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Histological classification and the Immunological spectrum of leprosy
Abstract
The clinical and histological manifestations of leprosy are known to be closely correlated with the immunological state of the patient, which determines prognosis and constitutes the natural basis for the classification of this disease. A classification based on this correlation has come to be widely used but needs to be brought up to date and expanded in the light of more recent experience. The author of the present paper presents a much fuller account of the histological side of the classification, taking into account the results of recent experience. This histological classification has been found to provide a workable and widely applicable system, different histologists achieving remarkably good agreement with one another.
... Hansen. Int., 7(1): [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24]1982 Aplicando a CLIM a concordância absoluta entre os examinadores ocorreu em 6 dos 8 casos; as discordâncias foram : T-TR e T-T em regressão, que não se afastam do pólo T. Estas pequenas diferenças encontradas nos casos 1 e 4 podem ser atribuídas pela valorização do edema dissociando o granuloma e pela identificação ou não de sinais regressivos, como por exemplo, maior participação de linfócitos e fibroblastos. histopatológicos realízados segundo os critérios da classificação de Madrid e a de Ridley-Jopiing Na CLRJ a concordância absoluta entre os examinadores foi registrada 3 vezes: 2 vezes TT e 1 vez BT. ...
... Hansen. Int., 7(1): [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24]1982 (índice baciloscópico 4/5.5), vide Ri-Dley 18,22 . Os casos 1, 3 e 5 tiveram resultados praticamente iguais, revelando fase involutiva final. ...
... A discordância entre os examinadores ocorreu quanto à CLRJ optando um por BB e outro por BT -a discordância Hansen. Int., 7(1): [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24]1982 deve ter sido quanto à valorização da quantidade de bacilos (maior em BB), diâmetro das terminações nervosas dérmicas envolvidas no processo (maior em BT), arranjo linfocitário mais organizado e acumulado em BT e mais difuso em BB. 3 4.11 Importância do modo diferente de agressão das terminações nervosas principalmente nos poios T e V. Reconhecer as dificuldades encontradas usando este critério para delimitar com segurança as formas intermediárias TR, B e seus subgrupos. 4.12 Inconveniência prática de estabelecer subgrupos histopatológicos que não encontram elementos de ordem clinica para estabelecer perfeita correlação. ...
Foi realizado um estudo histopatológico comparativo segundo os critérios das classificações de Ridley-Jopling (RJ) e do Congresso de Madrid (CM) em diferentes tipos clínicos e grupos de hanseníase. Foi encontrada concordância entre ambos os critérios no grupo Indeterminado e nas fases regressivas dos tipos Virchowiano (V), Tu-berculóide (T) e Tuberculóide Reacional (TR). Os TR clínicos foram confirmados pelo exame histopatológico em 81,2% dos casos de acordo com os critérios do CM, enquanto 46,2% foram considerados "Borderline" de acordo com os critérios de RJ. Dos 48 pacientes clinicamente V, 17 (35,4%) eram "Borderline" (BL-2, BL-1, e BB), mas praticamente todos eram também V do ponto de vista histopatológico de acordo com o CM. Conclui-se que não há conveniência prática no estabelecimento de subgrupos, baseados na histopatologia, que não concordem perfeitamente com os critérios clínicos. Os Autores destacam a importância do estudo dos plasmócitos nos infiltrados V; dos linfócitos nos granulomas e da maneira diferente de agressão das terminações nervosas, especialmente nos poios T e V. A coloração dos lipídios pelo Sudão III é útil para caracterizar perfeitamente o polo V, reconhecer as estruturas residuais V, separar os subgrupos BT, BB e BL, ajudar no diagnóstico precoce dos infiltrados V e na diferenciação da vacuolização citoplasmática por edema dos TR.
... In the 1960s, Ridley and Jopling [3] proposed a classification for leprosy which is named after them. This widely used classification is based on clinical, histological and immunological features. ...
... Granulomatous reaction on histology varies according to immunity of the host against M. Leprae. Tuberculoid and borderline tuberculoid type shows epithelioid cells, AFB are rarely seen while foamy macrophages, plasma cells and lymphocytes are main infiltrates of BL and LL forms with numerous AFB [3]. Presence of inflammatory cells in the dermal nerves in skin biopsies helps confirm the diagnosis of leprosy. ...
... The mild TT form is characterized by cell-mediated immunity with mainly type 1 helper T cell (Th1) immune response and CD4 + T cells. On the other hand, the severe LL form is defined by cell mediated immunity with mainly type 2 helper T cells (Th2) response and CD8 + T cells [3]. A similar dichotomy is seen in the lepra reactions. ...
Neuropathies form an integral part of the symptomatology of leprosy. Neuropathies of leprosy take various forms and shapes. At one end is the cutaneous nerve involvement adjacent to the anaesthetic skin patch and the other is of symmetrical pansensory neuropathy and the devastating sensory ataxia of leprous ganglionits. Lepra reactions add to the spectrum. Hosts immunological status largely decides the clinical manifestations seen in nerves and skin. A wide array of diagnostic techniques like ultrasonography, magnetic resonance neurography, serological markers, molecular tests, skin biopsy and in selected cases, the nerve biopsy with special stains and electron microscopy are obtainable to help the clinical diagnosis. The unsuspecting clinician, lack of community awareness and limited availability of diagnostic tests are important adverse factors in the total outcome. Multi drug therapy is efficacious and corticosteroids reduce the impact of nerve damage in leprosy. The efficacy, dose and duration of corticosteroid therapy are presently inexact and other immune suppressants like azathioprine are being evaluated. Chronic disabilities and residual deficits require attention of multiple specialties. In the coming time, focus on prevention could lead to favourable results.
This review will discuss the classification systems, common and uncommon clinical features, diagnostic armamentarium and therapeutic and preventive aspects of neuropathies of leprosy.
... Leprosy, caused by the intracellular bacterium Mycobacterium leprae, presents as a spectrum of disease in which the clinical manifestation correlates with the immunological state of the patient. At one end is the self-limiting tuberculoid form (T-lep) and the other end is the disseminated lepromatous form (L-lep) [4], thus comparisons of each form of leprosy affords the opportunity to uncover the critical intrinsic immune mechanisms needed to contain the infection. Each pole of the leprosy disease spectrum is accompanied by a distinct immunological profile defined by specific T cell subsets, MF populations and cytokine patterns [4]. ...
... At one end is the self-limiting tuberculoid form (T-lep) and the other end is the disseminated lepromatous form (L-lep) [4], thus comparisons of each form of leprosy affords the opportunity to uncover the critical intrinsic immune mechanisms needed to contain the infection. Each pole of the leprosy disease spectrum is accompanied by a distinct immunological profile defined by specific T cell subsets, MF populations and cytokine patterns [4]. Gene expression profiling of skin lesions from patients with the different forms of leprosy suggested a correlation between activation of the vitamin D pathway and favorable disease outcomes [5]. ...
... Skin biopsy specimens were collected from untreated patients at the Hansen's Disease Clinic at Los Angeles Country and University of Southern California Medical Center as well as the Leprosy Clinic at the Oswaldo Cruz Foundation in Brazil. The diagnosis and classification of patients were determined based on clinical and histopathological criteria of Ridley and Jopling [4,18]. Cryosections of skin lesions from T-lep, and L-lep patients were labeled for CYP27b1 (Santa Cruz Biotechnology, Dallas, TX). ...
Following infection, virulent mycobacteria persist and grow within the macrophage, suggesting that the intrinsic activation of an innate antimicrobial response is subverted by the intracellular pathogen. For Mycobacterium leprae, the intracellular bacterium that causes leprosy, the addition of exogenous innate or adaptive immune ligands to the infected monocytes/macrophages was required to detect a vitamin D-dependent antimicrobial activity. We investigated whether there is an intrinsic immune response to M. leprae in macrophages that is inhibited by the pathogen. Upon infection of monocytes with M. leprae, there was no upregulation of CYP27B1 nor its enzymatic activity converting the inactive prohormone form of vitamin D (25-hydroxyvitamin D) to the bioactive form (1,25α-dihydroxyvitamin D). Given that M. leprae-induced type I interferon (IFN) inhibited monocyte activation, we blocked the type I IFN receptor (IFNAR), revealing the intrinsic capacity of monocytes to recognize M. leprae and upregulate CYP27B1. Consistent with these in vitro studies, an inverse relationship between expression of CYP27B1 vs. type I IFN downstream gene OAS1 was detected in leprosy patient lesions, leading us to study cytokine-derived macrophages (MΦ) to model cellular responses at the site of disease. Infection of IL-15-derived MΦ, similar to MΦ in lesions from the self-limited form of leprosy, with M. leprae did not inhibit induction of the vitamin D antimicrobial pathway. In contrast, infection of IL-10-derived MΦ, similar to MΦ in lesions from patients with the progressive form of leprosy, resulted in induction of type I IFN and suppression of the vitamin D directed pathway. Importantly, blockade of the type I IFN response in infected IL-10 MΦ decreased M. leprae viability. These results indicate that M. leprae evades the intrinsic capacity of human monocytes/MΦ to activate the vitamin D-mediated antimicrobial pathway via the induction of type I IFN.
... Further, it also indicates the response of disease to the treatment. [8][9][10] Due to variations in the clinical and histopathological spectrum of leprosy, the present study was planned in a rural tertiary care centre with the aim to describe the spectrum of clinical and histological profile of leprosy especially in doubtful and difficult cases where clinical diagnosis alone is not sufficient. Further, to assess the concordance between clinical and histological profile of leprosy cases. ...
