Synergistic effect of macrophage activation and immune serum, especially IgG2, on resistance to infection with Treponema pallidum ssp. endemicum in hamsters.

Experimental studies have indicated that macrophages are involved in the pathogenesis of syphilis. Whether macrophages alone or with immune serum are ultimately responsible for killing of treponemes is disputed. We have demonstrated that BCG-vaccinated hamsters administered normal serum contained fewer treponemes in the inguinal and popliteal lymph nodes than did the nonvaccinated controls. When BCG-vaccinated hamsters were injected with syphilitic immune serum and challenged with Treponema pallidum ssp. endemicum, treponemicidal activity was enhanced. Treponemicidal activity was also detected in BCG-vaccinated hamsters challenged with treponemes treated in vitro with immune serum and its immunoglobulin fractions, especially IgG2. The immune IgG2 fraction had more treponemicidal activity than did the immune IgG1 fraction and the unfractionated immune serum. Our observations indicate an important synergistic role for macrophages and immune serum, especially IgG2, for elimination of T. pallidum ssp. endemicum from the host.

Asymptomatic poststreptococcal glomerulonephritis in relatives of patients with symptomatic glomerulonephritis. Diagnostic value of endostreptosin antibodies.

Our previous studies have shown that endostreptosin (ESS), a cytoplasmic protein of group A streptococci, in all probability is the causative agent of poststreptococcal acute glomerulonephritis (PSAGN). Elevated antibody levels to ESS have been shown to be diagnostic for PSAGN and to correlate well with the course of the pathologic disease process. One hundred and twenty-one completely asymptomatic family members of 29 index patients with overt PSAGN were studied. Of these 121 asymptomatic family members, 26 (21.5%) had two or more abnormalities warranting a diagnosis of asymptomatic glomerulonephritis (GN): proteinuria/hematuria (18), low C3 (10 less than 85 mg/dl), high antibody titers to streptolysin O (15). Twenty-three (88.5%) of these family members with evidence of asymptomatic GN had a significant elevation of ESS antibody titers. The mean arithmetic titer for the complement fixation test was 1:24 (normal less than 1:7.5) and the mean ELISA value 0.154 (normal less than 0.075). With a certain percentage of PSAGN cases, especially adults, progressing to chronicity, the ESS antibody determinations by complement fixation and/or ELISA may be simple methods to detect and to follow-up such asymptomatic patients at risk. The high incidence of asymptomatic PSAGN (26/121) in family members of patients with overt PSAGN makes these data very significant in respect to the question of the origin of chronic glomerulonephritis without a history of overt PSAGN. Since chronic PSAGN is probably a sequel of an undiagnosed, asymptomatic disease, it may contribute materially to the contingent of end-stage renal disease.

Effect of immune serum and its immunoglobulin fractions on hamsters challenged with Treponema pallidum ssp. pertenue.

Passive transfer of frambesial immune serum is capable of conferring complete protection on hamsters against challenge with Treponema pallidum ssp. pertenue. Treponemicidal activity in the pooled immune serum is relatively high. Immune serum and its immunoglobulin fractions, especially IgG2, also killed T. pallidum ssp. pertenue in vitro. Treponemicidal activity was present only when immune serum was administered to hamsters within a short time (three days) of frambesial challenge. By contrast, administration of pooled immune serum to hamsters infected for more than one week failed to reduce the number and size of lesions and the weight and number of treponemes in the lymph nodes. These results suggest that hamsters can develop the humoral components necessary to protect them against frambesial challenge, but these components are unable to destroy treponemes at the primary foci of infection.

The participation of activated peritoneal macrophages in Treponema pallidum subspecies pertenue infection in Syrian hamsters.

The role of cell-mediated immunity in hamsters during treponemal infection appears to involve the activated macrophage. To date, studies have been hindered by the inability to confirm that macrophages exhibit enhanced treponemicidal activity at the infection site. We show that lipopolysaccharide and thioglycollate-treated animals, when inoculated with Treponema pallidum subsp. pertenue, exhibit enhanced clearance of these organisms compared with controls. Macrophages from these infected groups display an enhanced respiratory burst, as detected by NBT reduction, as well as a marked increase in C3b receptor-mediated ingestion activity. Significant changes in these parameters indicate that alterations in macrophage activation are occurring in the infected compartment. Thus the stimulatory agents apparently modify the host's immune responses to promote subsequent reduction of treponemal infection. In addition, hamster peritoneal macrophages demonstrate enhanced activation behavior as a result of exposure to at least two signals, which may be prerequisite for processing this organism efficiently.

Inhibition of macrophage C3b-mediated ingestion by syphilitic hamster T cell-enriched fractions.

