<i>Borrelia burgdorferi</i>-Induced Tolerance as a Model of Persistence via Immunosuppression

Diterich, Isabel; Rauter, Carolin; Kirschning, Carsten J.; Hartung, Thomas

doi:10.1128/iai.71.7.3979-3987.2003

Cited by 59 publications

(40 citation statements)

References 44 publications

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“…While activation of monocytes/macrophages and mDCs by lipopeptides in vivo was not unexpected, the cytokine profile of the lipopeptide BFs, most notably the absence of TNF-␣ and the modestly elevated levels of IL-12, was surprising in light of in vitro and ex vivo studies with these same or related agonists (23,42,62,79). In contrast, elevated levels of TNF-␣ and markedly increased concentrations of IL-12 were observed in EM BFs.…”

Section: Discussionmentioning

confidence: 88%

Lipoprotein-Dependent and -Independent Immune Responses to Spirochetal Infection

Salazar

Pope

Moore

et al. 2005

Clin Vaccine Immunol

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In this study, we used the epidermal suction blister technique, in conjunction with multiparameter flow cytometry, to analyze the cellular and cytokine responses elicited by intradermal injection of human volunteers with synthetic analogs for spirochetal lipoproteins and compared the responses to findings previously reported from patients with erythema migrans (EM). Compared with peripheral blood (PB), lipopeptides derived from the N termini of the Borrelia burgdorferi outer surface protein C and the 17-kDa lipoprotein of Treponema pallidum (OspC-L and 17-L, respectively) elicited infiltrates enriched in monocytes/macrophages and dendritic cells (DCs) but also containing substantial percentages of neutrophils and T cells. Monocytoid (CD11c ؉ ) and plasmacytoid (CD11c ؊ ) DCs were selectively recruited to the skin in ratios similar to those in PB, but only the former expressed the activation/maturation surface markers CD80, CD83, and DC-SIGN. Monocytes/macrophages and monocytoid DCs, but not plasmacytoid DCs, displayed significant increases in surface expression of Toll-like receptor 1 (TLR1), TLR2, and TLR4. Staining for CD45RO and CD27 revealed that lipopeptides preferentially recruited antigen-experienced T-cell subsets; despite their lack of antigenicity, these agonists induced marked T-cell activation, as evidenced by surface expression of CD69, CD25, and CD71. Lipopeptides also induced significant increases in interleukin 12 (IL-12), IL-10, gamma interferon, and most notably IL-6 without corresponding increases in serum levels of these cytokines. Although lipopeptides and EM lesional infiltrates shared many similarities, differences were noted in a number of immunologic parameters. These studies have provided in situ evidence for a prominent "lipoprotein effect" during human infection while at the same time helping to pinpoint aspects of the cutaneous response that are uniquely driven by spirochetal pathogens.Syphilis and Lyme disease (LD) are acute and chronic inflammatory disorders caused by the spirochetal pathogens Treponema pallidum and Borrelia burgdorferi, respectively (49, 74). Both are major threats to public health within the United States and globally (37,75). Both diseases begin with a distinctive lesion at the site of inoculation (a genital sore or chancre in the case of syphilis versus erythema migrans in Lyme disease) followed by a variety of extracutaneous manifestations once the spirochetes disseminate hematogenously. Syphilis and LD also are characterized by highly similar histopathological abnormalities (24, 49), suggesting that their etiologic agents elicit inflammatory responses in skin and other tissues via common mechanisms and pathways.T. pallidum and B. burgdorferi lack lipopolysaccharide (LPS), the proinflammatory constituent in the outer membranes of gram-negative bacteria (81), but contain an abundance of lipoproteins (11,16,18,27,28). There is now an extensive body of in vitro evidence that spirochetal lipoproteins and synthetic lipoprotein analogs (lipopeptides) are potent acti...

