Leprosy pathophysiology: Difference between revisions
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==Overview== | ==Overview== | ||
Leprosy is a [[chronic disease]], whose clinical features depend on the [[immune response]] of the host towards the [[infection]]. Once the [[bacterial]] [[cells]] penetrate and multiply within host cells, predominately [[skin]] and [[peripheral nerve]] cells, the [[immune system]] develops a responses against those [[infected cells]], thereby justifying some of the [[symptoms]]. There have identified several [[gene]] [[SNPs]] related to susceptibility to the [[disease]], which has microscopic and gross manifestations. | |||
==Pathogenesis== | ==Pathogenesis== | ||
[[Mycobacterium leprae]] has predisposition to [[infect]] [[macrophages]]. It is usually collected inside these, in [[intracellular]] groups, also called ''globi''. This [[organism]] has an ideal growth temperature of 27-30ºC, which explains why it usually [[infection|infects]] areas such as the [[skin]], [[upper respiratory]] [[mucosa]] and [[peripheral nerves]]. It is able to [[infect]] [[cells]], particularly due to 2 structures:<ref name="EichelmannGonzález González2013">{{cite journal|last1=Eichelmann|first1=K.|last2=González González|first2=S.E.|last3=Salas-Alanis|first3=J.C.|last4=Ocampo-Candiani|first4=J.|title=Leprosy. An Update: Definition, Pathogenesis, Classification, Diagnosis, and Treatment|journal=Actas Dermo-Sifiliográficas (English Edition)|volume=104|issue=7|year=2013|pages=554–563|issn=15782190|doi=10.1016/j.adengl.2012.03.028}}</ref><ref name="pmid23870850">{{cite journal| author=Eichelmann K, González González SE, Salas-Alanis JC, Ocampo-Candiani J| title=Leprosy. An update: definition, pathogenesis, classification, diagnosis, and treatment. | journal=Actas Dermosifiliogr | year= 2013 | volume= 104 | issue= 7 | pages= 554-63 | pmid=23870850 | doi=10.1016/j.adengl.2012.03.028 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23870850 }} </ref><ref name="BrittonLockwood2004">{{cite journal|last1=Britton|first1=Warwick J|last2=Lockwood|first2=Diana NJ|title=Leprosy|journal=The Lancet|volume=363|issue=9416|year=2004|pages=1209–1219|issn=01406736|doi=10.1016/S0140-6736(04)15952-7}}</ref><ref name="GuliaFried2010">{{cite journal|last1=Gulia|first1=Andrea|last2=Fried|first2=Isabella|last3=Massone|first3=Cesare|title=New insights in the pathogenesis and genetics of leprosy|journal=F1000 Medicine Reports|volume=2|year=2010|issn=17575931|doi=10.3410/M2-30}}</ref> | [[Mycobacterium leprae]] has predisposition to [[infect]] [[macrophages]]. It is usually collected inside these, in [[intracellular]] groups, also called ''globi''. This [[organism]] has an ideal growth temperature of 27-30ºC, which explains why it usually [[infection|infects]] areas such as the [[skin]], [[upper respiratory]] [[mucosa]] and [[peripheral nerves]]. It is able to [[infect]] [[cells]], particularly due to 2 structures:<ref name="EichelmannGonzález González2013">{{cite journal|last1=Eichelmann|first1=K.|last2=González González|first2=S.E.|last3=Salas-Alanis|first3=J.C.|last4=Ocampo-Candiani|first4=J.|title=Leprosy. An Update: Definition, Pathogenesis, Classification, Diagnosis, and Treatment|journal=Actas Dermo-Sifiliográficas (English Edition)|volume=104|issue=7|year=2013|pages=554–563|issn=15782190|doi=10.1016/j.adengl.2012.03.028}}</ref><ref name="pmid23870850">{{cite journal| author=Eichelmann K, González González SE, Salas-Alanis JC, Ocampo-Candiani J| title=Leprosy. An update: definition, pathogenesis, classification, diagnosis, and treatment. | journal=Actas Dermosifiliogr | year= 2013 | volume= 104 | issue= 7 | pages= 554-63 | pmid=23870850 | doi=10.1016/j.adengl.2012.03.028 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23870850 }} </ref><ref name="BrittonLockwood2004">{{cite journal|last1=Britton|first1=Warwick J|last2=Lockwood|first2=Diana NJ|title=Leprosy|journal=The Lancet|volume=363|issue=9416|year=2004|pages=1209–1219|issn=01406736|doi=10.1016/S0140-6736(04)15952-7}}</ref><ref name="GuliaFried2010">{{cite journal|last1=Gulia|first1=Andrea|last2=Fried|first2=Isabella|last3=Massone|first3=Cesare|title=New insights in the pathogenesis and genetics of leprosy|journal=F1000 Medicine Reports|volume=2|year=2010|issn=17575931|doi=10.3410/M2-30}}</ref> | ||
