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S W Barthold

Publications and source records attributed to S W Barthold.

At least 55 records · Page 3Linked to original sources
PubMed1997

Borrelia burgdorferi P35 and P37 proteins, expressed in vivo, elicit protective immunity.

p35 and p37 are Borrelia burgdorferi genes encoding 35 and 37 kDa proteins. The gene products were identified by differential screening of a B. burgdorferi expression library with sera from B. burgdorferi infected- and B. burgdorferi-hyperimmunized mice. Northern blot and RT-PCR analyses confirmed that these genes were selectively expressed in vivo. ELISA, using P35 and P37, showed that infected mice (5 of 5, 100%) and patients (31 of 43, 72%) with Lyme borreliosis developed P35 or P37 antibodies. Mice developed peak IgG titers to P35 and P37 within 30 days, followed by decline. Mice given both P35 and P37 antisera were protected from challenge with 10(2) B. burgdorferi, and P35 and P37 antisera also afforded protection when administered 24 hr after spirochete challenge. The use of in vivo-expressed antigens such as P35 and P37 represents a new approach for Lyme disease serodiagnosis and for understanding the role of B. burgdorferi-specific immune responses in host immunity.

Amino Acid Sequence↗
PubMed1997

Lyme borreliosis in transgenic mice tolerant to OspA from Borrelia burgdorferi 25015.

Lyme borreliosis in transgenic mice tolerant to Borrelia burgdorferi outer surface protein A (OspA) from the weakly virulent B. burgdorferi 25015 was assessed because the response to OspA has been implicated in protective immunity and is suspected in disease pathogenesis. B. burgdorferi 25015 is infectious but does not cause significant arthritis in C3H/HeN mice. Tolerance of mice to B. burgdorferi N40 OspA had no effect on disease. Since B. burgdorferi N40 is more virulent than and genetically distinct from B. burgdorferi 25015, the generality of these findings was investigated. OspA-25015-transgenic mice were tolerant to OspA-25015 and did not develop OspA antibodies or cellular responses following immunization with OspA-25015. The development and resolution of Lyme arthritis was similar in transgenic and nontransgenic littermates, suggesting that ablation of the OspA-25015 response does not cause B. burgdorferi 25015 to become more arthritogenic.

Animals↗
PubMed1997

The early humoral response in human granulocytic ehrlichiosis.

The early antibody response in patients with human granulocytic ehrlichiosis (HGE) and in mice infected with the HGE agent was characterized by using sera to probe lysates of HL-60 cells infected with HGE organisms. Sera were obtained from 18 patients with HGE, mostly within the first 6 weeks of clinical infection, and from mice infected with the HGE agent for up to 3 weeks. A 44-kDa antigen was reactive with IgG in all 18 patients, and IgG to 40-, 65-, and 80-kDa antigens was present in 6, 8, and 7 patients, respectively. In addition, IgM to 40-, 44-, 65-, and 80-kDa antigens was found in 9, 5, 4, and 4 subjects. Immunoglobulins to antigens ranging between 95 and 125 kDa were detected less frequently. HGE agent-infected C3H/HeJ mice had an antibody response similar to that in humans. Thus, the 40- and 44-kDa proteins of the HGE agent elicit early strong antibody responses during infection. Characterization of the antigens recognized by antibodies during HGE should aid in diagnosis and understanding of the disease.

Animals↗
PubMed1997

Protective and arthritis-resolving activity in sera of mice infected with Borrelia burgdorferi.

Transfer of immune serum from immunocompetent mice infected with B. burgdorferi protects mice against syringe challenge, and transfer of immune serum after infection is established induces arthritis resolution but does not clear infection or spirochetemia or resolve carditis. Immune serum had very-high-titer passive protective activity against syringe challenge but failed to protect mice against host-adapted spirochetes when they were challenged with infected tissue transplants. Mice were passively immunized at selected intervals relative to challenge inoculation with antisera to recombinant forms of an immunodominant region of flagellin, P39, and OspC (which are recognized by immune serum), but none provided protection or modified existing infection or disease. Results suggest that spirochetes within joints, but not in other tissues, are selectively vulnerable to immune serum and that immune serum appears to contain antibody against yet-to-be-identified antigens that may be selectively expressed in the context of joint tissue.

