Mycobacterium indicus pranii protein MIP_05962 induces Th1 cell mediated immune response in mice.

Utility of Mycobacterium indicus pranii (MIP) as a multistage vaccine against mycobacterial infections demands identification of its protective antigens. We explored antigenicity and immunogenicity of a candidate protein MIP_05962 that depicts homology to HSP18 of M. leprae and antigen1 of Mycobacterium tuberculosis. This protein elicited substantial antibody response in immunized mice along with modulation of cellular immune response towards protective Th1 type. Both CD4+ and CD8+ subsets from immunized mice produced hallmark protective cytokines, IFN-γ, TNF-α and IL-2. This protein also enhanced the CD4+ effector memory that could act as first line of defence during infections. These results point to MIP_05962 as a protective antigen that contributes, in conjunction with others, to the protective immunity of this live vaccine candidate.

Leprosy and American cutaneous leishmaniasis coinfection.

Brazil is a country with a high prevalence of infectious diseases such as leprosy and leishmaniasis. However, coinfection of these diseases is still poorly understood. We report a case of a patient who presented with lepromatous leprosy and cutaneous-mucosal leishmaniasis at the same period. After clinical, laboratory, and histopathological diagnosis, the treatment was introduced and the patient showed important clinical improvement. He was followed in our outpatient clinic. Both pathologies play an important role in the immune system. Depending on the immune response profile of the host, diseases may present themselves in different ways. In this case, the patient showed a divergent immune response for each disease. We hypothesized that this response is specific for each pathogen.

Leprosy and American cutaneous leishmaniasis coinfection

Abstract: Brazil is a country with a high prevalence of infectious diseases such as leprosy and leishmaniasis. However, coinfection of these diseases is still poorly understood. We report a case of a patient who presented with lepromatous leprosy and cutaneous-mucosal leishmaniasis at the same period. After clinical, laboratory, and histopathological diagnosis, the treatment was introduced and the patient showed important clinical improvement. He was followed in our outpatient clinic. Both pathologies play an important role in the immune system. Depending on the immune response profile of the host, diseases may present themselves in different ways. In this case, the patient showed a divergent immune response for each disease. We hypothesized that this response is specific for each pathogen.

Pathways and Genes Associated with Immune Dysfunction in Sheep Paratuberculosis.

Multibacillary and paucibacillary paratuberculosis are both caused by Mycobacterium avium subspecies paratuberculosis. Multibacillary lesions are composed largely of infected epithelioid macrophages and paucibacillary lesions contain T cells but few bacteria. Multibacillary disease is similar to human lepromatous leprosy, with variable/high levels of antibody and a dysfunctional immune response. Animals with paucibacillary disease have high cell-mediated immunity and variable levels of antibody. This study aims to characterize the immunological dysfunction using TruSeq analysis of the ileocaecal lymph node that drains disease lesions. Immune dysfunction is highlighted by repression of TCR/CD3 genes, T cell co-receptors/co-stimulators, T cell activation and signal-transduction genes. Inflammation was an acute phase response and chronic inflammation, with little evidence of acute inflammation. The high levels of immunoglobulin and plasma cell transcripts is consistent with the anti-MAP antibody responses in paratuberculosis sheep. Also notable was the overwhelming reduction in mast cell transcripts, potentially affecting DC activation of the immune response. This study also shows that there were no fundamental differences in the gene expression patterns in multibacillary and paucibacillary disease, no shift in T cell genes from Th1 to Th2 pattern but rather an incremental decline into immune dysfunction leading to multibacillary pathology.

Th9 cytokines response and its possible implications in the immunopathogenesis of leprosy.

