Lower numbers of natural killer T cells in HIV-1 and Mycobacterium leprae co-infected patients.

Natural killer T (NKT) cells are a heterogeneous population of lymphocytes that recognize antigens presented by CD1d and have attracted attention because of their potential role linking innate and adaptive immune responses. Peripheral NKT cells display a memory-activated phenotype and can rapidly secrete large amounts of pro-inflammatory cytokines upon antigenic activation. In this study, we evaluated NKT cells in the context of patients co-infected with HIV-1 and Mycobacterium leprae. The volunteers were enrolled into four groups: 22 healthy controls, 23 HIV-1-infected patients, 20 patients with leprosy and 17 patients with leprosy and HIV-1-infection. Flow cytometry and ELISPOT assays were performed on peripheral blood mononuclear cells. We demonstrated that patients co-infected with HIV-1 and M. leprae have significantly lower NKT cell frequencies [median 0.022%, interquartile range (IQR): 0.007-0.051] in the peripheral blood when compared with healthy subjects (median 0.077%, IQR: 0.032-0.405, P < 0.01) or HIV-1 mono-infected patients (median 0.072%, IQR: 0.030-0.160, P < 0.05). Also, more NKT cells from co-infected patients secreted interferon-γ after stimulation with DimerX, when compared with leprosy mono-infected patients (P = 0.05). These results suggest that NKT cells are decreased in frequency in HIV-1 and M. leprae co-infected patients compared with HIV-1 mono-infected patients alone, but are at a more activated state. Innate immunity in human subjects is strongly influenced by their spectrum of chronic infections, and in HIV-1-infected subjects, a concurrent mycobacterial infection probably hyper-activates and lowers circulating NKT cell numbers.

A potential role for complement in immune evasion by Mycobacterium leprae.

Lepromatous leprosy is a model of immune evasion wherein pathogen-specific IL-10-secreting T cells and concomitant failure of Th-1 immunity permit uncontrolled proliferation of the intracellular pathogen, Mycobacterium leprae (M. leprae). The mechanism of this immune escape is unknown. Here, the authors report that phenolic glycolipid-1 (PGL-1), a major and distinguishing feature of the M. leprae cell wall, is expressed in the cell membrane of M. leprae-infected human dendritic cells, where it can activate complement in human serum. The authors demonstrate that PGL-1 and the C3 component of complement colocalize in lipid rafts in the dendritic cell membrane, and enter the immune synapse upon co-culture of M. leprae-infected DCs and T cells. Hence, activated C3 is strategically located to costimulate naïve T cells via the complement regulatory protein, CD46, a process known to stimulate the differentiation of IL-10-secreting regulatory T cells. These observations suggest a potential novel mechanism of immune evasion, wherein M. leprae may subvert host natural immunity to provoke an adaptive response that favors bacillary survival.

Immune cellular parameters of leprosy and human immunodeficiency virus-1 co-infected subjects.

Leprosy and human immunodeficiency virus-1 (HIV-1) are examples of human infections where interactions between the pathogen and the host cellular immunity determine the clinical manifestations of disease. Hence, a significant immunopathological interaction between HIV-1 and leprosy might be expected. In the present study we explored several aspects of cellular immunity in patients co-infected with HIV-1 and Mycobacterium leprae. Twenty-eight individuals were studied, comprising four groups: healthy controls, HIV-1 and M. leprae co-infection, HIV-1 mono-infection, and M. leprae mono-infection. Subjects in the mono-infection and co-infection groups were matched as far as possible for bacillary load and HIV disease status, as appropriate. Peripheral blood mononuclear cells (PBMC) were analysed using six- and seven-colour flow cytometry to evaluate T-cell subpopulations and their activation status, dendritic cell (DC) distribution phenotypes and expression of IL-4 by T cells. The co-infected group exhibited lower CD4 : CD8 ratios, higher levels of CD8(+) T-cell activation, increased V delta : V delta 2 T cell ratios and decreased percentages of plasmacytoid DC, compared with HIV-1 mono-infected subjects. Across infected groups, IL-4 production by CD4(+) T lymphocytes was positively correlated with the percentage of effector memory CD4(+) T cells, suggesting antigenically driven differentiation of this population of T cells in both HIV-1 and M. leprae infections. Co-infection with M. leprae may exacerbate the immunopathology of HIV-1 disease. A T helper 2 (Th2) bias in the CD4(+) T-cell response was evident in both HIV-1 infection and leprosy, but no additive effect was apparent in co-infected patients.

