Leishmaniasis is a spectrum of diseases ranging in severity from cutaneous (CL), post-kala-azar dermal (PKDL), and diffuse cutaneous (DCL) to mucocutaneous (MCL) and visceral (VL) infections that are endemic in 86 tropical and subtropical countries around the world, accounting for 75,000 deaths per year. Different forms of leishmaniases are generally caused by different distinct species of Leishmania having a digenetic life cycle alternating between an aflagellated amastigote form replicative within the macrophages of the host and a flagellated promastigote form that multiplies within the gut of the sandfly. VL, MCL, PKDL, DCL, and CL forms of the disease can be arranged on a priority basis in accordance with the humoral immune responses of host. Generally, the cell-mediated immunity, particularly the delayed-type hypersensitivity to leishmanial antigens, is associated with CL, MCL, PKDL, and cured VL cases. The serodiagnosis of leishmaniasis appears to be an alternative to parasite detection in b...

Serodiagnosis of Leishmaniasis

Chagas' disease is a major health problem in Latin America, where it constitutes one of the leading causes of heart failure. About one fourth of Trypanosoma cruzi-infected individuals develop chronic chagasic cardiomyopathy (CChC), the most severe form of the disease. CChC is histologically characterized by the presence of multifocal inflammatory infiltrates in the heart, composed mainly by mononuclear cells, usually adhered to myocytes and leading to myocytolysis, and frequently by interstitial fibrosis. The pathogenesis of CChC is still unclear, despite intense investigations both in human beings and in animal models of the disease. Although tissue parasitism is rare in the chronic phase of infection, an immune response targeted to persistent parasites or parasite antigens is suggested, by some authors, as the pathogenic mechanism of CChC. Other researchers affirm that the lack of correlation between tissue parasitism and intensity of inflammation suggests, along with the presence of autoreactive immune responses, that CChC results from the action of an autoimmune response. Herein we review reports from the literature and our own data, which together indicate, on one hand, the participation of parasite-specific immune responses and, on the other hand, clearly demonstrate the participation of heart-specific immune responses in the pathogenesis of CChC. Moreover, multiple factors may determine whether an individual in the indeterminate form of the disease will develop CChC. The mechanisms by which T. cruzi breaks immunological tolerance to heart antigens are also discussed.

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The pathogenesis of Chagas' disease: when autoimmune and parasite-specific immune responses meet

Post-kala-azar dermal leishmaniasis (PKDL) is a common complication of visceral leishmaniasis (VL) caused by Leishmania donovani. Because of its possible role in transmission it is considered a public health problem in VL endemic areas. The clinical features include a skin rash consisting of macules, papules or nodules in an otherwise healthy individual; this presentation is determined by the immune response towards parasites in the skin that probably persisted from the previous VL episode. The immune response in VL, cured VL and PKDL is the result of changes in the cytokine profile that only in part can be captured under the Th1 and Th2 dichotomy. Regulatory T cells and Th 17 cells also play a role. VL is characterized by an absent immune response to Leishmania with a predominantly Th2 type of response with high levels of IL-10; after successful treatment the patient will be immune with in vitro features of a Th1 type of response and in vivo a positive leishmanin skin test. PKDL takes an intermediate position with a dissociation of the immune response between the skin and the viscera, with a Th2 and Th1 type of response, respectively. It is likely that immune responses determine the different epidemiological and clinical characteristics of PKDL in Asia and Africa; various risk factors for PKDL may influence this, such as incomplete and inadequate treatment of VL, parasite resistance and genetic factors. It should be noted that PKDL is a heterogeneous and dynamic condition and patients differ with regard to time of onset after visceral leishmaniasis (VL), chronicity, extent and appearance of the rash including related immune responses, all of which may vary over time. Better understanding of these immune responses may offer opportunities for manipulation including combined chemotherapy and immunotherapy for VL to prevent PKDL from occurring and similarly in the treatment of chronic or treatment resistant PKDL cases.

