Leprosy pathophysiology: Difference between revisions

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{{Leprosy}}
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==Overview==
==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 polymorphism]]s such as [[TNF-α]], [[IL-10]], [[IFN-γ]], [[TLR 1]]  have been associated with a greater susceptibility to leprosy as have other genetic markers.


==Pathophysiology==
==Genetics==
The [[infection]] by the [[mycobacterium leprae]] and the course of the [[disease]] are influenced by [[genetic]] factors in the host.<ref name="BhatPrakash2012">{{cite journal|last1=Bhat|first1=Ramesh Marne|last2=Prakash|first2=Chaitra|title=Leprosy: An Overview of Pathophysiology|journal=Interdisciplinary Perspectives on Infectious Diseases|volume=2012|year=2012|pages=1–6|issn=1687-708X|doi=10.1155/2012/181089}}</ref><ref name="pmid18247059">{{cite journal| author=Alter A, Alcaïs A, Abel L, Schurr E| title=Leprosy as a genetic model for susceptibility to common infectious diseases. | journal=Hum Genet | year= 2008 | volume= 123 | issue= 3 | pages= 227-35 | pmid=18247059 | doi=10.1007/s00439-008-0474-z | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18247059  }} </ref> Some [[single-nucleotide polymorphism]] have been associated with a higher [[incidence]] of leprosy. These include:<ref name="BhatPrakash2012">{{cite journal|last1=Bhat|first1=Ramesh Marne|last2=Prakash|first2=Chaitra|title=Leprosy: An Overview of Pathophysiology|journal=Interdisciplinary Perspectives on Infectious Diseases|volume=2012|year=2012|pages=1–6|issn=1687-708X|doi=10.1155/2012/181089}}</ref><ref name="pmid17353895">{{cite journal| author=Alcaïs A, Alter A, Antoni G, Orlova M, Nguyen VT, Singh M et al.| title=Stepwise replication identifies a low-producing lymphotoxin-alpha allele as a major risk factor for early-onset leprosy. | journal=Nat Genet | year= 2007 | volume= 39 | issue= 4 | pages= 517-22 | pmid=17353895 | doi=10.1038/ng2000 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17353895  }} </ref><ref name="pmid12595904">{{cite journal| author=Mira MT, Alcais A, di Pietrantonio T, Thuc NV, Phuong MC, Abel L et al.| title=Segregation of HLA/TNF region is linked to leprosy clinical spectrum in families displaying mixed leprosy subtypes. | journal=Genes Immun | year= 2003 | volume= 4 | issue= 1 | pages= 67-73 | pmid=12595904 | doi=10.1038/sj.gene.6363911 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12595904  }} </ref><ref name="Correa-OliveiraMisch2008">{{cite journal|last1=Correa-Oliveira|first1=Rodrigo|last2=Misch|first2=Elizabeth A.|last3=Macdonald|first3=Murdo|last4=Ranjit|first4=Chaman|last5=Sapkota|first5=Bishwa R.|last6=Wells|first6=Richard D.|last7=Siddiqui|first7=M. Ruby|last8=Kaplan|first8=Gilla|last9=Hawn|first9=Thomas R.|title=Human TLR1 Deficiency Is Associated with Impaired Mycobacterial Signaling and Protection from Leprosy Reversal Reaction|journal=PLoS Neglected Tropical Diseases|volume=2|issue=5|year=2008|pages=e231|issn=1935-2735|doi=10.1371/journal.pntd.0000231}}</ref><ref name="pmid20714752">{{cite journal| author=Cardoso CC, Pereira AC, Brito-de-Souza VN, Dias-Baptista IM, Maniero VC, Venturini J et al.| title=IFNG +874 T>A single nucleotide polymorphism is associated with leprosy among Brazilians. | journal=Hum Genet | year= 2010 | volume= 128 | issue= 5 | pages= 481-90 | pmid=20714752 | doi=10.1007/s00439-010-0872-x | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20714752  }} </ref>
* 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.<ref name="pmid20350193">{{cite journal| author=Berrington WR, Macdonald M, Khadge S, Sapkota BR, Janer M, Hagge DA et al.| title=Common polymorphisms in the NOD2 gene region are associated with leprosy and its reactive states. | journal=J Infect Dis | year= 2010 | volume= 201 | issue= 9 | pages= 1422-35 | pmid=20350193 | doi=10.1086/651559 | pmc=PMC2853728 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20350193  }} </ref>


