A Study on the Impact of Genetic Polymorphisms of Cytokines TNFα, IFNγ and IL10 in South Indian Leprosy Patients.

BACKGROUND: Leprosy (Hansen's disease) is a chronic, debilitating disease predominantly of the peripheral nervous system characterized by the impairment of peripheral nerves and subsequent sensory loss caused by Mycobacterium leprae. The pro- and antiinflammatory cytokine genes play a major role in nerve damage in leprosy. AIMS AND OBJECTIVES: The objective of the present study is to ascertain the association of cytokine gene polymorphisms TNFα - 308G/A (rs 1800629), IFNγ +874A/T (rs 2430561), and IL10 - 1082G/A rs 1800896 in causation with leprosy. MATERIALS AND METHODS: The present study comprised 365 leprosy patients and 185 control subjects. The polymorphisms in TNFα-308, IFNγ+874, and IL10-1082 genes were typed using the amplification refractory mutation system polymerase chain reaction method (ARMS PCR). RESULTS: The present study found significant association between IL10-1082 GA heterozygote (P < 0.02) and IFNγ+874 AA (P < 0.001) genotype and leprosy. TNFα-308GA could not establish any association with the disease. CONCLUSION: The identification of genetic variations in pro- and antiinflammatory cytokines that are susceptible to leprosy would assist in better understanding of the pathogenesis of leprosy and perhaps lead to new approaches for diagnosis and treatment.

Risk of tuberculosis with anti-tumor necrosis factor-alpha therapy in patients with psoriasis and psoriatic arthritis in Indian population.

Anti-tumor necrosis factor-alpha (TNF-α) immunotherapy has revolutionized the treatment of inflammatory diseases, such as psoriasis and psoriatic arthritis. However, a major concern is that patients receiving this therapy have an increased risk of infection, particularly of reactivation of latent tuberculosis (TB). There were an estimated 10.4 million new cases of tuberculosis in 2016, worldwide, and India has one of the largest TB case burden with an estimated incidence of 2.79 million cases of TB in the same year. Anti-TNF agents like etanercept and infliximab are available in India approved for psoriasis and psoriatic arthritis. But long-term use of these agents possesses a risk of reactivation of latent TB. In this review article, we assessed the risk of TB with anti-TNF therapy especially in patients with psoriasis and psoriatic arthritis in India. At the end of the article, we have also suggested a recommendation for screening of latent tuberculosis and its management, before starting anti-TNF-α therapy.

Protective effect of Sesbania grandiflora on acetic acid induced ulcerative colitis in mice by inhibition of TNF-α and IL-6.

ETHNOPHARMACOLOGICAL RELEVANCE: The plant Sesbania grandiflora (Linn) belonging to the family Fabaceae is commonly known as sesbania, agathi, and katurai. The plant is accredited for alleviating a spectrum of ailments including inflammation, colitis, diarrhea, dysentery, leprosy, gout, rheumatism, jaundice, bronchitis, convulsion and anxiety. It is also used as antitumour, anthelmintic, and laxatives in Ayurveda and Siddha system of Indian traditional medicine. AIM: To reveal protective effect of Sesbania grandiflora in acetic acid induced ulcerative colitis in mice. MATERIALS AND METHOD: Polyphenol, flavonoid and flavanone contents of different extracts of S. grandiflora leaves were quantified and correlated with their antioxidant capacity in-vitro (DPPH assay) for identification of potential fraction. In further studies hydroalocholic extract (HASG, 100 and 200 mg/kg) was evaluated for protective effect towards acetic acid induced ulcerative colitis (UC) animals administered with 150 µl of 5% acetic acid once, intrarectally. The colonic mucosal injury was assessed by estimating disease activity index (DAI), which took into account weight loss, stool consistency and occult/gross bleeding. Macroscopic changes like colon length, spleen weights, ulcer area and ulcer index were determined. Haematological parameters like WBC count, RBC count, Hb (g/dL), HCT (%), PLT count and FFA level were determined. Biochemical analysis was carried out for asserting the levels of tissue myeloperoxidase (MPO) accumulation, SOD concentrations, reduced GSH and lipid peroxidation in UC induced and treated animals. The cardinal inflammatory biomarkers like nitric oxide (NO), tumor necrosis factor-α (TNF-α) and interleukin (IL-6) were determined. Histopathological investigation was carried out and scores were calculated. RESULTS: HASG showed presence of highly polymerized polyphenols and flavonoids amongst other extracts of S. grandiflora, which is correlated to its rich antioxidant potential (IC50 =19.21). HPLC fingerprinting quantifies the presence of quercetin in concentration of 81.7 µg/mg of HASG. HASG (200 mg/kg) and Prednisolone (2 mg/kg) significantly reduced DAI and macroscopic scores. The haematological changes in experimental animals were restored upon treatment with HASG and Prednisolone. HASG showed potent antioxidant activity (In-vivo) by restoring the levels of SOD, GSH, MPO, MDA and NO. HASG was found to inhibit FFA levels, which may indicate inhibition of TLR4 receptor mediated inflammation. The levels of serological biomarkers like TNF-α and IL-6 were found to be suppressed. Histopathological investigation reveals decrease signs of ulceration, necrosis, cellular infiltration, hyperaemia in HASG treated animals. The results of HASG (200 mg/kg) were found to be comparable with Prednisolone (2 mg/kg) significantly. CONCLUSION: The protective action of HASG against acetic acid induced UC is attributed to the antioxidant like action (In-vitro and In-vivo) of highly polymerized polyphenols and flavonoids especially quercetin. Also HASG was found to reduce the levels of TNF-α and IL-6, thereby suppressing their inflammatory response in UC.