/pdf/the-immunology-of-post-kala-azar-dermal-leishmaniasis-pkdl-42tuvuu6j4.pdf

The immunology of post-kala-azar dermal leishmaniasis (PKDL)

A Trypanosoma cruzi lambda gt11 cDNA clone, JL5, expressed a recombinant protein which was found to react predominantly with chronic Chagas' heart disease sera. The cloned 35-residue-long peptide was identified as the carboxyl-terminal portion of a T. cruzi ribosomal P protein. The JL5 13 carboxyl-terminal residues shared a high degree of homology with the systemic lupus erythematosus (SLE) ribosomal P protein epitope. Synthetic peptides comprising the 13 (R-13), 10 (R-10), and 7 (R-7) carboxyl-terminal residues of the JL5 protein were used to study, by enzyme-linked immunosorbent assay, the specificity of the Chagas' disease anti-JL5 and SLE anti-P antibodies. The R-13 peptide defined a linear antigenic determinant of the JL5 recombinant protein. As was proved for JL5, R-13 defined antibody specificities which were significantly increased in chronic Chagas' heart disease patients. Only SLE anti-P positive sera were found to react with JL5 and R-13. Fine epitope mapping showed that Chagas' disease anti-JL5 and SLE anti-P antibodies define similar epitopes within the R-13 peptide. The binding of the SLE sera to JL5 was completely blocked by the R-13 peptide, indicating that the shared specificity between anti-JL5 and anti-P autoantibodies was exclusively limited to the conserved linear epitope(s) within the R-13 peptide. The prevalence of high anti-R-13 antibody titers in Chagas' heart disease patients supports the hypothesis that postulates the existence of autoimmune disorders in Chagas' heart disease.

Major Trypanosoma cruzi antigenic determinant in Chagas' heart disease shares homology with the systemic lupus erythematosus ribosomal P protein epitope.

We have recently characterized a novel Leishmania major gene encoding a polypeptide of 30 kDa that was homologous to mammalian ribosomal protein S3a and was named LmS3a-related protein (LmS3arp). The protein was found to be expressed by all the Leishmania species so far examined (L. infantum, L. amazonensis, and L. mexicana). In the present study we have extended our approach to the analysis of LmS3arp activity on T- and B-cell functions in a murine model. The results presented in this report show that LmS3arp plays a dual role in the regulation of T- and B-cell reactivity. Indeed, we found that injection of the LmS3arp recombinant protein (rLmS3arp) into BALB/c mice induces preferential activation of B cells, as shown by the following criteria: (i) increased expression of CD69 molecules on immunoglobulin M (IgM)-secreting spleen cells, (ii) a considerable increase of IgM-secreting B cells, and (iii) elevated levels of IgM antibodies in the sera of injected animals. Moreover, the IgM antibodies are not specific to the Leishmania antigens but preferentially recognize heterologous antigens like myosin, thyroglobulin, DNA, and keyhole limpet hemocyanin. Furthermore, the strong polyclonal expansion of nonspecific, non-parasite-directed B-cell clones induced by rLmS3arp is concomitant with a marked inhibition of T-cell proliferation. Analysis of cytokine production revealed a significant downregulation of gamma interferon, interleukin-2 (IL-2), and IL-12 secretion. Taken together, our data suggest that rLmS3arp, through direct or indirect action toward B and T cells and cytokine secretion, could participate in the immunoregulatory processes that play a role in the balance of the Th1 and Th2 immune response.

https://iai.asm.org/content/iai/69/11/6588.full.pdf

Dual role of the Leishmania major ribosomal protein S3a homologue in regulation of T- and B-cell activation.

Sera from 29 patients with visceral leishmaniasis and 14 patients with cutaneous leishmaniasis were tested against a panel of nine nuclear antigens employing an enzyme-linked immunosorbent assay (ELISA). Anti- Sm, RNP, SS-A and SS-B antibodies were present in high titres in 83, 86, 36 and 73 per cent of the patients with visceral leishmaniasis and in 7, 14, 25 and 25 per cent of the patients with cutaneous leishmaniasis. One serum from a patient with visceral leishmaniasis which reacted strongly with Sm, RNP, SS-A and SS-B was examined by immunoblotting on extractable nuclear antigen from Hela cells. This serum binds to nine different antigenic bands (16, 23, 29, 30, 40, 50, 58, 100 and 115 kD). These same antigens were recognized by serum from a patient with systemic lupus erythematosus. The binding of visceral leishmaniasis serum antibodies to ribonucleoproteins was inhibited by prior incubation of serum with either leishmanial membrane antigens, from four different species of Leishmania, or intact cells of Leishmania donovani, implying molecular resemblance between common leishmanial antigens and ribonuclear antigens. It seems that appearance of autoantibodies to ribonucleoproteins in sera of patients infected with Leishmania is not only due to simply polyclonal activation of lymphocytes, but is also the result of a molecular mimicry between leishmanial antigens and ribonucleoproteins.

C L Jaffe

Papers

Autoantibody production by patients infected with Leishmania.