... The histopathological features were recorded along with the results of the Modified ZN stain for diagnosis of the spectrum of Hansen's disease according to Ridley and Jopling classification. [9,10] The clinical and histological diagnosis were correlated and compared with other previous studies in literature. ...
... Histological classification of leprosy by Ridley and Jopling which divides leprosy into five groups gives a wellaccepted means of standardization between patients at widely distant centers. [8][9][10] Thus, in the present study, we used Ridley and Jopling classification to categorize the cases clinically and histologically. ...
... These features are thought to contribute to the persistence of M. leprae in the host and result in worse infection out-comes. Indeed, patients with lepromatous leprosy (L-lep), a progressive disease with numerous lesions and plenty of intracellular bacteria, are found to have weak cellular immunity and elevated Foxp3 + regulatory T cells at the lesion site [6][7][8][9], while patients with tuberculoid leprosy (T-lep), a self-containing disease with fewer lesions and less bacteria, are found with robust Th1-skewing immunity [10,11]. These results raised the question of how live, but not dead, M. leprae promoted M2 macrophage skewing and whether there were strain differences between L-lep and T-lep patients. ...
... The source of uninfected peripheral blood mononuclear cells (PBMCs) was a healthy female individual who did not have leprosy, autoimmune disorders, other systemic diseases or leprosy in a family member (within third-degree relatives). All L-lep and T-lep participants were diagnosed by the consensus of two dermatologists based on Ridley and Jopling's criteria [6]. They were also free of M. tuberculosis infection and other chronic infections except M. leprae. ...
Previous studies demonstrated that live Mycobacterium leprae (M. leprae) infection promoted macrophage differentiation toward the M2 type, with elevated interleukin (IL)-10 production. The underlying mechanism is not entirely clear. In this study, we treated macrophages with primary M. leprae strains isolated from both lepromatous leprosy (L-lep) and tuberculoid leprosy (T-lep) patients. We found that infection by live M. leprae, regardless of the primary strain, resulted in M2 skewing in the infected macrophage. This skewing was associated with downregulated IRGM expression, a core organizer protein in the autophagy assembly and reduced autophagosome formation, and with lower annexin V staining and lower caspase 3 and caspase 9 activity. Moreover, live M. leprae-infected macrophages prevented efficient phagocytosis by uninfected bystander macrophages. As a result, the phagocytes secreted less pro-inflammatory cytokines, and preferentially primed anti-inflammatory T cell responses. Together, these results suggested that live M. leprae could employ a strain-independent mechanism to suppress inflammation, possibly involving the inhibition of autophagy and apoptosis in the infected macrophages.
... Leprosy is a spectral disease, ranging from tuberculoid leprosy, in which the host has good cell-mediated immunity against M. leprae with limited disease, to the lepromatous form, in which the host is anergic to M. leprae and the organism proliferates in the skin, peripheral nerves and other systems. At the center of this spectrum are intermediate forms called borderlines [8,9]. ...
... HIV and AIDS infection and the use of HAART were defined according to the guidelines of the Brazilian Ministry of Health with positive serology ELISA and western blot, flow cytometry for peripheral blood CD4 counts and criteria for AIDS (defined as a CD4 T lymphocyte count of 200 cells/mL and/or clinical conditions that define the disease) (MS, 2017). The diagnosis and classification of leprosy were made according to clinical criteria [28], complementary bacilloscopy and histopathology exams [9] and the WHO Operational Classification [29]. ...
Background
The geographical overlap of HIV (human immunodeficiency virus) and leprosy infection has become increasingly frequent and worrying, bringing many clinical issues. Peripheral neuropathy is very frequent in leprosy because of the predilection of its etiologic agent by Schwann cells of the peripheral nervous system, and it also affects individuals with HIV as one of the most common neurological manifestations.
Methodology/Principal findings
The present study compared a cohort of 63 patients diagnosed with leprosy and coinfected with HIV with a cohort of 64 patients with leprosy alone, who were followed at the outpatient clinic of the Nucleus of Tropical Medicine of the Federal University of Pará, Brazil. We observed that HIV-coinfected leprosy patients presented greater odds of overall peripheral nerve damage (nerve function impairment—NFI) than patients with leprosy alone. More sensitive damage was observed, especially in patients coinfected with multibacillary forms. Leprosy patients coinfected with HIV presented higher chances of motor damage with improvement over time using multidrug therapy (MDT) and highly active antiretroviral therapy (HAART), along with a greater extent of damage and occurrence of neuritis. The data suggest that in addition to patients presenting possible damage caused by leprosy, they also had a greater damage gradient attributable to HIV disease, but not related to HAART because most of these patients had been on the treatment for less than a year. Neuritis was treated with prednisone at doses recommended by the WHO, and coinfected patients had the highest rate of clinical improvement in the first 60 days.
Conclusions/Significance
The clinical characteristics of the two diseases should be considered in leprosy patients coinfected with HIV for better diagnosis and treatment of peripheral neuropathy. We suggest that new simplified assessment tools that allow the evaluation of the NFI of these patients be developed for use in the service.
... April 2018 | Volume 9 | Article 604 leprosy still garners a lot of attention mainly because M. leprae infection which evokes distinct polarized T cell responses in humans, which correlates with the clinical manifestations. The two polar forms of leprosy, known as tuberculoid type (TT) and lepromatous leprosy (LL), have clinical, microbiological, and immunological linkage [ (4,5), Figure 1]. TT is characterized by fewer skin lesions, low numbers of bacteria in lesions, and histologically well-formed granulomas containing abundant CD4+ T cells. ...
... However, most leprosy patients display a pathogenesis somewhere in between and are classified as either borderline tuberculoid (BT) or borderline lepromatous (BL) (4). Leprosy reactions known as type 1 reactions (T1R) (Figure 1) are common in these immunologically unstable borderline groups and involve an upregulation of the host response to M. leprae antigens (5). In patients with the disseminated LL, a reaction known as erythema nodosum leprosum (ENL) or type 2 reactions (T2R) is frequent, being observed in almost half of these patients receiving antimicrobial therapy (1). ...
Leprosy is a chronic intracellular infection caused by the acid-fast bacillus, Mycobacterium leprae. The disease chiefly affects the skin, peripheral nerves, mucosa of the upper respiratory tract, and the eyes. The damage to peripheral nerves results in sensory and motor impairment with characteristic deformities and disability. Presently, the disease remains concentrated in resource-poor countries in tropical and warm temperate regions with the largest number of cases reported from India. Even though innate immunity influences the clinical manifestation of the disease, it is the components of adaptive immune system which seem to tightly correlate with the characteristic spectrum of leprosy. M. leprae-specific T cell anergy with bacillary dissemination is the defining feature of lepromatous leprosy (LL) patients in contrast to tuberculoid leprosy (TT) patients, which is characterized by strong Th1-type cell response with localized lesions. Generation of Th1/Th2-like effector cells, however, cannot wholly explain the polarized state of immunity in leprosy. A comprehensive understanding of the role of various regulatory T cells, such as Treg and natural killer T cells, in deciding the polarized state of T cell immunity is crucial. Interaction of these T cell subsets with effector T cells like Th1 (IFN-γ dominant), Th2 (interluekin-4 dominant), and Th17 (IL-17+) cells through various regulatory cytokines and molecules (programmed death-1/programmed death ligand-1) may constitute key events in dictating the state of immune polarization, thus controlling the clinical manifestation. Studying these important components of the adaptive immune system in leprosy patients is essential for better understanding of immune function, correlate(s) the immunity and mechanism(s) of its containment.
... Understanding leprosy's clinical and immunological spectrum has provided the basis for recognizing the TB disease spectrum. Leprosy presents a clinical and immunological spectrum in which clinical manifestations correlate with the type of immune response (Ridley, 1974). At one pole, the localized form of leprosy, tuberculoid leprosy, skin granulomas contain macrophages, T cells, and few bacilli and are selflimited, indicating that the immune response efficiently contains the infection. ...
Great progress has been made over the past half-century, but TB remains a formidable global health problem, particularly in low- and middle-income countries. Understanding the mechanisms of pathogenesis and necessary and sufficient conditions for protection are critical. The need for inexpensive and sensitive point-of-care diagnostic tests for earlier detection of infection and disease, shorter and less-toxic drug regimens for drug-sensitive and -resistant TB, and a more effective vaccine than BCG is immense. New and better tools, greater support for international research, collaborations, and training will be required to dramatically reduce the burden of this devastating disease which still kills 1.6 million people annually.
... Fite Faraco stain was performed for calculating the bacillary index (BI) and IHC markers CD1a and Factor XIIIa were used for detecting epidermal and DD. BI was calculated based on Ridley logarithmic scale [4] as follows: ...
Background:
Leprosy is manifested in varied forms based on the immune status of the patient giving rise to the polar and borderline spectrum of tuberculoid (TT) and lepromatous leprosy (LL). The present study was conducted to assess the macrophage activation in the spectrum of leprosy using CD1a and Factor XIIIa immunohistochemical markers and to correlate the macrophage expression with the morphological spectrum and bacillary index.
Methodology:
The present study was an observational study.
Results:
The present study consisted of 40 biopsy-proven leprosy cases, in which a majority were males, and the most common age group was 20-40 years. The most common type encountered was borderline tuberculoid (BT) leprosy. Expression of epidermal dendritic cells and intensity of staining by CD1a was higher in TT (seven of 10 cases (70%)) when compared to LL (one of three cases (33%)). Similarly, Factor XIIIa showed higher expression of dermal dendritic cells in 90% of TT when compared to LL which was seen in 66%.
