TLR-9 Plays a Role in Mycobacterium leprae-Induced Innate Immune Activation of A549 Alveolar Epithelial Cells

The respiratory tract is considered the main port of entry of Mycobacterium leprae, the causative agent of leprosy. However, the great majority of individuals exposed to the leprosy bacillus will never manifest the disease due to their capacity to develop protective immunity. Besides acting as a physical barrier, airway epithelium cells are recognized as key players by initiating a local innate immune response that orchestrates subsequent adaptive immunity to control airborne infections. However, to date, studies exploring the interaction of M. leprae with the respiratory epithelium have been scarce. In this work, the capacity of M. leprae to immune activate human alveolar epithelial cells was investigated, demonstrating that M. leprae-infected A549 cells secrete significantly increased IL-8 that is dependent on NF-kB activation. M. leprae was also able to induce IL-8 production in human primary nasal epithelial cells. M. leprae-treated A549 cells also showed higher expression levels of human b-defensin-2 (hbD-2), MCP-1, MHC-II and the co-stimulatory molecule CD80. Furthermore, the TLR-9 antagonist inhibited both the secretion of IL-8 and NF-kB activation in response to M. leprae, indicating that bacterial DNA sensing by this Toll-like receptor constitutes an important innate immune pathway activated by the pathogen. Finally, evidence is presented suggesting that extracellular DNA molecules anchored to Hlp, a histone-like protein present on the M. leprae surface, constitute major TLR-9 ligands triggering this pathway. The ability of M. leprae to immune activate respiratory epithelial cells herein demonstrated may represent a very early event during infection that could possibly be essential to the generation of a protective response.(AU)

Immune Complex-Driven Generation of Human Macrophages with Anti-Inflammatory and Growth-Promoting Activity.

To maintain homeostasis, macrophages must be capable of assuming either an inflammatory or an anti-inflammatory phenotype. To better understand the latter, we stimulated human macrophages in vitro with TLR ligands in the presence of high-density immune complexes (IC). This combination of stimuli resulted in a broad suppression of inflammatory mediators and an upregulation of molecules involved in tissue remodeling and angiogenesis. Transcriptomic analysis of TLR stimulation in the presence of IC predicted the downstream activation of AKT and the inhibition of GSK3. Consequently, we pretreated LPS-stimulated human macrophages with small molecule inhibitors of GSK3 to partially phenocopy the regulatory effects of stimulation in the presence of IC. The upregulation of DC-STAMP and matrix metalloproteases was observed on these cells and may represent potential biomarkers for this regulatory activation state. To demonstrate the presence of these anti-inflammatory, growth-promoting macrophages in a human infectious disease, biopsies from patients with leprosy (Hanseniasis) were analyzed. The lepromatous form of this disease is characterized by hypergammaglobulinemia and defective cell-mediated immunity. Lesions in lepromatous leprosy contained macrophages with a regulatory phenotype expressing higher levels of DC-STAMP and lower levels of IL-12, relative to macrophages in tuberculoid leprosy lesions. Therefore, we propose that increased signaling by FcγR cross-linking on TLR-stimulated macrophages can paradoxically promote the resolution of inflammation and initiate processes critical to tissue growth and repair. It can also contribute to infectious disease progression.

Evaluation of Toll-like receptor expression profile in patients with psoriasis vulgaris.

TLRs are thought to play a role in the pathophysiology of such dermatological diseases as leprosy, acne and psoriasis. The study included 20 patients with plaque psoriasis, as well as 20 healthy age- and gender-matched control subjects. Real-time polymerase chain reaction evaluation was made of the messenger RNA expression of TLRs 1-10 in lesional tissue and peripheral blood mononuclear cell samples in psoriasis patients. TLR 3, 5, 6, 7, 9 and 10 lesional tissue mRNA expressions were increased significantly when compared to the expression levels in the PBMCs of the same patients (p = 0.0082, p = 0.0176, p = 0.0239, p = 0.0261, p = 0.0223, p = 0.0206). A comparison of the TLR expression in the PBMCs of healthy subjects and the PBMCs of patients with psoriasis showed a significant increase in the TLR 1, 8 and 10 mRNA expressions in the patient group (p < 0.0001, p < 0.0001, p = 0.0035). The TLR 5 mRNA expression was significantly higher in the control group than in the patient group (p = 0.0037). To the best of our knowledge, this is the first study in literature to evaluate mRNA TLR expression levels in the lesional tissue and PBMCs of patients with psoriasis.

