Post by Admin/ Traveler on Jan 25, 2019 22:12:13 GMT
This is an excellent article, albeit a long and technical one. I did NOT post the entire article, as there was even more technical information still. I think I reposted the more important parts though!
-------------------------------------------------------------------------------------------------------------------------------------------------------------------
Suppression of Long-Lived Humoral Immunity Following Borrelia burgdorferi Infection
"Abstract
Lyme Disease caused by infection with Borrelia burgdorferi is an emerging infectious disease and already by far the most common vector-borne disease in the U.S. Similar to many other infections, infection with B. burgdorferi results in strong antibody response induction, which can be used clinically as a diagnostic measure of prior exposure. However, clinical studies have shown a sometimes-precipitous decline of such antibodies shortly following antibiotic treatment, revealing a potential deficit in the host’s ability to induce and/or maintain long-term protective antibodies. This is further supported by reports of frequent repeat infections with B. burgdorferi in endemic areas. The mechanisms underlying such a lack of long-term humoral immunity, however, remain unknown.
We show here that B. burgdorferi infected mice show a similar rapid disappearance of Borrelia-specific antibodies after infection and subsequent antibiotic treatment. This failure was associated with development of only short-lived germinal centers, micro-anatomical locations from which long-lived immunity originates. These showed structural abnormalities and failed to induce memory B cells and long-lived plasma cells for months after the infection, rendering the mice susceptible to reinfection with the same strain of B. burgdorferi. The inability to induce long-lived immune responses was not due to the particular nature of the immunogenic antigens of B. burgdorferi, as antibodies to both T-dependent and T-independent Borrelia antigens lacked longevity and B cell memory induction. Furthermore, influenza immunization administered at the time of Borrelia infection also failed to induce robust antibody responses, dramatically reducing the protective antiviral capacity of the humoral response. Collectively, these studies show that B. burgdorferi-infection results in targeted and temporary immunosuppression of the host and bring new insight into the mechanisms underlying the failure to develop long-term immunity to this emerging disease threat.
Author Summary
Infections with the Lyme Disease agent, Borrelia burgdorferi, often fail to generate long-term protective immunity. We show here that this is because the immune system of the Borrelia-infected host generates only short-lived, structurally abnormal and non-functional germinal centers. These germinal centers fail to induce memory B cells and long-lived antibody-producing plasma cells, leaving the host susceptible to reinfection with Bb. This inability to induce long-term immunity was not due to the nature of Borrelia antigens, as even T-dependent antigens of Borrelia were unable to induce such responses. Moreover, influenza vaccine antigens, when applied during Borrelia-infection, failed to induce strong antibody responses and immune-protection from influenza challenge. This data illustrate the potent, if temporal, immune suppression induced by Borrelia-infection. Collectively, the data reveal a new mechanism by which B. burgdorferi subverts the adaptive immune response."
"Discussion
Our study demonstrates that Bb infection of mice causes a state of temporary immunosuppression that targets the hallmarks of adaptive immunity: its memory response. The lack of long-term antibody induction and memory formation was not due to previously identified immune evasion strategies of Bb, such as the down-regulation of immunogenic surface antigens, or the nature of the Borrelia antigens, such as high levels of lipidation or carbohydrate modifications, but affected responses even to co-administered highly immunogenic T-dependent influenza protein."
