.
  6. 6.0 6.1 Quatresooz P, Piérard GE (2009). "Skin homing of Treponema pallidum in early syphilis: an immunohistochemical study". Appl Immunohistochem Mol Morphol. 17 (1): 47–50. doi:10.1097/PAI.0b013e3181788186. PMID 18800002.
  7. 7.0 7.1 Tanabe JL, Huntley AC (1986). "Granulomatous tertiary syphilis". J Am Acad Dermatol. 15 (2 Pt 2): 341–4. PMID 3734178.
  8. Baker-Zander S, Sell S (1980). "A histopathologic and immunologic study of the course of syphilis in the experimentally infected rabbit. Demonstration of long-lasting cellular immunity". Am J Pathol. 101 (2): 387–414. PMC 1903600. PMID 7001910.
  9. 9.0 9.1 Sheffield JS, Wendel GD, McIntire DD, Norgard MV (2007). "Effect of genital ulcer disease on HIV-1 coreceptor expression in the female genital tract". J Infect Dis. 196 (10): 1509–16. doi:10.1086/522518. PMID 18008231.
  10. Abell E, Marks R, Jones EW (1975). "Secondary syphilis: a clinico-pathological review". Br J Dermatol. 93 (1): 53–61. PMID 1191529.
  11. 11.0 11.1 Pastuszczak M, Jakiela B, Jaworek AK, Wypasek E, Zeman J, Wojas-Pelc A (2015). "Association of Interleukin-10 promoter polymorphisms with neurosyphilis". Hum Immunol. 76 (7): 469–72. doi:10.1016/j.humimm.2015.06.010. PMID 26100683.

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