Correlates of immune exacerbations in leprosy.

Leprosy is still a considerable health threat in pockets of several low and middle income countries worldwide where intense transmission is witnessed, and often results in irreversible disabilities and deformities due to delayed- or misdiagnosis. Early detection of leprosy represents a substantial hurdle in present-day leprosy health care. The dearth of timely diagnosis has, however, particularly severe consequences in the case of inflammatory episodes, designated leprosy reactions, which represent the major cause of leprosy-associated irreversible neuropathy. There is currently no accurate, routine diagnostic test to reliably detect leprosy reactions, or to predict which patients will develop these immunological exacerbations. Identification of host biomarkers for leprosy reactions, particularly if correlating with early onset prior to development of clinical symptoms, will allow timely interventions that contribute to decreased morbidity. Development of a point-of-care (POC) test based on such correlates would be a definite game changer in leprosy health care. In this review, proteomic-, transcriptomic and metabolomic research strategies aiming at identification of host biomarker-based correlates of leprosy reactions are discussed, next to external factors associated with occurrence of these episodes. The vast diversity in research strategies combined with the variability in patient- and control cohorts argues for harmonisation of biomarker discovery studies with geographically overarching study sites. This will improve identification of specific correlates associated with risk of these damaging inflammatory episodes in leprosy and subsequent application to rapid field tests.

Envolvimento do receptor TLR-9 na resposta imune do hospedeiro durante o curso da infecção pelo Mycobacterium leprae / Involvement of the TLR9 receptor in host immune responses during infection by Mycobacterium leprae

Mycobacterium leprae, agente etiológico da hanseníase, expressa em abundância uma proteína catiônica semelhante às histonas, denominada Hlp, presente tanto no envelope como no nucleóide bacteriano. O reconhecimento do DNA bacteriano, rico em motivos CpG não metilados, pelo receptor TLR-9 representa uma importante via para a ativação da resposta imune inata, a qual pode levar à eliminação do agente infeccioso ou mediar manifestações patológicas. Foi mostrado ainda que complexos DNA-histona são mais potentes agonistas de TLR-9 que DNA sozinho. Assim, o presente trabalho teve como objetivo investigar o envolvimento do receptor TLR-9 na ativação da resposta imune do hospedeiro durante o curso da infecção pelo M. leprae.Inicialmente foi analisada a participação do TLR-9 na ativação da resposta imune inata em células epiteliais alveolares da linhagem A549 após estímulo com M. leprae. M. leprae foi capaz de induzir aumento das quimiocinas IL-8 eMCP-1 e a transcrição gênica do peptídeo antimicrobiano HbetaD-2 nas células epiteliais. O aumento da expressão de CD80 na superfície celular também foi observada após estímulo com o bacilo. O complexo CpG-Hlp micobacteriano solúvel também induziu aumento na produção de IL-8 nas células A549. Foi observado que o aumento de IL-8 induzido pelo M. leprae ocorre de forma dependente da translocação nuclear do NF-capaB e que o antagonista sintético deTLR-9 afetou a secreção de IL-8 induzida pelo M. leprae. A adição de CpG aoM. smegmatis selvagem, mas não mutante para o gene hlp, aumentou a produção de IL-8 pelas células epiteliais. Em conjunto, esses dados sugerem que as células epiteliais respiratórias podem reconhecer M. leprae via TLR-9 e,assim, participar da resposta imune inata no sítio inicial da infecção. Uma vez que o aparecimento do eritema nodoso hansênico (ENH) está associado a liberação massiva de antígenos micobacterianos, foi investigado o envolvimento do TLR-9 na patogênese do ENH...