The exact mechanism of transmission of leprosy is not known: prolonged close contact and transmission by nasal droplet have both been proposed, and, while the latter fits the pattern of disease, both remain unproved.<ref>{{cite journal |author=Reich CV |title=Leprosy: cause, transmission, and a new theory of pathogenesis |journal=Rev. Infect. Dis. |volume=9 |issue=3 |pages=590-4 |year=1987 |pmid=3299638 |doi=}}</ref> The only other animals besides humans to contract leprosy are the armadillo, chimpanzees, sooty mangabeys, and Crab-eating Macaque]].<ref>{{cite journal |author=Rojas-Espinosa O, Løvik M |title=Mycobacterium leprae and Mycobacterium lepraemurium infections in domestic and wild animals |journal=Rev. - Off. Int. Epizoot. |volume=20 |issue=1 |pages=219-51 |year=2001 |pmid=11288514 |doi=}}</ref> The bacterium can also be grown in the laboratory by injection into the footpads of mice.<ref>{{cite journal |author=Hastings RC, Gillis TP, Krahenbuhl JL, Franzblau SG |title=Leprosy |journal=Clin. Microbiol. Rev. |volume=1 |issue=3 |pages=330-48 |year=1988 |pmid=3058299 |url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=3058299}}</ref> There is evidence that not all people who are infected with ''M. leprae'' develop leprosy, and genetic factors have long been thought to play a role, due to the observation of clustering of leprosy around certain families, and the failure to understand why certain individuals develop lepromatous leprosy while others develop other types of leprosy.<ref>{{cite journal |author=Alcaïs A, Mira M, Casanova JL, Schurr E, Abel L |title=Genetic dissection of immunity in leprosy |journal=Curr. Opin. Immunol. |volume=17 |issue=1 |pages=44-8 |year=2005 |pmid=15653309 |doi=10.1016/j.coi.2004.11.006}}</ref> However, the role of genetic factors is not clear in determining this clinical expression. In addition, malnutrition and possible prior exposure to other environmental [[mycobacteria]] may play a role in development of the overt disease.
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 receptor]]s are located on the [[macrophage]]'s surface, they play an important role in [[phagocytosis]].<ref name="pmid20936290">{{cite journal| author=Alter A, Grant A, Abel L, Alcaïs A, Schurr E| title=Leprosy as a genetic disease. | journal=Mamm Genome | year= 2011 | volume= 22 | issue= 1-2 | pages= 19-31 | pmid=20936290 | doi=10.1007/s00335-010-9287-1 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20936290  }} </ref>


The most widely-held belief is that the disease is transmitted by contact between infected persons and healthy persons.<ref>{{cite journal |author=Kaur H, Van Brakel W |title=Dehabilitation of leprosy-affected people--a study on leprosy-affected beggars |journal=Leprosy review |volume=73 |issue=4 |pages=346-55 |year=2002 |pmid=12549842 |doi=}}</ref> In general, closeness of contact is related to the dose of infection, which in turn is related to the occurrence of disease. Of the various situations that promote close contact, contact within the household is the only one that is easily identified, although the actual incidence among contacts and the relative risk for them appear to vary considerably in different studies. In [[Incidence (epidemiology)|incidence studies]], infection rates for contacts of lepromatous leprosy have varied from 6.2 per 1000 per year in Cebu, Philippines<ref name=Doull_1942>{{cite journal | author = Doull JA, Guinto RA, Rodriguez RS, et al. | title = The incidence of leprosy in Cordova and Talisay, Cebu, Philippines | journal = International Journal of Leprosy | year = 1942 | volume = 10 | pages = 107–131 | url= }}</ref> to 55.8 per 1000 per year in a part of Southern India.<ref name=Noordeen_1978>{{cite journal |author=Noordeen S, Neelan P |title=Extended studies on chemoprophylaxis against leprosy |journal=Indian J Med Res |volume=67 |issue= |pages=515-27 |year=1978 |pmid=355134}}</ref>
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.


