Leprosy pathophysiology
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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
The clinical manifestations of leprosy largely reflect the immune response of the host towards the infection. Once the bacterial cells penetrate and multiply within the hosts skin and peripheral nerve cells, the immune system mounts a response toward the infected cells, which results in clinical symptoms. Several single-nucleotide polymorphisms such as TNF-α, IL-10, IFN-γ, TLR 1 have been associated with a greater susceptibility to leprosy as have other genetic markers.
Genetics
The infection by the mycobacterium leprae and the course of the disease are influenced by genetic factors in the host.[1][2] Some single-nucleotide polymorphism have been associated with a higher incidence of leprosy. These include:[1][3][4][5][6]
- 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 suggested a possible relationship between genetic variants of the NOD2 gene, increased susceptibility to leprosy and the development of type I and II reactions.[7]
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 are located on the macrophage's surface, they play an important role in phagocytosis.[8]
Additionally, the subtype 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.
Pathogenesis
Mycobacterium leprae has predisposition to infect macrophages. It is usually collected inside these, in intracellular groups, 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:[9][10][11][12]
- 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.[9][13]
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.[9]
Transmission
The locations of the body thought to be the source of transmission of Mycobacterium leprae include:
- Skin - studies have shown presence of large amounts of bacteria in the dermis of leprosy patients, however, it is not known if these are able to reach the epidermis in order to be transmitted to other individuals.[1][14] Conflicting reports have been issued on this matter, therefore whether or not the bacteria are able to reach the cell surface, remains uncertain.[15]A study showed presence of these organisms in sebaceous secretions of lepromatous leprosy patients, which leads to the hypothesis that these pathogens may exist the host's body through this manner.[16]
- Nasal mucosa - secretions from the nasal mucosa of lepromatous patients are rich in viable mycobacterium leprae, and may therefore be a source of transmission.[17][1]
The entry route into the human body is also still unknown, however, recent studies point to a predominance of the respiratory route as well.[1][18][19]
Associated Conditions
Leprosy Among Patients with HIV
There is no increased susceptibility to Mycobacterium leprae in HIV patients, nor are the clinical features altered. After initiation of antiretroviral therapy, latent leprosy can become clinically apparent in an HIV patient once the immune response is reestablished.[20][21]
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
- Anhidrosis
- 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.[22] These are thought to be related to changes in the immune system, such as following stressful situations, pregnancy or leprosy medications.[9] 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[23]
- 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 clinical manifestations of leprosy depend on the host's immune response towards the mycobacteria. Therefore, tuberculoid and lepromatous patients will show different histopathologic findings:[1][22][24]
Tuberculoid patients
These patients will show a strong immune response towards the bacteria, with:
- Production of IFN-γ
- Inflammatory infiltrate with multiple granulomas
- Granulomas containing giant cells, differentiated macrophages and epithelioid cells
- Predominance of CD4 cells
- Low bacterial index
- Commonly positive lepromin skin test
Lepromatous patients
These patients will show a weaker immune response, with:
- Weak cell-mediated response
- Absence of granulomas
- Straightened skin
- Predominance of CD8 cells
- High bacterial index
Gallery
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![Case of lepromatous or multibacillary leprosy, with photomicrograph revealing histopathologic changes in human testicular tissue, including a large number of “foam cells”. Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.[25]](/images/8/88/Leprosy-18.jpg)
Case of lepromatous or multibacillary leprosy, with photomicrograph revealing histopathologic changes in human testicular tissue, including a large number of “foam cells”. Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.[25]
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![Acid-fast-stained photomicrograph of tissue sample from a patient with leprosy, revealing chronic inflammatory lesion (granuloma) within which numerous red-colored Mycobacterium leprae bacteria are visible. Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.[25]](/images/f/f1/Leprosy-27.jpg)
Acid-fast-stained photomicrograph of tissue sample from a patient with leprosy, revealing chronic inflammatory lesion (granuloma) within which numerous red-colored Mycobacterium leprae bacteria are visible. Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.[25]
-
![Photomicrograph of a skin tissue sample from patient with leprosy revealing cutaneous nerve, which had been invaded by numerous Mycobacterium leprae bacteria. Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.[25]](/images/7/7a/Leprosy-28.jpg)
Photomicrograph of a skin tissue sample from patient with leprosy revealing cutaneous nerve, which had been invaded by numerous Mycobacterium leprae bacteria. Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.[25]
-
![Photomicrograph of histopathologic changes in skin section extracted from a case of leprosy, possibly tuberculoid form, is uncertain. Note depicted here a nerve, which had been surrounded by dense infiltrate of undifferentiated histiocytes and many lymphocytes. The nerve sheath and endoneural region were also infiltrated. Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.[25]](/images/4/44/Leprosy-30.jpg)
