Whole blood profiling of leprosy type 1(reversal) reactions highlights prominence of innate immune response genes.

BACKGROUND: The major factors contributing for nerve damage and permanent disabilities in leprosy are type 1 or reversal reactions (RR) and type 2 or erythema nodosum leprosum (ENL). Gene profiling of leprosy reactions have shown that different pathways are activated during the course of reactions, which is consistent with the exacerbated immune response exhibited by these patients. METHODS: We used qPCR to screen a panel of 90 genes related to the immune response in leprosy in RNA-derived peripheral leukocytes of patients with (N = 94) and without leprosy reactions (N = 57) in order to define expression signatures correlated to RR or ENL. RESULTS: Our results show that there is a marked signature for RR in the blood, comprising genes mostly related to the innate immune responses, including type I IFN components, autophagy, parkins and Toll like receptors. On the other hand, only Parkin was differentially expressed in the ENL group. CONCLUSIONS: The data put together corroborates previous work that brings evidence that an acute uncontrolled exacerbated immune response designed to contain the spread of M. leprae antigens might be cause of RR pathogenesis. Identifying a blood profile useful to predict leprosy reactions prior to its development might help to reduce the morbidity associated to this disabling disease.

Polymorphisms in genes TLR1, 2 and 4 are associated with differential cytokine and chemokine serum production in patients with leprosy.

BACKGROUND: Leprosy or hansen's disease is a spectral disease whose clinical forms mostly depends on host's immune and genetic factors. Different Toll-like receptors (TLR) variants have been described associated with leprosy, but with some lack of replication across different populations. OBJECTIVES: To evaluate the role of polymorphisms in genes TLR1, TLR2 and TLR4 and susceptibility to leprosy in a genetic case control study; to verify the association between genotypes of these markers and the immunological profile in the serum of patients with leprosy. METHODS: Pre-designed TaqMan® assays were used to genotype markers at TLR1 (rs4833095, rs5743551), TLR2 (rs7656411, rs3804099) and TLR4 (rs1927914, rs1927911). A panel of cytokines and chemokines was accessed by enzime-linked immunosorbent assay (ELISA) test in the serum of a subgroup of patients with and without leprosy reactions. FINDINGS: Our results show an association between the T allele of rs3804099 at the TLR2 gene and increased risk for leprosy per se [Odds ratio (OR) = 1.296, p = 0,022]. In addition, evaluating the association between different genotypes of the TLR1, 2 and 4 markers and cytokine/chemokine serological levels, IL-17 appears as an immunological marker regulated by the polymorphism of the three TLR genes evaluated, whereas different TLR1 genotypes were associated with differential production of IL-12p40 and MCP-1(CCL2). Furthermore, other relevant serum markers such as CXCL-10 and IL-6 seemed to be regulated by TLR2 variants and IL-1ß was related to TLR4 genotypes. MAIN CONCLUSIONS: All together our data points that the tested TLR markers may have a regulatory role in the immunity against Mycobacterium leprae, by driving the host's production of key cytokines and chemokines involved in the pathogenesis of this disease.

Role of urine neutrophil gelatinase-associated lipocalin in the early diagnosis of amphotericin B-induced acute kidney injury.

Determination of the neutrophil gelatinase-associated lipocalin (NGAL) level can be used to detect acute kidney injury (AKI) earlier than determination of the serum creatinine (SCr) level in settings such as cardiac surgery, contrast nephropathy, and intensive care units. We hypothesized that urine NGAL (UrNGAL) would be an early biomarker of drug nephrotoxicity. To test this, we studied hemodynamically stable patients treated with amphotericin B (AmB). We measured the SCr and UrNGAL levels at the baseline and daily after initiation of AmB up to day 14 or development of AKI by the use of the SCr criterion. AKI was defined according to a Kidney Disease: Improving Global Outcomes (KDIGO) criterion (an increase in the SCr level by ≥0.3 mg/dl within 48 h or an SCr level ≥1.5 times the baseline level within 7 days). We studied 24 patients with a mean age of 48.4 ± 16.4 years. Most patients were male, and the patients received AmB (12 received AmB deoxycholate and 12 received liposomal AmB) for the treatment of leishmaniasis (91.7%). Overall, 17/24 patients fulfilled a KDIGO criterion for AKI. Peak UrNGAL levels were higher in patients with AKI than in patients without AKI and in recipients of AmB deoxycholate than in recipients of liposomal AmB. The diagnostic performance of the UrNGAL level on day 5 for the detection of AKI was moderate, with the area under the curve (AUC) being 0.68 (95% confidence interval [CI], 0.41 to 0.95). In the subgroup receiving AmB deoxycholate, however, the AUC rose to 0.89 (95% CI, 0.67 to 1.00). In a patient-level analysis, we found that AKI could be detected 3.2 days earlier by the use of the UrNGAL criterion than by the use of the SCr criterion (times to AKI by the UrNGAL and SCr criteria, 3.7 ± 2.5 versus 6.9 ± 3.3 days, respectively; P = 0.001). Future studies should evaluate if a treatment strategy oriented toward evaluation of UrNGAL levels will improve outcomes. These findings for AmB-induced AKI in leishmaniasis patients could serve as a basis for the investigation of urine biomarkers in the early detection of drug nephrotoxicity in other clinical settings.