Two exit routes of ''M. leprae'' from the human body often described are the skin and the nasal mucosa, although their relative importance is not clear. It is true that lepromatous cases show large numbers of organisms deep down in the [[dermis]]. However, whether they reach the skin surface in sufficient numbers is doubtful. Although there are reports of [[Acid-fast|acid-fast bacilli]] being found in the desquamating [[epithelium]] of the skin, Weddell ''et al'' have reported that they could not find any acid-fast bacilli in the [[epidermis]], even after examining a very large number of specimens from patients and contacts.<ref name=Weddell_1963>{{cite journal |author=Weddell G, Palmer E |title=The pathogenesis of leprosy. An experimental approach |journal=Leprosy Review |volume=34 |issue= |pages=57-61 |year=1963 |pmid=13999438}}</ref> In a recent study, Job ''et al'' found fairly large numbers of ''M. leprae'' in the superficial [[keratin]] layer of the skin of lepromatous leprosy patients, suggesting that the organism could exit along with the [[Sebaceous gland|sebaceous]] secretions.<ref name=Job_1999>{{cite journal |author=Job C, Jayakumar J, Aschhoff M |title="Large numbers" of Mycobacterium leprae are discharged from the intact skin of lepromatous patients; a preliminary report |journal=Int J Lepr Other Mycobact Dis |volume=67 |issue=2 |pages=164-7 |year=1999 |pmid=10472371}}</ref>
==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 [[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>


The importance of the [[nasal mucosa]] was recognized as early as 1898 by Schäffer, particularly that of the ulcerated mucosa. <ref name=Schaffer_1898>''Arch Dermato Syphilis'' 1898; 44:159–174</ref> The quantity of bacilli from nasal mucosal lesions in lepromatous leprosy was demonstrated by Shepard as large, with counts ranging from 10,000 to 10,000,000.<ref name=Shepard_1960>{{cite journal |author=Shepard C |title=Acid-fast bacilli in nasal excretions in leprosy, and results of inoculation of mice |journal=Am J Hyg |volume=71 |issue= |pages=147-57 |year=1960 |pmid=14445823}}</ref> Pedley reported that the majority of lepromatous patients showed leprosy bacilli in their nasal secretions as collected through blowing the nose.<ref name=Pedley_1973>{{cite journal |author=Pedley J |title=The nasal mucus in leprosy |journal=Lepr Rev |volume=44 |issue=1 |pages=33-5 |year=1973 |pmid=4584261}}</ref> Davey and Rees  indicated that nasal secretions from lepromatous patients could yield as much as 10 million viable organisms per day.<ref name=Davey_1974>{{cite journal |author=Davey T, Rees R |title=The nasal dicharge in leprosy: clinical and bacteriological aspects |journal=Lepr Rev |volume=45 |issue=2 |pages=121-34 |year=1974 |pmid=4608620}}</ref>
* [[Capsule]] - target of intense humoral immune response (immunoglobulin M-mediated).  


The entry route of ''M. leprae'' into the human body is also not definitely known. The two seriously considered are the skin and the upper respiratory tract. While older research dealt with the skin route, recent research has increasingly favored the respiratory route. Rees and McDougall succeeded in the experimental transmission of leprosy through aerosols containing ''M. leprae'' in immune-suppressed mice, suggesting a similar possibility in humans.<ref name=Rees_1977>{{cite journal |author=Rees R, McDougall A |title=Airborne infection with Mycobacterium leprae in mice |journal=J Med Microbiol |volume=10 |issue=1 |pages=63-8 |year=1977 |pmid=320339}}</ref> Successful results have also been reported on experiments with [[nude mice]] when ''M. leprae'' were introduced into the nasal cavity by topical application. <ref name=Chehl_1985>{{cite journal |author=Chehl S, Job C, Hastings R |title=Transmission of leprosy in nude mice |journal=Am J Trop Med Hyg |volume=34 |issue=6 |pages=1161-6 |year=1985 |pmid=3914846}}</ref> In summary, entry through the respiratory route appears the most probable route, although other routes, particularly broken skin, cannot be ruled out. The CDC notes the following assertion about the transmission of the disease: "''Although the mode of transmission of Hansen's disease remains uncertain, most investigators think that ''M. leprae'' is usually spread from person to person in respiratory droplets''."<ref name=CDC_2005>{{cite web | title = Hansen's Disease (Leprosy) | work = Technical Information | publisher = Centers for Disease Control and Prevention | date = 2005-10-12 | url = http://www.cdc.gov/ncidod/dbmd/diseaseinfo/hansens_t.htm | accessdate = 2007-03-22}}</ref>
* [[Cell wall]] - particularly the ''lipoarabinomannan'', works as an [[antigen]] for the [[macrophages]].