Photomicrograph of histopathologic changes in skin section extracted from a case of leprosy, possibly tuberculoid form, is uncertain. Note depicted here a nerve, which had been surrounded by dense infiltrate of undifferentiated histiocytes and many lymphocytes. The nerve sheath and endoneural region were also infiltrated. Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.[25]
-
![Light photomicrograph revealing histopathologic cytoarchitectural characteristics in a mycobacterial skin infection. Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.[25]](/images/f/f6/Leprosy-34.jpg)
Light photomicrograph revealing histopathologic cytoarchitectural characteristics in a mycobacterial skin infection. Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.[25]
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![Light photomicrograph revealing histopathologic cytoarchitectural characteristics seen in mycobacterial skin infection. Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.[25]](/images/7/79/Leprosy-35.jpg)
Light photomicrograph revealing histopathologic cytoarchitectural characteristics seen in mycobacterial skin infection. Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.[25]
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![Light photomicrograph revealing histopathologic cytoarchitectural characteristics seen in mycobacterial skin infection. Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.[25]](/images/6/60/Leprosy-36.jpg)
Light photomicrograph revealing histopathologic cytoarchitectural characteristics seen in mycobacterial skin infection. Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.[25]
-
![Light photomicrograph revealing histopathologic cytoarchitectural characteristics seen in mycobacterial skin infection. Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.[25]](/images/9/93/Leprosy-37.jpg)
Light photomicrograph revealing histopathologic cytoarchitectural characteristics seen in mycobacterial skin infection. Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.[25]
-
![Light photomicrograph revealing histopathologic cytoarchitectural characteristics seen in mycobacterial skin infection. Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.[25]](/images/b/b5/Leprosy-38.jpg)
Light photomicrograph revealing histopathologic cytoarchitectural characteristics seen in mycobacterial skin infection. Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.[25]
![Case of lepromatous or multibacillary leprosy, with photomicrograph revealing histopathologic changes in human testicular tissue, including a large number of “foam cells”. Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.[25]](/index.php/File:Leprosy-18.jpg)
![Acid-fast-stained photomicrograph of tissue sample from a patient with leprosy, revealing chronic inflammatory lesion (granuloma) within which numerous red-colored Mycobacterium leprae bacteria are visible. Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.[25]](/index.php/File:Leprosy-27.jpg)
![Photomicrograph of a skin tissue sample from patient with leprosy revealing cutaneous nerve, which had been invaded by numerous Mycobacterium leprae bacteria. Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.[25]](/index.php/File:Leprosy-28.jpg)
![Photomicrograph of histopathologic changes in skin section extracted from a case of leprosy, possibly tuberculoid form, is uncertain. Note depicted here a nerve, which had been surrounded by dense infiltrate of undifferentiated histiocytes and many lymphocytes. The nerve sheath and endoneural region were also infiltrated. Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.[25]](/index.php/File:Leprosy-30.jpg)
![Light photomicrograph revealing histopathologic cytoarchitectural characteristics in a mycobacterial skin infection. Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.[25]](/index.php/File:Leprosy-34.jpg)
![Light photomicrograph revealing histopathologic cytoarchitectural characteristics seen in mycobacterial skin infection. Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.[25]](/index.php/File:Leprosy-35.jpg)
![Light photomicrograph revealing histopathologic cytoarchitectural characteristics seen in mycobacterial skin infection. Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.[25]](/index.php/File:Leprosy-36.jpg)
![Light photomicrograph revealing histopathologic cytoarchitectural characteristics seen in mycobacterial skin infection. Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.[25]](/index.php/File:Leprosy-37.jpg)
![Light photomicrograph revealing histopathologic cytoarchitectural characteristics seen in mycobacterial skin infection. Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.[25]](/index.php/File:Leprosy-38.jpg)
References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 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.
- ↑ 9.0 9.1 9.2 9.3 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.
- ↑ Scollard DM, Joyce MP, Gillis TP (2006). "Development of leprosy and type 1 leprosy reactions after treatment with infliximab: a report of 2 cases". Clin Infect Dis. 43 (2): e19–22. doi:10.1086/505222. PMID 16779736.
- ↑ Truman R (2005). "Leprosy in wild armadillos". Lepr Rev. 76 (3): 198–208. PMID 16248207.
- ↑ Valverde CR, Canfield D, Tarara R, Esteves MI, Gormus BJ (1998). "Spontaneous leprosy in a wild-caught cynomolgus macaque". Int J Lepr Other Mycobact Dis. 66 (2): 140–8. PMID 9728446.
- ↑ Gillis T, Vissa V, Matsuoka M, Young S, Richardus JH, Truman R; et al. (2009). "Characterisation of short tandem repeats for genotyping Mycobacterium leprae". Lepr Rev. 80 (3): 250–60. PMID 19994470.
- ↑ Han XY, Sizer KC, Tan HH (2012). "Identification of the leprosy agent Mycobacterium lepromatosis in Singapore". J Drugs Dermatol. 11 (2): 168–72. PMID 22270197.
- ↑ Han XY, Sizer KC, Thompson EJ, Kabanja J, Li J, Hu P; et al. (2009). "Comparative sequence analysis of Mycobacterium leprae and the new leprosy-causing Mycobacterium lepromatosis". J Bacteriol. 191 (19): 6067–74. doi:10.1128/JB.00762-09. PMC 2747882. PMID 19633074.
- ↑ 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.
- ↑ 22.0 22.1 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.
- ↑ 25.0 25.1 25.2 25.3 25.4 25.5 25.6 25.7 25.8 "Public Health Image Library (PHIL), Centers for Disease Control and Prevention".