Leprosy pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]

Overview[edit | edit source]

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[edit | edit source]

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[edit | edit source]

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[edit | edit source]

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[edit | edit source]

Leprosy Among Patients with HIV[edit | edit source]

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[edit | edit source]

Type of Leprosy[edit | edit source]

Tuberculoid Leprosy[edit | edit source]

• 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[edit | edit source]

• Papules and nodules, usually bilateral, symmetrical with ovoid shape
• Leonine facies
• Severe nerve involvement

Immunologic Reactions[edit | edit source]

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)[edit | edit source]

• 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)[edit | edit source]

• 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[edit | edit source]

Histopathology[edit | edit source]

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[edit | edit source]

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[edit | edit source]

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[edit | edit source]

• 

  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]

• 

  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]

• 

  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]

• 

  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]

• 

  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]

References[edit | edit source]

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