Xenophagy as a Strategy for Mycobacterium leprae Elimination during Type 1 or Type 2 Leprosy Reactions: A Systematic Review.

BACKGROUND: Mycobacterium leprae is an intracellular bacillus that causes leprosy, a neglected disease that affects macrophages and Schwann cells. Leprosy reactions are acute inflammatory responses to mycobacterial antigens, classified as type1 (T1R), a predominant cellular immune response, or type2 (T2R), a humoral phenomenon, leading to a high number of bacilli in infected cells and nerve structures. Xenophagy is a type of selective autophagy that targets intracellular bacteria for lysosomal degradation; however, its immune mechanisms during leprosy reactions are still unclear. This review summarizes the relationship between the autophagic process and M. leprae elimination during leprosy reactions. METHODS: Three databases, PubMed/Medline (n = 91), Scopus (n = 73), and ScienceDirect (n = 124), were searched. After applying the eligibility criteria, articles were selected for independent peer reviewers in August 2023. RESULTS: From a total of 288 studies retrieved, eight were included. In multibacillary (MB) patients who progressed to T1R, xenophagy blockade and increased inflammasome activation were observed, with IL-1ß secretion before the reactional episode occurrence. On the other hand, recent data actually observed increased IL-15 levels before the reaction began, as well as IFN-γ production and xenophagy induction. CONCLUSION: Our search results showed a dichotomy in the T1R development and their relationship with xenophagy. No T2R studies were found.

Respiratory allergy symptoms and cytokine profiles in the presence of anti-Ascaris antibody in Giardia lamblia-infected children.

Anti-Ascaris lumbricoides (Asc) IgE and IgG can immunomodulate the allergy; however, the influence of these isotypes has not been investigated in the giardiasis and allergy. Therefore, the frequency of respiratory allergy (RA) symptoms in Giardia lamblia-infected children, with or without anti-Asc IgE, IgG1, or IgG4 and Th1, Th2/Treg, and Th17 cytokine production, was evaluated. We performed a case-control study with children aged 2-10 years old selected by questionnaire and stool exams to form the groups: infected or uninfected with RA (G-RA, n = 55; nG-RA, n = 43); infected and uninfected without RA (G-nRA, n = 59; nG-nRA, n = 54). We performed blood leukocyte counts and in vitro culture. Cytokine levels in the supernatants (CBA), serum total IgE and anti-Asc IgE (ImmunoCAP), IgG1, IgG4, and total IgA (ELISA) were measured. Infection was not associated with allergy. Infected children showed increased levels of anti-Asc IgG1, IL-2, IFN-γ, IL-4, and IL-10. There was a lower frequency of allergy-related symptoms in anti-Asc IgG1-positive children than IgG1-negative (OR = 0.38; CI = 0.17-0.90, p = 0.027) and few eosinophils in G-RA than in G-nRA and more in G-nRA than in nG-nRA, whereas TNF-α levels were higher in the G-RA than in the nG-nRA group. For infected and positive anti-Asc IgG1, there was higher TNF-α and IL-10 production than G/-IgG1. IL-10 levels were lower in nG/ + IgG1 than in infected or non-infected, and both were negative for anti-Asc IgG1. Th1/Th2/IL-10 profiles were stimulated in the infected patients, and in those with circulating anti-Asc IgG1, the TNF-α production was strengthened with a lower risk for respiratory allergy symptoms.

Schistosoma mansoni infection decreases IL-33-mRNA expression and increases CXCL9 and CXCL10 production by peripheral blood cells.

Schistosoma mansoni infections, particularly egg antigens, induce Th2-dominant granulomatous responses accompanied by remarkable immunoregulatory mechanisms that avoid intense fibrosis. Interleukin (IL)-33 is a cytokine that stimulates the early activation of Th2 responses, and its soluble ST2 receptor (sST2) avoids granulomatous response, as well as CXCL9 and CXCL10 chemokines that have antifibrotic activity. However, in schistosomiasis, these molecules have not been suitably studied. Therefore, this study aimed to measure IL-33 and sST2 RNA, cytokines, and chemokines in peripheral blood cultures from individuals living in schistosomiasis-endemic areas. Peripheral blood cells from individuals with S. mansoni (n = 34) and non-infected individuals (n = 31) were cultured under mitogen stimulation. Supernatant chemokines and cytokines were evaluated using a cytometric bead array, and IL-33 and sST2 mRNA expression was measured using qPCR. Infected individuals showed higher levels of CXCL8, CXCL9, CXCL10, IFN-γ, TNF-α, IL-6, IL-2, IL-4, and IL-10; there was a lower expression of IL-33 mRNA and similar expression of sST2mRNA in infected than non-infected individuals. In conclusion, for the first time, we demonstrated lower IL-33mRNA expression and high levels of the antifibrotic chemokines CXCL9 and CXCL10 in schistosomiasis mansoni, which could control exacerbations of the disease in individuals from endemic areas.