AIMS: Leprosy is an infectious-contagious disease whose clinical evolution depends on the interaction of the infectious agent with the immune response of the host, leading to a clinical spectrum that ranges from lepromatous leprosy (susceptibility, LL) to tuberculoid leprosy (resistance, TT). The immune response profile will depend on the pattern of cytokine production and on the activity of macrophages during infection. Classically, the clinical evolution of leprosy has been associated with Th1/Th2 cytokine profiles, but the role of new cytokine profiles such as T helper 9 (Th9) remains to be elucidated. METHODS: To evaluate the tissue expression profile of these cytokines, a cross-sectional study was conducted using a sample of 30 leprosy skin lesion biopsies obtained from patients with leprosy, 16 TT and 14 lepromatous LL. RESULTS: Immunohistochemical analysis revealed a significant difference in interleukin (IL)-9, IL-4 transforming growth factor (TGF)-ß and IL-10 levels between the two groups. IL-9 was more expressed in TT lesions compared with LL lesions. Higher expression of IL-4, IL-10 and TGF-ß was observed in LL compared with TT. IL-4, IL-10 and TGF-ß tended to be negatively correlated with the expression of IL-9, indicating a possible antagonistic activity in tissue. CONCLUSIONS: The results suggest that Th9 lymphocytes may be involved in the response to Mycobacterium leprae, positively or negatively regulating microbicidal activity of the local immune system in the disease.

Leprosy as a model to understand cancer immunosurveillance and T cell anergy.

Leprosy is a disease caused by Mycobacterium leprae that presents on a spectrum of both clinical manifestations and T cell response. On one end of this spectrum, tuberculoid leprosy is a well-controlled disease, characterized by a cell-mediated immunity and immunosurveillance. On the opposite end of the spectrum, lepromatous leprosy is characterized by M. leprae proliferation and T cell anergy. Similar to progressive tumor cells, M. leprae escapes immunosurveillance in more severe forms of leprosy. The mechanisms by which M. leprae is able to evade the host immune response involve many, including the alterations of lipid droplets, microRNA, and Schwann cells, and involve the regulation of immune regulators, such as the negative checkpoint regulators CTLA-4, programmed death 1, and V-domain Ig suppressor of T cell activation-important targets in today's cancer immunotherapies. The means by which tumor cells become able to escape immunosurveillance through negative checkpoint regulators are evidenced by the successes of treatments, such as nivolumab and ipilimumab. Many parallels can be drawn between the immune responses seen in leprosy and cancer. Therefore, the understanding of how M. leprae encourages immune escape during proliferative disease states has potential to add to our understanding of cancer immunotherapy.

Analysis of Immune Response Markers in Jorge Lobo's Disease Lesions Suggests the Occurrence of Mixed T Helper Responses with the Dominance of Regulatory T Cell Activity.

Jorge Lobo's disease (JLD) is a chronic infection that affects the skin and subcutaneous tissues. Its etiologic agent is the fungus Lacazia loboi. Lesions are classified as localized, multifocal, or disseminated, depending on their location. Early diagnosis and the surgical removal of lesions are the best therapeutic options currently available for JLD. The few studies that evaluate the immunological response of JLD patients show a predominance of Th2 response, as well as a high frequency of TGF-ß and IL-10 positive cells in the lesions; however, the overall immunological status of the lesions in terms of their T cell phenotype has yet to be determined. Therefore, the objective of this study was to evaluate the pattern of Th1, Th2, Th17 and regulatory T cell (Treg) markers mRNA in JLD patients by means of real-time PCR. Biopsies of JLD lesions (N = 102) were classified according to their clinical and histopathological features and then analyzed using real-time PCR in order to determine the expression levels of TGF-ß1, FoxP3, CTLA4, IKZF2, IL-10, T-bet, IFN-γ, GATA3, IL-4, IL-5, IL-13, IL-33, RORC, IL-17A, IL-17F, and IL-22 and to compare these levels to those of healthy control skin (N = 12). The results showed an increased expression of FoxP3, CTLA4, TGF-ß1, IL-10, T-bet, IL-17F, and IL-17A in lesions, while GATA3 and IL-4 levels were found to be lower in diseased skin than in the control group. When the clinical forms were compared, TGF-ß1 was found to be highly expressed in patients with a single localized lesion while IL-5 and IL-17A levels were higher in patients with multiple/disseminated lesions. These results demonstrate the occurrence of mixed T helper responses and suggest the dominance of regulatory T cell activity, which could inhibit Th-dependent protective responses to intracellular fungi such as L. loboi. Therefore, Tregs may play a key role in JLD pathogenesis.