Conclusion:
The increased number and strong intensity of dendritic cells in the tuberculoid spectrum may indirectly indicate macrophage activation and possibly account for the low bacillary index.
... The patients who followed Ridley-Jopling Classification were included in this study. 11,12 The diagnosed leprosy patients with comorbidities and pregnant women were excluded from the study. Individuals with no history of leprosy in the family were included in the control group, whereas healthy individuals with a history of leprosy in the family and individuals who had taken any steroidal or analgesics in the past 2 months were excluded from the control group. ...
Background:
Mycobacterium leprae (slow-growing bacteria) is the etiological agent for leprosy infection, which is a chronic granulomatous disease. Symptoms initiate with the loss of sensation in the affected areas, which can lead to severe injuries, cuts and burns. IRAK2 (interleukin-1 receptor-associated kinases 2) is reported to function in the regulation of the NFκB pathway. The frequency of the IRAK2 polymorphism (rs708035) was unknown in the Pakistani population. Therefore, the study was designed to identify the role of the rs708035 SNP (single nucleotide polymorphism) in susceptibility to leprosy.
Methodology:
The case-control study was designed, and participants were selected by Ridley-Jopling Classification. Blood samples from healthy individuals and patients were collected after ethical approval. Genomic DNA was extracted for the amplification of selected polymorphisms by tetra-primer amplification refractory mutation system polymerase chain reaction. The desired products were observed via agarose gel (2.5%) electrophoresis followed by data analysis using bioinformatics tools (SNP Stats and SHEsis) and statistical tests (odds ratio, OR, and chi square).
Results:
The study revealed that the mutant genotype (TT) was found to be frequent among cases (22.80%) in comparison with the controls (1.66%). The SNP rs708035 was significantly associated with the progression of leprosy (χ2 = 17.62, p < 0.0001). The targeted SNP significantly increases the risk of leprosy 2.3 times (OR = 2.3119, 95% CI 1.2729-4.1989, p < 0.01). The genetic model also confirms the significant association of the A/T genotype with leprosy in the over-dominant model (OR = 2.83, 95% CI 1.16-6.89, p < 0.001).
Conclusions:
The study revealed a significant association of the targeted SNP with leprosy and provided baseline data regarding the association of rs708035. The current research could be utilized for the preparation of biomarkers by considering a larger sample size.
Highlights:
The patients suffering from leprosy faced various comorbidities, including hypertension and diabetes. The study reports for the first time a significant association of interleukin 1 receptor associated kinases 2 (IRAK2) single nucleotide polymorphism (SNP) rs708035 among the Pakistani population (Karachi). The current study provides baseline data to develop diagnostic biomarkers for early detection of leprosy.
... In addition, 33.3% of the patients were classified as PB and 66.7% as MB using the World Health Organization 9 (WHO) standard. Likewise, using the Ripley-Jopling classification in PB patients, 10 26.7% were classified as indeterminate leprosy and 73.3% as tuberculoid leprosy. Notably, this PB classification was made based on histopathological characteristics: 1. Indeterminate leprosy evidence of lymphohistiocytic infiltrates or lymphoplasmacytic around vascular, eccrine, follicular, or nerve structures; 2. Tuberculoid leprosy evidence of granuloma made up of epithelioid cells and multinucleated Langhans-type cells and involvement of nerve fillets by S-100 (Fig. 1). ...
Introduction:
Leprosy is an ancient and chronic infectious disease caused by 2 mycobacteria (Mycobacterium leprae and Mycobacterium lepromatosis). Recently, our research group observed that HES-1, an innate cellular component of the Notch signaling pathway, is related to the pathogenesis of leprosy. Therefore, it could be helpful in its detection.
Objective:
To determine the expression of HES-1 in the skin of patients with paucibacillary (PB) leprosy.
Methods:
A cross-sectional, descriptive, observational study was conducted. Forty-five skin samples from patients with leprosy were evaluated (30 samples from MB leprosy and 15 from PB leprosy) using immunohistochemistry of HES-1 and S-100.
Results:
PB leprosy biopsies revealed a reduction of HES-1 in 66.7% of the epidermis, 80% of the eccrine glands, and 62.5% of the hair follicles of these patients, with statistical differences in the control group (P < 0.0001). Besides, HES-1 showed similar utility to S-100 immunostaining in detecting the MB and PB leprosy.
Conclusions:
HES-1 is a transcriptional factor also reduced in PB patients' epidermis and skin appendages. Finally, our data show that HES-1 could be a biomarker in diagnosing PB and MB leprosy.
... The classification of PB and MB was adopted for easy administration of MDT under field conditions. The skin manifestations and nerve damage caused by leprosy are strongly influenced by the immune response of each patient and may show a variety of clinical manifestations and histopathologic morphology [128,246,247]. ...
Leprosy is caused by Mycobacterium leprae (M. leprae) and M. lepromatosis, an obligate intracellular organism, and over 200,000 new cases occur every year. M. leprae parasitizes histiocytes (skin macrophages) and Schwann cells in the peripheral nerves. Although leprosy can be treated by multidrug therapy, some patients relapse or have a prolonged clinical course and/or experience leprosy reaction. These varying outcomes depend on host factors such as immune responses against bacterial components that determine a range of symptoms. To understand these host responses, knowledge of the mechanisms by which M. leprae parasitizes host cells is important. This article describes the characteristics of leprosy through bacteriology, genetics, epidemiology, immunology, animal models, routes of infection, and clinical findings. It also discusses recent diagnostic methods, treatment, and measures according to the World Health Organization (WHO), including prevention. Recently, the antibacterial activities of anti-hyperlipidaemia agents against other pathogens, such as M. tuberculosis and Staphylococcus aureus have been investigated. Our laboratory has been focused on the metabolism of lipids which constitute the cell wall of M. leprae. Our findings may be useful for the development of future treatments.
... One fragment was used for histopathological processing and stained with the Hematoxylin-Eosin and Wade methods for diagnostic purposes, while the second fragment was immediately frozen by immersion in liquid nitrogen and used for transcriptome analysis. After MDT, lesions can be histologically clear according to the BI, which generally decreases around one log per year (Ridley, 1974;Job, 1994;Massone, 2012;Massone et al., 2015). Moreover, for unexplained reasons, some patients do not reduce their BI even after 12 doses of MDT or present only a modest reduction, smaller than one log. ...
Multidrug therapy (MDT) has been successfully used in the treatment of leprosy. However, although patients are cured after the completion of MDT, leprosy reactions, permanent disability, and occasional relapse/reinfection are frequently observed in patients. The immune system of multibacillary patients (MB) is not able to mount an effective cellular immune response against M. leprae. Consequently, clearance of bacilli from the body is a slow process and after 12 doses of MDT not all MB patients reduce bacillary index (BI). In this context, we recruited MB patients at the uptake and after 12-month of MDT. Patients were stratified according to the level of reduction of the BI after 12 doses MDT. A reduction of at least one log in BI was necessary to be considered a responder patient. We evaluated the pattern of host gene expression in skin samples with RNA sequencing before and after MDT and between samples from patients with or without one log reduction in BI. Our results demonstrated that after 12 doses of MDT there was a reduction in genes associated with lipid metabolism, inflammatory response, and cellular immune response among responders (APOBEC3A, LGALS17A, CXCL13, CXCL9, CALHM6, and IFNG). Also, by comparing MB patients with lower BI reduction versus responder patients, we identified high expression of CDH19, TMPRSS4, PAX3, FA2H, HLA-V, FABP7, and SERPINA11 before MDT. From the most differentially expressed genes, we observed that MDT modulates pathways related to immune response and lipid metabolism in skin cells from MB patients after MDT, with higher expression of genes like CYP11A1, that are associated with cholesterol metabolism in the group with the worst response to treatment. Altogether, the data presented contribute to elucidate gene signatures and identify differentially expressed genes associated with MDT outcomes in MB patients.
... In between these extremes lie immunologically unstable forms, borderline tuberculoid (BT), borderline borderline (BB) and borderline lepromatous (BL), which can evolve to either TT or LL poles by downgrading or upgrading. [16][17][18] A form where an immune response has not yet developed is called indeterminate leprosy. [19] Leprosy reactions are inflammatory reactions due to T-lymphocyte activation or circulating immune complexes resulting in leukocytoclastic vasculitis. ...
Background:
The World Health Organization announced a strategy to eliminate childhood leprosy infections, visible deformities and discriminatory legislation against leprosy patients by 2020. However, challenges in achieving a leprosy-free world and preventing neurological sequelae still exist. HIV infection is a challenge in South Africa (SA). HIV-leprosy co-infection may result in an increase in the frequency of leprosy reactions without affecting the spectrum of leprosy. From 1921 to 1997, the prevalence of leprosy remained <1 patient per 10 000 population. Current SA literature has very scanty information regarding leprosy infections.
Objectives:
To describe the trend of new leprosy patients at Chris Hani Baragwanath Academic Hospital, Johannesburg, SA, from 1999 to 2015, including demographics, clinical spectrum and treatment outcomes.
Methods:
A retrospective review of patients' clinical records was undertaken. Data on demographics, clinical spectrum including the leprosy classification, reactions, neurological involvement, association with HIV infection and treatment outcomes were extracted. Data analysis was performed using descriptive and inferential statistics and a time series analysis.
