Effect of Complement Component C3 Deficiency on Experimental Lyme Borreliosis in Mice

128

A newly recognized link between the complement system and adaptive immunity is that decay accelerating factor (DAF), a cell surface C3/C5 convertase regulator, exerts control over T cell responses. Extending these results, we show that cultures of Marilyn TCR-transgenic T cells stimulated with DAF-deficient (Daf1−/−) APCs produce significantly more IL-12, C5a, and IFN-γ compared with cultures containing wild-type APCs. DAF-regulated IL-12 production and subsequent T cell differentiation into IFN-γ-producing effectors was prevented by the deficiency of either C3 or C5a receptor (C5aR) in the APC, demonstrating a link between DAF, local complement activation, IL-12, and T cell-produced IFN-γ. Bone marrow chimera experiments verified that bone marrow cell-expressed C5aR is required for optimal differentiation into IFN-γ-producing effector T cells. Overall, our results indicate that APC-expressed DAF regulates local production/activation of C5a following cognate T cell/APC interactions. Through binding to its receptor on APCs the C5a up-regulates IL-12 production, this in turn, contributes to directing T cell differentiation toward an IFN-γ-producing phenotype. The findings have implications for design of therapies aimed at altering pathologic T cell immunity.

supporting

confidence: 56%

Decay Accelerating Factor Can Control T Cell Differentiation into IFN-γ-Producing Effector Cells via Regulating Local C5a-Induced IL-12 Production

Lalli

Strainic

Lin

et al. 2007

128

“…Likewise, mice lacking the B cell complement receptors CD21 and CD35 are not impaired in the host response to B. burgdorferi infection and even produce increased levels of Ag-specific IgM (64). However, infection of C3-deficient mice with larger numbers of B. burgdorferi produce the opposite result (65). Signaling through CD1d has also been proposed to explain how this molecule enhances MZ B cell production of B. hermsii-specific Ab (38).…”

Section: Discussionmentioning

confidence: 99%

The Loss and Gain of Marginal Zone and Peritoneal B Cells Is Different in Response to Relapsing Fever and Lyme Disease Borrelia

Malkiel

Kuhlow

Mena

et al. 2009

T cell-independent Abs are protective against Lyme disease and relapsing fever, illnesses caused by Borrelia spirochetes with distinct blood-borne phases of infection. To understand this protective response, we characterized splenic and peritoneal B cell compartments during infection using flow cytometry and immunohistochemistry. In the spleen, early after infection, Borrelia crocidurae, a relapsing fever species, induced a striking loss of marginal zone (MZ) B cells from the MZ, while Borrelia burgdorferi, the agent of Lyme disease, induced the expansion of this subset. At the same time, no significant changes were observed in follicular B cells in response to either species of Borrelia. In the peritoneal cavity, a further loss was demonstrated early in response to B. crocidurae in the B1b, B1c, and B2 cell subsets, but B1a cells were not significantly altered. The loss of B1c and B2 cells was sustained through subsequent peaks of spirochetemia, suggesting these subsets may be important in resolving relapsing episodes. In contrast, an early and significant increase in peritoneal B1a, B1b, and B1c cells, but not B2 cells, occurred in response to B. burgdorferi. Later in the course of infection, both species of Borrelia induced the selective expansion of peritoneal B1b cells, suggesting that B1b cells may participate in long-lasting immunity to Lyme and relapsing fever spirochetes. Our data demonstrate that different Borrelia can activate the same B cell subsets in distinct ways and they each elicit a complex interplay of MZ and multiple peritoneal B cell subsets in the early response to infection.

“…These findings suggest that MyD88-independent events facilitate recruitment of inflammatory cells into the joint tissue. Possible contributors to this response include localized production of chemokines (57), localized activation of complement (58), or release of chemotactic peptides by the invading bacterium.…”

Section: Discussionmentioning

confidence: 99%

MyD88 Plays a Unique Role in Host Defense but Not Arthritis Development in Lyme Disease

Bolz

Sundsbak

et al. 2004

Self Cite

140

152

To assess the contribution of TLR signaling in the host response to Borrelia burgdorferi, mice deficient in the common TLR adaptor protein, myeloid differentiation factor 88 (MyD88), were infected with B. burgdorferi. MyD88-deficient mice harbored extremely high levels of B. burgdorferi in tissues when compared with wild-type littermates and greater amounts of spirochetes in tissues than TLR2-deficient mice. These findings suggest that, in addition to TLR2, other MyD88-dependent pathways play a significant role in the host defense to B. burgdorferi. MyD88−/− mice maintained the ability to produce Abs directed against B. burgdorferi. Partial clearance of spirochetes was evident in long term infection studies and immune sera from MyD88-deficient mice were able to protect naive mice from infection with B. burgdorferi. Thus, the acquired immune response appeared to be functional in MyD88−/− mice, and the inability to control spirochete numbers was due to a failure of cells involved in innate defenses. Although macrophages from MyD88−/− mice responded poorly to Borrelia sonicate in vitro, MyD88−/− mice still developed an inflammatory arthritis after infection with B. burgdorferi characterized by an influx of neutrophils and mononuclear cells. The findings presented here point to a dichotomy between the recruitment of inflammatory cells to tissue and an inability of these cells to kill localized spirochetes.