Neurosyphilis pathophysiology: Difference between revisions
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__NOTOC__ | __NOTOC__ | ||
{{Neurosyphilis}} | {{Neurosyphilis}} | ||
{{CMG}} | {{CMG}} {{AE}}{{MMJ}} | ||
==Overview== | ==Overview== | ||
Neurosyphilis is caused by [[Treponema pallidum]], the bacteria that cause syphilis. It usually occurs about 10 - 20 years after a person is first infected with syphilis. Not everyone who has syphilis will develop this complication. | Neurosyphilis is caused by [[Treponema pallidum]], the bacteria that cause [[syphilis]]. It usually occurs about 10 - 20 years after a person is first infected with [[syphilis]]. Not everyone who has [[syphilis]] will develop this complication. [[Treponema pallidum|''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). Following transmission, [[Treponema pallidum|''Treponema pallidum'']] uses the intact or abraded [[mucous membrane]] to enter the body. It then disseminates to the [[lymphatics]] and blood stream to gain access to any organ of the body. Syphilis uses [[fibronectin]] molecules to attach to the [[endothelial]] surface of the vessels in organs resulting in inflammation and obliteration of the small blood vessels causing [[vasculitis]] ([[endarteritis obliterans]]). Organism has slow replication rate (30-33 hrs) and evades the initial host [[immune response]]. It may seed to different organs of the body especially the [[cardiovascular system]] and [[central nervous system]] resulting in tertiary [[syphilis]]. Different stages of [[syphilis]] results from the interaction between the [[antigen]] and the [[host immune 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]]. [[Cytotoxic T cells]] and an incomplete [[humoral immunity]] response is mainly responsible for persistence of infection and tissue damage in [[tertiary syphilis]]. Ineffective [[Type IV hypersensitivity|type 4 delayed hypersensitivity]] reaction containing [[macrophages]] and sensitized [[T cells]] is mainly responsible for the [[gumma]] formation in various organs. There is no known [[Genetics|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. In neurosyphilis, the brain tissue and preganglionic portion of the dorsal roots of spinal nerves is infiltrated with [[Lymphocyte|lymphocytes]] and [[plasma cells]], and invasion of [[treponema pallidum]] [[Spirochaete|spirochete]]<nowiki/>s to brain tissue and [[Posterior column|posterior columns]] of the [[spinal cord]] makes them [[Atrophy|atrophic]]. The [[demyelination]] of the [[Axoneme|axones]] of the [[neurons]] is the main cause of symptoms and it affects the [[neurons]] in the brain, [[Dorsal root ganglion|dorsal root ganglia]] and [[Posterior columns|posterior columns of the spinal cord]]. | ||
==Pathophysiology== | ==Pathophysiology== | ||
Neurosyphilis is | * Neurosyphilis is a manifestation of invasion of [[treponema pallidum]] [[Spirochaete|spirochete]]<nowiki/>s to the brain and [[Dorsal column|dorsal column of spinal cord]] in [[tertiary syphilis]].<ref name="pmid10194456">{{cite journal| author=Singh AE, Romanowski B| title=Syphilis: review with emphasis on clinical, epidemiologic, and some biologic features. | journal=Clin Microbiol Rev | year= 1999 | volume= 12 | issue= 2 | pages= 187-209 | pmid=10194456 | doi= | pmc=88914 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10194456 }} </ref><ref name="pmid17235095">{{cite journal| author=French P| title=Syphilis. | journal=BMJ | year= 2007 | volume= 334 | issue= 7585 | pages= 143-7 | pmid=17235095 | doi=10.1136/bmj.39085.518148.BE | pmc=1779891 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17235095 }} </ref> | ||
* Neurosyphilis usually occurs in patients who have untreated [[syphilis]] for a long time, usually about 10 to 20 years after first infection by [[treponema pallidum]] | |||
* Only 25%–40% of persons who are not treated with [[penicillin]] will develop neurosyphilis. | |||
The forms of presentation of neurosyphilis can be grouped in two categories:<ref name="pmid12235572">{{cite journal| author=Conde-Sendín MA, Hernández-Fleta JL, Cárdenes-Santana MA, Amela-Peris R| title=[Neurosyphilis: forms of presentation and clinical management]. | journal=Rev Neurol | year= 2002 | volume= 35 | issue= 4 | pages= 380-6 | pmid=12235572 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12235572 }} </ref> | |||
# Early ([[asymptomatic]] which is the most common form, [[Meninges|meningeal]] and meningovascular neurosyphilis) | |||
# late (progressive general paralysis and [[Tabes Dorsalis|tabes dorsalis]]). | |||
Other less important forms are: | |||
* [[Gumma (pathology)|Gummas]] | |||
* Ocular forms | |||
* Syphilitic [[amyotrophy]] or hypoacusis | |||