Animals↗
PubMed1997

Ablation of interleukin-12 exacerbates Lyme arthritis in SCID mice.

The administration of interleukin-12 (IL-12) antibodies to Borrelia burgdorferi-infected C3H/HeN-scid mice increased the severity of acute Lyme arthritis. These results contrasted with the reduction of Lyme arthritis by IL-12 antibodies in immunocompetent animals. These data suggest that downregulation of innate immunity in SCID mice in the absence of B- and T-cell responses leads to an exacerbation of joint inflammation.

Animals↗
PubMed1997

Borrelia burgdorferi strain-specific Osp C-mediated immunity in mice.

Antibodies to the outer surface proteins (Osps) A, B, and C of the spirochete Borrelia burgdorferi can prevent infection in animal models of Lyme borreliosis. We have previously demonstrated that immune serum from mice infected with B. burgdorferi N40 can also prevent challenge infection and induce disease regression in infected mice. The antigens targeted by protective and disease-modulating antibodies are presently unknown, but they do not include Osp A or Osp B. Because Osp C antibodies are present in immune mouse serum, we investigated the ability of hyperimmune serum to recombinant Osp C (N40) to protect mice against challenge infection with N40 spirochetes. In both active and passive immunization studies, Osp C (N40) antiserum failed to protect mice from challenge infection with cultured organisms. Mice actively immunized with recombinant Osp C (N40) were susceptible to tick-borne challenge infection, and nymphal ticks remained infected after feeding on Osp C-hyperimmunized mice. In contrast, similar immunization studies performed with Osp C (PKo) antiserum prevented challenge infection of mice with a clone of PKo spirochetes pathogenic for mice. Both Osp C (N40) and Osp C (PKo) antisera showed minimal in vitro borreliacidal activity, and immunofluorescence studies localized Osp C beneath the outer membrane of both N40 and PKo spirochetes. We conclude that Osp C antibody-mediated immunity is strain specific and propose that differences in Osp C surface expression by spirochetes in vivo may account for strain-specific immunity.

Animals↗
PubMed1997

B7-1 and B7-2 monoclonal antibodies modulate the severity of murine Lyme arthritis.

We assessed the role of B7-1 and B7-2 costimulatory molecules on the course of murine Lyme borreliosis because experimental Lyme arthritis is dependent, at least partially, upon the development of the host immune response and these costimulatory molecules have been implicated in CD4+ T-cell differentiation. We demonstrated that Borrelia burgdorferi infection upregulated the surface expression of B7-1 and B7-2 in macrophages and B7-2 expression in B cells. Anti-B7-2 monoclonal antibody (MAb) or both anti-B7-2 and anti-B7-1 MAbs produced a dose-dependent increase in the severity of Lyme arthritis in C3H/HeN mice. In contrast, the administration of an anti-B7-1 MAb reduced the degree of arthritis. These effects occurred independently of significant alteration in B. burgdorferi-specific immune responses, including splenocyte proliferative responses to B. burgdorferi, B. burgdorferi antibody levels and specificity, and mRNA levels of gamma interferon, interleukin-4 (IL-4), IL-10, and IL-12 in the spleen. These results demonstrate that signaling delivered by B7-1 and B7-2 plays a role in determining the severity of acute murine Lyme arthritis.

Animals↗
PubMed1997

T-helper-cell cytokines in the early evolution of murine Lyme arthritis.

Genetic susceptibility to murine Lyme arthritis has been correlated with the dominance of T-helper (Th1)- or Th2-cell-associated cytokines. To determine when commitment of the Th cell phenotype occurs, we examined the kinetics of gamma interferon (IFN-gamma) and interleukin-4 (IL-4) production by lymph node T cells of disease-susceptible C3H/HeN and disease-resistant BALB/c mice from days 2 through 30 of infection, a period encompassing the evolution of disease and early regression. BALB/c mice produced more IFN-gamma on day 2 of infection than did C3H/HeN mice, whereas IL-4 was first detected on day 14. In contrast, only IFN-gamma could be detected in C3H/HeN mice, and the levels steadily increased from day 2 to surpass those seen in BALB/c mice by day 14 of infection. Despite the difference in cytokine profiles, both BALB/c and C3H/HeN mice developed comparable arthritis assessed at 14 days of infection. Arthritis regressed by day 30 in BALB/c mice but persisted in C3H/HeN mice. These studies are the first to demonstrate that the Th2 response to Borrelia burgdorferi infection of BALB/c mice is preceded by a Th1 cytokine response. Moreover, the timing of the appearance of IL-4 suggests that its primary effect is not in preventing disease, as suggested by others, but, rather, in hastening the resolution of inflammation. The implications of these findings for the orchestration of host defense against B. burgdorferi infection are discussed.