Schistosoma mansoni infection is associated with decreased risk of respiratory allergy symptoms and low production of CCL2.

OBJECTIVES: We measured the production of cytokines, chemokines and antibodies involved in allergic responses and sCD23 levels during Schistosoma mansoni infection. METHODS: Individuals (n = 164) were selected using the ISAAC questionnaire and parasitological exams. The subjects were divided as follows: those infected individuals with allergy-related symptoms (A-I), those with allergy-related symptoms only (A-NI); those only infected (NA-I); and those non-infected individuals without allergy-related symptoms (NA-NI). We used supernatants from cell culture (mitogenic stimulation) to measure cytokine and chemokine levels using cytometric bead arrays. Serum levels of anti-Ascaris lumbricoides (Asc) and anti-Blomia tropicalis IgE were measured using ImmunoCAP, and sCD23 was measured using ELISA. RESULTS: Schistosoma mansoni infection was associated with a lower risk of allergy-related symptoms. In A-I, there were higher levels of TNF-α, IL-10, IL-6, IFN-γ and CXCL8 than in NA-NI group, with TNF-α and IL-6 also at higher levels compared to A-NI group. Levels of IL-6, CXCL8, total and anti-Asc IgE, as well as the numbers of eosinophils, were higher in NA-I than in NA-NI, and the antibodies were also lower in A-NI than in NA-I group. In AI and NA-I, there was less production of CCL2 than in NA-NI. There were no differences in the levels of IL-2, IL-4, IL-17, CCL5, sCD23 and anti-Blomia IgE. CONCLUSIONS: Patients with allergy-related symptoms and infected (simultaneously) had higher levels of IL-10; due to the infection, there was increased production of IL-6 and CXCL8 and less CCL2. These data may characterize deviation to Th1 or attenuation of the Th2 response in allergy sufferers in areas endemic for schistosomiasis.

Vasculature-associated fat macrophages readily adapt to inflammatory and metabolic challenges.

Tissue-resident macrophages are the most abundant immune cell population in healthy adipose tissue. Adipose tissue macrophages (ATMs) change during metabolic stress and are thought to contribute to metabolic syndrome. Here, we studied ATM subpopulations in steady state and in response to nutritional and infectious challenges. We found that tissue-resident macrophages from healthy epididymal white adipose tissue (eWAT) tightly associate with blood vessels, displaying very high endocytic capacity. We refer to these cells as vasculature-associated ATMs (VAMs). Chronic high-fat diet (HFD) results in the accumulation of a monocyte-derived CD11c+CD64+ double-positive (DP) macrophage eWAT population with a predominant anti-inflammatory/detoxifying gene profile, but reduced endocytic function. In contrast, fasting rapidly and reversibly leads to VAM depletion, while acute inflammatory stress induced by pathogens transiently depletes VAMs and simultaneously boosts DP macrophage accumulation. Our results indicate that ATM populations dynamically adapt to metabolic stress and inflammation, suggesting an important role for these cells in maintaining tissue homeostasis.

Gestation and breastfeeding in schistosomotic mothers differently modulate the immune response of adult offspring to postnatal Schistosoma mansoni infection.

Schistosoma mansoni antigens in the early life alter homologous and heterologous immunity during postnatal infections. We evaluate the immunity to parasite antigens and ovalbumin (OA) in adult mice born/suckled by schistosomotic mothers. Newborns were divided into: born (BIM), suckled (SIM) or born/suckled (BSIM) in schistosomotic mothers, and animals from noninfected mothers (control). When adults, the mice were infected and compared the hepatic granuloma size and cellularity. Some animals were OA + adjuvant immunised. We evaluated hypersensitivity reactions (HR), antibodies levels (IgG1/IgG2a) anti-soluble egg antigen and anti-soluble worm antigen preparation, and anti-OA, cytokine production, and CD4+FoxP3+T-cells by splenocytes. Compared to control group, BIM mice showed a greater quantity of granulomas and collagen deposition, whereas SIM and BSIM presented smaller granulomas. BSIM group exhibited the lowest levels of anti-parasite antibodies. For anti-OA immunity, immediate HR was suppressed in all groups, with greater intensity in SIM mice accompanied of the remarkable level of basal CD4+FoxP3+T-cells. BIM and SIM groups produced less interleukin (IL)-4 and interferon (IFN)-g. In BSIM, there was higher production of IL-10 and IFN-g, but lower levels of IL-4 and CD4+FoxP3+T-cells. Thus, pregnancy in schistosomotic mothers intensified hepatic fibrosis, whereas breastfeeding diminished granulomas in descendants. Separately, pregnancy and breastfeeding could suppress heterologous immunity; however, when combined, the responses could be partially restored in infected descendants.