Immunology of leprosy and diagnostic challenges.

Leprosy, caused by noncultivable Mycobacterium leprae (ML), has varied manifestations, which are associated with the host immune responses. The dermal involvement is accompanied by peripheral nerve damage, which leads to sensory motor loss and deformities. Both innate and acquired immune responses are involved. The main cell to be compromised is the CD4 + T helper cell, which shows antigen specific unresponsiveness to only ML and not to other common antigens in the bacilliferous generalized lepromatous form of the disease. In contrast, the paucibacillary localized tuberculoid form shows appropriate T cell functions and poor antibody response. The dichotomy between T cell functions and antibodies are discussed against the current information on cytokines, Th subsets, and regulatory T cells. During lepromatous reactions, there is a temporary, heightened T cell immunity, even in lepromatous subjects. The dermal lesions confirm many features observed with peripheral blood mononuclear cells and give additional information on local immune responses. Nerve damage involves both immune and nonimmune mechanisms. Leprosy is a model disease for understanding host immune responses to intracellular bacilli. There are challenges in diagnosing early leprosy. In spite of intensive efforts by many groups, consensus on a universal test suitable for endemic areas is awaited.

Analysis of immune response markers in Jorge Lobo's disease lesions suggests the occurrence of mixed T Helper responses with the dominance of regulatory T cell activity

Jorge Lobo's disease (JLD) is a chronic infection that affects the skin and subcutaneous tissues. Its etiologic agent is the fungus Lacazia loboi. Lesions are classified as localized, multifocal, or disseminated, depending on their location. Early diagnosis and the surgical removal of lesions are the best therapeutic options currently available for JLD. The few studies that evaluate the immunological response of JLD patients show a predominance of Th2 response, as well as a high frequency of TGF-ß and IL-10 positive cells in the lesions; however, the overall immunological status of the lesions in terms of their T cell phenotype has yet to be determined. Therefore, the objective of this study was to evaluate the pattern of Th1, Th2, Th17 and regulatory T cell (Treg) markers mRNA in JLD patients by means of real-time PCR. Biopsies of JLD lesions (N = 102) were classified according to their clinical and histopathological features and then analyzed using real-time PCR in order to determine the expression levels of TGF-ß1, FoxP3, CTLA4, IKZF2, IL-10, T-bet, IFN-γ, GATA3, IL-4, IL-5, IL-13, IL-33, RORC, IL-17A, IL-17F, and IL-22 and to compare these levels to those of healthy control skin (N = 12). The results showed an increased expression of FoxP3, CTLA4, TGF-ß1, IL-10, T-bet, IL-17F, and IL-17A in lesions, while GATA3 and IL-4 levels were found to be lower in diseased skin than in the control group. When the clinical forms were compared, TGF-ß1 was found to be highly expressed in patients with a single localized lesion while IL-5 and IL-17A levels were higher in patients with multiple/disseminated lesions. These results demonstrate the occurrence of mixed T helper responses and suggest the dominance of regulatory T cell activity, which could inhibit Th-dependent protective responses to intracellular fungi such as L. loboi. Therefore, Tregs may play a key role in JLD pathogenesis.

Lepromatous leprosy treated with combined chemotherapy and immunotherapy (injection BCG): three case reports.