In neurosyphilis, the brain tissue and preganglionic portion of the [[Dorsal root ganglion|dorsal roots of spinal nerves]] is infiltrated with [[Lymphocyte|lymphocytes]] and [[plasma cells]], and invasion of [[treponema pallidum]] [[Spirochaete|spirochete]]<nowiki/>s to brain tissue and [[Posterior column|posterior columns]] of the [[spinal cord]] makes them [[Atrophy|atrophic]].<ref name="pmid21694502">{{cite journal| author=Carlson JA, Dabiri G, Cribier B, Sell S| title=The immunopathobiology of syphilis: the manifestations and course of syphilis are determined by the level of delayed-type hypersensitivity. | journal=Am J Dermatopathol | year= 2011 | volume= 33 | issue= 5 | pages= 433-60 | pmid=21694502 | doi=10.1097/DAD.0b013e3181e8b587 | pmc=3690623 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21694502 }} </ref> | |||
* The [[demyelination]] of the [[Axoneme|axones]] of the [[neurons]] is the main cause of symptoms and it affects the [[neurons]] in the brain, [[Dorsal root ganglion|dorsal root ganglia]] and [[Posterior columns|posterior columns of the spinal cord]].<nowiki/><ref name="pmid21694502">{{cite journal| author=Carlson JA, Dabiri G, Cribier B, Sell S| title=The immunopathobiology of syphilis: the manifestations and course of syphilis are determined by the level of delayed-type hypersensitivity. | journal=Am J Dermatopathol | year= 2011 | volume= 33 | issue= 5 | pages= 433-60 | pmid=21694502 | doi=10.1097/DAD.0b013e3181e8b587 | pmc=3690623 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21694502 }} </ref> | |||
==Pathogenesis of the neurosyphilis== | |||
The pathogenesis of neuro[[syphilis]] may be described in the following steps:<ref name="pmid21694502" /><ref name="pmid1386838">{{cite journal| author=Fitzgerald TJ| title=The Th1/Th2-like switch in syphilitic infection: is it detrimental? | journal=Infect Immun | year= 1992 | volume= 60 | issue= 9 | pages= 3475-9 | pmid=1386838 | doi= | pmc=257347 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1386838 }} </ref><ref name="pmid10194456" /><ref name="pmid1911961">{{cite journal| author=Engelkens HJ, ten Kate FJ, Vuzevski VD, van der Sluis JJ, Stolz E| title=Primary and secondary syphilis: a histopathological study. | journal=Int J STD AIDS | year= 1991 | volume= 2 | issue= 4 | pages= 280-4 | pmid=1911961 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1911961 }} </ref><ref name="pmid3285346">{{cite journal| author=Thomas DD, Navab M, Haake DA, Fogelman AM, Miller JN, Lovett MA| title=Treponema pallidum invades intercellular junctions of endothelial cell monolayers. | journal=Proc Natl Acad Sci U S A | year= 1988 | volume= 85 | issue= 10 | pages= 3608-12 | pmid=3285346 | doi= | pmc=280263 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3285346 }} </ref><ref name="pmid18800002">{{cite journal| author=Quatresooz P, Piérard GE| title=Skin homing of Treponema pallidum in early syphilis: an immunohistochemical study. | journal=Appl Immunohistochem Mol Morphol | year= 2009 | volume= 17 | issue= 1 | pages= 47-50 | pmid=18800002 | doi=10.1097/PAI.0b013e3181788186 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18800002 }} </ref><ref name="pmid3734178">{{cite journal| author=Tanabe JL, Huntley AC| title=Granulomatous tertiary syphilis. | journal=J Am Acad Dermatol | year= 1986 | volume= 15 | issue= 2 Pt 2 | pages= 341-4 | pmid=3734178 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3734178 }} </ref><ref name="pmid7001910">{{cite journal| author=Baker-Zander S, Sell S| title=A histopathologic and immunologic study of the course of syphilis in the experimentally infected rabbit. Demonstration of long-lasting cellular immunity. | journal=Am J Pathol | year= 1980 | volume= 101 | issue= 2 | pages= 387-414 | pmid=7001910 | doi= | pmc=1903600 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7001910 }} </ref><ref name="pmid18008231">{{cite journal| author=Sheffield JS, Wendel GD, McIntire DD, Norgard MV| title=Effect of genital ulcer disease on HIV-1 coreceptor expression in the female genital tract. | journal=J Infect Dis | year= 2007 | volume= 196 | issue= 10 | pages= 1509-16 | pmid=18008231 | doi=10.1086/522518 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18008231 }} </ref><ref name="pmid1191529">{{cite journal| author=Abell E, Marks R, Jones EW| title=Secondary syphilis: a clinico-pathological review. | journal=Br J Dermatol | year= 1975 | volume= 93 | issue= 1 | pages= 53-61 | pmid=1191529 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1191529 }} </ref><ref name="pmid26100683">{{cite journal| author=Pastuszczak M, Jakiela B, Jaworek AK, Wypasek E, Zeman J, Wojas-Pelc A| title=Association of Interleukin-10 promoter polymorphisms with neurosyphilis. | journal=Hum Immunol | year= 2015 | volume= 76 | issue= 7 | pages= 469-72 | pmid=26100683 | doi=10.1016/j.humimm.2015.06.010 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26100683 }} </ref> | |||
===Transmission=== | |||
[[Treponema pallidum|''Treponema pallidum'']] is usually transmitted via direct contact with the infected lesion ([[sexual contact]]) or [[blood transfusion]] (rare). | |||
===Incubation=== | |||