Results:
An upward trend from 1999 to 2001 was followed by a decline in the number of new patients. Eighty patients were registered over a period of 17 years, with a male-to-female ratio of 3:1. Thirty-six patients were immigrants, and 5 were children aged <15 years. Multibacillary leprosy was the most common type (n=71 patients). Thirty-six patients had the lepromatous leprosy subtype, 22 were borderline lepromatous, 13 were borderline tuberculoid, 6 were borderline borderline, and 3 had tuberculoid leprosy. Thirty-one patients presented with reactions, type 1 in 9 patients and type 2 in 21 patients, with both types in 1 patient. Grade 2 neurological deformities were diagnosed in 37 patients, of whom 2 were children. Eight patients were found to have HIV-leprosy co-infection. Of 52 patients who completed treatment, 26 were cured and 26 were lost to follow-up. Twenty-one patients defaulted from treatment, while 3 patients relapsed.
Conclusions:
This study highlights the current status of leprosy in a low-endemic centre with declining numbers of new patients. Multibacillary forms with grade 2 disabilities (G2Ds) are common. The constant emergence of leprosy in our population highlights shortfalls in our control campaigns. Furthermore, a high rate of G2Ds necessitates scrutiny of education directed at early patient detection and follow-up strategies.
... Leprosy is recognized as a granulomatous disease caused by Mycobacterium leprae in which skin is mainly affected. The pathogenesis of leprosy is complex and its clinicopathological manifestations are the result of hostparasite interactions (1,2). ...
Background & objective:
Leprosy is characterized by various clinicopathological forms depending on the host's body. Therefore, the correlation of histopathological findings with bacteriological index is helpful in diagnosing, classification, and monitoring the treatment. We aimed to analyze the histomorphological findings correlation with the bacteriological index in different types of leprosy. Then, study the histopathological spectrum of leprosy.
Methods:
We carried out a histomorphological study of skin biopsies obtained from 100 new patients tested clinically in OPD (Out Patients Department) on the basis and calculation of bacteriological index on a slit-skin smear. The histomorphological findings correlation with the bacteriological index was to be found in different types of leprosy.
Results:
In the histopathological studies, 52% of the patients were diagnosed with borderline tuberculoid (BT) followed by 20% with borderline lepromatous (BL), 13% with lepromatous leprosy (LL), 8% with tuberculoid (TT), 4% with histoid Hansen's disease, and 3% with mid-borderline (BB). On the clinical and histopathological examinations, correlation was found for 80% of the cases. Considering the correlation of histopathological features with the bacteriological index, 63% of the cases showed good correlation which was comparable with that of other studies.
Conclusion:
Because of the underlying symptoms of leprosy, there is a difference between different types of leprosy and the clinical and environmental perceptions. Thus, the correlation of clinical, histopathological, and bacteriological indices could be more helpful in the diagnosis of leprosy rather than considering only one parameter.
... Leprosy produces a spectrum of disease that Ridley and Jopling classified into five types based on clinical, bacteriological, histological, and immunological features. M. leprae has a predilection for peripheral nerves and skin, and peripheral nerves are implicated across the spectrum of the disease [3,4] (Fig. 1). The WHO classification defines only two types based primarily on the number of lesions: paucibacillary (PB) and multibacillary (MB) [5]. ...
Neuropathy and related disabilities are the major medical consequences of leprosy, which remains a global medical concern. Despite major advances in understanding the mechanisms of M. leprae entry into peripheral nerves, most aspects of the pathogenesis of leprosy neuropathy remain poorly understood. Sensory loss is characteristic of leprosy, but neuropathic pain is sometimes observed. Effective anti-microbial therapy is available, but neuropathy remains a problem especially if diagnosis and treatment are delayed. Currently there is intense interest in post-exposure prophylaxis with single-dose rifampin in endemic areas, as well as with enhanced prophylactic regimens in some situations. Some degree of nerve involvement is seen in all cases and neuritis may occur in the absence of leprosy reactions, but acute neuritis commonly accompanies both Type 1 and Type 2 leprosy reactions and may be difficult to manage. A variety of established as well as new methods for the early diagnosis and assessment of leprosy neuropathy are reviewed. Corticosteroids offer the primary treatment for neuritis and for subclinical neuropathy in leprosy, but success is limited if nerve function impairment is present at the time of diagnosis. A candidate vaccine has shown apparent benefit in preventing nerve injury in the armadillo model. The development of new therapeutics for leprosy neuropathy is greatly needed.
... It is well known that, after MDT, lesions can histologically clear in 2 to 5 years or more (25)(26)(27). Moreover, for unexplained reasons, some patients do not reduce their bacillary index, even after 12 doses of MDT. ...
The treatment of multibacillary cases of leprosy with multidrug therapy (MDT) comprises 12 doses of a combination of rifampicin, dapsone and clofazimine. Previous studies have described the immunological phenotypic pattern in skin lesions in multibacillary patients. Here, we evaluated the effect of MDT on skin cell phenotype and on the Mycobacterium leprae-specific immune response. An analysis of skin cell phenotype demonstrated a significant decrease in MRS1 (SR-A), CXCL10 (IP-10) and IFNG (IFN-γ) gene and protein expression after MDT release. Patients were randomized according to whether they experienced a reduction in bacillary load after MDT. A reduction in CXCL10 (IP-10) in sera was associated with the absence of a reduction in the bacillary load at release. Although IFN-γ production in response to M. leprae was not affected by MDT, CXCL10 (IP-10) levels in response to M. leprae increased in cells from patients who experienced a reduction in bacillary load after treatment. Together, our results suggest that CXCL10 (IP-10) may be a good marker for monitoring treatment efficacy in multibacillary patients.
... Cases were grouped according to the Ridley and Jopling classification. [18][19][20] Controls were individuals living in Fortaleza who presented to the CDERM with other skin problems (skin cancer, infections, aesthetic skin issues and other skin diseases). No other matching criteria were applied. ...
Background
Mycobacterium leprae was the first microorganism directly associated with a disease, however, there are still important gaps in our understanding of transmission. Although household contacts are prioritized, there is evidence of the importance of extrahousehold contacts. The goal of this article is to contribute to our understanding of the transmission of leprosy ex-household.
Methods
We compare co-location data of 397 leprosy cases and 211 controls drawn from the Centro de Dermatologia Sanitária D. Libânia in Fortaleza, Brazil. We collected lifetime geolocation data related to residence, school attendance and workplace and developed novel methods to establish a critical distance (Rc) for exposure and evaluated the potential for transmission for residence, school and workplace.
Results
Our methods provide different threshold values of distance for residence, school and workplace. Residence networks demonstrate an Rc of about 500 m. Cases cluster in workplaces as well. Schools do not cluster cases.
Conclusions
Our novel network approach offers a promising opportunity to explore leprosy transmission. Our networks confirm the importance of coresidence, provide a boundary and suggest a role for transmission in workplaces. Schools, on the other hand, do not demonstrate a clustering of cases. Our findings may have programmatic relevance.
... Leprosy is a chronic infectious granulomatous disease caused by Mycobacterium leprae that affects the skin and peripheral nerves [12]. Clinically, it has two main types: the tuberculoid form, represented by a strong granulomatous reaction with few bacilli, and the lepromatous form, characterized by a high degree of bacilli infiltration [13,14]. Along the disease spectrum, there are borderline clinical forms with immunological instability and clinical characteristics of both types [15]. ...
Background
Recently developed immunosuppressive drugs, especially TNF antagonists, may enhance the risk of granulomatous infections, including leprosy. We aimed to evaluate the leprosy detection rate in patients under immunosuppression due to rheumatological, dermatological and gastroenterological diseases.
Methods
We performed a systematic review of the literature by searching the PubMed, EMBASE, LILACS, Web of Science and Scielo databases through 2018. No date or language restrictions were applied. We included all articles that reported the occurrence of leprosy in patients under medication-induced immunosuppression.
Results
The search strategy resulted in 15,103 articles; finally, 20 articles were included, with 4 reporting longitudinal designs. The detection rate of leprosy ranged from 0.13 to 116.18 per 100,000 patients/year in the USA and Brazil, respectively. In the meta-analysis, the detection rate of cases of leprosy per 100,000 immunosuppressed patients with rheumatic diseases was 84 (detection rate = 0.00084; 95% CI = 0.0000–0.00266; I² = 0%, p = 0.55).
Conclusion
Our analysis showed that leprosy was relatively frequently detected in medication-induced immunosuppressed patients suffering from rheumatological diseases, and further studies are needed. The lack of an active search for leprosy in the included articles precluded more precise conclusions.
Trial registration
This review is registered in PROSPERO with the registry number CRD42018116275.
... The Ridley-Jopling scale was developed to enable grouping of patients, determine duration of treatment and predict clinical outcomes, such as reactions. 1 This spectrum ranges from polar tuberculoid (TT) through borderline tuberculoid (BT),mid-borderline (BB), borderline lepromatous (BL) and polar lepromatous (LL). To make classification (for treatment) operationally easier for leprosy field staff in the light of recommendations for routine use of Multibacillary leprosy : more than 5 skin lesions and any cases with positive smear multi-drug therapy (MDT), a simpler two-group classification was introduced by the World Health Organization (WHO) in 1982, with patients being allocated to either paucibacillary or multibacillary groups. 2 These names were based on concept that patients with the different types of leprosy had either few bacteria or many bacteria. ...
... Leprosy reactions are acute systemic inflammatory complications that may occur in >50% of patients prior, during, or after treatment with antimicrobials [1][2][3][4]. There are 2 main reactional states as defined by Jopling [5]: type 1 (includes "reversal" or "upgrading" reaction), which usually manifests as edema and erythema of existing skin lesion in patients with paucibacillary leprosy; and type 2, including erythema nodosum leprosum, which generally presents with painful erythematous nodules and systemic symptoms among patients with multibacillary leprosy [3,6,7]. ...