Recurrence of strongyloides stercoralis infection in a patient with Hansen's disease: a case report.

In patients with immunosuppressive disorders, S. stercoralis infection may develop into a hyperinfection syndrome which, on rare occasions, may be a life-threatening condition. Therapy of S. stercoralis infection with thiabendazole has been limited, due to its numerous side effects, and has been replaced by albendazole and ivermectin. The present case report describes a case of Strongyloides Hyperinfection Syndrome (SHS) in a patient with Hansen's disease and lack of response to first-line anthelmintic treatment. A 38 year-old man was diagnosed as having borderline lepromatous leprosy. He developed Erythema Nodosum Leprosum and was treated with thalidomide and prednisone. In May 2010 he was diagnosed with S. stercoralis infection and was treated with albendazole. One year later, the stool examination showed continued presence of S. stercoralis larvae. He was treated with ivermectin (6 mg) in a double dose (given 1 month apart) which resulted in larvae excretion clearance. The absence of infection was confirmed three times during a 1 year followup period by stool examination and non-detection of anti-S. stercoralis IgG levels.

Clinical profile of vitiligo patients and relationship with immuno-inflammatory markers.

BACKGROUND: Vitiligo is the most common pigmentary disorder and is considered a chronic, cumulative, multifactorial disease. The crucial role of cytotoxic CD8+ T lymphocytes and the IFNγ/CXCL10 axis has been demonstrated in its pathogenesis. OBJECTIVE: To evaluate the clinical profile and immuno-inflammatory markers in patients with vitiligo in a reference medical center. METHODS: Cross-sectional study in which all patients with vitiligo seen at the medical center the from 2019 to 2022 were evaluated, to outline the clinical profile. Moreover, cardiovascular risk biomarkers (neutrophil/lymphocyte ratio and C-reactive protein levels) were measured, as well as cytokines and chemokines (TNFα, IFNγ, IL10, IL15 and CXCL10) in the serum of a subgroup of 30 patients. RESULTS: There was a predominance of females, with a mean age of 43 years. Most were phototypes IV or V (71.3%), without comorbidities (77.55%), and without a family history of vitiligo (70.41%). Higher levels of neutrophil/lymphocyte ratio, C-reactive protein, and inflammatory cytokines/chemokines were documented in vitiligo patients when compared to the control group (non-significant). As relevant data, the highest values of CXCL10 were detected in patients with vitiligo versus controls, as well as in patients with disease of shorter duration (p<0.05). STUDY LIMITATIONS: The number of assessed patients was small due to recruitment difficulties caused by the COVID-19 pandemic. CONCLUSION: The present data contribute to confirming the relevant role of the IFNγ/CXCL10 axis in the pathogenesis of vitiligo, highlighting CXCL10 as a possible activity marker.

The effect of antireaction medications on the association between periodontitis and leprosy reactions: An important methodological issue in periodontal medicine.

