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Lymphoadenopathy during lyme borreliosis is caused by spirochete migration-induced specific B cell activation.

Tunev SS, Hastey CJ, Hodzic E, Feng S, Barthold SW, Baumgarth N - PLoS Pathog. (2011)

Bottom Line: The induced B cell response does appear, however, to be largely antigen-specific.Finally, neither the quality nor the magnitude of the B cell responses was altered in mice lacking the Toll-like receptor adaptor molecule MyD88.Together, these findings suggest a novel evasion strategy for B. burgdorferi: subversion of the quality of a strongly induced, potentially protective borrelia-specific antibody response via B. burdorferi's accumulation in lymph nodes.

View Article: PubMed Central - PubMed

Affiliation: Center for Comparative Medicine, University of California Davis, Davis, California, United States of America.

ABSTRACT
Lymphadenopathy is a hallmark of acute infection with Borrelia burgdorferi, a tick-borne spirochete and causative agent of Lyme borreliosis, but the underlying causes and the functional consequences of this lymph node enlargement have not been revealed. The present study demonstrates that extracellular, live spirochetes accumulate in the cortical areas of lymph nodes following infection of mice with either host-adapted, or tick-borne B. burgdorferi and that they, but not inactivated spirochetes, drive the lymphadenopathy. The ensuing lymph node response is characterized by strong, rapid extrafollicular B cell proliferation and differentiation to plasma cells, as assessed by immunohistochemistry, flow cytometry and ELISPOT analysis, while germinal center reactions were not consistently observed. The extrafollicular nature of this B cell response and its strongly IgM-skewed isotype profile bear the hallmarks of a T-independent response. The induced B cell response does appear, however, to be largely antigen-specific. Use of a cocktail of recombinant, in vivo-expressed B. burgdorferi-antigens revealed the robust induction of borrelia-specific antibody-secreting cells by ELISPOT. Furthermore, nearly a quarter of hybridomas generated from regional lymph nodes during acute infection showed reactivity against a small number of recombinant Borrelia-antigens. Finally, neither the quality nor the magnitude of the B cell responses was altered in mice lacking the Toll-like receptor adaptor molecule MyD88. Together, these findings suggest a novel evasion strategy for B. burgdorferi: subversion of the quality of a strongly induced, potentially protective borrelia-specific antibody response via B. burdorferi's accumulation in lymph nodes.

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Related in: MedlinePlus

Tick-borne infection with B. burgdorferi causes systemic lymphadenopathy in mice.C3H/HeN mice (n = 30) were each exposed to five B. burgdorferi-infected nymphal Ixodes scapularis ticks (or non-infected ticks). At indicated times after tick-attachment, groups of five mice were necropsied and (A) cellularity of four indicated lymph nodes and (B) total antibody-forming cells (AFC) of these lymph nodes were assessed by hemocytometer count and ELISPOT analysis, respectively. Shown are mean values ± SD per timepoint for each lymph node type. ELISPOT analysis of lymph nodes from sham-infected mice showed no significant induction of antibody production (data not shown).
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ppat-1002066-g001: Tick-borne infection with B. burgdorferi causes systemic lymphadenopathy in mice.C3H/HeN mice (n = 30) were each exposed to five B. burgdorferi-infected nymphal Ixodes scapularis ticks (or non-infected ticks). At indicated times after tick-attachment, groups of five mice were necropsied and (A) cellularity of four indicated lymph nodes and (B) total antibody-forming cells (AFC) of these lymph nodes were assessed by hemocytometer count and ELISPOT analysis, respectively. Shown are mean values ± SD per timepoint for each lymph node type. ELISPOT analysis of lymph nodes from sham-infected mice showed no significant induction of antibody production (data not shown).

Mentions: Axillary, brachial, lumbar and inguinal lymph nodes, among others, were collected at various times after infection and examined for visible signs of enlargement (not shown) and to determine cell number counts. Lymph node enlargement was noticed for all lymph nodes from mice exposed to B. burgdorferi infected ticks but not uninfected ticks (Figure 1A and data not shown). By day 14 following infestation with infected ticks, the lymph nodes closest to the tick-attachment site (axillary and brachial) were visibly enlarged and contained significantly increased numbers of cells in comparison to the same lymph nodes collected from the sham-exposed mice. Lymph nodes more distant from the attachment site (inguinal and lumbar) showed a slightly delayed increase in cellularity (Figure 1A). Thus, infection of laboratory mice with tick-borne B. burgdorferi faithfully recapitulates the lymphadenopathy observed in naturally infected humans and dogs, and suggests a relationship between time of lymph node enlargement and proximity to the site of infection.