BACKGROUND: Lepromatous leprosy is associated with suppressed cell-mediated immunity (CMI). This results in failure of the body to mount an efficient immune response and may render chemotherapy ineffective. The lack of sufficient response may mimic drug resistance. Three case reports in which the immunity was stimulated by administering Injection BCG are presented. All three patients were initially anergic and showed no reaction at the Mantoux testing site, showing an inability to mount type IV hypersensitivity and characterized by live bacilli in smears. Following 1-4 doses of Injection BCG, all three showed dead bacilli in smears. CASE REPORTS: The first case, a 61-year-old man with lepromatous leprosy who continued to show live bacilli in smears after prolonged chemotherapy, was administered a total of four BCG injections, following which he achieved clearance. The second, a 40-year-old man with borderline lepromatous leprosy and severe type 2 reactions, achieved bacterial clearance and control of severe reactions following a single injection. The third, a 67-year-old man with histoid leprosy, achieved effective bacterial killing with a single dose of Injection BCG. RESULTS: All three patients achieved good results when chemotherapy was combined with Injection BCG. Following Injection BCG, all three showed a reaction at the Mantoux testing site. CONCLUSIONS: Suppressed CMI may be responsible for the lack of response in recalcitrant cases of lepromatous leprosy. These case reports would lead to the trend in combination therapy (immunotherapy combined with chemotherapy) for such cases, and help lower the tendency for inappropriate diagnosis of drug-resistant leprosy.

Reação reversa macular da hanseníase: relato de caso / Macular reversal reaction in leprosy: a case report

A reação reversa maculosa consiste no aparecimento abrupto de máculas hipocrômicas, ocorrendo em pacientes hansenianos dimorfos que completaram o tratamento com poliquimioterapia para hanseníase multibacilar. Em geral, surgem entre 6 a 12 meses da alta, com baciloscopia negativa e boa resposta a corticoterapia sistêmica. Ressaltamos a dificuldade em diferenciar recidiva de um episódio reacional, já que não existem critérios clínicos bem estabelecidos que possibilitem este diagnóstico, além de existirem poucos relatos em literatura. Relatamos um caso clínico com diagnóstico de reação reversa macular após período variável de alta do tratamento de hanseniase dimorfa-dimorfa. Foi feita investigação por meio de anamnese rigorosa, exame dermatológico, exame histopatológico da lesão e baciloscopia, excluindo-se os critérios de recidiva, além de analisados dados anteriores do prontuário.O paciente foi submetido a corticoterapia sistêmica,apresentando melhora das lesões. Conclui-seque a reação reversa maculosa deve ser lembrada nos diagnósticos diferenciais com hanseníase recidivada e episódios reacionais clássicos, evitando retratamentos desnecessários.

Macular reversal reaction is the abrupt onset of hypochromic lesions, occurring in borderline leprosy patients who completed treatment with multidrugtherapy for multibacillary leprosy. In general, these reactions appear 6 to 12 months after medical discharge, showing negative skin smear and good response to systemic corticosteroid therapy. We emphasize the difficulty in differentiating relapse cases from leprosy reactions, as there are no well-established clinical criteria that allow this diagnosis, and moreover there are few reports about it in the literature. We report a borderline leprosy case diagnosed with macular reversal reaction after variable period of discharge from treatment. Detailed anamnesis, dermatological and histopathological examination and bacilloscopy, analysis of previous medical records, excluding the relapse criteria, were used for the investigation. The patient was submitted to systemic corticosteroid therapy, with improvement of the lesions. It is concluded that macular reversal reaction should be considered in the differential diagnosis of relapsed leprosy and classic reactional episodes, avoiding unnecessary retreatment.

Gene expression profile and immunological evaluation of unique hypothetical unknown proteins of Mycobacterium leprae by using quantitative real-time PCR.