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Section: Discussionmentioning

confidence: 88%

Lipoprotein-Dependent and -Independent Immune Responses to Spirochetal Infection

Salazar

Pope

Moore

et al. 2005

Clin Vaccine Immunol

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“…Nevertheless, it is generally accepted that B. burgdorferi and its lipoproteins (75), as well as bacterial lipopeptides (76), transiently up-regulate and then downregulate TLR2 mRNA levels. This observation now has been confirmed and extended by showing that B. burgdorferi has the capacity to impact transcription of tlr2, tlr5, and tlr9 in a CD14-dependent fashion.…”

Section: Discussionmentioning

confidence: 99%

Signaling through CD14 Attenuates the Inflammatory Response toBorrelia burgdorferi, the Agent of Lyme Disease

Benhnia¹,

Wroblewski²,

Akhtar³

et al. 2005

The Journal of Immunology

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Lyme disease is a chronic inflammatory disorder caused by the spirochetal bacterium, Borrelia burgdorferi. In vitro evidence suggests that binding of spirochetal lipoproteins to CD14, a pattern recognition receptor expressed on monocytes/macrophages and polymorphonuclear cells, is a critical requirement for cellular activation and the subsequent release of proinflammatory cytokines that most likely contribute to symptomatology and clinical manifestations. To test the validity of this notion, we assessed the impact of CD14 deficiency on Lyme disease in C3H/HeN mice. Contrary to an anticipated diminution in pathology, CD14−/− mice exhibited more severe and persistent inflammation than did CD14+/+ mice. This disparity reflects altered gene regulation within immune cells that may engender the higher bacterial burden and serum cytokine levels observed in CD14−/− mice. Comparing their in vitro stimulatory activity, live spirochetes, but not lysed organisms, were a potent CD14-independent stimulus of cytokine production, triggering an exaggerated response by CD14−/− macrophages. Collectively, our in vivo and in vitro findings support the provocative notion that: 1) pattern recognition by CD14 is entirely dispensable for elaboration of an inflammatory response to B. burgdorferi, and 2) CD14-independent signaling pathways are inherently more destructive than CD14-dependent pathways. Continued study of CD14-independent signaling pathways may provide mechanistic insight into the inflammatory processes that underlie development of chronic inflammation.

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“…A number of TLRs, including TLR9, TLR7, and TLR4, have been suggested to be important in the pathogenesis of EAE (6,8,(23)(24)(25). Because there has been much evidence that TLR2 and TLR4 usually cross-tolerize each other (22,26), but less documentation that TLR2 can crosstolerize TLR7 and TLR9, we specifically asked whether our TLR2 tolerance induction protocol cross-tolerizes mice to TLR7 and TLR9.…”

Section: Induction Of Tlr2 Tolerance Cross-tolerizes To the Other Tlrmentioning

confidence: 99%

TLR Tolerance as a Treatment for Central Nervous System Autoimmunity

Anstadt

Fujiwara

Wasko

et al. 2016

The Journal of Immunology

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The role of TLR signaling in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) is unclear. This role is especially controversial in models of adoptive transfer EAE in which no adjuvant and no TLR ligands are administered. We recently reported that a microbiome-derived TLR2 ligand, Lipid 654 (L654), is present in healthy human serum but significantly decreased in the serum of MS patients. This suggested that microbiome products that gain access to the systemic circulation, rather than being proinflammatory, may normally play an immune-regulatory role by maintaining a state of relative TLR tolerance. Therefore, a loss of microbiome-mediated TLR tolerance, as suggested by lower serum levels of L654, may play a role in the pathogenesis of MS. As proof of concept we asked whether administering low-level TLR2 ligands in adoptive transfer EAE induces TLR2 tolerance and attenuates disease. We administered low-level Pam2CSK4 or L654 to mice receiving encephalitogenic cells and in doing so induced both TLR2 tolerance and attenuation of EAE. Disease attenuation was accompanied in the CNS by a decrease in macrophage activation, a decrease in a specific proinflammatory macrophage population, and a decrease in Th17 cells. In addition, disease attenuation was associated with an increase in splenic type 1 regulatory T cells. Kinetic tolerance induction studies revealed a critical period for TLR2 involvement in adoptive transfer EAE. Overall, these results suggest that inducing TLR tolerance may offer a new approach to treating CNS autoimmune diseases such as MS.

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Borrelia burgdorferi-Induced Tolerance as a Model of Persistence via Immunosuppression

Cited by 59 publications

References 44 publications

Lipoprotein-Dependent and -Independent Immune Responses to Spirochetal Infection

Lipoprotein-Dependent and -Independent Immune Responses to Spirochetal Infection

Signaling through CD14 Attenuates the Inflammatory Response toBorrelia burgdorferi, the Agent of Lyme Disease

TLR Tolerance as a Treatment for Central Nervous System Autoimmunity

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