Lymphoadenopathy during lyme borreliosis is caused by spirochete migration-induced specific B cell activation.

Tunev SS, Hastey CJ, Hodzic E, Feng S, Barthold SW, Baumgarth N - PLoS Pathog. (2011)

Tick-borne infection with B. burgdorferi causes systemic lymphadenopathy in mice.C3H/HeN mice (n = 30) were each exposed to five B. burgdorferi-infected nymphal Ixodes scapularis ticks (or non-infected ticks). At indicated times after tick-attachment, groups of five mice were necropsied and (A) cellularity of four indicated lymph nodes and (B) total antibody-forming cells (AFC) of these lymph nodes were assessed by hemocytometer count and ELISPOT analysis, respectively. Shown are mean values ± SD per timepoint for each lymph node type. ELISPOT analysis of lymph nodes from sham-infected mice showed no significant induction of antibody production (data not shown).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3102705&req=5

ppat-1002066-g001: Tick-borne infection with B. burgdorferi causes systemic lymphadenopathy in mice.C3H/HeN mice (n = 30) were each exposed to five B. burgdorferi-infected nymphal Ixodes scapularis ticks (or non-infected ticks). At indicated times after tick-attachment, groups of five mice were necropsied and (A) cellularity of four indicated lymph nodes and (B) total antibody-forming cells (AFC) of these lymph nodes were assessed by hemocytometer count and ELISPOT analysis, respectively. Shown are mean values ± SD per timepoint for each lymph node type. ELISPOT analysis of lymph nodes from sham-infected mice showed no significant induction of antibody production (data not shown).
Mentions: Axillary, brachial, lumbar and inguinal lymph nodes, among others, were collected at various times after infection and examined for visible signs of enlargement (not shown) and to determine cell number counts. Lymph node enlargement was noticed for all lymph nodes from mice exposed to B. burgdorferi infected ticks but not uninfected ticks (Figure 1A and data not shown). By day 14 following infestation with infected ticks, the lymph nodes closest to the tick-attachment site (axillary and brachial) were visibly enlarged and contained significantly increased numbers of cells in comparison to the same lymph nodes collected from the sham-exposed mice. Lymph nodes more distant from the attachment site (inguinal and lumbar) showed a slightly delayed increase in cellularity (Figure 1A). Thus, infection of laboratory mice with tick-borne B. burgdorferi faithfully recapitulates the lymphadenopathy observed in naturally infected humans and dogs, and suggests a relationship between time of lymph node enlargement and proximity to the site of infection.

Bottom Line: The induced B cell response does appear, however, to be largely antigen-specific.Finally, neither the quality nor the magnitude of the B cell responses was altered in mice lacking the Toll-like receptor adaptor molecule MyD88.Together, these findings suggest a novel evasion strategy for B. burgdorferi: subversion of the quality of a strongly induced, potentially protective borrelia-specific antibody response via B. burdorferi's accumulation in lymph nodes.

View Article: PubMed Central - PubMed

Affiliation: Center for Comparative Medicine, University of California Davis, Davis, California, United States of America.

ABSTRACT
Lymphadenopathy is a hallmark of acute infection with Borrelia burgdorferi, a tick-borne spirochete and causative agent of Lyme borreliosis, but the underlying causes and the functional consequences of this lymph node enlargement have not been revealed. The present study demonstrates that extracellular, live spirochetes accumulate in the cortical areas of lymph nodes following infection of mice with either host-adapted, or tick-borne B. burgdorferi and that they, but not inactivated spirochetes, drive the lymphadenopathy. The ensuing lymph node response is characterized by strong, rapid extrafollicular B cell proliferation and differentiation to plasma cells, as assessed by immunohistochemistry, flow cytometry and ELISPOT analysis, while germinal center reactions were not consistently observed. The extrafollicular nature of this B cell response and its strongly IgM-skewed isotype profile bear the hallmarks of a T-independent response. The induced B cell response does appear, however, to be largely antigen-specific. Use of a cocktail of recombinant, in vivo-expressed B. burgdorferi-antigens revealed the robust induction of borrelia-specific antibody-secreting cells by ELISPOT. Furthermore, nearly a quarter of hybridomas generated from regional lymph nodes during acute infection showed reactivity against a small number of recombinant Borrelia-antigens. Finally, neither the quality nor the magnitude of the B cell responses was altered in mice lacking the Toll-like receptor adaptor molecule MyD88. Together, these findings suggest a novel evasion strategy for B. burgdorferi: subversion of the quality of a strongly induced, potentially protective borrelia-specific antibody response via B. burdorferi's accumulation in lymph nodes.

Show MeSH
Related in: MedlinePlus