BACKGROUND: The treatment of leprosy reactions (LRs) involves thalidomide, corticosteroids, and other immunomodulatory medications. This study evaluated the effect of these treatments on the association between periodontitis and LRs, as well as factors associated with LRs. METHODS: This case-control study was conducted on 283 individuals followed at a leprosy outpatient clinic in Brazil. The case group was comprised of 158 individuals presenting type 1 or type 2 LRs, and the control group of 125 leprosy individuals without reactions. A complete oral examination was performed to diagnose periodontitis, the independent variable. Antireaction medication used was collected from medical records, and participants were classified according to the use of prednisone and/or thalidomide, time of use, or non-use of medication. Socioeconomic-demographic, clinical, and lifestyle covariables were collected by interview. Unconditional logistic regression analysis by subgroups evaluated the effect of antireaction medication on the association between periodontitis and LRs, estimating the odds ratio with a 95% confidence interval (OR; 95% CI). RESULTS: A relationship between periodontitis and LRs was observed only in the subgroup using the association prednisone and thalidomide: ORadjusted = 0.32; 95% CI = 0.11-0.95. Conversely, more severe periodontal clinical parameters were observed in cases versus controls. Several socioeconomic, health conditions, and lifestyle factors were associated with the presence of LRs. CONCLUSIONS: Although periodontal disease indicators were worse among the cases, the findings showed a negative relationship between periodontitis and LRs in individuals receiving associated prednisone and thalidomide. These medications appear to influence the inflammatory cascade between diseases, modifying and masking the manifestations of periodontitis.

The leprosy reaction is associated with salivary anti-Porphyromonas gingivalis IgA antibodies.

The aim of the study was to evaluate the association between salivary anti-Porphyromonas gingivalis IgA antibodies and the leprosy reaction. The levels of salivary anti - P. gingivalis IgA antibodies, together with salivary flow and pH were measured in individuals diagnosed with leprosy and associated with the development of the leprosy reaction. Saliva was collected from 202 individuals diagnosed with leprosy at a reference leprosy treatment center, 106 cases with the leprosy reaction and 96 controls without the leprosy reaction. Anti - P. gingivalis IgA was evaluated by indirect immunoenzyme assay. Non-conditional logistic regression analysis was employed to estimate the association between antibody levels and the leprosy reaction. There was a positive statistically significant association between the levels of anti - P. gingivalis IgA and the presence of the leprosy reaction, controlling for confounders: age, sex, level of education and alcoholic beverage consumption: ORajusted: 2.55; IC 95%: 1.34-4.87. Individuals with leprosy who had high levels of salivary anti - P. gingivalis IgA had approximately twice as many chances of developing the leprosy reaction. The findings suggest a possible relationship between salivary anti - P. gingivalis IgA antibodies and the leprosy reaction.

Association between an emerging disseminated form of leishmaniasis and Leishmania (Viannia) braziliensis strain polymorphisms.

Leishmania (Viannia) braziliensis causes three main types of American tegumentary leishmaniasis (ATL), localized cutaneous leishmaniasis (CL), mucosal leishmaniasis (ML), and disseminated leishmaniasis (DL). All forms are observed among individuals of Corte de Pedra, Brazil. We previously used random amplified markers to identify a multiclonal population among L. (V.) braziliensis isolates from ATL patients, defining parasite clades associated with different clinical syndromes. Herein we compared sequences of random amplified markers to identify genotypes of L. (V.) braziliensis recovered from lesions of CL, ML, and DL patients. Six polymorphic genomic loci were sequenced from 35 parasite isolates. Single-nucleotide polymorphisms (SNPs) and insertions-deletions (indels) at each locus allowed us to segregate the L. (V.) braziliensis population according to haplotypes. Several SNPs, indels, and haplotypes were significantly associated with an increased risk of DL. Molecular genotyping may provide markers to identify L. (V.) braziliensis strains likely to cause this emerging, hard-to-treat form of ATL.

The role of human T cell lymphotrophic virus type 1, hepatitis B virus and hepatitis C virus coinfections in leprosy.

Leprosy spectrum and outcome is associated with the host immune response against Mycobacterium leprae. The role of coinfections in leprosy patients may be related to a depression of cellular immunity or amplification of inflammatory responses. Leprosy remains endemic in several regions where human T cell lymphotrophic virus type 1 (HTLV-1), hepatitis B virus (HBV) or hepatitis C virus (HCV) are also endemic. We have evaluated the evidence for the possible role of these viruses in the clinical manifestations and outcomes of leprosy. HTLV-1, HBV and HCV are associated with leprosy in some regions and institutionalization is an important risk factor for these viral coinfections. Some studies show a higher prevalence of viral coinfection in lepromatous cases. Although HBV and HCV coinfection were associated with reversal reaction in one study, there is a lack of information about the consequences of viral coinfections in leprosy. It is not known whether clinical outcomes associated with leprosy, such as development of reactions or relapses could be attributed to a specific viral coinfection. Furthermore, whether the leprosy subtype may influence the progression of the viral coinfection is unknown. All of these important and intriguing questions await prospective studies to definitively establish the actual relationship between these entities.

