Murine visceral leishmaniasis: IgM and polyclonal B‐cell activation lead to disease exacerbation

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Abstract
In visceral leishmaniasis, the draining LN (DLN) is the initial site for colonization and establishment of infection after intradermal transmission by the sand fly vector; however, little is known about the developing immune response within this site. Using an intradermal infection model, which allows for parasite visceralization, we have examined the ongoing immune responses in the DLN of BALB/c mice infected with Leishmania infantum. Although not unexpected, at early times post‐infection there is a marked B‐cell expansion in the DLN, which persists throughout infection. However, the characteristics of this response were of interest; as early as day 7 post‐infection, polyclonal antibodies (TNP, OVA, chromatin) were observed and the levels appeared comparable to the specific anti‐leishmania response. Although B‐cell‐deficient JhD BALB/c mice are relatively resistant to infection, neither B‐cell‐derived IL‐10 nor B‐cell antigen presentation appear to be primarily responsible for the elevated parasitemia. However, passive transfer and reconstitution of JhD BALB/c with secretory immunoglobulins, (IgM or IgG; specific or non‐specific immune complexes) results in increased susceptibility to L. infantum infection. Further, JhD BALB/c mice transgenetically reconstituted to secrete IgM demonstrated exacerbated disease in comparison to WT BALB/c mice as early as 2 days post‐infection. Evidence suggests that complement activation (generation of C5a) and signaling via the C5a receptor (CD88) is related to the disease exacerbation caused by IgM rather than cytokine levels (IL‐10 or IFN‐γ). Overall these studies indicate that polyclonal B‐cell activation, which is known to be associated with human visceral leishmaniasis, is an early and intrinsic characteristic of disease and may represent a target for therapeutic intervention.
Funding Information
  • NIH grants (AI45044, AI27811, GM-62134, AI-068730, AI-43603)
  • NIH Training Grant (T32 AI07404)
  • Fort Dodge Animal Health

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