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

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 J h D 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 J h D BALB/c with secretory immunoglobulins, (IgM or IgG; specific or non-specific immune complexes) results in increased susceptibility to L. infantum infection. Further, J h D 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-c). 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.Key words: Antibody . C5a . Parasitic protozoan IntroductionVisceral leishmaniasis (VL) is a potentially fatal human disease caused by the intracellular protozoan parasites Leishmania donovani and L. infantum/L. chagasi. The immune response to VL is complex and has been shown to be organ-specific, differing significantly dependent upon the site of infection examined (liver versus spleen) [1,2]. Although the lymph node is thought to be analogous to the spleen, there are considerable developmental as well as structural and functional differences [3,4]. Reflective of this is the fact that although both spleens and lymph nodes from fatal human cases of VL exhibit destruction of normal architecture, follicular DC (FDC) and GC are lost in spleens, while continuing to be present in lymph nodes [5]. However, few Eur. J. Immunol. 2010. 40: 1355-1368 DOI 10.1002 Immunity to infection 1355 experimental studies to date have examined the lymph node responses that occur as a result of infection and have instead focused on the spleen where, akin to observations in humans, the destruction of FDC and GC is evident [6]. Although these observations in the spleen might appear to preclude a role for B cells in disea...

Adjuvant Activity of Naturally Occurring Monophosphoryl Lipopolysaccharide Preparations from Mucosa-Associated Bacteria

“…The results from this protocol were initially hampered by relatively higher titers of antigen-specific antibodies, especially IgM and IgG2b isotypes, in the preimmunization serum samples (data not shown), possibly caused by environmental exposure to ovalbumin in feed or bedding. A similar polyclonal antiovalbumin response was seen in unimmunized BALB/c mice infected with Leishmania infantum (37). After the third immunization, each LPS preparation tested increased the titers of the complement-fixing, Th1-associated isotype IgG2a in most vaccinated mice (Fig.…”

Marginal Zone B Cells Regulate Antigen-Specific T Cell Responses during Infection

“…It is known that B cells exacerbate Leishmania infections (5,(18)(19)(20). B cell-deficient (mMT) mice are indeed more resistant than WT mice to infection with L. donovani (see Supplemental -restricted CD8 T cell epitope of OVA 257-264 , were adoptively transferred into mMT mice.…”

“…Various studies have now demonstrated that B cells play a negative role in several experimental models of leishmaniasis (5,(18)(19)(20). B cell depletion was shown to enhance resistance to Leishmania tropica and Leishmania mexicana in BALB/c mice (18), and cotransfer of B cells converts T cell-reconstituted, Leishmania major-resistant, C.B-17 scid mice into a susceptible phenotype (21).…”

“…A recent study has suggested that IL-10 derived from L. major-induced regulatory B cells (Bregs) skews the balance toward unprotective Th2 responses (5). In contrast, Deak et al (19) recently proposed that IgM production and polyclonal B cell activation, which requires activation of complement, are the main cause of disease exacerbation in Leishmania infantuminfected mice rather than IL-10 production by B cells.…”

Protozoan Parasites and Type I IFNs

“…B cell-derived IL-10 was shown to suppress protective T cells responses and increase disease susceptibility (85). B cells are known to play a detrimental role during VL (86), not only by secreting IL-10 but also for their excessive antibody production (87). Indeed, hypergammaglobulinemia is a hallmark of VL.…”