The cell-mediated immunity (CMI)-based in vitro gamma interferon release assay (IGRA) of Mycobacterium leprae-specific antigens has potential as a promising diagnostic means to detect those individuals in the early stages of M. leprae infection. Diagnosis of leprosy is a major obstacle toward ultimate disease control and has been compromised in the past by the lack of specific markers. Comparative bioinformatic analysis among mycobacterial genomes identified potential M. leprae-specific proteins called "hypothetical unknowns." Due to massive gene decay and the prevalence of pseudogenes, it is unclear whether any of these proteins are expressed or are immunologically relevant. In this study, we performed cDNA-based quantitative real-time PCR to investigate the expression status of 131 putative open reading frames (ORFs) encoding hypothetical unknowns. Twenty-six of the M. leprae-specific antigen candidates showed significant levels of gene expression compared to that of ESAT-6 (ML0049), which is an important T cell antigen of low abundance in M. leprae. Fifteen of 26 selected antigen candidates were expressed and purified in Escherichia coli. The seroreactivity to these proteins of pooled sera from lepromatous leprosy patients and cavitary tuberculosis patients revealed that 9 of 15 recombinant hypothetical unknowns elicited M. leprae-specific immune responses. These nine proteins may be good diagnostic reagents to improve both the sensitivity and specificity of detection of individuals with asymptomatic leprosy.

In-vitro assessment of cell-mediated immunity by demonstrating effector-t cells for diagnosis of tuberculosis in Nepalese subjects.

The immune response against mycobacterium tuberculosis (MTB) is cell mediated. T-cells become sensitized when they encounter MTB antigens and subsequently activated effector T-cells produce a number of cytokines including interferon- gamma (INF-gamma) to fight the infecting organisms. Demonstration of either production of INF-gamma or presence of effector T-cells sensitized to MTB specific antigens in vitro can be diagnostic for TB infection. Aim of this study was to determine the efficacy of commercially available T-SPOT.TB kit which is used for the in vitro diagnosis of TB infection and to determine if this test has any cross reactivity in leprosy patients. Blood sample was taken from 30 sputum AFB positive, 30 sputum AFB negative healthy controls and 10 cases of paucibacillary leprosy patients. The blood samples were processed to separate peripheral blood mononuclear cells. The final cell suspensions were cultured along with MTB specific antigens namely- Early Secretory Antigenic Target (ESAT-6) and Culture Filtrate Protein (CFP 10) along with negative and positive controls. The production of INF-gamma was demonstrated by enzyme linked immunospot (ELISPOT) assay technique. All AFB positive samples produced INF-gamma after exposure to MTB specific antigens. 4 (16.6%) of healthy controls were also found reactive for INF-gamma. The sensitivity and "specificity" for active disease of the ELISPOT (T-SPOT.TB) in respect to AFB microscopy was 100% and 85.7% respectively. Assessment of CMI against tuberculosis, by demonstrating effector T-cell sensitized to MTB antigens can be use to aid the diagnosis of tuberculosis. T-SPOT.TB has no cross reactivity with leprosy patients.

Immune response to vaccination with DNA-Hsp65 in a phase I clinical trial with head and neck cancer patients.

DNA-hsp65, a DNA vaccine encoding the 65-kDa heat-shock protein of Mycobacterium leprae (Hsp65) is capable of inducing the reduction of established tumors in mouse models. We conducted a phase I clinical trial of DNA-hsp65 in patients with advanced head and neck carcinoma. In this article, we report on the vaccine's potential to induce immune responses to Hsp65 and to its human homologue, Hsp60, in these patients. Twenty-one patients with unresectable squamous cell carcinoma of the head and neck received three doses of 150, 400 or 600 microg naked DNA-hsp65 plasmid by ultrasound-guided intratumoral injection. Vaccination did not increase levels of circulating anti-hsp65 IgG or IgM antibody, or lead to detectable Hsp65-specific cell proliferation or interferon-gamma (IFN-gamma) production by blood mononuclear cells. Frequency of antigen-induced IL-10-producing cells increased after vaccination in 4 of 13 patients analyzed. Five patients showed disease stability or regression following immunization; however, we were unable to detect significant differences between these patients and those with disease progression using these parameters. There was also no increase in antibody or IFN-gamma responses to human Hsp60 in these patients. Our results suggest that although DNA-hsp65 was able to induce some degree of immunostimulation with no evidence of pathological autoimmunity, we were unable to differentiate between patients with different clinical outcomes based on the parameters measured. Future studies should focus on characterizing more reliable correlations between immune response parameters and clinical outcome that may be used as predictors of vaccine success in immunosuppressed individuals.