... Anesthesia Thickened peripheral nerves Skin lesions Presence of Acid-fast bacilli in slit skin smear For the diagnosis of leprosy, at least two of the three cardinal signs or demonstration of acid-fast bacilli is essential 9 . The histopathological examination is must for confirmation of diagnosis in doubtful cases of leprosy. ...
... In this form, the bacilli invade the nerves and selectively colonize the Schwann ceUs, multiply within them and slowly destroy them. The dermal nerve twigs are destroyed, and the larger nerves are swollen and destroyed by granulomas and surrounded by a zone of lymphocytes: occasionally, there may be caseation within a dermal nerve (Ridley, 1974). The nerve damage is nonspecific and arises as a consequence of the cell-mediated immune response. ...
In a preceding visit, 279 leprosy patients in the Baba Baghi Leprosy Sanatorium in Iran with long histories of treatment with dapsone, were subjected to skin-testing with 4 new tuberculins, and randomised to receive an injection of saline as placebo or killed M. vaccae as immunotherapy. A year later, in the first sampling visit, the study began on selected groups of these patients, each of whom provided sputum and skin-tissue fluid specimens for DNA studies, and serum samples for antibody estimation. Eighteen months later, in the second sampling visit, further samples were obtained from 50 of the same patients. The aim was to search for leprosy and tubercle bacilli by PCR in appropriate specimens, and relate the findings to the skin test, immunotherapy data, and immunoassays. Three different DNA extraction methods for preparation of template DNA were evaluated. The chosen DNA extraction method was based on the lysing and nuclease-inactivating properties of guanidine thiocyanate (GuSCN) together with the nucleic acid-binding properties of diatoms. Species-specific primers for a 530-bp fragment of the gene encoding the 36 kDa antigen of M. leprae and for a 123-bp fragment of the repetitive DNA sequence (IS6110) of M. tuberculosis were used for the study and PCR results were compared with conventional methods. Using the chosen techniques, 25% of the selected "fully treated" long-term leprosy patients were found to be PCR-positive for M. leprae and 13.6% of the same patients were found to be PCR-positive for M. tuberculosis. Comparison of PCR results showed no concurrent positivity for both organisms. The serum samples from the same selected patients were tested by indirect ELISA to determine the level of IgG against seven mycobacterial antigen preparations. A modified technique was used to measure the level of agalactosyl IgG (G₀). The serological results correlated very well with the molecular findings, 81.1% of the leprosy PCR-positive patients could be confirmed with PGL-I ELISA and 83.3% of the tuberculosis PCR-positive patients were confirmed by the G₀ assay. Additionally, 29 CSF specimens from patients thought to have tuberculous meningitis (TBM) were tested by the same PCR technique for tuberculosis and PCR results showed much more positivity than did microscopy or culture. For the first time, ancient DNA of M. leprae was extracted and amplified from a bone dating from 600 AD. The results illustrate the importance of tuberculin testing as a marker of M. tuberculosis infection and the value of leprosin A as a marker for M. leprae in long-treated leprosy patients. PCR results from M. leprae demonstrated the efficacy of immunotherapy for leprosy. The ELISA studies could differentiate between leprosy patients positive or negative by PCR for M. leprae. A ratio of antibodies to antigens of tuberculosis and leprosy, and G₀ were found to be valuable serological markers for tuberculosis in long-treated leprosy patients, and antibody to 65 kDa heat shock protein (hsp) was negatively associated with past immunotherapy with M. vaccae.
... Among bacterial diseases 38 cases (88.27%) of leprosy were included in the study and categorized according to Ridley Jopling Classification. 11 Among leprosy, number of cases of borderline tuberculoid leprosy was highest, 22 cases (51.1%), tuberculoid leprosy 13 cases (30.2%), lepromatous leprosy 3 cases (6.97%). Thakkar S, reported 40% patients in the borderline spectrum followed by tuberculoid leprosy (TT) (29.2%), lepromatous leprosy (LL) (26.8%), and 3.9% of indeterminate leprosy (IL). ...
Introduction: India being a large country with diverse population groups, varying climates and having different customs offers the perfect backdrop for a wide variety of peculiar and distinctive skin disorders.
Aim of our study was to determine the incidence and demographic distribution of various non neoplastic lesions of skin in patients attending the out patient department of dermatology of our institute.
Materials and Methods: The present prospective study was conducted from June 2008 to May 2010 in the department of dermatology and pathology, in NKP Salve Institute of Medical Sciences and Research Centre, Nagpur. A total of 205 patients were studied. Final histopathological diagnosis was given in each case correlating with the clinical findings. The results obtained were tabulated and analysed.
Results: Total number of cases included in the study were 205 out of which 22.43% of the patients were in the age group of 30 to 39 years. Macular lesion was the most common clinical presentation constituting 44.0% of all the cases. Non infectious erythematous, papular and squamous diseases were the most common histopathological diagnosis reported (31.21%) followed by bacterial diseases (20.98%) followed by non infectious vesicobullous vesicopustular diseases (17.097%).
Conclusion: In the present study, wide spectrum of skin lesions, common and rare were observed. Leprosy is a still a disease of increasing frequency. Vascular, viral, protozoan diseases are the rare lesions of skin
... leprae leads to a spectrum of disease where some patients can control the bacterial infection and others cannot. While the infiltration of myeloid cells from leprosy biopsy specimens has served as a key to histopathologic diagnosis of leprosy reactions, the role of these cells or other immune cells has not been evaluated in detail (Eichelmann et al., 2013;Modlin, 2010;Ridley, 1974). Herein, we identify an increase in immature myeloid cells displaying a cell surface phenotype of granulocytic MDSC (HLA-DR -CD33 + CD15 + ) in the blood of L-lep and ENL leprosy patients, both manifesting disseminated/progressive infection, but also in RR patients, who are undergoing a cellmediated immune response associated with the reduction of bacilli in lesions. ...
Myeloid derived suppressor cells (MDSC) are a population of immature myeloid cells that suppress adaptive immune function, yet the factors that regulate their suppressive function in patients with infection remain unclear. We studied MDSC in patients with leprosy, a disease caused by Mycobacterium leprae, where clinical manifestations present on a spectrum that correlate with immunity to the pathogen. We found that HLA-DR⁻CD33⁺CD15⁺ MDSC were increased in blood from patients with disseminated/progressive lepromatous leprosy and possessed T cell-suppressive activity as compared to self-limiting tuberculoid leprosy. Mechanistically, we found ER stress played a critical role in regulating the T cell suppressive activity in these MDSC. Further, ER stress augmented IL-10 production, contributing to MDSC activity while IFN-γ allowed T cells to overcome MDSC suppressive activity. These studies highlight a regulatory mechanism that links ER stress to IL-10 in mediating MDSC suppressive function in human infectious disease.
... (1966) for research purpose which is primarily based on immunity but has been correlated with clinical, histopathological and bacteriological findings. [10]. Ridley (1972) further endeavoured to improve on this classification. ...
Background: Leprosy caused by Mycobacterium Leprae is an important public health concern. Single lesions in leprosy are commonly seen in TT, BT and indeterminate leprosy. Aim: The aim of the present study is to evaluate histopathological features of single lesions in different clinical types of leprosy and evaluate clinico histopathological correlation. Methods: Scalpel biopsies of single leprosy lesions from all 40 patients were done followed by staining of slides with Haemotoxilin and Eosin stains. A thorough study of histopathological features of slides was done followed clinico- histopathological correlation. Results: There were 7 cases of indeterminate leprosy, 27 cases of BT type and 6 cases of TT type clinically. There were clinico- histopathological correlations in 32.5% of the total cases. More clinico histopathological correlation was seen among TT type and least correlation was seen among BT type. Conclusion: There is clinico histopatholgical correlation in 32.5% of the total cases. More correlation is seen TT type of leprosy than in BT type of leprosy in single lesions.
... 1714 | P a g e classification reflecting the immunological spectrum: Tuberculoid (TT), Borderline Tuberculoid (BT), Midborderline (BB), Lepromatous Borderline (BL) and Lepromatous (LL) [5]. Later they developed clinical and bacteriological finding in each group with respective immunological and histopathological findings [6]. Clinicians have also adopted the same nomenclature for classifying Hansen's disease on clinical grounds. ...
Background: Hansen’s disease still remains a significant public health problem worldwide, especially in developing countries like India. Patients suffering from Hansen’s disease can remain undiagnosed for a longtime, because of long incubation period, over dependence of clinical expertise and a lack of rapid and simple diagnostic tool. Cytology is an inexpensive, rapid and accurate procedure for diagnosis of skin lesions of Hansen’s disease. Aims: The aim of this prospective study was to assess the usefulness of Cytopathology in early diagnosis of Hansen’s disease and to correlate the cytological smear findings with clinical and histopathological features. Methods: The study is a hospital based prospective study carried out in the Department of Pathology and Department of Skin, VD, Leprosy, N.S.C.B. Medical College & Hospital, Jabalpur (M.P.) .Patients with new skin lesions were selected for the study. Fine needle aspiration cytology was performed and aspirates were evaluated for cytology and punch biopsy was collected. Results: Out of 50 cases, most patients belonged to 20-40 yrs of age, of which 35 (70%) were males and 15 (30%) were females. Borderline Tuberculoid was the most frequent morphologic type seen in both sexes. The clinical and cytological correlation was seen in 88% tuberculoid leprosy, 93.7% of borderline tuberculoid, 33% of borderline lepromatous leprosy and 66% of lepromatous leprosy. While clinical with histopathological correlation revealed 100% specificity in tuberculoid leprosy, borderline tuberculoid and 100% in Histoid leprosy, 66.6% in borderline lepromatous, 83.3% in lepromatous leprosy and 80% in indeterminate leprosy in our study. Concordant results between cytology and histopathology was seen in majority of cases (84.8%) studied. The overall cytodiagnostic accuracy has been 92%. Conclusion: Our study demonstrates that FNAC is a safe, simple, rapid, less-invasive, OPD procedure for early diagnosis and classification of leprosy in majority of cases.
