Anti-Non-Bilayer Phospholipid Arrangement Antibodies Trigger an Autoimmune Disease Similar to Systemic Lupus Erythematosus in Mice

Anti-lipid antibodies are present in some infectious and autoimmune diseases, such as Systemic Lupus Erythematosus (SLE). Particularly, anti-non-bilayer phospholipid arrangement (NPA) antibodies have been detected in patients with SLE, and these antibodies trigger a disease similar to human lupus in mice. NPA are lipid associations different from the lipid bilayer of cellular membranes and, since they are transient, they are not immunogenic. However, if NPA are stabilized by drugs, they induce an immune response with the production of anti-NPA antibodies, which bind to NPA on cell membranes and generate cell lysis. As a result, intracellular antigens are exposed and trigger an immune response that generates more auto-antibodies. In this chapter, we describe the formation and stabilization of NPA, the induction of B cell responses to generate anti-NPA antibodies, and the characteristics that the disease caused by these antibodies in mice shares with human lupus

Development of Novel Drugs for the Treatment of Chagas Disease

Chagas disease, or American trypanosomiasis, is a zoonosis caused by the hemoflagellate parasite Trypanosoma cruzi. It is mainly transmitted by the bite of blood-sucking insects. It is endemic in Latin America and emerging in the rest of the world, affecting approximately six million people. The drugs Benznidazole and Nifurtimox currently used for its treatment are not totally effective in the chronic phase of the disease. In addition, they are toxic, and there are many resistant Trigonoscuta cruzi strains. Therefore, developing new drugs for the treatment of Chagas disease is necessary. This chapter describes the development of drugs that inhibit α-hydroxy acid dehydrogenase isoenzyme II, a key enzyme in parasite energy metabolism. These drugs have shown more significant trypanocidal activity than the currently used drugs, and they have also prevented the development of chronic Chagas disease in infected mice

The Role of Lipopeptidophosphoglycan in the Immune Response to Entamoeba histolytica

The sensing of Pathogen Associated Molecular Patterns (PAMPs) by innate immune receptors, such as Toll-like receptors (TLRs), is the first step in the inflammatory response to pathogens. Entamoeba histolytica, the etiological agent of amebiasis, has a surface molecule with the characteristics of a PAMP. This molecule, which was termed lipopeptidophosphoglycan (LPPG), is recognized through TLR2 and TLR4 and leads to the release of cytokines from human monocytes, macrophages, and dendritic cells; LPPG-activated dendritic cells have increased expression of costimulatory molecules. LPPG activates NKT cells in a CD1d-dependent manner, and this interaction limits amebic liver abscess development. LPPG also induces antibody production, and anti-LPPG antibodies prevent disease development in animal models of amebiasis. Because LPPG is recognized by both the innate and the adaptive immune system (it is a “Pamptigen”), it may be a good candidate to develop a vaccine against E. histolytica infection and an effective adjuvant

Therapeutic Properties of <em>Trichinella spiralis</em> (Nematoda) in Chronic Degenerative Diseases

Diseases produced by helminth parasites occur frequently in underdeveloped countries where they present a serious public health problem. At the same time, in these regions, a lower rate of autoimmune and allergic diseases has been observed. Due to these observations, some researchers have proposed that some helminths, such as Trichinella spiralis or its proteins, have strong anti-inflammatory potential, or have assessed them as modulating agents of the immune response. T. spiralis shifts the host immune response from a Th1 profile, characterized by pro-inflammatory cytokines, to a Th2 profile, characterized by the release of different cytokines with anti-inflammatory properties. This parasite has shown high therapeutic potential in a wide variety of disease models. In one of the most promising, the experimental lupus model in mice, the release of anti-inflammatory cytokines IL-4 and IL-10 and delayed onset of the key clinical features of the experimental lupus model for at least 5 months were observed, when previously parasitized. This is the first study to date that focuses on the use of T. spiralis as an immunomodulator in lupus disease. In conclusion, further study of the immune response generated by the parasite is necessary to advance the development of new therapies for inflammatory diseases

Efectividad de la suspensión bacteriana sublingual en la prevención de infecciones de vías aéreas de repetición en pediatría

Antecedentes: Las infecciones de vías aéreas superiores (IVASR) son muy frecuentes en la población pediátrica. La mayoría de estas infecciones son leves, pero por la cronicidad afectan la calidad de vida (CdV), además de elevados costos por la atención médica. El uso de extractos bacterianos (EB) que estimulen la inmunidad general pueden reducir su frecuencia y mejorar la CdV del paciente. Objetivo: Evaluar la efectividad de un EB en la prevención de IVASR en niños de 1 a 6 años. Métodos: Se aleatorizaron niños entre 1 y 6 años, con diagnóstico IVASR en 3 grupos distintos, seguimiento médico a las 6 y 12 semanas tras el inicio. El EB se administró con dosis distintas a cada grupo. Se utiliza una prueba de ANOVA con un post hoc Tukey para comparaciones múltiples (error tipo I máximo de 0.05). Resultados: Se incluyeron 33 niños (12 niñas) con una media de edad de 3.11 años. La frecuencia de IVASR previo al tratamiento en promedio fue de 2.2 eventos/mes y de 0.9 y de 0.4 eventos/mes a las 6 y 12 semanas respectivamente. La IVARS se redujeron un 76.9% a los 3 meses de tratamiento. (Gráfica). No se reportaron efectos adversos. Conclusiones: El EB es seguro y efectivo en disminuir la frecuencia de IVASR en niños en concordancia con la literatura. No hay suficiente evidencia científica publicada pero el EB parece tener aplicación en la prevención y tratamiento de las IVASR. La administración sublingual es cómoda en este grupo etario 

