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Mycobacterium leprae

Intracellular pathogen Recognized by the innate immune system PAMP = lipoarabinomannan

The Contained form


known as tuberculoid leprosy The body mounts only a "Cell Mediated Immunity" (CMI) response activated only by T cells This most recognizable symptom of the contained form is the formation of Granulomas

The Aggressive form


known as "lepromatous leprosy The body mounts only a "Humoral" response activated only by B cells Common symptoms of the aggressive forms of mycobacterioses are perforation, fistulisation of the infected organs and abscess formation

Immunological Spectrum of Leprosy

nave CD4 T cells

Th1
cellular immunity

Th0

Th2
humoral immunity

Tuberculoid leprosy Granuloma formation Tissue damage may ensue

Lepromatous leprosy Persistence of M. leprae Disfiguring disorder

Immunology of leprosy
Mycobacterium leprae probably enters the body via the nose and then spreads to the skin and nerves via the circulation. The immunological response mounted by the host dictates the clinical phenotype that develops:
Tuberculoid disease is the result of high cell-mediated immunity with a largely Th1 type immune response. Lepromatous leprosy however is characterized by low cell-mediated immunity with a humoral Th2 response.

The highly conserved Toll-like receptors (TLRs) on the surface of monocytes and macrophages recognize mycobacterial lipoproteins
takes place mainly through the TLR2/1 heterodimer and leads to monocyte differentiation into macrophages and dendritic cells. The latter presents antigen and causes the activation of nave T cells by IL-12 secretion. The IL-12R2 portion of the IL-12 receptor is expressed more on Th1 lymphocytes preferentially shifting the immune response further towards a Th1 response.

Immunology of leprosy
TLR stimulation also activates the nuclear transcription factor NF-B, which modulates the transcription of many immune response genes . In tuberculoid disease, interferon (IFN)-, IL-2 and lymphotoxin- are secreted in lesions and these result in intense phagocytic activity. Macrophages under the influence of cytokines, particularly TNF together with lymphocytes, form granulomas. CD4+ cells are found mainly within the granuloma and CD8+ cells in the mantle area surrounding it. T cells in tuberculoid granulomas produce the antimicrobial protein granulysin. Lepromatous disease is characterized by poor granuloma formation. mRNA production is predominantly for cytokines IL-4, IL-5 and IL-10. IL-4 has been shown to downregulate TLR2 on monocytes,and IL-10 will suppress production of IL-12.

Immunology of leprosy
Innate immune response
Initial responses in Macrophages and dendritic cells:
TLR-2 mediates NFkB, and TNF secretion, and binds to the M. leprae and M. tuberculosis wall. Some researchers think that the effective functioning of TLR-2 is necessary to the development of the less severe tuberculoid leprosy, in contrast to a systemic lepromatous disease manifestation. In lepromatous leprosy, these studies have shown that a significant number of patients have a defective TLR-2 receptor, which then prohibits any cellular immune response from starting. Such a lack of cellular immunity apparently causes the M. leprae bacterium to proliferate much more efficiently in the human body. TLR-4 may also play a role in M. leprae binding, but to what extent, researchers are not sure. The presence of CD14 on the APC surface increases cell mediated responses to M. leprae up to two-fold, but is not necessary for the initiation of the signaling cascade. Studies also show that in lepromatous leprosy, cytokines and chemokines are not released by macrophages - and neither are MHC-I or II significantly expressed. In fact, this inhibition of chemical release may serve instead to enhance bacterial growth. When macrophages (or dendritic cells) do get activated by infection with M. leprae, a number of receptors and inflammatory molecules are upregulated. The interleukins IL-1, IL-2 IL-12, and IL18 (which acts on both NK and T-cells) are expressed. TNF-alpha is secreted in order to activate NK cells. M. leprae induces apoptosis in macrophages in a dose-dependent manner. Apparently, this is correlated with high levels of TNF-alpha, as well as various apoptotic receptors. It is thought that this apoptosis helps to inhibit bacterial proliferation of the mycobacterium since mycobacteria are not efficient at replicating outside of the cell. In fact, researchers claim that this may be one of the main differences between tuberculoid and lepromatous leprosy - this initial clearing of bacterial load through macrophage apoptosis .