"The here shown data may also explain the previously described loss of protective serum antibodies after early antibiotic treatment, in humans and mice [16,17]. It is likely, however, that it is not just the quantity but also the quality of the antibody response that changes over the course of infection. The eventual appearance of long-lived responses, demonstrated by the accumulation of bone marrow plasma cells after day 100 of infection [22] and the presence of Arp-specific memory B cells after one year of infection (Fig 5C), suggests that the ongoing Bb infection continuously shapes and reshapes the host immune response, and that later-exerted immune-mediated control of the bacteria overcomes some of the early-induced immunosuppressive effects of the infection. "
"The studies here focused on B cell responses to Bb induced in the lymph nodes, as we found Bb spirochetes by culture and by histology as early as 24h after infection [20]. While the lymph nodes then remained culture positive throughout the infection, the spleen was largely culture negative [20]. The reasons for this lack of splenic involvement during disseminated systemic Bb infection that would be expected to result in antigen presentation and immune response induction also in the spleen are unclear. Interestingly, a study on Ehrlichia muris infection, another tick-transmitted disease, similarly noted the absence of splenic involvement in the immune response to both E. muris and a co-administered model antigen, but found lymph node responses to be unaffected [38]."
"The results of this study may impact the interpretation of current efforts to enhance serological testing for Lyme disease. Should humans fail to generate long-lived plasma cells and memory B cells, similar to what we demonstrate here for mice, then serological testing for antibodies to Bb as a means to assess prior exposure rates is a strategy of limited scope. This would be true even if such assays were improved, such as the use of recombinant proteins generated from highly immunogenic Bb proteins, because the rate of positivity for a given test would not be affected by exposure rates but rather by the time between the last Bb exposure and testing. Previous findings in patients, showing that disseminated disease or long-term infection prior to diagnosis and antibiotic treatment are correlated with higher serological responses, are consistent with the here reported findings in mice [18,19]. However, we also note that robust IgG responses to the four here used recombinant Bb antigens were measurable in the serum of mice starting around day 15 of infection [22] and continue to be present for as long as the infection remained (Fig 2). Antibody responses were detectable significantly earlier when lymph nodes were harvested for ELISPOT analysis, around days 7/8 of infection [20,22]. Biopsy of a lymph node for early serological detection of infection is obviously not a feasible clinical approach, but the generation of early plasma blast responses after Bb infection might be measurable in the blood and has been used in other infections to assess effective immune induction [40]. The main limitation of this approach is the usually tight window, spanning only 1–2 days, in which such cells are present at measurable numbers in the blood.
Our studies in mice may provide impetus for systematic clinical studies of long-lived immunity to Bb in humans. The herein described immune-suppressive effect of Bb-infection might be considered as a rationale for testing vaccine-efficacy to unrelated antigens in Bb-infected humans or animals. It may also affect the pathogenesis of co-infections transmitted via the same tick-bite, an area of emerging interest [41,42]. A recent study reported that 1.5% and 7.8% of nymph and adult Ixodes spp. ticks, respectively, sampled in upstate New York were co-infected with Anaplasma phagocytophilum or Babesia microti [43]. Consistent with that report, 4% and 22% of patients, respectively, suspected of a tick-borne infection were co-infected with either Bb and Anaplasma or Bb and Babesia [41]. Increased susceptibility of Bb-infected individuals to co-infections is indicated by data provided in this study and should encourage vigorous clinical testing.
Considering the epidemiology of Bb, the suppression of long-term immunity could serve to maintain a pool of susceptible individuals, even in highly endemic areas. Based on the current literature an our data, it appears that when reinfection with Bb occur shortly after primary infection, while antibody titers and passive protective capacity are still high, such infections might preferentially be due to different strains of Bb, or Bb expressing different variable surface antigens and thus are able to evade existing immunity. However, as antibody protective capacity wanes due to a lack of long-lived immunity and declining antibody titers, individuals would be vulnerable to reinfection independently of the degree of similarity of the newly encountered Bb strain with the original Bb strain. A recent study by Nadelman et al [9] followed human patients that showed recurrent skin lesions, erythema migrants, which is indicative of infection with Bb. In 16 of 17 patients Bb cultured from these patients showed that the infecting Bb strain was distinct from that of the initial infection as measured by sequencing the polymorphic OspC gene. One patient showed signs of repeat infection with the same strain of Bb. The data thus support our findings that at least some human patients remain vulnerable to reinfection with the same Bb strain. Whether the others were not exposed to the same strain of Bb, or where infected with a distinct strain because of protective pre-existing antibody levels to the original strain are important questions that remain to be addressed in the future."