Exuberant case of verrucous cutaneous leishmaniasis.

Cutaneous leishmaniasis represents a public health problem that affects 85 countries. It is an endemic disease in Brazil, having an important socioeconomic impact. An exuberant case of cutaneous leishmaniasis is reported herein. A 28-year-old male patient with Down syndrome had had verrucous plaques on the back for over a year, with progressive growth. PCR of a lesion sample was positive for Leishmania braziliensis. The patient's condition was classified as atypical cutaneous leishmaniasis. He was successfully treated with amphotericin B and miltefosine. The treatment remains a challenge, given the toxicity and low cure rate of the currently recommended drugs.

Effect of immunonutrition on serum levels of C-reactive protein and lymphocytes in patients with COVID-19: a randomized, controlled, double-blind clinical trial.

INTRODUCTION: Introduction: patients with COVID-19 undergo changes in leukocyte count, respiratory disorders, and an increase in inflammatory substances. To improve the inflammatory condition, some nutrients can be used, including arginine, omega-3 fatty acids and nucleotides. This study aims to evaluate how oral immunonutrient supplements affects serum C-reactive protein (CRP) levels and lymphocyte count in patients with COVID-19. Methods: in this double-blind clinical trial, we randomized 43 adult patients with COVID-19 to receive a standard high-protein normocaloric supplement (control) or an immunonutrient-enriched supplement (experiment) for 7 days. The primary outcome was to evaluate changes in total lymphocyte count and serum level of CRP. The assessment of risk and nutritional status of these patients was also performed. Results: forty-three patients with mean age of 41.5 (± 1.8) years were followed up, 39.5 % of them women. The mean body mass index was 27.6 (± 0.8) kg/m² and 58.1 % had low nutritional risk. In the experiment group, there was a CRP reduction of 23.6 (± 7.5) mg/L, while in the control branch the decrease was 14.8 (± 12.1) mg/L (p = 0.002). There was an increase in lymphocytes in the experiment group (+367.5 ± 401.8 cells/mm³) and a reduction in the control group (-282.8 ± 327.8 cells/mm³), although there was no statistical significance (p = 0.369). Relative risk (RR) of treatment in reducing CRP by 30 % or more was 4.45 (p < 0.001; 95 % CI, 1.79-11.07). RR in increasing lymphocyte count by 30 % or more was 1.28 (p = 0.327; 95 % CI, 0.67-2.45). Conclusion: we conclude that immunonutrient supplements seem to reduce CRP levels more than standard high-protein normocaloric supplements.

INTRODUCCIÓN: Introducción: los pacientes con COVID-19 sufren cambios en el recuento de leucocitos, trastornos respiratorios y aumento de sustancias inflamatorias. Para mejorar la condición inflamatoria se pueden usar algunos nutrientes, como la arginina, los ácidos grasos omega-3 y los nucleótidos. Este estudio tiene como objetivo evaluar cómo los suplementos de inmunonutrientes orales afectan a los niveles séricos de proteína C-reactiva (PCR) y al recuento de linfocitos en pacientes con COVID-19. Métodos: en este ensayo clínico doble ciego, aleatorizamos a 43 pacientes adultos con COVID-19 para recibir un suplemento normocalórico estándar alto en proteínas (control) o un suplemento enriquecido con inmunonutrientes (experimento) durante 7 días. El resultado primario fue evaluar los cambios en el recuento total de linfocitos y el nivel sérico de PCR. También se realizó la evaluación del riesgo y el estado nutricional de estos pacientes. Resultados: cuarenta y tres pacientes con edad media de 41,5 (± 1,8) años fueron seguidos, el 39,5 % de ellos mujeres. El índice de masa corporal medio fue de 27,6 (± 0,8) kg/m² y el 58,1 % tenían bajo riesgo nutricional. En el grupo experimental hubo una reducción de la PCR de 23,6 (± 7,5) mg/L, mientras que en la rama de control la disminución fue de 14,8 (± 12,1) mg/L (p = 0,002). Hubo un aumento de linfocitos en el grupo experimental (+367,5 ± 401,8 células/mm³) y una reducción en el grupo de control (-282,8 ± 327,8 células/mm³), aunque no hubo significación estadística (p = 0,369). El riesgo relativo (RR) del tratamiento para reducir la PCR en un 30 % o más fue de 4,45 (p < 0,001; IC 95 %: 1,79-11,07). El RR en el aumento del recuento de linfocitos en un 30 % o más fue de 1,28 (p = 0,327; IC 95 %: 0,67-2,45). Conclusión: se concluye que los suplementos de inmunonutrientes parecen reducir los niveles de PCR más que los suplementos normocalóricos estándar altos en proteína.