Immunology of leprosy
Innate immune response
Initial responses in Macrophages and dendritic cells:
The cell membrane of M. leprae is highly antigenic, and dendritic cells recognize it readily. Upon recognition, the dendritic cells produce IL-12. MMP II is a protein on the surface of M. leprae that stimulates expression of HLA-ABC, HLA-DR, CD86, and CD83 antigens in dendritic cells, and also induces maturation. All of this indicates that MMP-II is the protein on M. leprae that binds to TLR-2 on the APC surface. Studies also show that the expression of CD1 by dendritic cells is also critical to the activation of T-cells in the later adaptive immune response of the body. The deal is, CD8+ cells are critical to defeating M. leprae once infection has happened. The CD8+ cells go around and kill any M. leprae bacteria they can find using perforin and granulysin. This is great because they are quite efficient at getting rid of the bacteria that are killing the macrophages. However, the T-cells must first be activated and that is often done by dendritic cells. So far, dendritic cells presenting CD1+, CD83+, and the CD40 ligand have been found in areas of M. leprae infection, indicating that they do, in fact, play a significant role in activating T-cell immunity. So far, it is difficult to determine how effective dendritic cells are at activating T-cells specifically during M. lepraeinfection. Studies have shown that infection with M. leprae downregulates the presentation of both MHC-I and II on the surface of dendritic cells, in addition to a lack of significant upregulation of either CD83+ or IFN-gamma.

Immunology of leprosy
Innate immune response
Initial Responses in neutrophils and NK cells:
Both neutrophils and NK cells are very important in inducing further immune response after infection with M. leprae . NK cells are required to induce IFNgamma production, which further activates macrophages and dendritic cells. NK cells then help to activate T-cells and promote the differentiation of Th1 cells - a vital part of the defense system against M. leprae infection. The activity of NK cells at the site of infection is generally used as a determinant of how successful host defense is, as they serve to both kill infected cells and also heavily activate other members of both the innate and adaptive immune system. NK cells also secrete IL-13, though in smaller amounts compared to T-cells. This is interesting, because IL-13 is a known cytokine inhibitor, and generally stops any further IFNgamma production - and therefore essentially stops the inflammatory process.

Immunology of leprosy
Humoral immune response
Humoral immunity involves the interaction of circulating antibodies in blood serum in addition to the actions of B-cells as activated by Th2-cytokine profiled T-cells. In other words, humoral immunity involves the adaptive portion of the immune system response that which takes a period of days to take effect after infection has begun.

Immunology of leprosy
Humoral immune response
Activation of B-cells:
B-cells are only significantly activated during the immune response by the cytokines produced by Th2 T-cells: specifically, IL-4, Il-5, and Il-10 . Furthermore, a Th2-predominant T-cell response implies an ineffectual immune response to the pathogen and results in a severe, often fatal form of leprosy: lepromatous leprosy. This is likely because of the mycobacteriums unique lifecycle that requires it to replicate inside host cells instead of free in tissue or blood. Having to replicate inside of cells prevents much recognition of the bacterial cell wall and limits any recognition of infection to somatic cell presentation of bacterial epitopes on MHC-I.

Immunology of leprosy
Humoral immune response
Interaction of B-cells and M. leprae:
There is not much information on M. lepraes interaction with B-cells. It does seem clear, however, that in the specific case of M. leprae, B-cell activation does not play a significant role in clearing the bacteria from the body. As evidenced, IgG and IgM blood serum levels are high during lepromatous leprosy infection, while the immunoglobulin levels are anywhere from high to undetectable levels during tuberculoid leprosy infection, depending on the activity of the disease in the specific patient. In general, however, this study found that patients with lepromatous leprosy had a stronger IgG and IgM response than patients with tuberculoid leprosy. This trend is indicative of an unnecessary antibody response, given that the milder tuberculoid leprosy causes a wide range of reactions, including no immunoglobulin secreted at all. During infection of M. avium (a mycobacterium related to M. leprae which infects the gastrointestinal tract of cattle), an increasing humoral immune response to the pathogen is paired with higher bacterial shedding in the feces and eventually death. Researchers further posit that this trend found in M. avium can be applied to similar mycobacterial infections. Infection with M. avium proved to both lower antigen-specific B-cell levels and also to raise unspecific, circulating peripheral B-cells (4). These seemingly contradictory conclusions have not yet been fully described, and their role in promoting further infection by mycobacteria are not understood.

Immunology of leprosy
Humoral immune response
Cellular response:
Cell mediated immunity is the part of the immune response that involves actions of macrophages, natural killer (NK) cells, activated killer T cells (CD8+), and the actions of various cytokines. Cell mediated immunity is extremely important during the infection process of M. leprae due to the inability of B-cells to mount a useful immune response to pathogen.

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