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Abstract
Leishmania infantum is a causative agent of a disseminating disease known as visceral leishmaniasis, responsible for considerable worldwide morbidity and mortality. The parasite has a tropism for the liver and lymphoid organs. Immune responses to Leishmania infantum are organ-specific; parasites may clear from the liver, but persist in the bone marrow, spleen, and lymph nodes. The lymph node is the first site where Leishmania infantum parasites colonize and thrive after intradermal transmission by an infected sand fly vector. Immune responses occurring in the lymph node could potentially determine visceralization. An understanding of these events is therefore critical to our understanding of the disease. However, few studies have looked at this organ as a prime site for host-parasite interactions in visceral leishmaniasis. This dissertation examines the immune response to Leishmania infantum infection in the draining lymph nodes. In particular, it explores the marked early and persistent polyclonal B cell expansion that occurs in the draining lymph node of BALB/c mice infected intradermally with L. infantum. The role that B cells play in visceral leishmania pathogenesis was explored. BALB/c B cell deficient mice were determined to be relatively resistant to infection in comparison to wild-type mice. Neither B cell IL-10 nor B cell antigen presentation was found to be involved in L. infantum pathogenesis. However, the presence of secretory immunoglobulins, IgG and IgM, specific and non-specific, increased susceptibility to L. infantum infection. Observations were made in regards to involvement of immune complexes and cellular recruitment, implicating complement-mediation. Treatment with a cyclic peptide antagonist to the C5a receptor reversed the increased susceptibility due to the presence of antibody, indicating a role for complement and possibly cell recruitment in disease pathogenesis. These findings establish an intrinsic and early induction of B cell activation associated with visceral leishmania infection, and a critical role for C5a in immunoglobulin mediated susceptibility to visceral leishmaniasis.