Maternal schistosomiasis alters costimulatory molecules expression in antigen-presenting cells from adult offspring mice.

Adult offspring of Schistosoma mansoni-infected mice showed alterations in immunity to a heterologous antigen, ovalbumin (OA). Prior breastfeeding induced increased production of anti-OA antibodies, while pregnancy impaired it. Here, we investigated the expression of costimulatory molecules on antigen-presenting cells (APCs) of the adult offspring of S. mansoni-infected mothers in response to OA. Newborn mice were divided into three groups: animals Born Infected Mothers (BIM) suckled by non-infected mothers; animals from non-infected mothers Suckled Infected Mothers (SIM); and another group of mice born from and suckled by non-infected mothers (CONTROL). The adult offspring were immunized with subcutaneous OA+adjuvant, and 3-8days following immunization, double labeling was performed (CD45R/B220 or CD11c and CD80, CD86, CD40 or HLA-DR) on spleen cells. In comparison to the CONTROL group, an early increased frequency of CD40+/CD80+ B cells was observed in SIM mice (p<0.001/p<0.05), but no alteration of CD11c+ cells was observed. In contrast, in BIM mice, the frequency of CD86+/CD11c+ cells (p<0.05) and CD40+/CD80+/CD86+ B cells (p<0.01/p<0.01/p<0.05) was drastically reduced. In conclusion, previous suckling by S. mansoni-infected mothers enabled improved antigen presentation by B cells in adult offspring, whereas gestation in these mothers imprinted offspring with weak antigen presentation by APCs during the immune response to a non-related antigen.

Transferência passiva de anticorpos específicos para antígenos de Schistosoma mansoni em camundongos nascidos ou amamentados em mães esquistossomóticas / Passive transfer of Schistosoma mansoni antigens-specific antibodies in mice born or suckled by schistosomotic mothers

Objetivo - Estudos experimentais demonstraram que mães infectadas pelo Schistosoma mansoni modulam a imunidade para antígenos homólogos, dos descendentes adultos, através do contato prévio com anticorpos anti-Schistosoma durante o período pré-natal junto à amamentação. Descendentes adultos de mães esquistossomóticas apresentaram alteração na imunidade para um antígeno heterólogo, Ovalbumina (OA): amamentação induziu maior produção de imunoglobulinas anti-OA, enquanto a gestação levou à supressão destas imunoglobulinas. A fim de esclarecer a participação dos anticorpos anti-Schistosoma maternos na alteração da imunidade dos descendentes adultos, os anticorpos contra antígenos solúveis dos ovos (SEA) e dos vermes (SWAP) em descendentes gerados ou apenas amamentados em mães esquistossomóticas foram dosados. Métodos - Camundongos recém-nascidos foram divididos em: animais nascidos de Mães Infectadas (MI) e amamentados em mães não-infectadas; animais nascidos de mães não-infectadas e Amamentados em mães Infectadas (AI); animais nascidos e amamentados em mães infectadas (MIAI) ou não-infectadas (Controle). Os animais foram sangrados 21, 45, 60 e 77 dias, após nascimento e os isótipos IgG1 e IgG2a dosados, no plasma, por ELISA. Resultados - Foi detectado IgG1, mas não IgG2a, principalmente anti-SEA, tanto no grupo MI como nos grupos AI e MIAI. A transferência pela amamentação foi mais efetiva (maiores níveis e manutenção durante a cinética). Conclusões - O isótipo IgG1 anti-SEA presente no grupo MI, bem como no grupo AI, exclui a associação dos anticorpos antiparasita e melhora da imunidade heteróloga dos descendentes amamentados em mães esquistossomótica. Este estudo enfoca o importante papel da amamentação em transferir de forma eficaz anticorpos anti-SEA para indivíduos de área endêmica para esquistossomose.