Mycobacterium leprae, etiological agent of leprosy, expresses in abundance acationic protein similar to histones, called histone-like protein (Hlp), present inthe envelope as well as in bacterial nucleoid.The recognition of bacterial DNArich in unmethylated CpG motifs by TLR-9 is an important pathway for activationof the innate immune response, which can lead to the elimination of theinfectious agent or mediate pathological manifestations. Moreover, studiesshowed that DNA-histone complexes are more potent agonists of TLR-9 thanDNA alone. This study aimed to investigate the involvement of TLR-9 in theactivation of the host immune response during the course of M. leprae infection.Initially, we analyzed the participation of TLR-9 activation on the innate immuneresponse in A549 alveolar epithelial cells after stimulation with M. leprae. It wasshown that M. leprae was able to induce the chemokines IL-8 and MCP-1, andgene transcription of antimicrobial peptide HbetaD-2 in epithelial cells. Theincrease of CD80 expression on the cell surface was also observed afterstimulation with bacillus. Soluble mycobacterial CpG-Hlp complex also inducedan increase in IL-8 in A549 cells. It was observed that the increase of IL-8,induced by M. leprae, occurs dependently nuclear translocation of NF-capaB andsynthetic TLR-9 antagonist affected IL-8 secretion induced by M. leprae. Theaddition of CpG to wild type M. smegmatis, but not to the mutant gene hlp,increased IL-8 production by epithelial cells. As a whole, these results suggestthat respiratory epithelial cells can recognize M. leprae via TLR-9 and thusparticipate in the innate immune response in the initial infection site. Since theappearance of erythema nodosum leprosum (ENL) is associated with themassive release of mycobacterial antigens, it was investigated the involvementof TLR-9 in the pathogenesis of ENL...

Role of toll-interacting protein gene polymorphisms in leprosy Mexican patients.

BACKGROUND: Leprosy is a debilitating infectious disease of human skin and nerves. Genetics factors of the host play an important role in the disease susceptibility. Toll-interacting protein (TOLLIP) is an inhibitory adaptor protein within the toll-like receptor (TLR) pathway, which recognizes structurally conserved molecular patterns of microbial pathogens, initiating immune responses. The objective of this study was to investigate the association of variants in the TOLLIP gene with susceptibility to leprosy in Mexican patients. METHODS: TOLLIP polymorphisms were studied using a case-control design of Mexican patients with lepromatous leprosy (LL). The polymorphisms of TOLLIP at loci -526 C>G (rs5743854), 1309956C>T (rs3750920), 1298430C>A (rs5744015), and 1292831 G>A (rs3750919) were analyzed by PCR, with sequence-specific primers in LL patients and healthy subjects (HS) as controls. RESULTS: Genotype distributions were in Hardy Weinberg equilibrium for all sites except for rs3750920. Neither genotype nor allele frequencies were statistically different between LL patients and controls (P > 0.05). The maximum pairwise D' coefficient reached was 0.44 of linkage (P = 0.01) for all the polymorphisms except for rs5743854. The three loci haplotype comparison yielded no significant differences between groups. CONCLUSIONS: Just the individuals with genotype C/C of rs3750920 have a trend of protective effect to developing LL.

An association study of TOLL and CARD with leprosy susceptibility in Chinese population.

Previous genome-wide association studies (GWASs) identified multiple susceptibility loci that have highlighted the important role of TLR (Toll-like receptor) and CARD (caspase recruitment domain) genes in leprosy. A large three-stage candidate gene-based association study of 30 TLR and 47 CARD genes was performed in the leprosy samples of Chinese Han. Of 4363 SNPs investigated, eight SNPs showed suggestive association (P < 0.01) in our previously published GWAS datasets (Stage 1). Of the eight SNPs, rs2735591 and rs4889841 showed significant association (P < 0.001) in an independent series of 1504 cases and 1502 controls (Stage 2), but only rs2735591 (next to BCL10) showed significant association in the second independent series of 938 cases and 5827 controls (Stage 3). Rs2735591 showed consistent association across the three stages (P > 0.05 for heterogeneity test), significant association in the combined validation samples (Pcorrected = 5.54 × 10(-4) after correction for 4363 SNPs tested) and genome-wide significance in the whole GWAS and validation samples (P = 1.03 × 10(-9), OR = 1.24). In addition, we demonstrated the lower expression of BCL10 in leprosy lesions than normal skins and a significant gene connection between BCL10 and the eight previously identified leprosy loci that are associated with NFκB, a major regulator of downstream inflammatory responses, which provides further biological evidence for the association. We have discovered a novel susceptibility locus on 1p22, which implicates BCL10 as a new susceptibility gene for leprosy. Our finding highlights the important role of both innate and adaptive immune responses in leprosy.

Leprosy and the natural selection for psoriasis.