The [[incubation period]] varies with the size of innoculum (9-90 days). | |||
===Dissemination=== | |||
*Following transmission, [[Treponema pallidum|''Treponema pallidum'']] uses the intact or abraded [[mucous membrane]] to enter the body. | |||
*It then disseminates to the [[lymphatics]] and blood stream to gain access to any organ of the body like brain and [[spinal cord]]. | |||
===Seeding=== | |||
*Syphilis uses [[fibronectin]] molecules to attach to the [[endothelial]] surface of the vessels in organs resulting in inflammation and obliteration of the small blood vessels causing [[vasculitis]] ([[endarteritis obliterans]]). | |||
*Organism has slow replication rate (30-33 hrs) and evades the initial host [[immune response]]. | |||
*It may seed to different organs of the body especially the [[cardiovascular system]] and [[central nervous system]] resulting in tertiary [[syphilis]]. | |||
===Immune response=== | |||
Different stages of [[syphilis]] results from the interaction between the [[antigen]] and the [[host immune response]].<ref name="pmid21694502" /><ref name="pmid1386838" /> | |||
'''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]]. | |||
*In neurosyphilis the main immune response is caused by [[Th2 response]]. | |||
'''Chronic ''' | |||
*[[Cytotoxic T cells]] and an incomplete [[humoral immunity]] response is mainly responsible for persistence of infection and tissue damage in [[tertiary syphilis]]. | |||
*Ineffective [[Type IV hypersensitivity|type 4 delayed hypersensitivity]] reaction containing [[macrophages]] and sensitized [[T cells]] is mainly responsible for the [[gumma]] formation in various organs like brain and [[spinal cord]]. | |||
===Genetics=== | |||
There is no known [[Genetics|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.<ref name="pmid26100683" /> | |||
===Associated conditions=== | |||
Neurosyphilis 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 [[Human Immunodeficiency Virus (HIV)|HIV]].<ref name="pmid18008231" /> | |||
===Microscopic pathology=== | |||
* [[Treponema pallidum]] may invade the [[central nervous system]] is any stage of [[Syphilis|syphilis disease]] and cause neurosyphilis. | |||
* 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''' | |||
*Small vessel inflammation ([[endarteritis obliterans]]) | |||
*Granulomatous lesions ([[gumma]]) containing central necrosis, inflammatory cells, such as [[lymphocytes]], [[macrophages]], [[plasma cells]] and [[Fibroblast|fibroblasts]]. | |||
==References== | ==References== | ||
{{Reflist|2}} | {{Reflist|2}} | ||
<references /> | |||
[[Category:Disease]] | [[Category:Disease]] | ||
[[Category:Gynecology]] | [[Category:Gynecology]] | ||
[[Category:Bacterial diseases]] | [[Category:Bacterial diseases]] | ||
[[Category:Sexually transmitted diseases]] | [[Category:Sexually transmitted diseases]] | ||
[[Category:Needs content]] | [[Category:Needs content]] | ||
Latest revision as of 14:39, 5 March 2018
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Mohamadmostafa Jahansouz M.D.[2]
Overview
Neurosyphilis is caused by Treponema pallidum, the bacteria that cause syphilis. It usually occurs about 10 - 20 years after a person is first infected with syphilis. Not everyone who has syphilis will develop this complication. 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). Following transmission, Treponema pallidum uses the intact or abraded mucous membrane to enter the body. It then disseminates to the lymphatics and blood stream to gain access to any organ of the body. Syphilis uses fibronectin molecules to attach to the endothelial surface of the vessels in organs resulting in inflammation and obliteration of the small blood vessels causing vasculitis (endarteritis obliterans). Organism has slow replication rate (30-33 hrs) and evades the initial host immune response. It may seed to different organs of the body especially the cardiovascular system and central nervous system resulting in tertiary syphilis. Different stages of syphilis results from the interaction between the antigen and the host immune 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. Cytotoxic T cells and an incomplete humoral immunity response is mainly responsible for persistence of infection and tissue damage in tertiary syphilis. Ineffective type 4 delayed hypersensitivity reaction containing macrophages and sensitized T cells is mainly responsible for the gumma formation in various organs. 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. In neurosyphilis, the brain tissue and preganglionic portion of the dorsal roots of spinal nerves is infiltrated with lymphocytes and plasma cells, and invasion of treponema pallidum spirochetes to brain tissue and posterior columns of the spinal cord makes them atrophic. The demyelination of the axones of the neurons is the main cause of symptoms and it affects the neurons in the brain, dorsal root ganglia and posterior columns of the spinal cord.