Macrophages are important for host defense against syphilitic infection. Our results show that C3b-mediated ingestion (C3bMI), a characteristic of activated macrophages, was inhibited in vitro by nonadherent cells from hamsters infected with Treponema pallidum subspecies endemicum. When macrophage target cells from normal, syphilitic, or lipopolysaccharide-treated animals were co-cultured with nonadherent cells derived from normal or syphilitic hamsters, noticeable differences were detected. Nonadherent syphilitic cells significantly suppressed macrophage C3bMI, whereas normal nonadherent cells displayed little or no suppressive activity. In general, macrophage C3bMI was reduced by nonadherent cells obtained throughout the course of syphilitic infection, although it eventually began to recover. The syphilitic nonadherent cells with maximum suppressive effect were those obtained from hamsters infected for 3 to 6 wk. The addition of treponemal antigens additionally inhibited C3bMI. The inhibitory effect of syphilitic nonadherent cells on either lipopolysaccharide-treated or syphilitic macrophages was sustained even when the nonadherent cells were removed from the cultures, and the effect continued for at least 72 hr thereafter. Fractionation of syphilitic nonadherent cell populations by two independent methods produced T cell-enriched preparations with significantly more suppressive activity than non-T cell-enriched preparations. These observations may account for the chronicity of syphilitic infection.

Cobra venom factor abrogates passive humoral resistance to syphilitic infection in hamsters.

Cobra venom factor, an agent commonly used to deplete complement, lowered the resistance of hamsters to infection with Treponema pallidum subsp. endemicum , as shown by a more rapid development of cutaneous lesions in infected animals treated with cobra venom factor than in infected, untreated animals. Cobra venom factor also abrogated the passive transfer of resistance by injection of serum from syphilitic immune hamsters. These results indicate that complement influences the pathogenesis of treponemal infection.

Immune serum confers protection against syphilitic infection on hamsters.

Pooled serum from hamsters immune to syphilitic infection conferred complete protection on recipient hamsters challenged with Treponema pallidum subsp. endemicum. Cutaneous lesions did not develop, and the recipients' lymph nodes weighed less than those of controls and contained no treponemes. Treponemicidal activity in the pooled immune serum was relatively high. When treponemes were incubated in immune serum and complement and the suspension was then inoculated into hamsters, recipients developed neither lesions nor enlarged lymph nodes teeming with treponemes. With hamsters already infected for several weeks, however, immune serum failed to impair or influence the progression of syphilis. Treponemes were eliminated only when immune serum was administered within a short time of syphilitic infection. These results demonstrate that hamsters develop an effective serum-mediated treponemicidal response, but this response is not sufficient to eliminate treponemes at the primary foci of infection.

Effect of local and systemic macrophage activation in hamsters on infection with Treponema pertenue and Treponema pallidum Bosnia A.

The role of nonspecific macrophage activation in the destruction of treponemes needs to be defined. Studies have been hindered by an inability to confirm that macrophages have enhanced bactericidal activity at the site of treponemal infection. We show that subcutaneous and intravenous vaccination with BCG (Mycobacterium bovis) induces macrophage activation in hamsters, as determined by an enhanced ability to suppress the growth of Listeria monocytogenes in the livers, spleens, and inguinal lymph nodes. However, hamsters challenged in the inguinal region with Treponema pertenue during periods of enhanced microbial resistance (3 to 8 weeks after BCG vaccination) developed lesions faster and with more necrosis. Increased numbers of treponemes were recovered from the regional lymph nodes of BCG-vaccinated hamsters than from nonvaccinated controls, although the differences were not statistically significant. No pathological differences were detected in BCG-vaccinated and non-vaccinated hamsters challenged with Treponema pallidum Bosnia A. These studies demonstrate that BCG vaccination influences the pathogenesis of some treponemal diseases without inducing macrophage-mediated treponemicidal activity.

Acquired resistance of hamsters to challenge with homologous and heterologous virulent treponemes.

Hamsters infected with Treponema pallidum Nichols (venereal syphilis), T. pallidum Bosnia A (endemic syphilis), or T. pertenue (frambesia, or yaws) developed substantial resistance to homologous reinfection. Hamsters infected for 10 weeks developed no lesions, and their lymph nodes contained fewer treponemes after reinfection with the same strain. The degree of cross-resistance among the treponemes correlated well with pathological changes occurring in infected hamsters and with the persistence of treponemal antigen during primary infection. Only hamsters infected with T. pallidum Bosnia A developed substantial resistance to heterologous reinfection. These animals also had extensive chronic skin lesions and lymph nodes containing measurable numbers of treponemes. Frambesial hamsters had less extensive lesions and were resistant to T. pallidum Nichols and, to a lesser extent, to T. pallidum Bosnia A. Hamsters infected with T. pallidum Nichols developed no cutaneous lesions and were resistant only to reinfection with T. pertenue. Confirmation of these results was obtained in normal hamsters infused with syphilitic (Nichols or Bosnia A) or frambesial immune cells and challenged with homologous or heterologous treponemes.