The Immunopathobiology of Syphilis: The Manifestations and Course of Syphilis Are Determined by the Level of Delayed-Type Hypersensitivity

Abstract

Syphilis has plagued mankind for centuries and is currently resurgent in the Western hemisphere. While there has been a significant reduction of tertiary disease, and recognition of facilitative interactions with HIV infection, the natural history of syphilis has remained largely unchanged; thus, new strategies are required to more effectively combat this pathogen. The immunopathologic features of experimental syphilis in the rabbit; the course, stages, and pathology of human syphilis; and a comparison of human syphilis with leprosy suggest that the clinical course of syphilis and its tissue manifestations are determined by the balance between delayed type hypersensitivity (DTH) and humoral immunity to the causative agent, Treponema pallidum. A strong DTH response is associated with clearance of the infecting organisms in a well-developed chancre, whereas a cytotoxic T-cell response or strong humoral antibody response is associated with prolonged infection and progression to tertiary disease. Many of the protean symptoms/appearances of secondary and tertiary human syphilis are manifestations of immune reactions that fail to clear the organism, due to a lack of recruitment and more importantly, activation of macrophages by sensitized CD4 T-cells. The Bacillus Calmette Guerin (BCG) vaccination can enhance DTH and has been shown to produce a low, but measurable beneficial effect in the prevention of leprosy, a disease that shows a disease spectrum with characteristics in common with syphilis. In the prevention of syphilis, a potential vaccine protective against syphilis should be designed to augment the DTH response.

Lymphocytic Arteritis in Epstein–Barr Virus Vulvar Ulceration (Lipschütz Disease)

“…The relative proportion of CD4, CD8, and CD20 lymphocytes and neutrophils could represent the balance between humoral-and cell-mediated immune responses and EBV infection. 39 The report of a case of lymphocytic vasculitis in EBVVU documents precedence. 20 In addition, numerous reports chronicle the frequent association of EBV and other herpesviridae with large vessel vasculitis, giant cell arteritis, Kawasaki-like vasculitis, polyarteritis nodosa, and smallmuscular vessel vasculitis.…”

“…Overall, this constellation of histopathologies points to a cell-mediated, type-IV, hypersensitivity response, and/or cytotoxic T-cell response. 39 EBV LMP1 or other undetectable EBV antigens, locally expressed by vulvar tissue might trigger and promote a pathologic immune response that causes vulvar ulceration. 37 The prominent neutrophilic response found in many of the specimens, in part, maybe attracted to the site secondarily to the presence of necrotic tissue, and/or they could represent a concomitant type-III hypersensitivity reaction.…”

Syphilis the great pretender: when is cancer not cancer?

“…The underlying pathophysiology is of an obliterative endarteritis 2. Although it predates the HIV epidemic, it is rarely described in the HIV uninfected population (incidence 0.12%–0.36%) 3…”

Vaccine development for syphilis

“…Primary lesions in humans as well as primary and secondary lesions in rabbits contain predominantly CD4 + T-cells, macrophages, and natural killer (NK) cells, whereas analysis of the cellular infiltrate of human secondary lesions reveals a higher abundance of CD8 + T-cells relative to CD4 + T-cells [60,61]. The induction of a strong delayed-type hypersensitivity (DTH) reaction is critical to the efficient clearance of T. pallidum from lesion sites [62]. Such a response requires local production of Th1 cytokines including interferon-γ (IFN-γ), interleukin-2 (IL-2), and interleukin-12 (IL-12) [58,63–67].…”