... Depending on the clinical prognosis, leprosy is classified into two types: paucibacillary leprosy (PB) and multibacillary leprosy (MB) (Walker and Lockwood 2007;Ridley 1974). Based on the visual symptoms and the presence or absence of bacilli, the World Health Organization (WHO 1998) recommended that patients containing 1 to 5 diagnostic skin patches in the absence of bacilli in slit-skin smears should be considered paucibacillary; for 1 lesion it is often termed as paucibacillary single lesion leprosy. ...
Leprosy is an ancient insidious disease caused by Mycobacterium leprae, where the skin and peripheral nerves undergo chronic granulomatous infections, leading to sensory and motor impairment with characteristic deformities. In this chapter, we present cellular morphology and the genomic uniqueness of M. leprae, and how the pathogen shows tropism for Schwann cells, macrophages and dendritic cells. Susceptibility to leprosy and its disease state are determined by the manifestation of innate immune resistance mediated by cells of monocyte lineage. Only with insufficient innate resistance granulomatous infection is established, influencing the specific cellular immunity. The clinical presentation of leprosy ranges from two stable polar forms (tuberculoid to lepromatous) with three unstable borderline forms in between. The tuberculoid form involves Th1 response characterized by a well demarcated granuloma, infiltrated by CD4+ T lymphocytes, containing epitheloid and multinucleated giant cells. In the lepromatous leprosy, there is no characteristic granuloma but only unstructured accumulations of ineffective macrophages containing engulfed pathogens. Th1 response is characterised by IFN-γ and IL-2 production, which activate macrophages in order to kill intracellular pathogens. Conversely, a Th2 response is characterized by the production of IL-4, IL-5 and IL-10, which help in antibody production and consequently downregulates the CMI induced by the Th1 response. In spite of significant improvements in research on leprosy, it is still a poorly understood infectious disease, mostly because M. lepare has a long generation time and its inability to grow in culture. The nine-banded armadillo still remains the best clinical and immunological model to study host- pathogen interaction in leprosy.
... In between two poles are borderline-tuberculoid (BT), borderline (BB), and borderline lepromatous (BL). [6] ~ 300 ~ Hence, the present study was conducted to study clinicopathologic correlation of different types of leprosy lesions. ...
... Among bacterial diseases 38 cases (88.27%) of leprosy were included in the study and categorized according to Ridley Jopling Classification. 11 Among leprosy, number of cases of borderline tuberculoid leprosy was highest, 22 cases (51.1%), tuberculoid leprosy 13 cases (30.2%), lepromatous leprosy 3 cases (6.97%). Thakkar S, reported 40% patients in the borderline spectrum followed by tuberculoid leprosy (TT) (29.2%), lepromatous leprosy (LL) (26.8%), and 3.9% of indeterminate leprosy (IL). ...
... It was noted that these cases demonstrate high bacillary load with BI greater than 2+ and belong to lepromatous leprosy. Lepromatous leprosy (LL) is characterized by high bacillary loads and low M. leprae specific cell-mediated immune responses 32 There is no definitive test to differentiate relapse (due to bacterial persisters) from reinfection except for recent observations in whole genome analysis 4 , which is a difficult technique to perform in a diagnostic laboratory setting in tropical countries that are endemic to leprosy. It is therefore not known whether the four cases in the current study were re-infected with the drug-resistant bacilli or possess bacterial persisters that turned resistant to rifampin by inducing mutations over time. ...
The rpoB gene encodes the β-subunit of RNA polymerase holoenzyme in Mycobacterium leprae (M. leprae). Missense mutations in the rpoB gene were identified as etiological factors for rifampin resistance in leprosy. In the present study, we identified mutations corresponding to rifampin resistance in relapsed leprosy cases from three hospitals in southern India which treat leprosy patients. DNA was extracted from skin biopsies of 35 relapse/multidrug therapy non-respondent leprosy cases, and PCR was performed to amplify the 276bp rifampin resistance-determining region of the rpoB gene. PCR products were sequenced, and mutations were identified in four out of the 35 cases at codon positions D441Y, D441V, S437L and H476R. The structural and functional effects of these mutations were assessed in the context of three-dimensional comparative models of wild-type and mutant M. leprae RNA polymerase holoenzyme (RNAP), based on the recently solved crystal structures of RNAP of Mycobacterium tuberculosis, containing a synthetic nucleic acid scaffold and rifampin. The resistance mutations were observed to alter the hydrogen-bonding and hydrophobic interactions of rifampin and the 5' ribonucleotide of the growing RNA transcript. This study demonstrates that rifampin-resistant strains of M. leprae among leprosy patients in southern India are likely to arise from mutations that affect the drug-binding site and stability of RNAP.
... The clinical presentation of leprosy in a patient can vary over time, so there are borderline leprosy types where the immune response is unstable. It can show a wide range of clinical presentations from tuberculoid leprosy (TT) through borderline forms: borderline tuberculoid (BT), borderline borderline (BB), borderline lepromatous (BL) to lepromatous leprosy (LL) [34]. A recent World Health Organization classification scheme recognises a simplified two-category system of either paucibacillary or multibacillary forms of leprosy [35]. ...
Human leprosy is primarily caused by Mycobacterium leprae, but also by the related ‘M. lepromatosis’. Ancient leprosy can be recognised in archaeological materials by the paleopathology associated with multi-bacillary or lepromatous forms of the disease. Whole M. leprae genomes have been obtained from human skeletons, and diagnostic aDNA fragments have been recovered. The derived M. leprae phylogenies, based on single nucleotide polymorphisms, mirror past human migrations, as M. leprae is usually an obligate pathogen. The detection of M. leprae in historical leprosy cases is assisted by the hydrophobic M. leprae cell envelope, which is composed of unusual lipids that can be used as specific biomarkers. Lipid biomarkers are more stable than aDNA and can be detected directly without amplification. Indigenous human leprosy is extinct in Western Europe, but recently, both M. leprae and ‘M. lepromatosis’ were found in British red squirrels. Leprosy may also be found in ninebanded armadillos (Dasypus novemcinctus) where it can cause a zoonotic human infection. Certain leprosy-like diseases, caused by uncultivable species in cats, for example, may be related to M. leprae. The closest extant relatives of leprosy bacilli are probably members of the M. haemophilum taxon, emerging pathogens with genomic and lipid biomarker similarities.
... It was noted that these cases demonstrate high bacillary load with BI greater than 2+ and belong to lepromatous leprosy. Lepromatous leprosy (LL) is characterized by high bacillary loads and low M. leprae specific cell-mediated immune responses 32 There is no definitive test to differentiate relapse (due to bacterial persisters) from reinfection except for recent observations in whole genome analysis 4 , which is a difficult technique to perform in a diagnostic laboratory setting in tropical countries that are endemic to leprosy. It is therefore not known whether the four cases in the current study were re-infected with the drug-resistant bacilli or possess bacterial persisters that turned resistant to rifampin by inducing mutations over time. ...
The rpoB gene encodes the beta subunit of RNA polymerase holoenzyme in Mycobacterium leprae (M. leprae). Missense mutations in the rpoB gene were identified as etiological factors for rifampin resistance in leprosy. In the present study, we identified mutations corresponding to rifampin resistance in relapsed leprosy cases from three hospitals in southern India which treat leprosy patients. DNA was extracted from skin biopsies of 35 relapse/multidrug therapy non-respondent leprosy cases, and PCR was performed to amplify the 276bp rifampin resistance-determining region of the rpoB gene. PCR products were sequenced, and mutations were identified in four out of the 35 cases at codon positions D441Y, D441V, S437L and H476R. The structural and functional effects of these mutations were assessed in the context of three-dimensional comparative models of wild-type and mutant M. leprae RNA polymerase holoenzyme (RNAP), based on the recently solved crystal structures of RNAP of Mycobacterium tuberculosis, containing a synthetic nucleic acid scaffold and rifampin. The resistance mutations were observed to alter the hydrogen-bonding and hydrophobic interactions of rifampin and the 5’ ribonucleotide of the growing RNA transcript. This study demonstrates that rifampin-resistant strains of M. leprae among leprosy patients in southern India are likely to arise from mutations that affect the drug-binding site and stability of RNAP.
... If these signs were evident, diagnosis was confirmed by histopathological changes and analysis of bacillary loads in a slit skin smear test (SSS). Classification was performed according to Ridley and Jopling [20,21]. In cases in which there was no confirmation through the previously mentioned routine tests, a polymerase chain reaction (PCR) was performed to detect M. leprae DNA, as previously described [22]. ...
Background
The high rate of leprosy cases among children under 15 years of age in Brazil indicates ongoing transmission within the community. The identification of the new leprosy cases among contacts can help identify the source of infection and interrupt the transmission chain. This study aims to determine the detection rate of previously undiagnosed cases of leprosy among schoolchildren who are under 15 years of age living in Manaus, Amazonas, Brazil, and their possible source of infection by contact tracing.
