B-cell activating factor deficiency suppresses splenomegaly during Leishmania donovani infection.

B-cell activating factor (BAFF) is a critical regulator for B-cell development and differentiation. We previously reported elevation of serum BAFF levels in patients with visceral leishmaniasis (VL). In this study, we examined if BAFF is involved in pathologies during infection of Leishmania donovani. BALB/cA mice infected with L. donovani showed significant elevation in serum BAFF and IgG levels as seen in VL patients. In contrast, elevation of serum IgG by L. donovani infection was significantly suppressed in BAFF-deficient mice. The spleen weight of the BAFF-deficient mice after infection was significantly lower than that of the infected wild-type mice, whereas comparable degree of hepatomegaly and anemia were observed in those mice. In the enlarged spleen of L. donovani-infected wild-type mice, increase of CD19+ lymphocytes was more prominent than that of CD3+ cells, suggesting the contribution of B cell increase to splenomegaly during VL. Besides, increase of CD19+ lymphocytes was not found in BAFF-deficient mice after L. donovani infection. Taken together, these results suggest that BAFF is involved in strong B cell activation, which has a pathological role in splenomegaly but not in hepatomegaly or anemia, during VL.

Variable dependency on BAFF in IgG antibody production during Leishmania infection.

B-cell activating factor (BAFF) is known as a cytokine responsible for survival and activation of B cells. However, involvement of the molecule in IgG antibody production during infection remains elusive. In this study, dependency of antibody production in Leishmania infection on BAFF was examined by using BAFF-knockout (BAFF-KO) mice. When BAFF-KO mice were infected with L. major, there was no significant difference in lesion development or parasite burden from those in infected wildtype mice. In contrast, levels of IgG antibodies to Leishmania crude antigen were lower in BAFF-KO mice, suggesting that antibody production during L. major infection is BAFF-dependent. ELISA using defined leishmanial antigens demonstrated that the influence of BAFF on antibody production during L. major varies depending on antigens; IgG production to tandem repeat proteins were more affected by BAFF than non-repeat antigens. On the contrary, all of the defined antigens tested were strongly affected by BAFF for IgG antibody production during L. donovani infection. These results suggest degree of BAFF contribution to antibody production during infection is variable depending on the type of infection and even on the type of antigen in a given infection. These results may explain contradictory roles of BAFF in antibody production in previous works.

Pathological roles of MRP14 in anemia and splenomegaly during experimental visceral leishmaniasis.

Myeloid-related protein 14 (MRP14) belongs to the S100 calcium-binding protein family and is expressed in neutrophils and inflammatory macrophages. Increase in the number of MRP14+ cells or serum level of MRP14 is associated with various diseases such as autoimmune diseases and infectious diseases, suggesting the involvement of the molecule in pathogenesis of those diseases. In this study, to examine the pathological involvement of MRP14 during cutaneous and visceral leishmaniasis, wild-type (WT) and MRP14 knockout (MRP14KO) mice were infected with Leishmania major and L. donovani. Increase in the number of MRP14+ cells at the infection sites in wild-type mice was commonly found in the skin during L. major infection as well as the spleen and liver during L. donovani infection. In contrast, the influence of MRP14 to the pathology seemed different between the two infections. MRP14 depletion exacerbated the lesion development and ulcer formation in L. major infection. On the other hand, the depletion improved anemia and splenomegaly but not hepatomegaly at 24 weeks of L. donovani infection. These results suggest that, distinct from its protective role in CL, MRP14 is involved in exacerbation of some symptoms during VL.