Cytokine and Chemokines Alterations in the Endemic Form of Pemphigus Foliaceus (Fogo Selvagem)

IntroductionThe endemic form (fogo selvagem—FS) of pemphigus foliaceus is an autoimmune disease characterized by the presence of IgG autoantibodies against desmoglein-1. Despite the array of findings, the role of chemokines and cytokines that dictate the immune response and disease outcome is still poorly investigated.Materials and methodsSerum from 64 patients diagnosed with FS was used to draw and establish the levels of these molecules on this disease and establish the levels of these molecules with the severity of FS, and influence of treatment.ResultsIn comparison to healthy subjects, FS patients, newly diagnosed and still without therapeutic intervention, had higher levels of IL-22 and CXCL-8, and reduced levels of IFN-γ, IL-2, IL-15, and CCL-11. Furthermore, treatment using immunosuppressant drugs augmented the production of IFN-γ, IL-2, CCL-5, and CCL-11 besides reducing the levels of IL-22 and CXCL-10. Immunosuppressive therapy seemed to have long-lasting effects on the production of higher amounts of IFN-γ, IL-2, and CCL-5, besides keeping lowered the levels of IL-22 in remission FS patients.ConclusionTaken together, our findings suggest a putative role of IL-22 in the pathogenesis of FS. Finally, data presented here may contribute for better understanding the immune aspects that control disease outcome

Complexity and Controversies over the Cytokine Profiles of T Helper Cell Subpopulations in Tuberculosis

Tuberculosis (TB) is a contagious infectious disease caused by the TB-causing bacillus Mycobacterium tuberculosis and is considered a public health problem with enormous social impact. Disease progression is determined mainly by the balance between the microorganism and the host defense systems. Although the immune system controls the infection, this control does not necessarily lead to sterilization. Over recent decades, the patterns of CD4+ T cell responses have been studied with a goal of complete understanding of the immunological mechanisms involved in the maintenance of latent or active tuberculosis infection and of the clinical cure after treatment. Conflicting results have been suggested over the years, particularly in studies comparing experimental models and human disease. In recent years, in addition to Th1, Th2, and Th17 profiles, new standards of cellular immune responses, such as Th9, Th22, and IFN-γ-IL-10 double-producing Th cells, discussed here, have also been described. Additionally, many new roles and cellular sources have been described for IL-10, demonstrating a critical role for this cytokine as regulatory, rather than merely pathogenic cytokine, involved in the establishment of chronic latent infection, in the clinical cure after treatment and in keeping antibacillary effector mechanisms active to prevent immune-mediated damage

Th1/Th17-Related Cytokines and Chemokines and Their Implications in the Pathogenesis of Pemphigus Vulgaris

Pemphigus vulgaris (PV) is an autoimmune disease characterized by the presence of IgG autoantibodies against desmoglein-3. Despite the variety of findings, the chemokine and cytokine profiles that characterize the immune response in the disease are still poorly explored. Thus, 20 PV patients and 20 controls were grouped according to gender, ethnicity, place of residence, and clinical parameters of the disease. Then, the levels of chemokines and of Th1/Th2/Th17/Treg/Th9/Th22-related cytokines were assessed in the serum. PV patients had higher levels of inflammatory Th1/Th17 cytokines (IFN-γ, IL-17, and IL-23), as well as higher levels of CXCL8 and reduced levels of Th1/Th2-related chemokines (IP-10 and CCL11). However, no differences in the levels of IL-2, IL-6, TNF-α, IL-1β, IL-4, IL-9, IL-12, TGF-β, IL-33, MCP-1, RANTES, and MIP-1α were found between PV patients and their control counterparts. Furthermore, PV patients with skin lesions had higher serum levels of IL-6 and CXCL8 when compared to PV patients without lesions. Taken together, our findings describe the role of cytokines and chemokines associated with Th1/Th17 immune response in PV patients. Finally, these data are important for better understanding of the immune aspects that control disease outcome, and they may also provide important information about why patients develop autoantibodies against desmogleins

Genetic variation of FcγRIIa induces higher uptake of Leishmania infantum and modulates cytokine production by adherent mononuclear cells in vitro