Plantar ulcer as an atypical manifestation of cutaneous leishmaniasis.

Cutaneous leishmaniasis is characterized by ulcers with raised edges and a granular bottom, mainly on the lower limbs. This is a case report of a male patient with an ulcer on the left plantar region. The diagnosis was confirmed by positive PCR for L. braziliensis and the presence of amastigotes of Leishmania sp. in the histopathological examination. After treatment with Glucantime, the patient showed full healing of the ulcer. The unusual location of the ulceration calls attention to atypical presentations of leishmaniasis, and the importance of histopathological examination and PCR, leading to the appropriate diagnosis and treatment.

Immunoassay standardization for the detection of immunoglobulin A (IgA) against Porphyromonas gingivalis antigens in saliva of individuals with and without leprosy.

Leprosy reactions are immune processes that cause neural damage in individuals with leprosy. As periodontitis is an infectious disease related to its development, specific antibodies to periodontal pathogens must be evaluated to better understand the humoral mechanisms underlying this relationship. Therefore, the objective of this study was to standardize an immunoassay to measure IgA specific to P. gingivalis antigens in the saliva of individuals with leprosy. An ELISA checkerboard titration was performed. A validation test involving 53 individuals with leprosy, 24 with and 19 without periodontitis, was conducted and a ROC curve constructed to calculate sensitivity and specificity. The coefficient of the optical densities was 2.21 and 2.66 for P. gingivalis crude extract and the recombinant protein HmuY, respectively. Sensitivity and specificity for the P. gingivalis crude extract were 66.7% and 73.7%, respectively, and for HmuY, were 62.5% and 52.6%, respectively. Specific recognition of P. gingivalis occurred predominantly in individuals with periodontitis, which validates the use of this test for studying periodontitis in individuals with leprosy.Trial registration CAEE 64476117.3.0000.0049, 21/07/2017, retrospectively registered.

Tissue Damage in Human Cutaneous Leishmaniasis: Correlations Between Inflammatory Cells and Molecule Expression.

Cutaneous leishmaniasis (CL) is caused by the bite of the infected sand fly, which inoculates parasites of Leishmania spp and triggers an immune response. An exacerbated cutaneous inflammatory response is crucial for controlling parasite burden but can also promote tissue damage. This study aimed to characterize the populations of natural killer (NK), CD57+, CD4+, and CD8+ T cells, CD20+ B cells, as well as CD68+ macrophages, in biopsies of ulcerated CL lesions, and quantify the production of perforin+, grazyme B+, interleukin 1 beta (IL-1ß+) and Tumor Necrosis Factor (TNF-α+ cells). We then correlated these parameters with necrosis, inflammation and the number of amastigotes. CD4+ T cells were positively correlated to the extent of inflammation, B cells and IL-1ß+ were associated with the extent of necrosis, CD68+ macrophages and perforin were correlated with the number of amastigotes, and CD57+ NK cells was correlated to CD68+ macrophages and amastigotes. In sum, the finding suggests that the production of cytotoxic granules and cytokines by inflammatory cells contributes to tissue damage in CL lesions.

Human CD8+ T Cells Release Extracellular Traps Co-Localized With Cytotoxic Vesicles That Are Associated With Lesion Progression and Severity in Human Leishmaniasis.

