Serological markers of disease activity in tuberculosis and HIV infection

HIV and Mycobacterium tuberculosis are important pathogens leading to persistent infection in humans. The majority of HIV-infected patients progress to AIDS. Only about 10% of patients are non-progressors and remain free of AIDS for many years. In contrast, most subjects infected with M. tuberculosis will remain free of disease and only 5–10% will develop clinical tuberculosis (TB). Markers of disease activity are needed to evaluate disease progression and to monitor response to therapy. A number of serological markers of disease activity have been studied in HIV and M. tuberculosis-infected patients. They are generally referred to as markers of immune activation. This state of immune activation reflects a complex host response to the pathogens and could play an important role in the pathogenesis of the disease. The pattern of serological markers of immune activation could vary according to the pathogen. Markers discriminating co-pathogens would be particularly useful for the monitoring of HIV infection. In this issue, Lawn et al. present data suggesting that soluble tumour necrosis factor receptor type 1 (sTNF-RI) and β₂-microglobulin (β₂-M) could be used as independent markers of disease activity in TB and HIV infection, respectively.

Patients with HIV infection have elevated serum concentrations of a number of markers of immune activation. Some of these markers, including β₂-M, neopterin, soluble IL-2 receptor and sTNF-RII, have been shown to have prognostic significance [1–5]. Lederman et al. recently suggested that sTNF-RII is the marker of immune activation most independently correlated with HIV viral load [6]. In developing countries where CD4 count and viral load can often not be assessed, serological markers of immune activation could represent an affordable alternative to monitor disease progression and to assist management of patients. In addition, these molecules could also provide unique information about disease activity. Data reported by Salazar-Gonzalez et al. indicate that immune activation precedes, sometimes by several years, the increase in viral load and the loss of CD4 lymphocytes [7]. This observation supports the concept that immune activation plays a role in the pathogenesis of AIDS. Immune activation could accelerate disease progression by stimulating viral replication and by inducing apoptosis of T lymphocytes. Michel et al. reported that serum concentrations of β₂-M are correlated with apoptosis of CD4 and CD8 lymphocytes in patients with HIV-1 or HIV-2 infection [8]. Moreover, patients with HIV-2 infection who have slower disease progression compared with patients with HIV-1 infection also show lower immune activation and lymphocyte apoptosis [8]. The TNF pathway could play an important role in disease progression. The interaction between TNF-α and the TNF-RII mediates the apoptosis of CD8 lymphocytes induced by HIV [9]. TNF-α was shown either to stimulate HIV replication through its interaction with TNF-RI or to inhibit viral replication through TNF-RII [10]. The preferential increase in the serum concentration of sTNF-RII compared with sTNF-RI in HIV-infected patients [3,11] (Lawn et al., this issue) could be related to the role played by sTNF-RII in the control of HIV replication and death of CD8 cells [10,12]. Another marker of immune activation which could play an important role in the pathogenesis of AIDS is IL-16. IL-16 is a ligand for CD4 and was shown to inhibit HIV replication [13,14]. Amiel et al. reported that serum IL-16 concentrations are elevated in patients with asymptomatic HIV infection and decrease with disease progression [13]. The combination of markers of immune activation that are up-regulated or down-regulated during disease progression could increase their prognostic significance. The monitoring of HIV infection requires markers that are not directly stimulated by co-pathogens. Data reported in this issue by Lawn et al. indicate that the serum concentration of β₂-M is not influenced by TB in HIV-infected patients. Prospective studies are needed to confirm this observation and to evaluate the effect of other co-infections on the serum concentrations of β₂-M and other markers of immune activation [15–18]. The relative stability of serum concentrations of β₂-M further supports its potential interest in the monitoring of HIV infection [19]. Another important use of serological markers in HIV-infected patients could be the monitoring of anti-retroviral therapy [20,21].

Little is known about the effect of primary M. tuberculosis infection on markers of immune activation. Data reported by Juffermans et al. indicate that contacts of TB cases have elevated serum concentrations of sTNF-RII, and to a lesser extent sTNF-RI [22]. As for HIV, the initial immune response could determine the ability of the host to control the infection with M. tuberculosis. Serological markers of immune activation could be useful in the identification of individuals at higher risk of developing TB and who would benefit from anti-mycobacterial chemotherapy. TB disease is associated with the increase of a number of soluble markers of immune activation [22–27]. As in HIV infection, this immune activation is associated with a state of immunosuppression [24]. Compared with healthy contacts, TB patients have defective interferon-gamma (IFN-γ) responses and increased apoptosis of CD4 lymphocytes [28]. Recent data obtained in mice suggest that the increased apoptosis of CD4 cells is a consequence of immune activation and is dependent on IFN-γ[29]. Other molecules, like TNF-α, could also be involved. IFN-γ plays a central role in the defence against mycobacteria [30]. Its suppression in TB patients could therefore play an important role in the pathogenesis of the disease. In contrast to HIV infection, patients with TB have high serum concentrations of sTNFR-1 [22] (Lawn et al., this issue). Interestingly, among patients with leprosy, elevated serum concentrations of sTNF-RI were only observed in subjects with lepromatous leprosy and type II reactions to therapy [31]. This suggests that during mycobacterial infections, the shedding of sTNF-RI is associated only with some types of immune responses. The shedding of sTNRs is induced by TNF-α and their serum concentrations could therefore reflect TNF-α bioactivity [32]. In soluble form, sTNF-Rs can neutralize or stabilize the bioactivity of TNF-α[32]. Among the other markers of disease activity in TB, IgE could be of special interest. Adams et al. recently reported that in patients with TB, therapy is associated with a reduction of serum IgE concentrations [33]. These data suggest that TB is associated with a T helper type 2 (Th2) response and that markers of Th2 activity could be useful in the monitoring of the disease. Other markers of immune activation have been studied in TB patients under anti-mycobacterial therapy. Some markers were found to be rapidly modulated by therapy but others remain elevated for several months [22,26,27,34].

Prospective studies are needed to evaluate markers that could be specifically associated with HIV infection, tuberculosis or infection with other co-pathogens. Standardized quality control of laboratory measurements will be required [35].