Asymptomatic Borrelia-seropositive individuals display the same incidence of Borrelia-specific interferon-gamma (IFN-γ)-secreting cells in blood as patients with clinical Borrelia infection

Lyme disease is a complex disorder that sometimes becomes chronic. There are contradictory reports of experimental Borrelia infections regarding which type of T cell cytokine responses, i.e. Th1 or Th2, are needed to eradicate the Borrelia spirochaetes. In human borreliosis a predominance of Borrelia-specific Th1-like responses has been shown. In this study, spontaneous, as well as Borrelia-specific, secretion of IFN-γ (Th1) and IL-4 (Th2) in Borrelia-seropositive healthy asymptomatic individuals (n = 17) was investigated in peripheral blood by a sensitive ELISPOT assay, and compared with previously reported responses in patients with clinical Borrelia infection (n = 25). The seropositive asymptomatic individuals displayed the same predominance of Borrelia-specific IFN-γ-secreting cells as the patients with clinical Borrelia infection. Interestingly, the proportion of spontaneously IL-4-secreting cells, reflecting the unstimulated in vivo secretion, was lower in the seropositive asymptomatic individuals compared with patients with chronic Borrelia infections (n = 13, P = 0.02), whereas no such difference was found compared with subacute Borrelia infections (n = 12). These findings indicate that IFN-γ secretion alone is not sufficient to eliminate Borrelia spirochaetes in humans, although IFN-γ may still have a beneficial role in borreliosis acting in concert with other mechanisms

CD4(+) T Helper 1 Cells Facilitate Regression of Murine Lyme Carditis

Murine Lyme borreliosis, caused by infection with the spirochete Borrelia burgdorferi, results in acute arthritis and carditis that regress as a result of B. burgdorferi-specific immune responses. B. burgdorferi-specific antibodies can attenuate arthritis in mice deficient in both B cells and T cells but have no effect on carditis. Because macrophages comprise the principal immune cell in carditis, T-cell responses that augment cell-mediated immunity may be important for carditis regression. To investigate this hypothesis, we examined the course of Lyme carditis in mice selectively deficient in B cells or αβ T cells. Our results show that carditis regresses in B-cell-deficient B10.A(k) mice but not in αβ T-cell-deficient mice, independently of the mouse strain background. Despite prominent macrophage infiltrates, hearts from B. burgdorferi-infected αβ T-cell-deficient mice had less mRNA for tumor necrosis factor alpha as measured by reverse transcription-PCR compared to infected control mice. Anti-inflammatory cytokine mRNA levels were equivalent. Adoptive transfer of gamma interferon-secreting CD4(+) T cells into infected αβ T-cell-deficient mice promoted carditis resolution. These results show that αβ T cells can promote resolution of murine Lyme carditis and are the first demonstration of a beneficial role for CD4(+) T helper 1 cells in this disease

Coinfection with Borrelia burgdorferi and the Agent of Human Granulocytic Ehrlichiosis Alters Murine Immune Responses, Pathogen Burden, and Severity of Lyme Arthritis

Lyme disease and human granulocytic ehrlichiosis (HGE) are tick-borne illnesses caused by Borrelia burgdorferi and the agent of HGE, respectively. We investigated the influence of dual infection with B. burgdorferi and the HGE agent on the course of murine Lyme arthritis and granulocytic ehrlichiosis. Coinfection resulted in increased levels of both pathogens and more severe Lyme arthritis compared with those in mice infected with B. burgdorferi alone. The increase in bacterial burden during dual infection was associated with enhanced acquisition of both organisms by larval ticks that were allowed to engorge upon infected mice. Coinfection also resulted in diminished interleukin-12 (IL-12), gamma interferon (IFN-γ), and tumor necrosis factor alpha levels and elevated IL-6 levels in murine sera. During dual infection, IFN-γ receptor expression on macrophages was also reduced, implying a decrease in phagocyte activation. These results suggest that coinfection of mice with B. burgdorferi and the HGE agent modulates host immune responses, resulting in increased bacterial burden, Lyme arthritis, and pathogen transmission to the vector

Immunohistochemical Analysis of Lyme Disease in the Skin of Naive and Infection-Immune Rabbits following Challenge

In this study, skin histopathology from naive and infection-derived immune rabbits was compared following intradermal challenge using Borrelia burgdorferi B31 strain. The presence or absence of spirochetes in relationship to host cellular immune responses was determined from the time of intradermal inoculation to the time of erythema migrans (EM) development (∼7 days in naive rabbits) and through development of challenge immunity (∼5 months in naive rabbits). Skin biopsies were obtained and analyzed for the presence of spirochetes, B cells, T cells, polymorphonuclear cells (PMNs), and macrophages by immunohistochemical techniques. In infected naive animals, morphologically identifiable spirochetes were detected at 2 h and up to 3 weeks postinfection. At 12 and 24 h postinfection there was a marked PMN response that decreased by 36 to 48 h; by 72 h the PMNs were replaced by a few infiltrating macrophages. At the time of EM development and 14 days postinfection, the PMNs and macrophages were replaced by a lymphocytic infiltrate. There was a greater number of spirochetes at 14 days, a time when EM had resolved, than at 7 days postinfection. By 3 weeks postinfection there were few organisms and lymphocytes detectable. In contrast to infected naive rabbits, intact spirochetes were never visualized in skin biopsies from infection-immune rabbits; only spirochetal antigen was detected at 2, 12, and 24 h in the presence of a numerous PMN infiltrate. By 36 h postchallenge, spirochetal antigen could not be detected and the PMN response was replaced by a few infiltrating macrophages. By 72 h postchallenge, PMNs and macrophages were absent from the skin; B and T cells were never detected at any time point in skin from infection-immune rabbits. The destruction of spirochetes in immune animals in the presence of PMNs and in the absence of a lymphocytic infiltrate suggests that infection-derived immunity is antibody mediated