Leishmaniasis and The Immune System

In order to develop a successful parasitic relationship with its host, the leishmania must evade both the innate and adaptive immune responses. When leishmania first enters the human body, it is in the promastigote form. Promastigotes are engulfed by macrophages but are resistant to proteolysis and degradation in the phagosome. Once inside the macrophage, the organism is termed an amastigote. By continuing to live inside the macrophage, leishmania effectively avoids the humoral branch of the immune system. During each of the steps described, the protozoa evade and at times manipulate the human immune system and avoid digestion.

Opsonization and Phagocytosis

The complement protein C3b is one of the most potent immune opsonins. C3b binds to foreign material and promotes its uptake, via C3b receptors on phagocytic cells. As expected, C3b binds to the leishmania protozoa. This results in uptake by the macrophage. The leishmania have a special surface glycoprotein, called gp63, which converts C3b into iC3b. This is favorable from the microrganism's standpoint because this conversion would favor phagocytic clearance rather than lytic clearance. As stated earlier, Leishmania are very resistance to degradation once phagocytosed. Therefore this conversion makes sense in terms of leishmania's survival. Another interesting point is that iC3b may also promote phagocytosis by B cells. Because opsonin-mediated phagocytosis is a non antigen-specific phenomenon, it would result in a humoral response against irrelevant epitopes which, as explained later, is ineffective against leishmania.

After being engulfed, the leishmania must endure harsh conditions inside the phagosome. For example, the macrophage uses an oxidative burst to destroy foreign material in the phagosome. This process consists of an attack by superoxide and hydroxyl radicals on the parasite. Leishmania produces acid phosphatases on its surface which inhibit this burst. In addition to the oxidative burst, macrophages often attempt to degrade parasites with acidic enzymes. This occurs when lysosomes fuse with the phagosome. The protozoa is resistant to this attack as well because it has a proton pump in the surface which allows its intracellular pH to remain close to neutral. Also, the protozoan molecule lipophosphoglycan (LPG) plays an active role by inhibiting lysosomal enzymes. (Immunity to Leishmaniasis Webpage)

Cellular and Humoral Immunity in Leishmaniasis

Because Leishmania manipulates the complement system in order to expedite phagocytosis, humoral immunity is largely ineffective against the organism. This has been proven in many experiments. For example, the course of the infection is unaltered in animals that have been depleted of B-cells. Thus, the current reasoning is that cell mediated immunity is critical in producing immunity to Leishmania.

This idea was further explored in Reiner and Locksley's seminal experiments in the 80's. In a key experiment, they showed that athymic mice developed Leishmaniasis whereas control mice did not. Thus, Reiner and Locksley proved that immunity to the disease was regulated by T cells.

A further set of experiments were key not only in furthering knowledge about the disease but also resulted in the development of the TH1/TH2 paradigm of immunity. showed that various strains of mice differed in their susceptibility to the disease. For example, C57/BL6 mice recovered after a L. major challenge, whereas Balb/C mice did not. Cytokine studies showed that the serum from the resistant C57/BL6 mice contained high levels of Interferon Gamma and IL-2, but low levels of IL-4 and IL-10. Conversely, the susceptible BALB/C mice had low levels of Interferon Gamma and IL-2, but high levels of IL-4 and IL-10. (Locksley, 1991)

In further studies it was clearly demonstrated that these cytokines are responsible for biasing the nature of the immune response. The authors found that treating a BALB/C susceptible mouse with anti-IL-4 after infection with Leishmaniasis results in recovery. Therefore, inhibiting IL-4 leads to clearing of the pathogen. Resistant C57/BL6 mice were treated with anti-Interferon Gamma after infection with Leishmaniasis and then died. Therefore, Interferon Gamma is essential in eliminating Leishmania. These studies suggested that IL-2 and Interferon Gamma are key cytokines in directing an immune response toward intracellular pathogens. Conversely, IL-4 and IL-10 gear the immune response toward the clearance of extracellular pathogens. Further experiments with this model led to further developments of the TH1/TH2 paradigm. (Reiner, 1995)

References:
University of East London: Leishmaniasis and the immune system http://www.uel.ac.uk/pers/2738m/tim4.htm

Immunity to Leishmaniasis http://www.icp.ucl.ac.be/~opperd/parasites/

How Leishmaniasis Fools the Immune System http://www.cnrs.fr/Cnrspresse/en31a1.html

Neuroimmune Interactions in Cutaneous Leishmaniasis http://diss.kib.ki.se/1998/19980925ahme.cfm

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