IntroductionSingle nucleotide variations (SNVs) are specific genetic variations that commonly occur in a population and often do not manifest phenotypically. However, depending on their location and the type of nucleotide exchanged, an SNV can alter or inhibit the function of the gene in which it occurs. Immunoglobulin G (IgG) receptor genes have exhibited several polymorphisms, including rs1801274, which is found in the FcgRIIa gene. The replacement of A with T results in a Histidine (H) to Arginine (R) substitution, altering the affinity of the IgG receptor for IgG subtypes and C-reactive protein (CRP). In this study, we analyzed rs1801274 and its functional implications concerning L. Infantum uptake and cytokine production.MethodsWe genotyped 201 individuals from an endemic area for visceral leishmaniasis to assess the presence of rs1801274 using Taqman probes for a candidate gene study. Additionally, we included seventy individuals from a non-endemic area for a functional study. Subsequently, we isolated and cultivated one-week adherent mononuclear cells (AMCs) derived from the peripheral blood of participants residing in the non-endemic region in the presence of L. infantum promastigotes, with and without antigen-specific IgG and/or CRP. We analyzed the rate of phagocytosis and the production of nitric oxide (NO), tumor necrosis factor (TNF)-a, interleukin (IL)-10, IL-12 p70, IL-1b, IL- 6, and IL-8 in the culture supernatants.Results and discussionIn participants from the endemic region, the A/G (H/R isoform) heterozygous genotype was significantly associated with susceptibility to the disease. Furthermore, SNVs induced a change in the phagocytosis rate in an opsonin-dependent manner. Opsonization with IgG increased the production of IL-10, TNF-a, and IL-6 in AMCs with the H/R isoform, followed by a decrease in NO production. The results presented here suggest that the rs1801274 polymorphism is linked to a higher susceptibility to visceral leishmaniasis

Image_1_Genetic variation of FcγRIIa induces higher uptake of Leishmania infantum and modulates cytokine production by adherent mononuclear cells in vitro.jpeg

IntroductionSingle nucleotide variations (SNVs) are specific genetic variations that commonly occur in a population and often do not manifest phenotypically. However, depending on their location and the type of nucleotide exchanged, an SNV can alter or inhibit the function of the gene in which it occurs. Immunoglobulin G (IgG) receptor genes have exhibited several polymorphisms, including rs1801274, which is found in the FcgRIIa gene. The replacement of A with T results in a Histidine (H) to Arginine (R) substitution, altering the affinity of the IgG receptor for IgG subtypes and C-reactive protein (CRP). In this study, we analyzed rs1801274 and its functional implications concerning L. Infantum uptake and cytokine production.MethodsWe genotyped 201 individuals from an endemic area for visceral leishmaniasis to assess the presence of rs1801274 using Taqman probes for a candidate gene study. Additionally, we included seventy individuals from a non-endemic area for a functional study. Subsequently, we isolated and cultivated one-week adherent mononuclear cells (AMCs) derived from the peripheral blood of participants residing in the non-endemic region in the presence of L. infantum promastigotes, with and without antigen-specific IgG and/or CRP. We analyzed the rate of phagocytosis and the production of nitric oxide (NO), tumor necrosis factor (TNF)-a, interleukin (IL)-10, IL-12 p70, IL-1b, IL- 6, and IL-8 in the culture supernatants.Results and discussionIn participants from the endemic region, the A/G (H/R isoform) heterozygous genotype was significantly associated with susceptibility to the disease. Furthermore, SNVs induced a change in the phagocytosis rate in an opsonin-dependent manner. Opsonization with IgG increased the production of IL-10, TNF-a, and IL-6 in AMCs with the H/R isoform, followed by a decrease in NO production. The results presented here suggest that the rs1801274 polymorphism is linked to a higher susceptibility to visceral leishmaniasis.</p

Image_2_Genetic variation of FcγRIIa induces higher uptake of Leishmania infantum and modulates cytokine production by adherent mononuclear cells in vitro.jpeg