Psoriasis is a genetically determined, almost worldwide-distributed inflammatory skin disease with overall higher prevalence among people of northern European ancestry. Since enhanced innate immunity is an important feature of the pathophysiology of this disease, it has been proposed that differences in the prevalence of psoriasis in different populations mainly result from differences in natural selection for gene polymorphisms associated with more vigorous immunity against infectious agents. However the infectious agent(s) that could have acted upon human population as selection pressure for psoriasis is still obscure. Based on the remarkable clinical observation that psoriasis and leprosy are almost mutually exclusive, a fact that is further supported by divergent HLA patterns in patients with psoriasis and leprosy we propose that "resisting leprosy" may have been the evolutionary advantage that favoured the expansion of some psoriasis-associated genotypes especially in the progenitors of modern Europeans. Moreover, we suggest that the spreading out of a certain genetic resistance trait may offer a supplementary explanation for the better understanding of the relatively rapid decline of leprosy in the late medieval epoch in Europe. Both genetic and paleoepidemiologic methods could be employed in order to challenge the present hypothesis.

Toll-like receptors and skin.

Toll-like receptors are important pattern recognition receptors which have key roles in both innate and adaptive immune responses. They are strongly associated with the pathogenesis of inflammatory and autoimmune diseases. Furthermore, Toll-like receptors have also been implicated in the pathogenesis of several skin diseases such as skin infections, psoriasis, acne vulgaris, lichen planus, Behçet's disease, leprosy, syphilis, Lyme disease, atopic dermatitis and allergic contact dermatitis, mycosis fungoides, non-melanoma skin cancers and melanoma. In this manuscript, the structure and functions of Toll-like receptors in immune responses, their impact on skin diseases and recent advances on therapeutic usage have been reviewed.

Mycobacterium leprae actively modulates the cytokine response in naive human monocytes.

Leprosy is a chronic but treatable infectious disease caused by the intracellular pathogen Mycobacterium leprae. Host immunity to M. leprae determines the diversity of clinical manifestations seen in patients, from tuberculoid leprosy with robust production of Th1-type cytokines to lepromatous disease, characterized by elevated levels of Th2-type cytokines and a suboptimal proinflammatory response. Previous reports have indicated that M. leprae is a poor activator of macrophages and dendritic cells in vitro. To understand whether M. leprae fails to elicit an optimal Th1 immune response or actively interferes with its induction, we have examined the early interactions between M. leprae and monocytes from healthy human donors. We found that, in naïve monocytes, M. leprae induced high levels of the negative regulatory molecules MCP-1 and interleukin-1 (IL-1) receptor antagonist (IL-1Ra), while suppressing IL-6 production through phosphoinositide-3 kinase (PI3K)-dependent mechanisms. In addition, low levels of proinflammatory cytokines were observed in association with reduced activation of nuclear factor-kappaB (NF-kappaB) and delayed activation of IL-1beta-converting enzyme, ICE (caspase-1), in monocytes stimulated with M. leprae compared with Mycobacterium bovis BCG stimulation. Interestingly, although in itself a weak stimulator of cytokines, M. leprae primed the cells for increased production of tumor necrosis factor alpha and IL-10 in response to a strongly inducing secondary stimulus. Taken together, our results suggest that M. leprae plays an active role to control the release of cytokines from monocytes by providing both positive and negative regulatory signals via multiple signaling pathways involving PI3K, NF-kappaB, and caspase-1.

Lipid droplet formation in leprosy: Toll-like receptor-regulated organelles involved in eicosanoid formation and Mycobacterium leprae pathogenesis.

A hallmark of LL is the accumulation of Virchow's foamy macrophages. However, the origin and nature of these lipids, as well as their function and contribution to leprosy disease, remain unclear. We herein show that macrophages present in LL dermal lesions are highly positive for ADRP, suggesting that their foamy aspect is at least in part derived from LD (also known as lipid bodies) accumulation induced during ML infection. Indeed, the capacity of ML to induce LD formation was confirmed in vivo via an experimental model of mouse pleurisy and in in vitro studies with human peripheral monocytes and murine peritoneal macrophages. Furthermore, infected cells were shown to propagate LD induction to uninfected, neighboring cells by generating a paracrine signal, for which TLR2 and TLR6 were demonstrated to be essential. However, TLR2 and TLR6 deletions affected LD formation in bacterium-bearing cells only partially, suggesting the involvement of alternative receptors of the innate immune response besides TLR2/6 for ML recognition by macrophages. Finally, a direct correlation between LD formation and PGE(2) production was observed, indicating that ML-induced LDs constitute intracellular sites for eicosanoid synthesis and that foamy cells may be critical regulators in subverting the immune response in leprosy.

The role of toll-like receptors in host defenses and their relevance to dermatologic diseases.