Revision as of 05:46, 7 July 2014
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]
Overview
Leprosy is a chronic disease, whose clinical features depend on the immune response of the host towards the infection. Once the bacterial cells penetrate and multiply within host cells, predominately skin and peripheral nerve cells, the immune system develops a responses against those infected cells, thereby justifying some of the symptoms. There have identified several gene SNPs related to susceptibility to the disease, which has microscopic and gross manifestations.
Pathogenesis
Mycobacterium leprae has predisposition to infect macrophages. It is usually collected inside these, in intracellular groups, also called globi. This organism has an ideal growth temperature of 27-30ºC, which explains why it usually infects areas such as the skin, upper respiratory mucosa and peripheral nerves. It is able to infect cells, particularly due to 2 structures:[1][2][3][4]
- Capsule - target of intense humoral immune response (immunoglobulin M-mediated).
- Cell wall - particularly the lipoarabinomannan, works as an antigen for the macrophages.
The bacillus is known to target Schwann cells, specifically the G domain of the laminin-α2 chain. This domain is predominantly expressed in the basal lamina of peripheral nerves, thereby explaining the neuropathy felt in this condition. The pathogen then penetrates the cell, at which time it will multiply, until the infected cell is finally recognized by the immune system and a an inflammatory reaction is started.[1][5]
This mechanism explains the reason why the clinical manifestations of the disease will depend on the immunologic status of the patient and the intensity of the response developed following the infection of the host cells.[1]
Genetics
The infection by the mycobacterium leprae and the course of the disease are influenced by certain genetic factors of the host.[6][7] Some single-nucleotide polymorphism have been associated with a higher incidence of leprosy. These include:[6][8][9][10][11]
- Low occurrence of a lymphotoxin-α-producing allele.
- Vitamin D receptor gene.
- TNF-α gene.
- IL-10 gene.
- IFN-γ gene.
- TLR 1 gene.
Another study has also suggested a possible relationship between genetic variants of the NOD2 gene and increased susceptibility to leprosy and the development of type I and II reactions.[12]
It has also been suggested an association between leprosy and a locus in chromosome 10p13, in the proximity of the mannose receptor 1 gene since the mannose receptors located on macrophage's surface play an important role in phagocytosis.[13]
Additionally, the class of leprosy developed in a patient has been associated with genes of the class II HLA/major histocompatibility complex, at chromosome 6. Accordingly:
- HLA-DR2 and HLA-DR3 are considered to be linked with the tuberculoid class.
- HLA-DQ1 is considered to be linked with the lepromatous class.
Associated Conditions
Association with HIV
Although previously suspected, there is no increased susceptibility to Mycobacterium leprae in HIV patients, nor are the clinical features altered. The only apparent relationship between these two conditions is the manifestation of latent leprosy, in HIV patients, once the immune response is reestablished, after initiation of antiretroviral therapy.[14][15]
Gross Pathology
Type of Leprosy
Tuberculoid Leprosy
- May resolve spontaneously.
- Well-defined macules.
- Hypopigmented skin lesions.
- Borders of lesions are commonly erythematous and elevated, with depressed centers.
- Sensation on the face commonly unaffected.
- Anhydrosis.