Cell death plays a fundamental role in mounting protective and pathogenic immunity. Etosis is a cell death mechanism defined by the release of extracellular traps (ETs), which can foster inflammation and exert microbicidal activity. While etosis is often associated with innate cells, recent studies showed that B cells and CD4+ T cells can release ETs. Here we investigate whether CD8+ T cells can also release ETs, which might be related to cytotoxicity and tissue pathology. To these ends, we first employed an in vitro system stimulating human CD8+ T cells isolated from healthy volunteers with anti-CD3/anti-CD28. Using time-frame video, confocal and electron microscopy, we demonstrate that human CD8+ T cells release ETs upon stimulation (herein LETs - lymphocyte extracellular traps), which display unique morphology and functional characteristics. CD8+ T cell-derived LETs form long strands that co-localize with CD107a, a marker of vesicles containing cytotoxic granules. In addition, these structures connect the LET-releasing cell to other neighboring cells, often resulting in cell death. After demonstrating the release of LETs by human CD8+ T cells in vitro, we went on to study the occurrence of CD8-derived LETs in a human disease setting. Thus, we evaluated the occurrence of CD8-derived LETs in lesions from patients with human tegumentary leishmaniasis, where CD8+ T cells play a key role in mediating pathology. In addition, we evaluated the association of these structures with the intensity of the inflammatory infiltrate in early and late cutaneous, as well as in mucosal leishmaniasis lesions. We demonstrated that progression and severity of debilitating and mutilating forms of human tegumentary leishmaniasis are associated with the frequency of CD8+ T cells in etosis, as well as the occurrence of CD8-derived LETs carrying CD107a+ vesicles in the lesions. We propose that CD8+ T cell derived LETs may serve as a tool for delivering cytotoxic vesicles to distant target cells, providing insights into mechanisms of CD8+ T cell mediated pathology.

Phonotherapeutic Intervention in Patients With Mucosal Leishmaniasis Sequelae.

PURPOSE: To characterize the voice before and after speech-language intervention, with Humming nasal sound in patients with sequelae Mucosal Leishmaniasis (ML) and Cutaneous Leishmaniasis (CL). METHODS: Collection of phonation /a:/ from 44 patients with ML and CL for perceptual voice analysis and computed acoustic. The Wilcoxon nonparametric test and Fisher's exact test were used, with significance level of 5%. RESULTS: It was observed, prespeech therapy, that 27.7% of participants with ML presented asthenic vocal quality, and for the acoustics characteristics there was a statistically significant result for measures of frequency, frequency disturbance, noise, and subharmonic measurements, indicating phonatory instability, weakness, and noise emission giving the emission a feeling of vocal weakness. After therapy, the subharmonic segment measurements for the group with ML, showing reduction noise emission. Patients with CL had more grade 1 instability (36.4%), indicating tremor in vocal tract structures. After speech therapy, this group presented a reduction in the degree of roughness and reduction of the frequency disturbance measures, indicating a decrease in tension in the larynx and pharynx. CONCLUSION: Even after completing treatment for LM, patients may experience vocal changes due to the sequelae of the disease, like vocal alterations due to nasal lesions or in other locations that interfere in the correct vocal emission. As for participants with CL, no vocal changes would be expected, since these patients present thorax, leg and arm lesions that would not cause problems for the voice. Nevertheless, the two groups of participants presented vocal changes to different degrees before vocal therapy. However, it was observed that patients with ML present vocal alterations with more severe degrees. After the speech-language intervention, the participants of both groups showed vocal improvement, but the group with CL presented more vocal benefits, possibly due to the previous vocal alterations not being so severe.

Disseminated leishmaniasis: clinical, pathogenic, and therapeutic aspects.

Disseminated leishmaniasis is a severe and emerging form of American tegumentary leishmaniasis. Disseminated leishmaniasis is defined by the presence of more than 10 polymorphic cutaneous lesions, distributed over more than two noncontiguous parts of the body. Nasal mucosal involvement is observed in almost half of cases. Disseminated leishmaniasis patients present with a decreased production of Th1 cytokines in the peripheral blood due to the attraction of leishmania- activated T cells to the multiple cutaneous lesions. Disseminated leishmaniasis development is poorly understood and is related to a complex network involving environmental, host immune response, and parasite factors, in which L. braziliensis polymorphism plays an important role. Disseminated leishmaniasis is a challenging disease to cure, presenting a high failure rate of 75% to pentavalent antimony therapy. Despite its importance and severity, this form of American tegumentary leishmaniasis has been poorly studied and documented, deserving greater attention from professionals working in endemic areas.