The family of toll-like receptors (TLRs) plays a central role in the cutaneous immune defense system. To date, different TLRs have been found on several major cell populations of the skin, such as keratinocytes, fibroblasts, antigen-presenting cells, and melanocytes. Activation of TLRs leads, via different intracellular signaling pathways, to the production of pro-inflammatory stimuli, and is considered a danger signal that should transform the skin in to the functional state of defense. However, TLRs have also been implicated in tissue homeostasis and renewal. Within the group of TLRs, two types have been identified: surface-expressed TLRs, which are predominantly active against bacterial cell wall compounds; and intracellular receptors, which preferentially recognize virus-associated pattern molecules. In addition, surface-expressed receptors trigger phagocytotic and maturation signals, while the intracellular TLRs lead to the induction of antiviral genes. Our review aims to outline the importance of TLRs in the pathogenesis of numerous skin diseases and the potential of TLR agonists as a treatment option for various skin diseases.

Vaccination with the ML0276 antigen reduces local inflammation but not bacterial burden during experimental Mycobacterium leprae infection.

Leprosy elimination has been a goal of the WHO for the past 15 years. Widespread BCG vaccination and multidrug therapy have dramatically reduced worldwide leprosy prevalence, but new case detection rates have remained relatively constant. These data suggest that additional control strategies, such as a subunit vaccine, are required to block transmission and to improve leprosy control. We recently identified several Mycobacterium leprae antigens that stimulate gamma interferon (IFN-gamma) secretion upon incubation with blood from paucibacillary leprosy patients, a group who limit M. leprae growth and dissemination. In this study, we demonstrate that M. leprae-specific mouse T-cell lines recognize several of these antigens, with the ML0276 protein stimulating the most IFN-gamma secretion. We then examined if the ML0276 protein could be used in a subunit vaccine to provide protection against experimental M. leprae infection. Our data demonstrate that combining ML0276 with either a Toll-like receptor 4 (TLR4) (EM005), TLR7 (imiquimod), or TLR9 (CpG DNA) agonist during immunization induces Th1 responses that limit local inflammation upon experimental M. leprae infection. Our data indicate that only the ML0276/EM005 regimen is able to elicit a response that is transferable to recipient mice. Despite the potent Th1 response induced by this regimen, it could not provide protection in terms of limiting bacterial growth. We conclude that EM005 is the most potent adjuvant for stimulating a Th1 response and indicate that while a subunit vaccine containing the ML0276 protein may be useful for the prevention of immune pathology during leprosy, it will not control bacterial burden and is therefore unlikely to interrupt disease transmission.

[New paradigm of host defense against intracellular pathogens by nitric oxide].

Nitric oxide (NO) produced by inducible NO synthase (iNOS) during infection plays a crucial role in host defense mechanisms, via its antimicrobial and cytoprotective activities. Infection of Salmonella typhimurium in mice induces excessive production of NO, as a host defense response. We found much greater bacterial growth and apoptotic changes in iNOS-deficient (iNOS-/-) mice than in wild-type mice. However, the mechanism of NO-mediated cytoprotection during Salmonella infection remained unclear. An important signaling mechanism induced by NO is heme oxygenase (HO)-1, a significant cytoprotective molecule produced by oxidative stress. Thus, we sought to clarify NO-dependent cytoprotective and antimicrobial host defense, with a particular focus on the signaling mechanism of HO-1 induction. We recently discovered a nitrated cyclic nucleotide, 8-nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP), which is formed via NO possibly with reactive oxygen species. We observed strong immunoreactivity for 8-nitro-cGMP in Salmonella-infected wild-type mouse liver and peritoneal macrophages in culture but not in iNOS-/- mouse liver and macrophages. Moreover, a higher apoptosis was observed in iNOS-/- macrophages compared with wild-type macrophages after Salmonella infection, but the difference was nullified when iNOS-/- cells were treated with 8-nitro-cGMP. Finally, authentic 8-nitro-cGMP induced HO-1 in cultured macrophages infected with Salmonella. The signaling function of 8-nitro-cGMP appears to be mediated by its unique reaction with the sulfhydryl group of cysteine, thus forming a proteinS-cGMP adduct, which is an important mechanism of post-translational modification of proteins called protein S-guanylation. More importantly, we found 8-nitro-cGMP-dependent S-guanylation of Keap1, a regulatory protein of transcription factor Nrf2, which regulates the transcription of HO-1. In this review, we focus on a unique mechanism of NO-mediated host defense via formation of a novel signaling molecule, 8-nitro-cGMP in microbial infections.