- Loss of adnexal structures.
Lepromatous Leprosy
- Papules and nodules, usually bilateral, symmetrical with ovoid shape.
- Leonine facies.
- Severe nerve involvement.
Immunologic Reactions
Systemic inflammatory reactions may occur before, during or after the treatment of leprosy.[16] These are thought to be related to changes in the immune system, such as following stress situations, pregnancy or leprosy medications.[1] There are two different types of reactions, which are thought to have different underlying immunologic mechanisms.
Tipe 1 (T1R) or Reversal Reaction (RR)
- Predominant in borderline disease.
- Predominant type IV hypersensitivity.[17]
- Red patches developing in previous skin lesions, commonly on the face or nerve trunks.
- Erythema of previous skin lesions.
- Inflammation may lead to nerve lesion and paralysis.
- Edema of hands and feet.
- Arthralgia, predominantly of smaller joints.
- Ulcerated lesions.
- Pain or tenderness on lesions.
Type 2 (T2R) or Erythema Nodosum Leprosum (ENL)
- Predominant in lepromatous disease.
- Predominant type III hypersensitivity.
- Sudden occurrence of painful nodules.
- Nodules may lead to pustules or ulcers.
- Pustules may discharge pus containing polymorphonuclear cells and degenerating mycobacteria.
- After lesions resolve, brawn skin lesions may remain.
- Occasionally may occur: orchitis, muscle and lymphadenopathy tenderness and/or swollen joints.
- Without treatment usually lasts for 2 weeks.
Microscopic Pathology
Histopathology
The manifestations of leprosy depend on the host's immune response towards the mycobacteria. Therefore, tuberculoid and lepromatous patients will show different histopathologic findings:[6][16][18]
- Tuberculoid patients - These patients will show a strong immune response towards the bacteria, with production of IFN-γ and commonly showing a positive lepromin skin test.
- Inflammatory infiltrate with multiple granulomas.
- Granulomas containing giant cells, differentiated macrophages and epithelioid cells.
- Predominance of CD4 cells.
- Low bacterial index.
- Lepromatous patients - These patients will show a weaker immune response towards the bacteria, particularly a weak cell-mediated response.
- Absence of granulomas.
- Straightened skin.
- Predominance of CD8 cells.
- High bacterial index.
References
- ↑ 1.0 1.1 1.2 1.3 Eichelmann, K.; González González, S.E.; Salas-Alanis, J.C.; Ocampo-Candiani, J. (2013). "Leprosy. An Update: Definition, Pathogenesis, Classification, Diagnosis, and Treatment". Actas Dermo-Sifiliográficas (English Edition). 104 (7): 554–563. doi:10.1016/j.adengl.2012.03.028. ISSN 1578-2190.
- ↑ Eichelmann K, González González SE, Salas-Alanis JC, Ocampo-Candiani J (2013). "Leprosy. An update: definition, pathogenesis, classification, diagnosis, and treatment". Actas Dermosifiliogr. 104 (7): 554–63. doi:10.1016/j.adengl.2012.03.028. PMID 23870850.
- ↑ Britton, Warwick J; Lockwood, Diana NJ (2004). "Leprosy". The Lancet. 363 (9416): 1209–1219. doi:10.1016/S0140-6736(04)15952-7. ISSN 0140-6736.
- ↑ Gulia, Andrea; Fried, Isabella; Massone, Cesare (2010). "New insights in the pathogenesis and genetics of leprosy". F1000 Medicine Reports. 2. doi:10.3410/M2-30. ISSN 1757-5931.
- ↑ Shimoji Y, Ng V, Matsumura K, Fischetti VA, Rambukkana A (1999). "A 21-kDa surface protein of Mycobacterium leprae binds peripheral nerve laminin-2 and mediates Schwann cell invasion". Proc Natl Acad Sci U S A. 96 (17): 9857–62. PMC 22300. PMID 10449784.
- ↑ 6.0 6.1 6.2 Bhat, Ramesh Marne; Prakash, Chaitra (2012). "Leprosy: An Overview of Pathophysiology". Interdisciplinary Perspectives on Infectious Diseases. 2012: 1–6. doi:10.1155/2012/181089. ISSN 1687-708X.