Animals↗
PubMed1996

Identification of a Borrelia burgdorferi OspA T cell epitope that promotes anti-OspA IgG in mice.

Lyme disease, due to infection with the tick-borne spirochete Borrelia burgdorferi, is a multisystem disorder that can lead to chronic disabling symptoms. Abs to the outer surface protein A (OspA) of B. burgdorferi provide protection against infection, and OspA is now the basis of a first generation recombinant vaccine undergoing phase III efficacy studies. Recent studies have suggested that T cells reactive with N-terminal epitopes in OspA could contribute to the development of treatment-resistant Lyme arthritis. In the present studies, we use the murine model of Lyme borreliosis to define an OspA T cell epitope located in the carboxyl terminus that accelerates anti-OspA IgG production after infection. In addition, we show that this T cell epitope is elicited by immunization with rOspA or with a truncated form of OspA that contains the B cell epitope targeted by protective OspA mAb. Polyclonal antisera to the truncated OspA fragment can protect mice from challenge infection. These results are the first demonstration of a B. burgdorferi-specific peptide that elicits a biologically important T cell response in vivo and have implications for the design of a second generation OspA-based subunit vaccine.

Amino Acid Sequence↗
PubMed1996

Characterization of two genes, p11 and p5, on the Borrelia burgdorferi 49-kilo base linear plasmid.

A putative operon encoding two Borrelia burgdorferi N40 genes, p11 and p5 was cloned and localized to the 49 kilobase linear plasmid. p11 encodes an 11 kDa protein and p5 encodes a 5 kDa protein. The first 88 nucleotides of p11 have 81% identity with orf5 on a circular plasmid from Borrelia afzelii strain Ip21, suggesting that homologues of these genes may be present in different regions of the B. burgdorferi genome.

Animals↗
PubMed1996

Protective antibodies in murine Lyme disease arise independently of CD40 ligand.

Borrelia burgdorferi-infected mice develop acute arthritis that undergoes Ab-mediated resolution. To further investigate the role of B. burgdorferi-specific Abs in Lyme borreliosis, CD40 ligand-deficient (CD40L-deficient) mice were infected with B. burgdorferi. The development and regression of arthritis were similar in CD40L-deficient and control mice. Although CD40L-deficient mice have defects in Ig class switching, infected CD40L-deficient mice developed B. burgdorferi-specific IgG2b Abs. Moreover, the transfer of serum from B. burgdorferi-infected CD40L-deficient animals prevented infection in severe combined immunodeficient mice. These data show that B. burgdorferi-infected CD40L-deficient mice are capable of producing Abs that are protective, despite the inability of these mice to mediate T-dependent immune responses.

Animals↗
PubMed1996

Effect of anti-interleukin 12 treatment on murine lyme borreliosis.

The effect of anti-interleukin (IL-12 treatment on Lyme borreliosis in C3H/HeN (C3H) mice was assessed because other studies have implicated CD4+ T cell helper (Th) type 1 responses in the genesis of disease caused by Borrelia burgdorferi. Infection of inbred mice with B. burgdorferi results in varying degrees of arthritis: BALB/c mice develop mild disease and C3H mice develop severe arthritis that is most pronounced 2-4 wk after infection. Since IL-12 is a major inducer of Th1 responses, we blocked this cytokine in vivo in B. burgdorferi infected C3H mice, and evaluated the effects of treatment on the development of arthritis at the peak of acute joint inflammation (14 d) and in the resolution phase (60 d) of disease. As expected, intraperitoneal administration of an anti-IL-12 monoclonal antibody (mAb) to C3H mice resulted in a decrease in both IFN-gamma and B. burgdorferi-specific IgG2a in serum, indicative of diminished Th1 responses. No IL-4 production was detected in serum of anti-IL-12 mAb treated or control mice. IgG1 and IgG2b levels did not increase in B. burgdorferi infected mice treated with anti-IL-12 mAb compared with controls suggesting that Th2 responses were not affected. Nevertheless, CD4+ T cells from both control and anti-IL-12 mAb treated mice had similar in vitro responses to B. burgdorferi antigens. Treatment with anti-IL-12 mAb produced a significant reduction in peak arthritis severity, and an increase in the number of spirochetes in ear tissue. These data show that treatment of B. burgdorferi infected mice with anti-IL-12 mAb results in a reduction of the Th1 and/or innate immune responses in vivo and a reduction in the severity of acute murine Lyme arthritis.