-------------------------------------------------------------------------------------------------------------------------------------------------------------------
Suppression of Long-Lived Humoral Immunity Following Borrelia burgdorferi Infection
"Abstract
Lyme Disease caused by infection with Borrelia burgdorferi is an emerging infectious disease and already by far the most common vector-borne disease in the U.S. Similar to many other infections, infection with B. burgdorferi results in strong antibody response induction, which can be used clinically as a diagnostic measure of prior exposure. However, clinical studies have shown a sometimes-precipitous decline of such antibodies shortly following antibiotic treatment, revealing a potential deficit in the host’s ability to induce and/or maintain long-term protective antibodies. This is further supported by reports of frequent repeat infections with B. burgdorferi in endemic areas. The mechanisms underlying such a lack of long-term humoral immunity, however, remain unknown.
We show here that B. burgdorferi infected mice show a similar rapid disappearance of Borrelia-specific antibodies after infection and subsequent antibiotic treatment. This failure was associated with development of only short-lived germinal centers, micro-anatomical locations from which long-lived immunity originates. These showed structural abnormalities and failed to induce memory B cells and long-lived plasma cells for months after the infection, rendering the mice susceptible to reinfection with the same strain of B. burgdorferi. The inability to induce long-lived immune responses was not due to the particular nature of the immunogenic antigens of B. burgdorferi, as antibodies to both T-dependent and T-independent Borrelia antigens lacked longevity and B cell memory induction. Furthermore, influenza immunization administered at the time of Borrelia infection also failed to induce robust antibody responses, dramatically reducing the protective antiviral capacity of the humoral response. Collectively, these studies show that B. burgdorferi-infection results in targeted and temporary immunosuppression of the host and bring new insight into the mechanisms underlying the failure to develop long-term immunity to this emerging disease threat.
Author Summary
Infections with the Lyme Disease agent, Borrelia burgdorferi, often fail to generate long-term protective immunity. We show here that this is because the immune system of the Borrelia-infected host generates only short-lived, structurally abnormal and non-functional germinal centers. These germinal centers fail to induce memory B cells and long-lived antibody-producing plasma cells, leaving the host susceptible to reinfection with Bb. This inability to induce long-term immunity was not due to the nature of Borrelia antigens, as even T-dependent antigens of Borrelia were unable to induce such responses. Moreover, influenza vaccine antigens, when applied during Borrelia-infection, failed to induce strong antibody responses and immune-protection from influenza challenge. This data illustrate the potent, if temporal, immune suppression induced by Borrelia-infection. Collectively, the data reveal a new mechanism by which B. burgdorferi subverts the adaptive immune response."
"Discussion
Our study demonstrates that Bb infection of mice causes a state of temporary immunosuppression that targets the hallmarks of adaptive immunity: its memory response. The lack of long-term antibody induction and memory formation was not due to previously identified immune evasion strategies of Bb, such as the down-regulation of immunogenic surface antigens, or the nature of the Borrelia antigens, such as high levels of lipidation or carbohydrate modifications, but affected responses even to co-administered highly immunogenic T-dependent influenza protein."
"The here shown data may also explain the previously described loss of protective serum antibodies after early antibiotic treatment, in humans and mice [16,17]. It is likely, however, that it is not just the quantity but also the quality of the antibody response that changes over the course of infection. The eventual appearance of long-lived responses, demonstrated by the accumulation of bone marrow plasma cells after day 100 of infection [22] and the presence of Arp-specific memory B cells after one year of infection (Fig 5C), suggests that the ongoing Bb infection continuously shapes and reshapes the host immune response, and that later-exerted immune-mediated control of the bacteria overcomes some of the early-induced immunosuppressive effects of the infection. "
"The studies here focused on B cell responses to Bb induced in the lymph nodes, as we found Bb spirochetes by culture and by histology as early as 24h after infection [20]. While the lymph nodes then remained culture positive throughout the infection, the spleen was largely culture negative [20]. The reasons for this lack of splenic involvement during disseminated systemic Bb infection that would be expected to result in antigen presentation and immune response induction also in the spleen are unclear. Interestingly, a study on Ehrlichia muris infection, another tick-transmitted disease, similarly noted the absence of splenic involvement in the immune response to both E. muris and a co-administered model antigen, but found lymph node responses to be unaffected [38]."
