Role of dendritic cell-derived CXCL13 in the pathogenesis of Bartonella henselae B-rich granuloma

Abstract

Dendritic cells (DCs) initiate adaptive immunity and regulate the inflammatory response by producing inflammatory chemokines. This study was aimed to elucidate their role in the pathogenesis of the suppurative granuloma induced by Bartonella henselae infection, which characterizes cat scratch disease (CSD). In vitro DC infection by B. henselae results in internalization of bacteria, phenotypic maturation with increased expression of HLA-DR and CD86, and induction of CD83, CD208, and CCR7. In comparison to LPSactivated DCs, B henselae-infected DCs produce higher amounts of IL-10, whereas the production of IL-12p70 is reduced. Infected DCs also produce high levels of CXCL8 and CXCL13, 2 chemokines active respectively on neutrophils and B lymphocytes. These results provide the molecular basis for the morphogenesis of CSD granuloma, which typically contains high numbers of neutrophils and B cells. Remarkably, CSD granulomas in vivo contain CXCL13-producing DCs. We further demonstrate that the B cells in CSD granulomas are represented by monocytoid B cells and, worth noting, they express T-bet, a transcription factor able to induce a T-independent immunoglobulin (Ig) class switch in B lymphocytes. These findings suggest that the humoral immune response to B henselae initiates in the extrafollicular areas of infected lymph nodes and is regulated by DCs. IntroductionThe orchestration of the immune response against infections strictly relies on the interaction of pathogens with professional antigen-presenting cells in peripheral tissues. Among them, dendritic cells (DCs) have the unique ability to induce a potent antigen-dependent stimulation and play a central role in the initiation of the primary immune response. 1,2 Indeed, upon exposure to microbial pathogens, DCs migrate to lymph nodes and undergo maturation into potent stimulatory cells. [3][4][5] This process is usually accompanied by Toll-like receptor (TLR) activation that leads to phenotypic and functional changes and by inflammatory cytokine and chemokine production culminating in the recruitment and activation of effector cells. In vivo, DC-derived chemokines are believed to contribute to the recruitment of precursor cells and immature DCs at peripheral inflammation sites and within lymph nodes, where they play a role in T-and B-cell localization. [6][7][8] In terms of immune protection against infectious diseases, nodal granuloma reactions control the systemic spread of pathogens and represent an intriguing model for the effector phase of immune response. The cytokine network involved in the recruitment of DCs in pathologies like the hypersensitivity-type granulomas, typically observed in mycobacterial lymphadenitis, has been extensively investigated. [9][10][11] Hypersensitive-type granulomas are mainly composed by macrophages, macrophage-derived cells such as epithelioid and giant cells, and numerous T lymphocytes, bearing a T-helper 1 (Th1) phenotype. 12 Granulomas resulting from Bartonella henselae infection and associated with cat scratch disease (CS...

Genome-Wide Expression Analysis of Placental Malaria Reveals Features of Lymphoid Neogenesis during Chronic Infection

“…In our study, B cells were not aggregated in follicular structures and did not express the germinal center marker Bcl-6. Similarly, T-bet expression but not Bcl-6 expression has been observed in B cell infiltrates of B. henselae granulomas (31).…”

“…The lymphoid chemokine CXCL13 is chemotactic for B cells expressing the Burkitt's lymphoma receptor CXCR5 and is essential for lymph node development in mice (28). CXCL13 expression has been associated with lymphoid neogenesis in autoimmune diseases (26,27,29) and during Helicobacter pylori and Bartonella henselae infection (30,31). Although B cells contribute to the placental infiltrate during PM, no reports have characterized the B cells nor has CXCL13 been examined in malaria-infected individuals.…”

Cytokines and T-Lymphocute count in patients in the acute and chronic phases of Bartonella bacilliformis infection in an endemic area in peru: a pilot study

“…The bacterias are therefore able to bind and to invade red blood cells 6,21,28 . In addition, the lack of activation of dendritic cells will prevent the reversal of Treg cells in anergic states 15,34 . Thus, preventing the activation of dendritic cells, B. bacilliformis may establish and maintain an immune peripheral tolerance in the host 6,32 .…”

“…In summary, the varied severity of clinical presentation by patients with acute-phase HB should be considered to be related to the patient's immune status, with a state of immune peripheral tolerance needed to establish persistent infection 2,14,15,34 . Our findings of statistically significant elevation of the anti-inflammatory cytokine IL-10 and numeric abnormalities in the CD4 + and CD8 + T-Lymphocyte counts correlates with an immune state unfavorable for infection clearance.…”

Bartonella and Brucella--Weapons and Strategies for Stealth Attack

“…Conversely, the glucose polymer b1,2-cyclic glucan activates DC in a TLR4 Myd88-dependent manner, thus counteracting Btp1-mediated inhibition of DC maturation . Whether Bartonella has a similar DC maturation fine-tuning as Brucella is unclear, but Bartonella is hitherto known to stimulate DC maturation in a TLR2-dependent manner (Vermi et al 2006;Pulliainen and Dehio 2012).…”