Objective - Experimental studies have demonstrated that Schistosoma mansoni infected mothers modulate immunity to homologous antigen, in their adult offspring, through prior contact with anti-Schistosoma antibodies during the prenatal period plus breastfeeding. Adult offspring of schistosomotic mothers showed alterations in immunity to a heterologous antigen, ovalbumin (OA): breastfeeding induced higher production of anti-OA immunoglobulin, while the pregnancy led to suppression of this immunoglobulin. In order to study the participation of the maternal anti-Schistosoma antibodies and change in the heterologous immunity in adult offspring, antibodies against soluble egg antigen (SEA) and worms (SWAP) in offspring born or only breastfed by schistosomotic mothers were measured. Methods - Newborn mice were divided into: animals Born from Infected Mothers (BIM) suckled by non-infected mothers; animals from non-infected mothers Suckled by Infected Mothers (SIM); and mice Born and Suckled in Infected Mothers (BSIM) or non-infected (Control) mothers. The animals were bled 21,45, 60, 77 days, after birth, and IgG1 and IgG2a serum isotypes were measured by ELISA. Results - It was detected IgG1, but not IgG2a, mainly anti-SEA in a group BIM and in the groups SIM and BSIM. The transfer by breastfeeding was more effective (higher levels and maintenance during the kinetic). Conclusions - The anti-SEA IgG1 isotype detected in the group BIM, as well as, in the SIM, excludes the association of anti-parasite antibodies and the improvement of heterologous immunity in offspring nursed by schistosomotic mothers. This study highlights the important role of breastfeeding as effective way to transfer anti-SEA antibodies for individuals from an endemic area for schistosomiasis.

Influence of maternal schistosomiasis on the immunity of adult offspring mice.

Schistosoma mansoni infection modulates the immunity to unrelated antigens in the host. In this study, we have investigated the effect of pregnancy and nursing from schistosomotic mother mice on the immune response to ovalbumin (OA), in adult offspring. Then, newborn mice were divided into four groups: animals born from infected mothers (BIM) suckled by non-infected mothers; animals from non-infected mothers suckled by infected mothers (SIM); and two other groups that were mice born and suckled in infected mothers (BSIM) or non-infected (control) mothers. The adult offspring were immunized with OA plus adjuvant. We compared the OA-specific hypersensitivity reactions (HR), antibodies levels (IgG, IgG2a) and the cytokine production in splenocyte cultures. Remarkable interleukin (IL)-10 synthesis was observed in mice BIM; while the anti-OA antibodies levels and immediate HR were impaired. IL-10 neutralization recovered this suppression. Differently, in mice SIM and BSIM there was an enhancement in the anti-OA humoral response and high IL-2 production, however low level of the IL-10 was detected in mice BSIM. In conclusion, schistosomotic pregnancy provides an immunosuppressive potential, IL-10 dependent, which was sustained throughout adult life. Regardless, suckling by infected mothers induces great responsiveness to an unrelated antigen and repairs the inhibitory potential acquired during prenatal stage.

Correlação da hidroxiprolina urinária com a carga parasitária na esquistossomose mansonica / correlation of urinary hidroxiproline with the parasitary burden in mansonic schistosomiasis

Os exames laboratoriais não invasivos específicos para o seguimento de pacientes com esquistossomose mansônica após o tratamento específico estão restritos a contagem de ovos nas fezes que avalia a cura parasitológica e a ultra-sonografia hepática que avalia a evolução da fibrose periportal após o tratamento. A fibrose hepática é decorrente de um processo dinâmico de síntese e degradação do colageno. Esta atividade fibrogênica é observada apenas em estudos histólogicos de biópsias hepáticas que é um procedimento invasivo de risco não desprezível. A dosagem da hidroxiprolina, um aminoácido do colágeno pode ser utilizada como um meio indireto para avaliar a atividade fibrogênica hepática. A excreção urinária de hidroxiprolina pode indicar o metabolismo do colágeno recém-formado e a sua relação com o número de ovos eliminados das fezes de pacientes com esquistossomose mansônica podera comprovar a relação da intensidade da fibrose hepática com a carga parasitária e ser utilizada como um método indireto na avaliação da atividade fibrogênica hepática. Em uma casuística de 40 pacientes com o diagnóstico de esquistossomose mansônica na forma hepatoesplênica, de uma demanda espontânea do ambulatório de esquistossomose do Serviço de Gastroenterologia dos Hospital das Clínicas da UFPE, foi dosada a excreção urinária de hidroxiprolina pelo método de Pondenphant e a contagem de ovos eliminados nas fezes, pelo método de Kato Katz. Como controle foi utilizado um grupo de sete indivíduos adultos, sadios da mesma classe sócio-econômica. Toda casuística submeteu-se a exames clínico e laboratorial para o diagnóstico de esquistossomose e exclusão de doenças associadas segundo o protocolo do ambulatório. O valor médio da excreção urinária de hidroxiprolina nos pacientes esquistossomósticos com Kato Katz positivo foi de 14,6mg/L, diferente do grupo controle com o valor médio de 2,7mg/L. O estudo de correlação mão paramétrico, Spearman's rho aplicado entre os valores de excreção urinária de hidroxiprolina e do número de ovos eliminados nas fezes dos pacientes estudados, resultou em uma correlação significante, r=0,724,p=0,0018. O reultdo pode está correlacionado com a atividade fibrogênica hepática nos pacientes com esquistossomose mansônica.