Methodology/Principal findings
This was a school-based, cross-sectional study in which the identification of active leprosy cases was conducted in 277 out of 622 randomly selected public schools in Manaus, Amazonas, Brazil. Suspected cases of leprosy were referred to the Alfredo da Matta Foundation, a reference center for leprosy in Manaus. A total of 34,547 schoolchildren were examined, and 40 new leprosy cases were diagnosed. Among new cases, 57.5% were males, and 80.0% demonstrated paucibacillary leprosy. A total of 196 of 206 registered contacts were screened, and 52.5% of the newly diagnosed children’s cases had at least one positive household contact. In these contacts, grandparents (52.4%) were the most common co-prevalent cases, while 14.3% were uncles, 9.5% were parents and 9.5% were granduncles. Seven contacts (5.0%), including four siblings of child patients were newly diagnosed. Our data indicate that the prevalence is 11.58 per 10,000, which is 17 times higher than the registered rate.
Conclusions/Significance
This study suggests that the prevalence of leprosy among schoolchildren may have remained unchanged over the past thirty years. It also indicates that that active case finding is necessary for reaching the World Health Organization’s goals of zero detection among children, especially in endemic areas where the prevalence of leprosy is obscure. Moreover, we assert that all children must have their household contacts examined in order to identify the possible source of infection and interrupt the disease’s transmission. Novel strategies to reinforce contact tracing associated with large-scale strategies of chemo- and immune-prophylaxis should be expanded to prevent the perpetuation of the disease cycle.
... Leprosy is a chronic infectious disease caused by Mycobacterium leprae, a slow-growing intracellular Mycobacterium, with tropism for Schwann cell in nerves and macrophages in the skin. 1 It shows a wide range of clinical presentations from tuberculoid (TT) through borderline forms (borderline tuberculoid [BT], mid borderline [BB], and borderline lepromatous [BL]) to lepromatous (LL). 2 Similarly, histopathology of skin lesions varies from compact granulomas to diffuse infiltration of dermis, which largely depends on the immune status of the patient and may not be in agreement with the clinical diagnosis. 3,4 In the absence of a definition defined as a gold standard, various clinical and laboratory criteria are used. ...
In Central America, few cases of leprosy have been reported, but the disease may be unrecognized. Diagnosis is based on clinical criteria and histology. Preliminary field work in Nicaragua and Honduras found patients, including many children, with skin lesions clinically suggestive of atypical cutaneous leishmaniasis or indeterminate leprosy. Histology could not distinguish these diseases although acid-fast organisms were visible in a few biopsies. Lesions healed after standard antimicrobial therapy for leprosy. In the present study, patients, family members, and other community members were skin-tested and provided nasal swabs and blood samples. Biopsies were taken from a subgroup of patients with clinical signs of infection. Two laboratories analyzed samples, using local in-house techniques. Mycobacterium leprae, Leishmania spp. and Leishmania infantum were detected using polymerase chain reactions. Mycobacterium leprae DNA was detected in blood samples and nasal swabs, including some cases where leprosy was not clinically suspected. Leishmania spp. were also detected in blood and nasal swabs. Most biopsies contained Leishmania DNA and colocation of Leishmania spp. with M. leprae occurred in 33% of cases. Mycobacterium leprae DNA was also detected and sequenced from Nicaraguan and Honduran environmental samples. In conclusion, leprosy and leishmaniasis are present in both regions, and leprosy appears to be widespread. The nature of any relationship between these two pathogens and the epidemiology of these infections need to be elucidated.
© The American Society of Tropical Medicine and Hygiene
Despite low prevalence of leprosy worldwide, new cases continue to present and require swift evaluation and diagnosis to prevent complications. Here, we describe a case of lepromatous leprosy with Lucio’s phenomenon initially presenting with facial and periorbital edema. A 38-year-old Brazilian woman presented to the emergency department with facial swelling and erythema, initially treated as cellulitis. Due to rapid worsening despite broad-spectrum antibiotics, she underwent soft tissue exploration and biopsy due to concern for necrotizing fasciitis. During her course, she also developed retiform purpura of bilateral upper and lower extremities. Periorbital and lower extremity pathological specimens ultimately revealed acid-fast bacilli consistent with Mycobacterium leprae , and the patient improved with multidrug therapy. This case illustrates the diagnostic difficulty of lepromatous leprosy with Lucio’s phenomenon, which can initially present with periorbital edema.
The perineurium surrounds each fascicle in peripheral nerves, forming part of the blood-nerve barrier. We describe its normal anatomy and function. "Perineuritis" refers to both a nonspecific histopathological finding and more specific clinicopathological entity, primary perineuritis (PP). Patients with PP are often assumed to have nonsystemic vasculitic neuropathy until nerve biopsy is performed. We systematically reviewed the literature on PP and developed a differential diagnosis for histopathologically defined perineuritis. We searched PubMed, Embase, Scopus, and Web of Science for "perineuritis." We identified 20 cases (11 M/9F) of PP: progressive, unexplained neuropathy with biopsy showing perineuritis without vasculitis or other known predisposing condition. Patients ranged in age from 18 to 75 (mean 53.7) y and had symptoms 2-24 (median 4.5) mo before diagnosis. Neuropathy was usually sensory-motor (15/20), painful (18/19), multifocal (16/20), and distal-predominant (16/17) with legs more affected than arms. Truncal numbness occurred in 6/17; 10/18 had elevated cerebrospinal fluid (CSF) protein. Electromyography (EMG) and nerve conduction studies (NCS) demonstrated primarily axonal changes. Nerve biopsies showed T-cell-predominant inflammation, widening, and fibrosis of perineurium; infiltrates in epineurium in 10/20 and endoneurium in 7/20; and non-uniform axonal degeneration. Six had epithelioid cells. 19/20 received corticosteroids, 8 with additional immunomodulators; 18/19 improved. Two patients did not respond to intravenous immunoglobulin (IVIg). At final follow-up, 13/16 patients had mild and 2/16 moderate disability; 1/16 died. Secondary causes of perineuritis include leprosy, vasculitis, neurosarcoidosis, neuroborreliosis, neurolymphomatosis, toxic oil syndrome, eosinophilia-myalgia syndrome, and rarer conditions. PP appears to be an immune-mediated, corticosteroid-responsive disorder. It mimics nonsystemic vasculitic neuropathy. Cases with epithelioid cells might represent peripheral nervous system (PNS)-restricted forms of sarcoidosis.
The most important stage in activating an appropriate immune response during an infection is pathogen detection. Pattern recognition receptors (PRRs) are innate sensors used for pathogen detection that mould and link the innate and adaptive immune responses by the host. Toll Like receptors (TLRs) specifically TLR2 and TLR4, are PRRs, which have gained prominence due to their exceptional capacity to recognize unique molecular patterns from invading pathogens. They also play a critical role in maintaining the balance between Th1 and Th2 responses, which are necessary for the host's survival. Leprosy is a spectral disease with a wide range of immunological manifestations in the host. Cells of both the innate and adaptive branches play crucial roles in this polarized immune state. Here, we have analysed the proportional expression patterns of TLR2 and TLR4 on the surface of CD3+, CD4+, CD8+, CD19+ and CD161+ lymphocytes and CD14+ monocytes in different groups of leprosy patients. Further, these TLRs positive cells were correlated with the surface markers of cell exhaustion such as Programmed Death-1 (PD-1) and its ligand (PD-L1), which indicated their role in immunosuppression. Additionally, the blocking the interaction of PD-1 with PD-L1 in lymphocytes demonstrated visible improvement in their immune activation status through release of pro-inflammatory cytokines (IFN-γ and TNF-α).
Disabilities in persons affected by leprosy pose a life-long disease burden, both for patient and the responsible medical service. The obligate intracellular pathogen Mycobacterium leprae affects skin, as well as peripheral nerve cells, and can result in leprosy reactions, which can be intensifications of the host’s immune response, or antibody reactions to immune complexes. Leprosy can thus lead to disabilities, that are currently graded in three categories. The proportion of grade-2 disabilities in newly diagnosed leprosy patients (G2D) is one of the main indicators for leprosy monitoring. In total numbers, G2D are declining according to the size of the analyzed populations. The G2D-Rate per 1 Million persons however, shows fluctuations, which correspond to the efforts made in case-finding, and the public awareness concerning early reporting. Furthermore, no global data has been published yet, regarding the development of grade-0 and grade-1 disabilities throughout the course of treatment and beyond. The practical prevention of disabilities, and the exacerbation of those in already impaired persons, poses a great difficulty, especially in India, where historically stigmatization is present, the integration of leprosy services into the public health sector was described as failure, and funding is scarce, due to the fact, that leprosy was officially eliminated on a public health level in 2005.