In leprosy both the reference points for measuring the [[incubation period]] and the times of infection and onset of disease are difficult to define; the former because of the lack of adequate immunological tools and the latter because of the disease's slow onset. Even so, several investigators have attempted to measure the incubation period for leprosy. The minimum incubation period reported is as short as a few weeks and this is based on the very occasional occurrence of leprosy among young infants. <ref name=Montestruc_1954>{{cite journal |author=Montestruc E, Berdonneau R |title=2 New cases of leprosy in infants in Martinique. |journal=Bull Soc Pathol Exot Filiales |volume=47 |issue=6 | language = French | pages=781-3 |year=1954 |pmid=14378912}}</ref> The maximum incubation period reported is as long as 30 years, or over, as observed among war veterans known to have been exposed for short periods in endemic areas but otherwise living in non-endemic areas.  It is generally agreed that the average incubation period is between 3 to 5 years.
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.<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="pmid10449784">{{cite journal| author=Shimoji Y, Ng V, Matsumura K, Fischetti VA, Rambukkana A| title=A 21-kDa surface protein of Mycobacterium leprae binds peripheral nerve laminin-2 and mediates Schwann cell invasion. | journal=Proc Natl Acad Sci U S A | year= 1999 | volume= 96 | issue= 17 | pages= 9857-62 | pmid=10449784 | doi= | pmc=PMC22300 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10449784  }} </ref>
 
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]].<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>
 