Etanercept in erythema nodosum leprosum

Abstract: One of the biggest challenges in treating leprosy is the control of reaction events. Patients with lepromatous leprosy may present reaction type II, or erythema nodosum leprosum, during treatment, and this reaction can remain in a recurrent form after being released from the hospital, requiring the use of thalidomide and/or prednisone for long periods of time, in turn increasing the risk of side effects. Two reports of the use of antiTNF to treat erythema nodosum leprosum were found in the literature. A good response was found after an assay with infliximab and etanercept. This study reports on a patient with lepromatous leprosy and recurrent reaction, controlled by using etanercept and a 10-month follow-up, with the interruption of thalidomide and the maintenance of prednisone at 10 mg/day.

Inflammatory Cytokines Are Involved in Focal Demyelination in Leprosy Neuritis.

Mycobacterium leprae (ML) infection causes nerve damage that often leads to permanent loss of cutaneous sensitivity and limb deformities, but understanding of the pathogenesis of leprous neuropathy that would lead to more effective treatments is incomplete. We studied reactional leprosy patients with (n = 9) and without (n = 8) acute neuritis. Nerve conduction studies over the course of the reactional episode showed the findings of demyelination in all patients with neuritis. Evaluation of patient sera revealed no correlation of the presence of antibodies against gangliosides and the clinical demyelination. In nerve biopsies of 3 patients with neuritis, we identified tumor necrosis factor (TNF), TNF receptors, and TNF-converting enzyme in Schwann cells (SCs) using immunofluorescence. To elucidate immunopathogenetic mechanisms, we performed experiments using a human SC line. ML induced transmembrane TNF and TNF receptor 1 expression in the SCs; TNF also induced interleukin (IL)- 6 and IL-8 production by the SCs; and ML induced IL-23 secretion, indicating involvement of this previously unrecognized factor in leprosy nerve damage. These data suggest that ML may contribute to TNF-mediated inflammation and focal demyelination by rendering SCs more sensitive to TNF within the nerves of patients with leprous neuropathy.

The -308 bp TNF gene polymorphism influences tumor necrosis factor expression in leprosy patients in Bahia State, Brazil.

Leprosy or Hansen's disease is a debilitating chronic granulomatous disease caused by Mycobacterium leprae, with high incidence and prevalence in Brazil. The -308 bp G/A single nucleotide polymorphism (SNP rs1800629) in the tumor necrosis factor (TNF) gene promoter is a proposed risk factor for leprosy. In Brazil, Northern India, Egypt and Nepal, the common G allele was associated with leprosy. In Eastern India, Thailand and Malawi the minor A allele was the risk factor. Allele A was previously associated with high TNF. We genotyped rs1800629 in 326 leprosy cases from Bahia State, Brazil, including 72 paucibacillary (PB) and 47 multibacillary (MB) without reactions, and 69 reversal reaction (RR) and 78 erythema nodosum leprosum (ENL) with reactions. Logistic regression was used to compare patient groups with 331 healthy controls. Relative TNF mRNA was determined in peripheral blood leukocytes by QRTPCR, and serum TNF levels measured by ELISA. We found that TNF mRNA expression was higher (P=0.03) in leprosy patients compared to endemic controls, but did not differ significantly between clinical subgroups. Carriage of the minor A allele was associated (P=0.003) with low TNF mRNA across leprosy patients. Nevertheless, we found no evidence for either allele at this SNP as a risk factor for leprosy per se (OR=1.12, 95% CI 0.79-1.60, P=0.52), PB (OR=0.99, 95% CI 0.54-1.81, P=0.97), MB (OR=0.86, 95% CI 0.40-1.83, P=0.70), RR (OR=1.37, 95% CI 0.79-2.38, P=0.27) or ENL (OR=0.76, 95% CI 0.40-1.45, P=0.42) when compared to endemic controls. Further studies are required to determine whether the influence of the minor A allele on TNF mRNA levels determines response to treatment, particularly in the context of ENL reaction treatment with anti-TNF therapies and RR reactions where treatment with prednisolone is known to reduce TNF levels. Our findings contribute to understanding TNF as an important determinant of leprosy immunopathology in Brazil.