Clinical profile of vitiligo patients and relationship with immuno-inflammatory markers

Abstract Background Vitiligo is the most common pigmentary disorder and is considered a chronic, cumulative, multifactorial disease. The crucial role of cytotoxic CD8+ T lymphocytes and the IFNγ/CXCL10 axis has been demonstrated in its pathogenesis. Objective To evaluate the clinical profile and immuno-inflammatory markers in patients with vitiligo in a reference medical center. Methods Cross-sectional study in which all patients with vitiligo seen at the medical center the from 2019 to 2022 were evaluated, to outline the clinical profile. Moreover, cardiovascular risk biomarkers (neutrophil/lymphocyte ratio and C-reactive protein levels) were measured, as well as cytokines and chemokines (TNFα, IFNγ, IL10, IL15 and CXCL10) in the serum of a subgroup of 30 patients. Results There was a predominance of females, with a mean age of 43 years. Most were phototypes IV or V (71.3%), without comorbidities (77.55%), and without a family history of vitiligo (70.41%). Higher levels of neutrophil/lymphocyte ratio, C-reactive protein, and inflammatory cytokines/chemokines were documented in vitiligo patients when compared to the control group (non-significant). As relevant data, the highest values of CXCL10 were detected in patients with vitiligo versus controls, as well as in patients with disease of shorter duration (p < 0.05). Study limitations The number of assessed patients was small due to recruitment difficulties caused by the COVID-19 pandemic. Conclusion The present data contribute to confirming the relevant role of the IFNγ/CXCL10 axis in the pathogenesis of vitiligo, highlighting CXCL10 as a possible activity marker.

In Situ Cellular Response Underlying Successful Treatment of Mucosal Leishmaniasis with a Combination of Pentavalent Antimonial and Pentoxifylline.

Mucosal leishmaniasis (ML) is characterized by high production of inflammatory cytokines. Administration of pentoxifylline (PTX), an inhibitor of TNF-alpha, with pentavalent antimony (Sbv), has been successfully used as alternative treatment for refractory ML. Our study aims to investigate the in situ cellular response underlying the effectiveness of this therapy, by evaluating the intensity of the inflammatory infiltrate, cellular composition, and expression of cytokines and granzyme A in lesions from ML before and after treatment with Sbv alone or in combination with PTX. Our data showed no differences in the intensity of inflammatory infiltrate comparing before and after treatment, and comparing between different treatments. However, although the number and frequency of CD4+ and CD8+ cells were not different before and after treatments or comparing different treatments, frequency of CD68+ cells decreased after treatment with Sbv + PTX, but not with Sbv. This was due to a reduction in CD68+ TNF-alpha+ and not in CD68+ IL-10+ cells. The frequency of TNF-alpha+ cells was correlated with the intensity of the inflammatory infiltrate before treatment, but this correlation was lost after treatment with Sbv + PTX. Although the total expression of granzyme A did not significantly change after treatments, a clear trend of decrease was observed after treatment with Sbv + PTX. Interestingly, patients who took longer to heal, regardless of the treatment, displayed a higher frequency of granzyme A+ cells. Our data suggest that treatment with Sbv + PTX acts in CD68+ cells reducing the expression of TNF-alpha but not IL-10, resulting in more efficient modulation of the inflammatory response, accelerating the healing process.

Pentoxifylline down modulate in vitro T cell responses and attenuate pathology in Leishmania and HTLV-I infections.

Tumor necrosis factor-alpha (TNF-alpha) is known to have numerous biological properties relating to inflammation. This cytokine participates in the tissue damage of chronic inflammatory, autoimmune and infectious diseases. Pentoxifylline is a methylxanthine that inhibits phosphodiesterase IV, which inhibits the degradation of the cAMP and prostanoids. The increased intracellular concentration of the cAMP leads to a negative regulation of NF-kappaB and NF-AT transcription factors and suppresses TNF-alpha production. This review describes studies that support evidences that TNF-alpha is involved in the pathogenesis of HTLV-1 associated myelopathy and of cutaneous and mucosal leishmaniasis. Additionally, it demonstrates the effect of pentoxifylline in vitro in inhibiting TNF-alpha and IFN-gamma spontaneous production in PBMC from HTLV-1-infected patients, as well as its in vivo effect in inhibiting TNF-alpha in sera from mucosal leishmaniasis patients. Moreover, we review the results of clinical studies from the last 10 years using pentoxifylline to treat HTLV-1 associated myelopathy and cutaneous and mucosal leishmaniasis.