Pathophysiology
- Neurosyphilis is a manifestation of invasion of treponema pallidum spirochetes to the brain and dorsal column of spinal cord in tertiary syphilis.[1][2]
- Neurosyphilis usually occurs in patients who have untreated syphilis for a long time, usually about 10 to 20 years after first infection by treponema pallidum
- Only 25%–40% of persons who are not treated with penicillin will develop neurosyphilis.
The forms of presentation of neurosyphilis can be grouped in two categories:[3]
- Early (asymptomatic which is the most common form, meningeal and meningovascular neurosyphilis)
- late (progressive general paralysis and tabes dorsalis).
Other less important forms are:
- Gummas
- Ocular forms
- Syphilitic amyotrophy or hypoacusis
In neurosyphilis, the brain tissue and preganglionic portion of the dorsal roots of spinal nerves is infiltrated with lymphocytes and plasma cells, and invasion of treponema pallidum spirochetes to brain tissue and posterior columns of the spinal cord makes them atrophic.[4]
- The demyelination of the axones of the neurons is the main cause of symptoms and it affects the neurons in the brain, dorsal root ganglia and posterior columns of the spinal cord.[4]
Pathogenesis of the neurosyphilis
The pathogenesis of neurosyphilis may be described in the following steps:[4][5][1][6][7][8][9][10][11][12][13]
Transmission
Treponema pallidum is usually transmitted via direct contact with the infected lesion (sexual contact) or blood transfusion (rare).
Incubation
The incubation period varies with the size of innoculum (9-90 days).
Dissemination
- Following transmission, Treponema pallidum uses the intact or abraded mucous membrane to enter the body.
- It then disseminates to the lymphatics and blood stream to gain access to any organ of the body like brain and spinal cord.
Seeding
- Syphilis uses fibronectin molecules to attach to the endothelial surface of the vessels in organs resulting in inflammation and obliteration of the small blood vessels causing vasculitis (endarteritis obliterans).
- Organism has slow replication rate (30-33 hrs) and evades the initial host immune response.
- It may seed to different organs of the body especially the cardiovascular system and central nervous system resulting in tertiary syphilis.
Immune response
Different stages of syphilis results from the interaction between the antigen and the host immune response.[4][5]
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.
- In neurosyphilis the main immune response is caused by Th2 response.
Chronic
- Cytotoxic T cells and an incomplete humoral immunity response is mainly responsible for persistence of infection and tissue damage in tertiary syphilis.
- Ineffective type 4 delayed hypersensitivity reaction containing macrophages and sensitized T cells is mainly responsible for the gumma formation in various organs like brain and spinal cord.
Genetics
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.[13]
Associated conditions
Neurosyphilis 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.[11]
Microscopic pathology
- Treponema pallidum may invade the central nervous system is any stage of syphilis disease and cause neurosyphilis.
- 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
- Small vessel inflammation (endarteritis obliterans)
- Granulomatous lesions (gumma) containing central necrosis, inflammatory cells, such as lymphocytes, macrophages, plasma cells and fibroblasts.
References
- ↑ 1.0 1.1 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.
- ↑ French P (2007). "Syphilis". BMJ. 334 (7585): 143–7. doi:10.1136/bmj.39085.518148.BE. PMC 1779891. PMID 17235095.
- ↑ Conde-Sendín MA, Hernández-Fleta JL, Cárdenes-Santana MA, Amela-Peris R (2002). "[Neurosyphilis: forms of presentation and clinical management]". Rev Neurol. 35 (4): 380–6. PMID 12235572.
- ↑ 4.0 4.1 4.2 4.3 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.
- ↑ 5.0 5.1 Fitzgerald TJ (1992). "The Th1/Th2-like switch in syphilitic infection: is it detrimental?". Infect Immun. 60 (9): 3475–9. PMC 257347. PMID 1386838.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ Tanabe JL, Huntley AC (1986). "Granulomatous tertiary syphilis". J Am Acad Dermatol. 15 (2 Pt 2): 341–4. PMID 3734178.
- ↑ 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.
- ↑ 11.0 11.1 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.
- ↑ Abell E, Marks R, Jones EW (1975). "Secondary syphilis: a clinico-pathological review". Br J Dermatol. 93 (1): 53–61. PMID 1191529.
- ↑ 13.0 13.1 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.