- ↑ Alter A, Alcaïs A, Abel L, Schurr E (2008). "Leprosy as a genetic model for susceptibility to common infectious diseases". Hum Genet. 123 (3): 227–35. doi:10.1007/s00439-008-0474-z. PMID 18247059.
- ↑ Alcaïs A, Alter A, Antoni G, Orlova M, Nguyen VT, Singh M; et al. (2007). "Stepwise replication identifies a low-producing lymphotoxin-alpha allele as a major risk factor for early-onset leprosy". Nat Genet. 39 (4): 517–22. doi:10.1038/ng2000. PMID 17353895.
- ↑ Mira MT, Alcais A, di Pietrantonio T, Thuc NV, Phuong MC, Abel L; et al. (2003). "Segregation of HLA/TNF region is linked to leprosy clinical spectrum in families displaying mixed leprosy subtypes". Genes Immun. 4 (1): 67–73. doi:10.1038/sj.gene.6363911. PMID 12595904.
- ↑ Correa-Oliveira, Rodrigo; Misch, Elizabeth A.; Macdonald, Murdo; Ranjit, Chaman; Sapkota, Bishwa R.; Wells, Richard D.; Siddiqui, M. Ruby; Kaplan, Gilla; Hawn, Thomas R. (2008). "Human TLR1 Deficiency Is Associated with Impaired Mycobacterial Signaling and Protection from Leprosy Reversal Reaction". PLoS Neglected Tropical Diseases. 2 (5): e231. doi:10.1371/journal.pntd.0000231. ISSN 1935-2735.
- ↑ Cardoso CC, Pereira AC, Brito-de-Souza VN, Dias-Baptista IM, Maniero VC, Venturini J; et al. (2010). "IFNG +874 T>A single nucleotide polymorphism is associated with leprosy among Brazilians". Hum Genet. 128 (5): 481–90. doi:10.1007/s00439-010-0872-x. PMID 20714752.
- ↑ Berrington WR, Macdonald M, Khadge S, Sapkota BR, Janer M, Hagge DA; et al. (2010). "Common polymorphisms in the NOD2 gene region are associated with leprosy and its reactive states". J Infect Dis. 201 (9): 1422–35. doi:10.1086/651559. PMC 2853728. PMID 20350193.
- ↑ Alter A, Grant A, Abel L, Alcaïs A, Schurr E (2011). "Leprosy as a genetic disease". Mamm Genome. 22 (1–2): 19–31. doi:10.1007/s00335-010-9287-1. PMID 20936290.
- ↑ Walker, Stephen L.; Lockwood, Dina N.J. (2007). "Leprosy". Clinics in Dermatology. 25 (2): 165–172. doi:10.1016/j.clindermatol.2006.05.012. ISSN 0738-081X.
- ↑ Ustianowski AP, Lawn SD, Lockwood DN (2006). "Interactions between HIV infection and leprosy: a paradox". Lancet Infect Dis. 6 (6): 350–60. doi:10.1016/S1473-3099(06)70493-5. PMID 16728321.
- ↑ 16.0 16.1 Modlin RL, Hofman FM, Taylor CR, Rea TH (1983). "T lymphocyte subsets in the skin lesions of patients with leprosy". J Am Acad Dermatol. 8 (2): 182–9. PMID 6219136.
- ↑ Balagon, M. V. F.; Gelber, R. H.; Abalos, R. M.; Cellona, R. V. (2010). "Reactions Following Completion of 1 and 2 Year Multidrug Therapy (MDT)". American Journal of Tropical Medicine and Hygiene. 83 (3): 637–644. doi:10.4269/ajtmh.2010.09-0586. ISSN 0002-9637.
- ↑ Wallach D, Flageul B, Bach MA, Cottenot F (1984). "The cellular content of dermal leprous granulomas: an immuno-histological approach". Int J Lepr Other Mycobact Dis. 52 (3): 318–26. PMID 6332791.