Association of leptin/receptor and TNF-α gene variants with adolescent obesity in Malaysia.

BACKGROUND: Leptin (LEP) G-2548A (rs7799039), leptin receptor (LEPR) Q223R (rs1137101) and tumor necrosis factor (TNF)-α G-308A (rs1800629) gene variants have been reported to be associated with obesity, although results for subjects from different countries have been controversial. The aim of this study was to determine the prevalence of overweight and obesity in Malaysian adolescents and the association of these polymorphisms with overweight and obese or over-fat adolescents. METHODS: A total of 613 adolescents (241 Malay, 219 Chinese, 153 Indian) were enrolled. Anthropometric measurements of body mass index (BMI) and body fat percentage were used to classify subjects as controls (non-overweight/obese or normal fat) or as cases (overweight/obese or over-fat). Genomic DNA was extracted from oral buccal mucosa cells for genotyping using polymerase chain reaction-restriction fragment length polymorphism and data obtained were statistically analyzed. RESULTS: A total of 23.3% of subjects were overweight/obese whereas 11.4% were over-fat; there were significantly more overweight/obese and over-fat Indian and Malay adolescents compared to Chinese (P < 0.001). A allele was the minor one for LEPR Q223R and TNF-α G-308A in all ethnic groups, whereas G allele was minor for LEP G-2548A in Chinese and Malay adolescents, except for Indian adolescents. Indian male adolescents with AA genotype for LEP G-2548A were associated with overweight/obesity (P = 0.025; odds ratio, 3.64; 95% confidence interval: 1.15-11.54). Despite the lack of association observed for LEPR Q223R and TNF-α G-308A, Indian and Chinese subjects with AA risk genotype for LEPR Q223R/LEP G-2548A and TNF-α G-308A/LEP G-2548A, respectively, had increased mean BMI (P = 0.049, P = 0.016). CONCLUSIONS: Genotype distribution and association of these polymorphisms with overweight/obesity vary between ethnic groups and genders. Nevertheless, the LEP G-2548A risk allele may be associated with overweight/obese Indian male adolescents in Malaysia.

Biological agents: investigation into leprosy and other infectious diseases before indication / Agentes biologicos: pesquisa de hanseniase e outras doencas infecciosas antes da indicacao

Biological agents are widely used for various immune-mediated diseases, with remarkable effectiveness in the treatment of rheumatoid arthritis (RA), psoriasis, psoriatic arthritis, ankylosing spondylitis and Crohn's disease. However, attention needs to be drawn to the adverse effects of these therapies and the risk of reactivating underlying granulomatous infectious diseases such as tuberculosis, leprosy, syphilis, leishmaniasis, among others. The objective of this paper is to describe a case of leprosy in a patient with RA using anti-TNF alfa, demonstrating the need for systematic investigation of skin lesions suggestive of leprosy in patients who require rheumatoid arthritis therapeutic treatment, especially in endemic regions like Brazil.

Os agentes biológicos são amplamente utilizados em diversas doenças imuno-mediadas, com marcante eficácia no tratamento da Artrite Reumatóide (AR), Psoríase, Artrite Psoriática, Espondilite Anquilosante e Doença de Crohn. No entanto, deve-se atentar quanto aos efeitos adversos de tais terapêuticas, como o risco de reativar doenças infecciosas granulomatosas latentes, como a tuberculose, hanseníase, sífilis, leishmaniose, entre outras. O objetivo deste artigo é descrever um caso de hanseníase em paciente portador de AR em uso de terapia anti-TNF alfa, mostrando, assim, a necessidade de investigação sistematizada de lesões cutâneas sugestivas de hanseníase em pacientes com indicação de terapia anti-TNF alfa, especialmente, em regiões endêmicas como o Brasil.

Micobacterioses relacionadas às terapias com imunobiológicos (anti-TNF-a) / Mycobacteriosis related to the immunobiological therapy (anti-TNF-a)

Os antagonistas do fator de necrose tumoral alpha (TNF-a) representam importante avanço na terapia de doenças imunomediadas, tendo mostrado marcante eficácia no tratamento destas, principalmente artrite reumatoide, psoríase, artrite psoriásica, espondilite anquilosante e doença de Crohn. O tratamento é comprovadamente eficaz, porém apresenta risco elevado para o desenvolvimento de micobacterioses, a exemplo da tuberculose e da hanseníase...