BAFF Produced by Neutrophils and Dendritic Cells Is Regulated Differently and Has Distinct Roles in Antibody Responses and Protective Immunity against West Nile Virus

Abstract

B cell activating factor (BAFF) is essential for B cells to develop and respond to Ags. Dysregulation of BAFF contributes to the development of some autoimmune diseases and malignancies. Little is known about when, where, and how BAFF is produced in vivo and about which BAFF-producing cells contribute to B cell responses. To better understand BAFF functions, we created BAFF reporter (BAFF-RFP) mice and Baff floxed (Baff fl/fl ) mice. Splenic and bone marrow neutrophils (Nphs) from BAFF-RFP mice expressed the highest constitutive levels of BAFF; other myeloid subsets, including conventional dendritic cells (cDCs) and monocyte (MO) subsets, expressed lower levels. Treatment of BAFF-RFP mice with polyinosinic:polycytidylic acid increased BAFF expression in splenic Ly6C hi inflammatory MOs, CD11b hi activated NK subset, and in bone marrow myeloid precursors. Postinfection with West Nile virus (WNV), BAFF increased in CD8 2 cDCs and Nphs, and BAFF + CD11b hi NK cells expanded in draining lymph nodes. The cell-and tissue-specific increases in BAFF expression were dependent on type I IFN signaling. MAVS also was required or contributed to BAFF expression in dendritic cell and MO subsets, respectively. Mice with deletion of Baff in either cDCs or Nphs had reduced Ab responses after NP-Ficoll immunization; thus, BAFF produced by both cDCs and Nphs contributes to T cell-independent Ab responses. Conversely, mice with a cDC Baff deficiency had increased mortality after WNV infection and decreased WNV-specific IgG and neutralizing Ab responses. BAFF produced by Nphs and cDCs is regulated differently and has key roles in Ab responses and protective immunity.

Immunomodulatory Role of NK Cells during Antiviral Antibody Therapy

“…These results are in an agreement with the B-cell helper role of neutrophils in mAb-treated infected mice that we previously reported and which was associated with increased frequencies of IFN-γ-secreting NK cells. Moreover, taking into consideration that BAFF production by neutrophils contributes to the enhancement of humoral responses, including in the context of viral infections and antiviral mAb-therapy [ 19 , 51 , 81 , 82 ], our work suggests that the effect of NK cells in modulating the antiviral humoral response upon mAb therapy might be in part mediated by enhancing the B-cell helper function of neutrophils via IFN-γ production. However, other mechanisms might also be involved, such as the enhancement of T-cell helper CD4 + responses as a consequence of NK–DC cross-talk, as previously reported [ 28 , 29 , 31 ].…”

Increased BAFF Levels in Children with Acute Brucellosis

“…Age, gender, Rose-Bengal test results, transaminase levels, and other laboratory parameters were not significantly different between the patients with and without complication(s) ( Table 2). The symptomatic periods were not different between the patients with and without complications [30(20-60) vs. 25 (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30), p=0.07]. BAFF and APRIL levels were also indiscriminative between the patients, as shown in Table 2.…”

“…In animal studies, it was seen that when BAFF was overexpressed, B-cells secreting malaria-specific antibodies increased, hence mice were protected from lethal malaria infection (17) . Also, BAFF deficiency was shown to result in increased mortality rates related to West Nile virus infection and decreased virus-specific IgG and neutralizing antibody responses (18) . However overexpression of BAFF has been associated with progression of infectious diseases as HIV/SIV (19) .…”

Current Understanding of the Neutrophil Transcriptome in Health and Disease

“…Neutrophils from people with multiple sclerosis exhibit increased responsiveness to stimulation over non-disease neutrophils [67]. It is also noted that B cells in the marginal zone express high levels of the receptor for B cell activation factor (BAFF) and splenic neutrophils express the highest levels of the Baff gene amongst immune cells [68].…”