Leprosy pathogenesis has not been definitively understood. However, three points are indisputable: the etiological agent is Mycobacterium leprae (M. leprae), the disease develops only in susceptible individuals, and in endemic countries the environment (low socioeconomic status and overcrowding) plays a role in the transmission of the infection. Leprosy disease and clinical manifestations are the result of a dynamic interactive process between M. leprae and the cell-mediated immunity (CMI) of genetically predisposed subjects. Subjects with a predominantly Th1 immune response will develop a high degree of CMI and localized disease with few bacilli (tuberculoid leprosy). On the contrary, individuals with a predominantly response will develop a weak CMI with an increased humoral immunity: bacilli will survive and replicate, developing a systemic disease (lepromatous leprosy).KeywordsSchwann cellLepromatous leprosy
Mycobacterium leprae
Epithelioid granulomaTuberculoid leprosy
Leprosy histopathology is characterized by granulomatous infiltrate with only few exceptions (indeterminate leprosy and some particular forms). The clinical spectrum of the disease has its direct correlate on histopathology, reflecting the different grades of cell-mediated immune response. The tuberculoid pole is characterized by multifocal epithelioid granulomas with giant cells, neural involvement, and no or very few bacilli, while the lepromatous pole is characterized by macrophage infiltrate without true granuloma formation and presence of foamy cells (Virchow cells) with many bacilli. Perivascular and periadnexal and/or perineural lymphohistiocytic infiltrate is found in indeterminate leprosy. Dermal edema, intragranuloma edema, and giant cell size are typical features of type 1 reaction, while edema in the dermis and neutrophilic infiltrate with background changes of preexisting lepromatous lesions are the diagnostic clues for erythema nodosum leprosum. Final diagnosis can be based only on accurate clinico-bacteriological–pathologic correlation.KeywordsEpithelioid granulomaMacrophage granulomaVirchow cellsGranulomatous infiltrateFite–FaracoIndeterminate leprosyTuberculoid leprosyBorderline leprosyBorderline lepromatousLepromatous leprosyType 1 reactionErythema nodosum leprosumEpithelioid cellsMacrophages
The widely accepted Cytokine Milieu Hypothesis proposes that the cytokine milieu, in which antigen activates CD4 T cells, from a non‐T cell source, primarily determines the Th subset to which the ensuing effector Th cells belong. We focus on the generation of Th1 and Th2 cells. We briefly restate the grounds for the Threshold Hypothesis we favor for how the Th1/Th2 phenotype of a response is primarily determined: tentative and robust thresholds of antigen‐mediated CD4 T cell interactions lead to the generation of Th1 and Th2 cells. The component antigens of pathogens are present in different amounts. It is expected, within the context of the threshold mechanism that, although there is often an initial predominance of Th1 or Th2 cells, some Th cells of the opposing type are initially generated. An initially somewhat heterogeneous Th response is known to become with time more “coherent” in its Th1/Th2 phenotype. I propose The Cytokine Implementation Hypothesis as a mechanism for how coherence is achieved. Most cytokines made by Th cells of one subset tend to facilitate the further generation of Th cells of this subset and/or inhibit the generation of Th cells of opposing subsets, accounting for how coherence may be achieved. Many observations on which The Cytokine Milieu Hypothesis is based are accounted for by this alternative hypothesis. We outline predictions of the new hypothesis and discuss the importance of coherence of immune responses for their efficacy in protecting against foreign invaders.
Leprosy is one of the most notorious diseases in history, widely associated with social stigma and exclusion. This study builds on previous work to re‐evaluate the medicohistorical evidence for social stigma in relation to leprosy. This is achieved by isotopic and palaeopathological analyses of adolescent skeletons (10 – 25 years old) from the Anglo‐Scandinavian (10th – 11th centuries AD) parish cemetery of St. John at the Castle Gate in Norwich (Eastern England/East Anglia). Core enamel samples from premolar and molar teeth from 10 young individuals with diagnostic lesions for leprosy were selected for radiogenic strontium (87Sr/86Sr) and oxygen (ẟ18O) stable isotope analyses. Isotope data did not exclude anyone from the regional range. Palaeopathological data and archaeological contexts suggest that those with visible signs of leprosy were buried with their local community and in a normative manner, thus challenging the notion of social exclusion experienced by people with leprosy throughout the Medieval Period. This study underscores the importance of bioarchaeological data in challenging broad medicohistorical and archaeological narratives.
Background:
Perls Prussian blue stain (PPB) for hemosiderin, a marker of vascular injury is often employed as an adjunct in the diagnosis of vasculitic neuropathies. However, inflammation/vascular injury is also seen in leprosy, immune mediated, paraproteinemic, diabetic neuropathies, etc. The frequency of detection of hemosiderin in these neuropathies and its utility in diagnosis of vasculitis has not been explored.
Objective:
We evaluated 208 peripheral nerve biopsies for hemosiderin deposits by PPB stain in vasculitis (78) and compared with inflammatory/immune neuropathies [leprous neuritis-32, chronic inflammatory demyelinating polyneuropathy (CIDP)-15, paraproteinemic neuropathies (POEMS)-12, diabetic neuropathy-37] and nonimmune neuropathies [Charcot-Marie-Tooth (CMT) disease-15, vitamin B12 deficiency-7, and ischemic neuropathy in aged-12)].
Results:
Hemosiderin deposits were most frequent in vasculitis (48.72%) [59.2% in systemic; 43.1% in nonsystemic vasculitides] and enhanced the sensitivity of diagnosis in "probable" vasculitis (34.48%) that lacked transmural inflammation. Hemosiderin was also detected in infectious/immune-mediated neuropathies (leprous neuritis-56%, POEMS-33.3%, diabetes-18.9%) but absent in CMT, B12 deficiency, and ischemic neuropathy. Hemosiderin deposits involved epineurium in vasculitis, compared to endoneurial/perineurial location in leprosy and perineurial in POEMS and diabetic neuropathy. The sensitivity of detection was high in vasculitic neuropathy (49.35%) compared to other inflammatory neuropathies (22.3%) (P < 0.05) with high specificity (77.69% [positive predictive value (PPV)-56.71%; negative predictive value (NPV)-71.6%]. The specificity increased to 89% if leprous neuropathy was excluded, with PPV-77.5% while NPV dropped to 68.5%.
Conclusion:
These findings suggest that PPB stain for detection of hemosiderin is a useful adjunct in diagnosis of vasculitic neuropathy with high specificity but low sensitivity.
The pathogenesis of leprosy is still not fully understood. Several studies have been performed on the involvement of T cells in leprosy and more recently have focused on genetic factors and innate immune response. There are still only few reports about the role of B cells in active leprosy lesions in different spectral forms of the disease. The literature on tuberculosis suggests that B cells play an important role in the regulation of the granulomas, in cytokine production, T-cell response, and antigen presentation. Only few studies investigated the role of B cell in leprosy. We investigated the distribution of B cells in 85 leprosy biopsies covering all forms of the disease and compared results with 13 biopsies of tuberculosis and atypical mycobacteriosis, expanding the previous experiences. A statistically significant difference in the number of CD20 (P = 0.014) and CD138+ (P = 0.01) cells between the different forms of leprosy was observed. A remarkable amount of CD138+ cells could also be detected in borderline tuberculoid. The median of the CD20 cells decreased from the bacilloscopy-negative samples to the bacilloscopy-positive samples by 50% (P = 0.004). Contrarily, the median of CD138+ cells showed an increase from bacilloscopy-negative to bacilloscopy-positive samples of 966.67% (P = 0.001). In our experience, tuberculoid leprosy showed more B cells and less plasma cells than lepromatous leprosy. Our results show that B cells might be implicated in leprosy pathogenesis, not only in the lepromatous pole as previously postulated, but also in tuberculoid granuloma formation and type 1 reactions.
Context:
Neural granulomas are hallmark of leprosy. Challenges faced in diagnosing paucibacillary leprosy include: (i) Difficult visualization of nerve twigs on hematoxylin and eosin (H and E) sections due to their small size and (ii) Paucity of organisms on acid-fast bacilli stain.
Aims:
(1) This study aimed to test the role of S100 immunostain in demonstrating neural granulomas in skin biopsies of paucibacillary leprosy, (2) to compare morphology of S100 staining of nerves inside granulomas among clinicohistologically defined different types of leprosy, and (3) to test whether the pattern of S100 immunostaining can distinguish nerve fragmentation/destruction from a normal intact nerve in skin biopsy.
Materials and methods:
Sixty four diagnosed cases of leprosy were included in this study. Five skin biopsies with no significant pathology (for studying intact nerve) and nine nonleprosy cutaneous granulomas were also studied.
Results:
(i) In demonstrating neural granuloma, sensitivity of H and E was 48.27% and that of S100 was 100%, (ii) Morphology of nerve fragments on S100 stain for cases of leprosy was fragmented and infiltrated in 37, intact and infiltrated in 19, reduced, fragmented, and infiltrated in seven, and absent in one, (iii) There was a significant difference (P <0.001) in the pattern of staining of S100 on intact nerve and nerves involved by granuloma in leprosy, and (iv) The probability to differentiate between leprosy and nonleprosy granuloma was statistically significant (P <0.001).
Conclusion:
S100 immunostaining showed to be an effective adjuvant to histopathology in diagnosing paucibacillary leprosy and differentiating it from nonleprosy cutaneous granuloma.
Active vitamin D metabolites play a major role in key functions of the innate immune response. Triggering of the vitamin D receptor (VDR) by those metabolites has been demonstrated to mediate the expression of antimicrobial peptides, induction of autophagy, and the production of reactive oxygen species and reactive nitrogen species as mechanisms of host defense. The role of vitamin D has been well characterized in the context of tuberculosis and leprosy from a molecular standpoint. Activation of Toll-like receptors, a family of innate immune pattern recognition receptors, on human macrophages with Mycobacterium tuberculosis-derived ligands results in activation of the vitamin D pathway, including (1) the conversion of 25-hydroxyvitamin D (25(OH)D) to 1,25-dihydroxyvitamin D (1,25(OH)2D), (2) activation of the VDR, and (3) antimicrobial activity against intracellular M. tuberculosis infection. This provides a potential explanation for the association between the host vitamin D status with susceptibility to tuberculosis infection and disease. This chapter will examine the role of vitamin D in the innate immune system and host defense against microbial disease, focusing on human infectious diseases, such as tuberculosis and leprosy.