Leprosy: diagnostic and control challenges for a worldwide disease.

Leprosy is a curable disease with well-defined etiology, but lacks better diagnostic tools, preventive and therapeutic strategies. The continued application of the Ridley-Jopling clinical classification that recognizes the natural diversity of the immune response has provided the basis for understanding leprosy, and this review proposes its implementation in all Reference Centers in order to standardize the diagnostic resources, aiming at the improvement of the disease control. Due to the broad bioepidemiological aspects of infection its eradication is difficult, and proper diagnosis of the disease and the correct clinical classification are required to ensure proper treatment. Tools and markers for diagnosis and prognosis, and the novel use of nanotechnology, as well as strategies for disease control and monitoring populations at higher risk are still continuous challenges, which will be specifically reviewed with additional insights. The use of the current diagnostic tools, such as ELISA and PCR has a very limited approach for leprosy that has been considered as a marginal disease; therefore, the current diagnostic tools must be applied extensively in the routine to accumulate clinical experience in order to improve their precise application, like what has been done in many other infectious diseases. Since a vaccine for leprosy presents an unpredictable future, the proposed chemoprophylaxis of contacts (healthy carriers and/or with subclinical infection) must also be employed in referral centers of endemic countries not only to evaluate its efficacy, but also because of the favorable cost-benefit ratio, given that there is no other available approach, besides the multi-drug therapy of patients. This strategy should readily be applied as a public health policy, and may lead to a substantial breakage of the transmission chain aiming a world without leprosy.

Challenges in the post genomic era for the development of tests for leprosy diagnosis.

Leprosy diagnosis is based mainly on clinical manifestations and no laboratory test is available to diagnose asymptomatic disease or to predict disease progression among exposed individuals. Novel comparative genomic in silico analyses and molecular biology tools have discovered unique Mycobacterium leprae proteins with potential diagnostic application. Tuberculoid paucibacillary leprosy (PB) shows low antibodies titers and strong Th1 type/ IFN-gamma specific cell mediated immunity (CMI), while lepromatous multibacillary patients (MB) show high antibody titers and low CMI. Therefore, laboratory tests for PB and MB leprosy diagnosis will require CMI and antibody based assays. Serologically reactive recombinant Mycobacterium leprae proteins were identified and may be used in conjunction with PGL-I to improve MB patient diagnosis. Mycobacterium leprae recombinant proteins and synthetic peptides have been tested for CMI-interferon gamma based assays for PB diagnosis. Modified PGL-I serology incorporating new Mycobacterium leprae antigens and CMI tests based on IFN-gamma gamma production may permit the detection of leprosy PB and MB forms in endemic countries.

Desafios na era pós genômica para o desenvolvimento de testes laboratoriais para o diagnóstico da hanseníase / Challenges in the post genomic era for the development of tests for leprosy diagnosis

O diagnóstico da hanseníase se baseia em manifestações clínicas e não existe teste laboratorial para diagnosticar casos assintomáticos ou para prever progressão da doença entre indivíduos expostos. Novas análises genômicas comparativas in silico e ferramentas de biologia molecular têm sido empregadas para revelar proteínas exclusivas do Mycobacterium leprae que apresentem potencial aplicação diagnóstica. A hanseníase tuberculóide paucibacilar (PB) apresenta baixo nível de anticorpos e forte resposta imune celular (RIC) tipo Th1/interferon gamma (IFN-γ). A doença lepromatosa multibacilar (MB) apresenta sorologia positiva e fraca RIC. Portanto, testes laboratoriais para diagnosticar hanseníase PB e MB devem contemplar testes de RIC e sorologia. Proteínas recombinantes do Mycobacterium leprae sorologicamente reativas podem ser incorporadas ao antígeno PGLI para melhorar o diagnóstico sorológico de pacientes MB. Proteínas recombinantes e peptídeos sintéticos do Mycobacterium leprae têm sido testados em ensaios de RIC/IFN-γ para diagnosticar casos PB. Sorologia anti-PGLI modificada incorporando novos antígenos do Mycobacterium leprae e ensaios baseados na RIC/produção de IFN-γ devem permitir a detecção precoce de casos MB e PB em países endêmicos.