Leprosy pathogenetic background: a review and lessons from other mycobacterial diseases.

Leprosy is a disease caused by Mycobacterium leprae that initially affects the peripheral nervous system with patients exhibiting contrasting clinical, immunological, and pathological manifestations despite minimal genetic variation among bacilli isolates. Its clinical manifestations are related to M. leprae survival, innate and acquired immune responses, and interactions between host and bacterial proteins, preventing their invasion and infection, or promoting their development and pathogenesis. The complex molecular interactions in affected individuals influenced by the pathogenetic background will be explored in this review. However, the great genetic diversity imposes difficulty for understanding disease development, and it is likely that many factors and metabolic pathways regulating the immense and contrasting symptomatology will yet be revealed. Four pathways may play a central role in leprosy, including the TLR/LIR-7, VDR, TNF-alpha, and TGF-beta1 for which a large amount of gene polymorphisms have been described that could potentially affect the clinical outcome. Cross-talk pathways may significantly change the course of the disease, depending on the specific disequilibrium of genic homeostasis, which is highly dependent on the environment, antigens that are presented to the host cell, and specific polymorphisms that interact with other genes, external factors, and pathogen survival, culminating in leprosy occurrence. Currently, the microarray-based genomic survey of gene polymorphisms, multiple gene expression analyses, and proteomic technologies, such as mass spectrometry and phage display applied in the discovery of antigens, represent a great potential for evaluating individual responses of leprosy patients and contacts to predict the outcome and progression of the disease. At present, none of the genes is good prognostic marker; however, in the near future we may use multiple targets to predict infection and leprosy development.

C-type lectin DC-SIGN modulates Toll-like receptor signaling via Raf-1 kinase-dependent acetylation of transcription factor NF-kappaB.

Adaptive immune responses by dendritic cells (DCs) are critically controlled by Toll-like receptor (TLR) function. Little is known about modulation of TLR-specific signaling by other pathogen receptors. Here, we have identified a molecular signaling pathway induced by the C-type lectin DC-SIGN that modulates TLR signaling at the level of the transcription factor NF-kappaB. We demonstrated that pathogens trigger DC-SIGN on human DCs to activate the serine and threonine kinase Raf-1, which subsequently leads to acetylation of the NF-kappaB subunit p65, but only after TLR-induced activation of NF-kappaB. Acetylation of p65 both prolonged and increased IL10 transcription to enhance anti-inflammatory cytokine responses. We demonstrated that different pathogens such as Mycobacterium tuberculosis, M. leprae, Candida albicans, measles virus, and human immunodeficiency virus-1 interacted with DC-SIGN to activate the Raf-1-acetylation-dependent signaling pathway to modulate signaling by different TLRs. Thus, this pathway is involved in regulation of adaptive immunity by DCs to bacterial, fungal, and viral pathogens.

Genética humana na susceptibilidade a hanseníase / Human genetic in leprosy susceptibility

Dados de investigações familiares, de estudos comgêmeos e da genômica do Mycobacterium leprae, bemcomo observações sobre a epidemiologia da hanseníase,têm apontado a importância da genética humanacomo determinante do curso da doença desde a resistênciaà dicotomia imunológica que definem os pólostuberculóide e virchowiano. Nesse contexto, estudosde varredura genômica e de associação têm apontadoalgumas regiões genômicas cujas variações são candidatasa fatores de risco para a doença. Entretanto, asassociações já descritas são discretas e não se replicamem todos os estudos, o que evidencia a distinção entreos fatores de risco para diferentes populações, alémde divergências nos desenhos destes estudos, comocausadores destas controvérsias. Assim, esta revisão temo propósito de compilação dos dados já descritos paraas diversas regiões genômicas humanas que devemparticipar do controle genético da hanseníase

Data from familiar investigations, studies involving twins and from Mycobacterium leprae genomic, as well epidemiological observations of leprosy have shown the importance of the human genetic as determinant of the disease’s course, from the resistance, to the immunological dichotomy which defines tuberculoid and lepromatous poles. Thus, studies using genome-wide scan and association methods have shown some genomic regions whose alterations are candidates to risk factors for leprosy. However, these associations are weak and are not repeated in all different studies, which put in evidence the divergence in risk factors for different populations as well in design studies as causatives of this controversial data. In this manner, this review has as purpose the data collection which have already been described about human genomic regions that must participate in the genetic control of leprosy.