==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 [[transmission|transmitted]] to other individuals.<ref name="BhatPrakash2012">{{cite journal|last1=Bhat|first1=Ramesh Marne|last2=Prakash|first2=Chaitra|title=Leprosy: An Overview of Pathophysiology|journal=Interdisciplinary Perspectives on Infectious Diseases|volume=2012|year=2012|pages=1–6|issn=1687-708X|doi=10.1155/2012/181089}}</ref><ref name="pmid16779736">{{cite journal| author=Scollard DM, Joyce MP, Gillis TP| title=Development of leprosy and type 1 leprosy reactions after treatment with infliximab: a report of 2 cases. | journal=Clin Infect Dis | year= 2006 | volume= 43 | issue= 2 | pages= e19-22 | pmid=16779736 | doi=10.1086/505222 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16779736  }} </ref> Conflicting reports have been issued on this matter, therefore whether or not the bacteria are able to reach the cell surface, remains uncertain.<ref name="pmid16248207">{{cite journal| author=Truman R| title=Leprosy in wild armadillos. | journal=Lepr Rev | year= 2005 | volume= 76 | issue= 3 | pages= 198-208 | pmid=16248207 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16248207  }} </ref>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.<ref name="pmid9728446">{{cite journal| author=Valverde CR, Canfield D, Tarara R, Esteves MI, Gormus BJ| title=Spontaneous leprosy in a wild-caught cynomolgus macaque. | journal=Int J Lepr Other Mycobact Dis | year= 1998 | volume= 66 | issue= 2 | pages= 140-8 | pmid=9728446 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9728446  }} </ref>
* '''''Nasal mucosa''''' - [[secretions]] from the [[nasal mucosa]] of ''lepromatous patients'' are rich in viable [[mycobacterium leprae]], and may therefore be a source of [[transmission]].<ref name="pmid19994470">{{cite journal| author=Gillis T, Vissa V, Matsuoka M, Young S, Richardus JH, Truman R et al.| title=Characterisation of short tandem repeats for genotyping Mycobacterium leprae. | journal=Lepr Rev | year= 2009 | volume= 80 | issue= 3 | pages= 250-60 | pmid=19994470 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19994470  }} </ref><ref name="BhatPrakash2012">{{cite journal|last1=Bhat|first1=Ramesh Marne|last2=Prakash|first2=Chaitra|title=Leprosy: An Overview of Pathophysiology|journal=Interdisciplinary Perspectives on Infectious Diseases|volume=2012|year=2012|pages=1–6|issn=1687-708X|doi=10.1155/2012/181089}}</ref>
The entry route into the [[human body]] is also still unknown, however, recent studies point to a predominance of the [[respiratory]] route as well.<ref name="BhatPrakash2012">{{cite journal|last1=Bhat|first1=Ramesh Marne|last2=Prakash|first2=Chaitra|title=Leprosy: An Overview of Pathophysiology|journal=Interdisciplinary Perspectives on Infectious Diseases|volume=2012|year=2012|pages=1–6|issn=1687-708X|doi=10.1155/2012/181089}}</ref><ref name="pmid22270197">{{cite journal| author=Han XY, Sizer KC, Tan HH| title=Identification of the leprosy agent Mycobacterium lepromatosis in Singapore. | journal=J Drugs Dermatol | year= 2012 | volume= 11 | issue= 2 | pages= 168-72 | pmid=22270197 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22270197  }} </ref><ref name="pmid19633074">{{cite journal| author=Han XY, Sizer KC, Thompson EJ, Kabanja J, Li J, Hu P et al.| title=Comparative sequence analysis of Mycobacterium leprae and the new leprosy-causing Mycobacterium lepromatosis. | journal=J Bacteriol | year= 2009 | volume= 191 | issue= 19 | pages= 6067-74 | pmid=19633074 | doi=10.1128/JB.00762-09 | pmc=PMC2747882 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19633074  }} </ref>
 
==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.<ref name="WalkerLockwood2007">{{cite journal|last1=Walker|first1=Stephen L.|last2=Lockwood|first2=Dina N.J.|title=Leprosy|journal=Clinics in Dermatology|volume=25|issue=2|year=2007|pages=165–172|issn=0738081X|doi=10.1016/j.clindermatol.2006.05.012}}</ref><ref name="pmid16728321">{{cite journal| author=Ustianowski AP, Lawn SD, Lockwood DN| title=Interactions between HIV infection and leprosy: a paradox. | journal=Lancet Infect Dis | year= 2006 | volume= 6 | issue= 6 | pages= 350-60 | pmid=16728321 | doi=10.1016/S1473-3099(06)70493-5 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16728321  }} </ref>
 
