Peripheral anergy and local immune hyperactivation in sarcoidosis: a paradox or birds of a feather

Abstract

Sarcoidosis is a multisystem non-caseating granulomatous disorder, which is frequently self-limiting. Not only does its aetiology remain an enigma, but equally curious is its immunological background, which appears to be pathognomonic for this disease. Studies have shown aberrant cell-mediated active, if not overactive, immune responses at sites of inflammation [1] in the presence of hypergammaglobulinaemia [2] and cutaneous anergy to particular antigens, including tuberculoprotein but not Kveim antigen [3]. This apparent paradox in peripheral and local cellular immune responses, with preferential activation at the organ level, has provoked a great deal of interest over the years, and begged the question of whether the proposed depression in peripheral cellmediated immunity in sarcoidosis is in fact real or apparent. The accumulation of activated oligoclonal CD4 T lymphocytes [4] and specific subpopulations of macrophages [5,6], together with a release of various proinflammatory cytokines [7], determine the immune phenomena as well as the development and fate of granulomata at the sites of sarcoid inflammation. The recruitment of CD4 T lymphocytes around granulomata is more prominent within fresh active lesions, and tends to diminish as the granulomata mature [8]. Indeed, as lesions become less active, these cell types decrease, and T cells expressing CD8 surface antigens predominate [8]. A similar switch in immunoregulatory T cells has also been observed in animal models of granulomatous lung disease [9,10]. In patients with active sarcoidosis, the increase in activated T cell numbers at sites of granulomatous inflammation is simultaneously accompanied by an absolute decrease in the number of circulating T cells in autologous peripheral blood. One of the earliest immunological abnormalities to be observed in active sarcoidosis is a partial to complete anergy to tuberculin purified protein derivative (PPD). Such skin anergy also extends to certain antigens, e.g. Trichophyton, mumps virus, streptokinase/ streptodornase, Candida, as well as dinitrochlorobenzene. The incidence of anergy to tuberculoprotein and other antigens in sarcoid patients varies from 30% to 70%, depending on the number of antigens used [3,11,12]. This anergy appears to parallel disease severity, being especially marked when the sarcoidosis is clinically active, and disappearing months to years after resolution of the disease. Usually such cutaneous anergy is associated with depressed cellular immunity. The partial cutaneous anergy observed in sarcoidosis is frequently attributed to a reduction in the number and function of circulating T lymphocytes [13]. It has been suggested that the reduction of delayed-type skin test reactivity could reflect a depletion of the population of immunoreactive cells being sampled from the skin. It is recognized that in granulomatous disease there is an altered circulating pattern for T lymphocytes with the onset of inflammation. In particular, CD4 T cells become sequestrated in central lymphoid organs and sites of inflammation, leaving proportionately increased numbers of CD8 T cells in the peripheral blood [14]. In sarcoid patients, the ratio of CD4 to CD8 T cells in the blood may be normal or slightly decreased, with corresponding T cell ratio in the lung being 4–10 times greater than normal [15]. At the height of inflammation, the compartmentalized CD4 T cells have been shown to express IL-2R, very late activation Ag1, and DR class II MHC molecules: the hallmarks of antigenstimulated T cells [16,17]. In addition, it appears that these CD4 T lymphocytes are oligoclonal, consistent with a conventional antigen-driven process [18,19] (albeit the nature of the antigenic stimulus in sarcoidosis remains unclear). However, whilst T cells obtained from inflamed sites appear to be activated both morphologically and functionally, with augmented responses to external stimuli such as lectins and antigens, the functional response of autologous peripheral blood lymphocytes to mitogen and recall antigen is impaired, with consequent depression of B cell function in vitro. In addition, inhibitory factors, partly derived from monocytes, have been isolated from the blood of active sarcoid patients, and shown to inhibit the in vitro response of normal lymphocytes to mitogens and antigens [13,20,21]. Such findings in the peripheral blood have been related to the observed depression in certain cutaneous delayed hypersensitivity responses [13,22]. Despite this apparent cutaneous anergy, patients with sarcoidosis are uniquely capable of mounting a positive cutaneous reaction to a Kveim antigen. The mechanisms of this Kveim response are not entirely clear. Although Kveim test lesions exhibit histopathologic similarities to sarcoid granulomata, there are marked differences between the Kveim reaction and the classic DTH skin response. The most obvious difference is in the kinetics of the two reactions. DTH reaction begins at 8 h, peaks at 24–48 h, and resolves by 96–120 h. By contrast, the Kveim reaction takes 4–6 weeks to develop. Furthermore, no specific antigen in the Kveim preparation has been identified as the inducing agent in this response, and no convincing data have been generated to show reproducibly that sarcoid lymphocytes are actively sensitized to the Clin Exp Immunol 1997; 110:1–3