Animals↗
PubMed1996

Borrelia burgdorferi OspA is an arthropod-specific transmission-blocking Lyme disease vaccine.

Borrelia burgdorferi, the spirochetal agent of Lyme disease, is transmitted by Ixodes ticks. A vaccine based on B. burgdorferi outer surface protein (Osp) A protects mice from spirochete infection. Here we report on the expression of OspA on spirochetes inside engorging ticks and relate OspA expression to antispirochetal immunity. Spirochetes in the gut of unfed nymphal ticks were stained by an OspA antibody, whereas in feeding ticks, the majority of spirochetes in the gut and salivary glands did not stain with the antibody. Thus, OspA was not expressed on most spirochetes during transmission from the vector to the vertebrate host. To examine the mechanism of protection afforded by OspA antibody, mice were passively immunized with OspA antibody at different times relative to tick attachment. When OspA antibody was administered to mice before or at the time of tick attachment, spirochetal development events in the vector, such as growth and salivary gland invasion, were blocked and the mice were protected from B. burgdorferi infection. When OspA antibody was administered to mice 48 h after tick attachment, spirochetes persisted in the nymphs and the mice were not protected despite the presence of circulating antibodies in the host as well as in the tick blood meal. Thus, OspA immunity appears to be effective only during a narrow window time at the beginning of the blood meal when antibodies bind to OspA-expressing spirochetes in the tick gut and block transmission from the vector to the host.

Animals↗
PubMed1996

Nesidioblastosis associated with hyperglycemia in two squirrel monkeys (Saimiri sciureus).

Nesidioblastosis associated with progressive weight loss and hyperglycemia was diagnosed in two mid-adult, wild-caught, male squirrel monkeys (Saimiri sciureus). Hyperglycemia, glucosuria, and abnormal glucose tolerance test results were found when the monkeys were presented for clinical evaluation for chronic weight loss, episodic dehydration, hypothermia, and lethargy. Immunohistochemical studies of the pancreatic tissue demonstrated that the proliferating endocrine cells stained predominantly glucagon-positive in the most severely affected monkey.

Animals↗
PubMed1996

Colonic adenocarcinoma in a rhesus macaque (Macaca mulatta).

A spontaneous colonic adenocarcinoma and endometriosis was diagnosed in a 34-year-old female rhesus macaque (Macaca mulatta). The tumor caused partial obstruction of the ascending colon and histologically resembled the commonly described napkin-ring tumors of the descending and sigmoid colon found in humans. Serum levels of CA 125, a high-molecular-weight glycoprotein antigen that has been reported elevated in a variety of pathological conditions of the pelvic cavity in humans, was severely elevated. Both the adenocarcinoma and the endometriosis may have contributed to this finding.

Adenocarcinoma↗
PubMed1996

P55, an immunogenic but nonprotective 55-kilodalton Borrelia burgdorferi protein in murine Lyme disease.

Immunization of C3H mice with P55 (previously called S1), a 55-kDa Borrelia burgdorferi antigen that is immunogenic after infection, elicited a strong antibody response but did not protect mice against B. burgdorferi challenge. Mice immunized with a P55 fusion protein in complete Freund's adjuvant developed anti-P55 antibodies, detectable at a titer of 1:10,000 by immunoblotting. To determine, if a protective response had been elicited, P55-vaccinated mice were fed upon by ticks infected with B. burgdorferi. The frequency of B. burgdorferi infection was similar in P55-immunized and control mice, and spirochetes were not destroyed within ticks that fed on P55-vaccinated mice. P55 is an immunogenic antigen that does not induce a protective response in the vertebrate or invertebrate host.

Animals↗