User:V1scerale1shman1asis

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Protective immunity[edit]

Immunity to Leishmania is determined by the interplay of white blood cells, cytokines, immune complexes, and genetic and environmental factors. [1] Protective immunity develops either after successful treatment of VL (cured) or after asymptomatic infections that resolve without development of VL (asymptomatic). [2] [3] Both types of immunity are characterized by cell-mediated immunity (CMI), including skin test positivity, proliferation, and interleukin 2 (IL-2), interferon gamma (IFN-γ), and interleukin 12 (IL-12) secretion by peripheral blood mononuclear cells (PBMC) in response to leishmania antigens. [4] [5] [6][7] [8] T cells isolated from both cured and asymptomatic PBMC activate autologous macrophages to kill intracellular amastigotes. [9] IFN-γ activates macrophages to kill intracellular parasites so its role in VL has been studied extensively and IFN-γ production is often used as a marker of protective immunity. Cured PBMC generally secrete less IFN-γ and and more interleukin 10 (IL-10) in response to leishmania antigens than asymptomatic PBMC.[10] IL-12 is important in the development and maintenance of Type 1 T helper cell responses and protective immunity so its role in VL has also been studied. Addition of IL-12 to some VL PBMC increases proliferation and IFN-γ secretion in response to leishmania antigens and anti-IL-12 inhibits proliferation and IFN-γ secretion by some cured PBMC. [11] [12] [8] [13] Other cytokines also appear to be important in immunity to Leishmania but their roles are not as well characterized.

Leishmania antigen stimulation of PBMC from cured patients show a mixed T helper cell and regulatory T cell response. [14] Both CD4+ and CD8+ T cells contributed to IFN-γ production. [15] [16] Studies of leishmania antigen specific T cell clones from cured patient PBMC confirm that cured patients have a mixed T cell response that involves both CD4+ helper T cells and CD4+ and CD8+ regulatory T cells. [17] [18] [19] Two studies of asymptomatic T cell clones show that most have Type 1 profiles and secrete more IFN-γ than T cell clones from cured patients. Neither study revealed the presence of Type 2 or regulatory T cells. [10] [18] Some clones secreted soluble factors that caused the death of CD8+ regulatory T cells but not CD4+ T cells from VL patients, which might explain the strong protective immunity of asymptomatic patients. [12]

Non-protective immunity[edit]

VL patients are unable to clear their infections because they lack CMI. This anergy may be limited to leishmania antigens or extend to mitogens and other antigens as the disease progresses. [20] In addition to skin test negativity, VL patient PBMC do not proliferate or secrete IL-2 or IFN-γ in response to leishmania antigens. [4] [21] [5] Memory T cells maybe depleted in VL patient PBMC. [22] [23] Since IL-10 is known to suppress innate and acquired immunity and prevent IFN-γ from activating macrophages, its role in VL has been studied extensively and elevated IL-10 production is often used as a marker of non-protective immunity in VL. Elevated levels of IL-10 in the plasma, infected tissues, and PBMC of VL patients accompany the anergy of VL. [10] [24] [25] [26] [22] [27] PKDL patients also have elevated IL-10 levels.[28] VL patients with the highest IL-10 levels are more likely to be unresponsive to treatment and progress to PKDL. [29] [30] PBMC secretion of IL-10 without the addition of leishmania antigen (endogenous) is inversely correlated with antigen specific IFN-γ secretion but leishmania antigen specific IL-10 and IFN-γ secretion are not correlated, suggesting that endogenous secretion is more important in pathology. [19] Addition of anti-IL-10 increases proliferation and IFN-γ secretion by PBMC from some patients. [7][12] Both CD4+ and CD8+ T cells have been shown to contribute to IL-10 secretion by VL PBMC. [31] [15] The high level of immune complexes characteristic of VL have also been shown to increase IL-10 levels. [32]

Regulatory T and B cells in visceral leishmaniasis[edit]

The CMI that kills Leishmania also produces inflammation. If the inflammation is excessive, it can cause tissue damage. The role of regulatory T and regulatory B cells is to suppress CMI enough to prevent tissue damage. [33] [34] However, an excessive regulatory response can prevent clearance of Leishmania and could explain the anergy of VL, poor response to drug treatment, development of PKDL, and relapses. A role for regulatory cells in VL has long been suspected. [35] A variety of regulatory T and B cells have been implicated in VL, including Type 1 T helper cells that secrete IL-10 in addition to IFN-γ, natural T reg, Tr1, CD8+ T reg, and B reg. All of these lymphocytes act, at least in part, by secreting IL-10 and other suppressive cytokines.

CD4+ T regs are present at increased frequency in the bone marrow of VL patients, are one source of IL-10, and proliferate in response to leishmania antigen. [30] Levels of FoxP3 mRNA were also up-regulated in lesional tissue from PKDL patients.[28] However, T regs are not elevated in spleen cells from VL patients nor does depletion of T regs increase leishmania antigen specific IFN-γ secretion [36] The highest levels of IL-10 mRNA in spleen cells is in CD8+ and other non-FoxP3+ T cells. [16]. White blood cell CD8+ T cells from VL patients have elevated IL-10 levels. [31] There is a 9.6 fold increase in IL-10 expressing CD8+ T cells among PBMC lymphocytes from PKDL patients. [28] In the one study of T cell clones from VL patients, the clones isolated from VL PBMC were 100% CD8+. [10] When mixed with self PBMC one or three years after successful treatment the CD8+ T cells decreased leishmania antigen specific proliferation and IFN-γ secretion and increased IL-10 secretion. Depletion of CD8+ T cells from VL PBMC stopped endogenous IL-10 secretion but increased leishmania antigen specific IL-10 secretion, suggesting that CD8+ regulatory T cells are responsible for endogenous IL-10 secretion. [19] CD4+ clones could only be isolated from VL PBMC after CD8+ T cell depletion. The CD4+ clones had little effect on IL-10 secretion but decreased IFN-γ secretion when mixed with self PBMC collected after successful treatment.

Regulatory B cells are known to favor development of regulatory T cells and suppress development of Type 1 T helper cells by producing IL-10 and other down-regulatory cytokines. [34] IL-10 levels are elevated in B cells from VL PBMC. [31] A study of dogs with naturally acquired VL showed that the percentage of regulatory B cells increased three-fold during VL. [37] Depletion of B cells increased CD4+ T cell proliferation and IFN-γ secretion but decreased IL-10 secretion. Blocking IL-10 or programmed cell death receptors on B cells increased leishmania antigen specific T cell proliferation and IFN-γ secretion. Co-culture of T cells with B cells decreased the percentage of CD4+ T cell proliferation and IFN-γ secretion four-fold.

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