==Gross Pathology==
 
===Type of Leprosy===
 
====Tuberculoid Leprosy====
* May resolve spontaneously
* Well-defined [[macules]]
* [[hypopigmentation|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 [[therapy|treatment]] of leprosy.<ref name="pmid6219136">{{cite journal| author=Modlin RL, Hofman FM, Taylor CR, Rea TH| title=T lymphocyte subsets in the skin lesions of patients with leprosy. | journal=J Am Acad Dermatol | year= 1983 | volume= 8 | issue= 2 | pages= 182-9 | pmid=6219136 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6219136  }} </ref> These are thought to be related to changes in the [[immune system]], such as following stressful situations, [[pregnancy]] or leprosy medications.<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> 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]]<ref name="BalagonGelber2010">{{cite journal|last1=Balagon|first1=M. V. F.|last2=Gelber|first2=R. H.|last3=Abalos|first3=R. M.|last4=Cellona|first4=R. V.|title=Reactions Following Completion of 1 and 2 Year Multidrug Therapy (MDT)|journal=American Journal of Tropical Medicine and Hygiene|volume=83|issue=3|year=2010|pages=637–644|issn=0002-9637|doi=10.4269/ajtmh.2010.09-0586}}</ref>
* 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]]
* [[Ulcer|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:<ref name="BhatPrakash2012">{{cite journal|last1=Bhat|first1=Ramesh Marne|last2=Prakash|first2=Chaitra|title=Leprosy: An Overview of Pathophysiology|journal=Interdisciplinary Perspectives on Infectious Diseases|volume=2012|year=2012|pages=1–6|issn=1687-708X|doi=10.1155/2012/181089}}</ref><ref name="pmid6219136">{{cite journal| author=Modlin RL, Hofman FM, Taylor CR, Rea TH| title=T lymphocyte subsets in the skin lesions of patients with leprosy. | journal=J Am Acad Dermatol | year= 1983 | volume= 8 | issue= 2 | pages= 182-9 | pmid=6219136 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6219136  }} </ref><ref name="pmid6332791">{{cite journal| author=Wallach D, Flageul B, Bach MA, Cottenot F| title=The cellular content of dermal leprous granulomas: an immuno-histological approach. | journal=Int J Lepr Other Mycobact Dis | year= 1984 | volume= 52 | issue= 3 | pages= 318-26 | pmid=6332791 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6332791  }} </ref>
====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 [[macrophage]]s 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 immunity|cell-mediated response]]
* Absence of [[granulomas]]
* Straightened [[skin]]
* Predominance of [[CD8]] [[cells]]
* High [[bacterial]] index
 
==Gallery==
<gallery>
Image: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”. <SMALL><SMALL>''[http://phil.cdc.gov/phil/  Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
 
Image: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. <SMALL><SMALL>''[http://phil.cdc.gov/phil/  Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
 
Image: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. <SMALL><SMALL>''[http://phil.cdc.gov/phil/  Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
 
Image: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. <SMALL><SMALL>''[http://phil.cdc.gov/phil/  Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
 
Image:Leprosy-34.jpg|Light photomicrograph revealing histopathologic cytoarchitectural characteristics in a mycobacterial skin infection. <SMALL><SMALL>''[http://phil.cdc.gov/phil/  Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
 
Image:Leprosy-35.jpg|Light photomicrograph revealing histopathologic cytoarchitectural characteristics seen in mycobacterial skin infection. <SMALL><SMALL>''[http://phil.cdc.gov/phil/  Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
 
Image:Leprosy-36.jpg|Light photomicrograph revealing histopathologic cytoarchitectural characteristics seen in mycobacterial skin infection. <SMALL><SMALL>''[http://phil.cdc.gov/phil/  Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
 
Image:Leprosy-37.jpg|Light photomicrograph revealing histopathologic cytoarchitectural characteristics seen in mycobacterial skin infection. <SMALL><SMALL>''[http://phil.cdc.gov/phil/  Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
 
Image:Leprosy-38.jpg|Light photomicrograph revealing histopathologic cytoarchitectural characteristics seen in mycobacterial skin infection. <SMALL><SMALL>''[http://phil.cdc.gov/phil/ Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
 
</gallery>


==References==
==References==
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[[Category:Disease]]
[[Category:Disease]]
[[Category:Dermatology]]
[[Category:Dermatology]]
[[Category:Infectious disease]]
 
[[Category:Tropical disease]]
[[Category:Tropical disease]]
[[Category:Leprosy]]
[[Category:Infectious skin diseases]]
[[Category:Bacterial diseases]]
[[Category:Neglected diseases]]

Latest revision as of 18:10, 18 September 2017

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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]

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).

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

Lepromatous Leprosy

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)

Type 2 (T2R) or Erythema Nodosum Leprosum (ENL)

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:

Lepromatous patients

These patients will show a weaker immune response, with:

Gallery

References

  1. ↑ 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.
  2. ↑ 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.
  3. ↑ 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.
  4. ↑ 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.
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ 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. ↑ 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.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ Truman R (2005). "Leprosy in wild armadillos". Lepr Rev. 76 (3): 198–208. PMID 16248207.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ 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.
  19. ↑ 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.
  20. ↑ 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.
  21. ↑ 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. ↑ 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.
  23. ↑ 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.
  24. ↑ 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. ↑ 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".


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