"The results of this study may impact the interpretation of current efforts to enhance serological testing for Lyme disease. Should humans fail to generate long-lived plasma cells and memory B cells, similar to what we demonstrate here for mice, then serological testing for antibodies to Bb as a means to assess prior exposure rates is a strategy of limited scope. This would be true even if such assays were improved, such as the use of recombinant proteins generated from highly immunogenic Bb proteins, because the rate of positivity for a given test would not be affected by exposure rates but rather by the time between the last Bb exposure and testing. Previous findings in patients, showing that disseminated disease or long-term infection prior to diagnosis and antibiotic treatment are correlated with higher serological responses, are consistent with the here reported findings in mice [18,19]. However, we also note that robust IgG responses to the four here used recombinant Bb antigens were measurable in the serum of mice starting around day 15 of infection [22] and continue to be present for as long as the infection remained (Fig 2). Antibody responses were detectable significantly earlier when lymph nodes were harvested for ELISPOT analysis, around days 7/8 of infection [20,22]. Biopsy of a lymph node for early serological detection of infection is obviously not a feasible clinical approach, but the generation of early plasma blast responses after Bb infection might be measurable in the blood and has been used in other infections to assess effective immune induction [40]. The main limitation of this approach is the usually tight window, spanning only 1–2 days, in which such cells are present at measurable numbers in the blood.
Our studies in mice may provide impetus for systematic clinical studies of long-lived immunity to Bb in humans. The herein described immune-suppressive effect of Bb-infection might be considered as a rationale for testing vaccine-efficacy to unrelated antigens in Bb-infected humans or animals. It may also affect the pathogenesis of co-infections transmitted via the same tick-bite, an area of emerging interest [41,42]. A recent study reported that 1.5% and 7.8% of nymph and adult Ixodes spp. ticks, respectively, sampled in upstate New York were co-infected with Anaplasma phagocytophilum or Babesia microti [43]. Consistent with that report, 4% and 22% of patients, respectively, suspected of a tick-borne infection were co-infected with either Bb and Anaplasma or Bb and Babesia [41]. Increased susceptibility of Bb-infected individuals to co-infections is indicated by data provided in this study and should encourage vigorous clinical testing.
Considering the epidemiology of Bb, the suppression of long-term immunity could serve to maintain a pool of susceptible individuals, even in highly endemic areas. Based on the current literature an our data, it appears that when reinfection with Bb occur shortly after primary infection, while antibody titers and passive protective capacity are still high, such infections might preferentially be due to different strains of Bb, or Bb expressing different variable surface antigens and thus are able to evade existing immunity. However, as antibody protective capacity wanes due to a lack of long-lived immunity and declining antibody titers, individuals would be vulnerable to reinfection independently of the degree of similarity of the newly encountered Bb strain with the original Bb strain. A recent study by Nadelman et al [9] followed human patients that showed recurrent skin lesions, erythema migrants, which is indicative of infection with Bb. In 16 of 17 patients Bb cultured from these patients showed that the infecting Bb strain was distinct from that of the initial infection as measured by sequencing the polymorphic OspC gene. One patient showed signs of repeat infection with the same strain of Bb. The data thus support our findings that at least some human patients remain vulnerable to reinfection with the same Bb strain. Whether the others were not exposed to the same strain of Bb, or where infected with a distinct strain because of protective pre-existing antibody levels to the original strain are important questions that remain to be addressed in the future."