Extracellular vesicles from Mycobacterium tuberculosis-infected neutrophils induce maturation of monocyte-derived dendritic cells and activation of antigen-specific Th1 cells

Tuberculosis remains one of the leading public health problems in the world. The mechanisms that lead to the activation of the immune response against Mycobacterium tuberculosis have been extensively studied, with a focus on the role of cytokines as the main signals for immune cell communication. However, less is known about the role of other signals, such as extracellular vesicles, in the communication between immune cells, particularly during the activation of the adaptive immune response. In this study, we determined that extracellular vesicles released by human neutrophils infected with M. tuberculosis contained several host proteins that are ectosome markers. In addition, we demonstrated that extracellular vesicles released by human neutrophils infected with M. tuberculosis released after only 30 min of infection carried mycobacterial antigens and pathogen-associated molecular patterns, and we identified 15 mycobacterial proteins that were consistently found in high concentrations in extracellular vesicles released by human neutrophils infected with M. tuberculosis; these proteins contain epitopes for CD4 T-cell activation. We found that extracellular vesicles released by human neutrophils infected with M. tuberculosis increased the expression of the costimulatory molecule CD80 and of the coinhibitory molecule PD-L1 on immature monocyte-derived dendritic cells. We also found that immature and mature dendritic cells treated with extracellular vesicles released by human neutrophils infected with M. tuberculosis were able to induce IFN-γ production by autologous M. tuberculosis antigen-specific CD4 T cells, indicating that these extracellular vesicles acted as antigen carriers and transferred mycobacterial proteins to the antigen-presenting cells. Our results provide evidence that extracellular vesicles released by human neutrophils infected with M. tuberculosis participate in the activation of the adaptive immune response against M. tuberculosis.This work was supported by Consejo Nacional de Ciencia y Tecnología (CONACYT grant A1-S-16113 to IEG) and by Secretaría de Investigación y Posgrado, Instituto Politécnico Nacional (IPN). L.V.-F., E.S.P., M.G.-M., and D.B. were recipients of CONACYT fellowships. J.S.-L., R.C.-S., S.E.-P., and I.E.-G. are fellows of Comisión de Operación y Fomento de Actividades Académicas (COFAA)–IPN. J.S.-L., R.C.-S., S.E.-P., I.E.-G., and I.W.-B. are fellows of Estímulos al Desempeño de los Investigadores (EDI)–IPN

Activation-induced killer cell immunoglobulin-like receptor 3DL2 binding to HLA-B27 licenses pathogenic T cell differentiation in spondyloarthritis

Objective In the spondyloarthritides (SpA), increased numbers of CD4+ T cells express killer cell immunoglobulin-like receptor 3DL2 (KIR-3DL2). The aim of this study was to determine the factors that induce KIR-3DL2 expression, and to characterize the relationship between HLA–B27 and the phenotype and function of KIR-3DL2–expressing CD4+ T cells in SpA. Methods In total, 34 B27+ patients with SpA, 28 age- and sex-matched healthy controls (20 B27− and 8 B27+), and 9 patients with rheumatoid arthritis were studied. KIR-3DL2 expression and other phenotypic characteristics of peripheral blood and synovial fluid CD4+ T cells were studied by flow cytometry, quantitative polymerase chain reaction, and Western blotting. T cell receptor clonality was determined by template-switch anchored reverse transcription–polymerase chain reaction and sequencing analysis. Cytokines were measured by enzyme-linked immunosorbent assay. Results Cellular activation induced KIR-3DL2 expression on both naive and effector CD4+ T cells. KIR-3DL2 binding to B27+ cells promoted expression of KIR-3DL2, the Th17-specific transcription factor retinoic acid receptor–related orphan nuclear receptor γt, and the antiapoptotic factor B cell lymphoma 2. KIR-3DL2+CD4+ T cells in patients with ankylosing spondylitis were oligoclonal and enriched for markers of T cell activation and for the gut homing receptor CCR9. In the presence of B27+ antigen-presenting cells, KIR-3DL2+CD4+ T cells produced less interleukin-2 (IL-2) but more IL-17. This effect was blocked by HC10, an antibody that inhibits the binding of KIR-3DL2 to B27 heavy chains. Conclusion KIR-3DL2 binding to HLA–B27 licenses Th17 cell differentiation in SpA. These findings raise the therapeutic potential of targeting HLA–B27–KIR-3DL2 interactions for the treatment of B27+ patients with SpA