Leprosy diagnosis is based mainly on clinical manifestations and no laboratory test is available to diagnose asymptomatic disease or to predict disease progression among exposed individuals. Novel comparative genomic in silico analyses and molecular biology tools have discovered unique Mycobacterium leprae proteins with potential diagnostic application. Tuberculoid paucibacillary leprosy (PB) shows low antibodies titers and strong Th1 type/ IFN-γ specific cell mediated immunity (CMI), while lepromatous multibacillary patients (MB) show high antibody titers and low CMI. Therefore, laboratory tests for PB and MB leprosy diagnosis will require CMI and antibody based assays. Serologically reactive recombinant Mycobacterium leprae proteins were identified and may be used in conjunction with PGL-I to improve MB patient diagnosis. Mycobacterium leprae recombinant proteins and synthetic peptides have been tested for CMI-interferon gamma based assays for PB diagnosis. Modified PGL-I serology incorporating new Mycobacterium leprae antigens and CMI tests based on IFN-γ γ production may permit the detection of leprosy PB and MB forms in endemic countries.

Immunostimulatory activity of major membrane protein-II from Mycobacterium leprae.

We examined the antigenicity of an immunomodulatory protein, major membrane protein (MMP)-II, from Mycobacterium leprae, since host defense against M. leprae largely depends on adaptive immunity. Both unprimed and memory T cells from healthy individuals were stimulated by autologous MMP-II-pulsed monocyte-derived dendritic cells (DCs) to produce IFN-gamma. The DC-mediated IFN-gamma production was dependent on the expression of MHC, CD86, and MMP-II antigens. Memory T cells from paucibacillary (PB) leprosy more extensively responded to MMP-II-pulsed DCs than T cells from healthy individuals, while comparable IFN-gamma was produced by unprimed T cells. Memory T cells from multibacillary leprosy, which are normally believed to be anergic, were activated similarly to those from healthy individuals by MMP-II-pulsed DCs. These results suggest that memory T cells from PB leprosy are primed with MMP-II prior to the manifestation of the disease, and MMP-II is highly antigenic in terms of activation of adaptive immunity.

Control of human host immunity to mycobacteria.

Infection with Mycobacterium tuberculosis results in disease in 5-10% of exposed individuals, whereas the remainder controls infection effectively. Similar inter-individual differences in disease susceptibility are characteristic features of leprosy, typhoid fever, leishmaniasis and other chronic infectious diseases, including viral infections. Although the outcome of infection is influenced by many factors, it is clear that genetic host factors play an important role in controlling disease susceptibility to intracellular pathogens. Knowledge of the genes involved and their downstream cellular pathways will provide new insights for the design of improved and rationalized strategies to enhance host-resistance, e.g. by vaccination. In addition, this knowledge will aid in identifying better biomarkers of protection and disease, which are essential tools for the monitoring of vaccination and other intervention trials. The recent identification of patients with deleterious mutations in genes that encode major proteins in the type-1 cytokine (IL-12/IL23-IFN-gamma) axis, that suffered from severe infections due to otherwise poorly pathogenic mycobacteria (non-tuberculous mycobacteria (NTM) or M. bovis Bacille Calmette-Guerin (BCG)) or Salmonella species has revealed the major role of this system in innate and adaptive immunity to mycobacteria and salmonellae. Clinical tuberculosis has now been described in a number of patients with IL-12/IL23-IFN-gamma system defects. Moreover, unusual mycobacterial infections were reported in several patients with genetic defects in NEMO, a key regulatory molecule in the NFkappaB pathway. These new findings will be discussed since they provide further insights into the role of type-1 cytokines in immunity to mycobacteria, including M. tuberculosis.