IntroductionSingle nucleotide variations (SNVs) are specific genetic variations that commonly occur in a population and often do not manifest phenotypically. However, depending on their location and the type of nucleotide exchanged, an SNV can alter or inhibit the function of the gene in which it occurs. Immunoglobulin G (IgG) receptor genes have exhibited several polymorphisms, including rs1801274, which is found in the FcgRIIa gene. The replacement of A with T results in a Histidine (H) to Arginine (R) substitution, altering the affinity of the IgG receptor for IgG subtypes and C-reactive protein (CRP). In this study, we analyzed rs1801274 and its functional implications concerning L. Infantum uptake and cytokine production.MethodsWe genotyped 201 individuals from an endemic area for visceral leishmaniasis to assess the presence of rs1801274 using Taqman probes for a candidate gene study. Additionally, we included seventy individuals from a non-endemic area for a functional study. Subsequently, we isolated and cultivated one-week adherent mononuclear cells (AMCs) derived from the peripheral blood of participants residing in the non-endemic region in the presence of L. infantum promastigotes, with and without antigen-specific IgG and/or CRP. We analyzed the rate of phagocytosis and the production of nitric oxide (NO), tumor necrosis factor (TNF)-a, interleukin (IL)-10, IL-12 p70, IL-1b, IL- 6, and IL-8 in the culture supernatants.Results and discussionIn participants from the endemic region, the A/G (H/R isoform) heterozygous genotype was significantly associated with susceptibility to the disease. Furthermore, SNVs induced a change in the phagocytosis rate in an opsonin-dependent manner. Opsonization with IgG increased the production of IL-10, TNF-a, and IL-6 in AMCs with the H/R isoform, followed by a decrease in NO production. The results presented here suggest that the rs1801274 polymorphism is linked to a higher susceptibility to visceral leishmaniasis.</p

TNF-α blockade impairs <i>in vitro</i> tuberculous granuloma formation and down modulate Th1, Th17 and Treg cytokines

<div><p>Tuberculosis (TB) is a granulomatous disease that has affected humanity for thousands of years. The production of cytokines, such as IFN-γ and TNF-α, is fundamental in the formation and maintenance of granulomas and in the control of the disease. Recently, the introduction of TNF-α-blocking monoclonal antibodies, such as Infliximab, has brought improvements in the treatment of patients with chronic inflammatory diseases, but this treatment also increases the risk of reactivation of latent tuberculosis. Our objective was to analyze, in an <i>in vitro</i> model, the influence of Infliximab on the granulomatous reactions and on the production of antigen-specific cytokines (TNF-α, IFN-γ, IL-12p40, IL-10 and IL-17) from beads sensitized with soluble Bacillus Calmette-Guérin (BCG) antigens cultured in the presence of peripheral blood mononuclear cells (PBMC) from TB patients. We evaluated 76 individuals, with tuberculosis active, treated and subjects with positive PPD. Granuloma formation was induced in the presence or absence of Infliximab for up to 10 days. The use of Infliximab in cultures significantly blocked TNF-α production (p <0.05), and led to significant changes in granuloma structure, <i>in vitro</i>, only in the treated TB group. On the other hand, there was a significant reduction in the levels of IFN-γ, IL-12p40, IL-10 and IL-17 after TNF-α blockade in the three experimental groups (p <0.05). Taken together, our results demonstrate that TNF-α blockade by Infliximab directly influenced the structure of granuloma only in the treated TB group, but negatively modulated the production of Th1, Th17 and regulatory T cytokines in the three groups analyzed.</p></div

Role of Cytokines, Chemokines and IFN-&gamma;+ IL-17+ Double-Positive CD4+ T Cells in Patients with Multiple Sclerosis

Multiple sclerosis is mediated by self-reactive myelin T and B cells that lead to axonal and myelin damage. The immune response in multiple sclerosis involves the participation of CD4+ T cells that produce cytokines and chemokines. This participation is important to find markers for the diagnosis and progression of the disease. In our work, we evaluated the profile of cytokines and chemokines, as well as the production of double positive CD4+ T cells for the production of IFN&gamma; IL-17 in patients with multiple sclerosis, at different stages of the disease and undergoing different treatments. We found that relapsing&ndash;remitting patients had a significant increase in IL-12 production. About IL-5, its production showed significantly higher levels in secondarily progressive patients when compared to relapsing&ndash;remitting patients. IFN-&gamma; production by PBMCs from secondarily progressive patients showed significantly higher levels. This group also had a higher percentage of CD4+ IFN&gamma;+ IL-17+ T cells. The combination of changes in certain cytokines and chemokines together with the presence of IFN&gamma;+ IL-17+ double positive lymphocytes can be used to better understand the clinical forms of the disease and its progression

Effect of TNF-α blockade on cytokines production in active Tb group.

<p>Level of cytokines after granuloma formation, <i>in vitro</i>, Active Tb group (A-F) under different culture conditions—Medium or Antigen Medium and Bead or BCG-Bead, in the presence or absence of Infliximab. *Statistical differences between the conditions tested after the addition of Infliximab, in the different cytokines. Wilcoxon and Kruskal-Wallis tests, p-value <0.05. The horizontal lines represent the medians, the bars represent the 25–75% percentiles and the vertical lines represent the 10–90% percentiles.</p