Effective treatment of erythema nodosum leprosum with thalidomide is associated with immune stimulation.

The immunomodulatory drug thalidomide is the treatment of choice for erythema nodosum leprosum (ENL), an inflammatory cutaneous and systemic complication of multibacillary leprosy. To elucidate the mechanism of action of thalidomide in this syndrome, we prospectively investigated 20 patients with ENL who were treated with thalidomide for 21 days. All patients responded to treatment, with the majority of them having complete resolution of cutaneous lesions within 7 days. This response was associated with a marked but transient increase in ex vivo mitogen-induced expression of interleukin (IL)-2 and interferon- gamma by CD4(+) and CD8(+) T cells that was observed on treatment day 7, but these returned to pretreatment levels by day 21. Plasma tumor necrosis factor- alpha levels were not high at baseline, and they increased modestly during treatment. Plasma levels of IL-12 increased steadily during thalidomide treatment. Hence, the therapeutic effect of thalidomide in ENL appears to be associated with transient immune stimulation, which suggests that the drug may promote an active immunoregulatory response.

Regulation of acquired immunity by gamma delta T-cell/dendritic-cell interactions.

In humans, innate immune recognition of mycobacteria, including Mycobacterium tuberculosis and Mycobacterium leprae, involves toll-like receptor-2 (TLR-2), expressed on immature dendritic cells (DCs), and the T-cell gammadelta receptor expressed by a subpopulation of T cells that utilize Vdelta2 (Vdelta2 T cells). To investigate modulatory relationships between these host-cell populations in a microbial context, in vitro experiments were performed with human DCs and Vdelta2 T cells stimulated with model TLR-2 ligands and phosphoantigens, respectively. We observed that TLR-2-stimulated DCs enhanced interferon-gamma (IFN-gamma) production by Vdelta2 T cells; conversely, activated Vdelta2 T cells enhanced TLR-2-induced DC maturation via soluble factors including IFN-gamma, which costimulated interleukin-12 (IL-12) p70 secretion by DCs. Exposure of DCs to activated Vdelta2 T cells was critical for Th1 T-cell priming when TLR-2 stimulation was limiting. These results suggest that Vdelta2 T cells may play an adjuvant role in priming protective antimycobacterial immunity when TLR-2 stimulation is lacking, as may occur if the infectious inoculum is small, or if the pathogen is an intrinsically weak activator of DCs.

Mycobacterium tuberculosis inhibits maturation of human monocyte-derived dendritic cells in vitro.

To induce effector immunity, dendritic cells (DCs) must differentiate into fully mature cells. We show that, after human monocyte-derived DCs were infected with virulent Mycobacterium tuberculosis, up-regulation of cellular-surface maturation markers was minimal and reversible. In the presence of a potent stimulus for maturation (tumor necrosis factor [TNF]-alpha, interleukin [IL]-1beta, and prostaglandin E2 [PGE2]), M. tuberculosis inhibited phenotypic DC maturation. M. tuberculosis-infected DCs had an impaired ability to induce allogeneic lymphoproliferation and activated autologous memory CD4+ and CD8+ T cells optimally only in the presence of TNF-alpha, IL-1beta, and PGE2. Thus, virulent M. tuberculosis inhibits phenotypic and functional maturation of human monocyte-derived DCs. This mechanism, which has been described elsewhere for various viruses and for the virulent mycobacterium M. leprae, may be a novel mechanism that this pathogen uses to evade the host's immune response.

Local nerve damage in leprosy does not lead to an impaired cellular immune response or decreased wound healing in the skin.

This study investigated whether peripheral nerve damage in patients with leprosy impairs local cellular immune responses, thereby reducing wound healing and leading to chronic skin ulceration. Anesthetic and contralateral sensitive skin sites in 42 patients with leprosy were compared for delayed-type hypersensitivity responses to purified protein derivative (PPD) of tuberculin. Leukocyte recruitment, epidermal activation, keratinocyte proliferation, and rates of wound healing after skin biopsy were compared. No significant differences in PPD-induced induration, epidermal activation and thickening or numbers of total T cells, CD8+ T cells, CD1a+ Langerhans cells, and proliferating Ki67+ keratinocytes were observed between anesthetic and sensitive skin sites. Similarly, rates of wound healing over 5 days after skin biopsy did not differ significantly. Thus, local leprosy-associated anesthesia does not appear to contribute to local immune compromise or impaired wound healing. Rather, chronic cutaneous ulceration in leprosy most likely results from repeated trauma associated with loss of sensation.