Facilitation of colonic T cell immune responses is associated with an exacerbation of dextran sodium sulfate–induced colitis in mice lacking microsomal prostaglandin E synthase-1

Background Microsomal prostaglandin E synthase-1 (mPGES-1) is a key enzyme that acts downstream of cyclooxygenase and plays a major role in inflammation by converting prostaglandin (PG) H2 to PGE2. The present study investigated the effect of genetic deletion of mPGES-1 on the development of immunologic responses to experimental colitis induced by dextran sodium sulfate (DSS), a well-established model of inflammatory bowel disease (IBD). Methods Colitis was induced in mice lacking mPGES-1 (mPGES-1−/− mice) and wild-type (WT) mice by administering DSS for 7 days. Colitis was assessed by body weight loss, diarrhea, fecal bleeding, and histological features. The colonic expression of mPGES-1 was determined by real-time PCR, western blotting, and immunohistochemistry. The impact of mPGES-1 deficiency on T cell immunity was determined by flow cytometry and T cell depletion in vivo. Results After administration of DSS, mPGES-1−/− mice exhibited more severe weight loss, diarrhea, and fecal bleeding than WT mice. Histological analysis further showed significant exacerbation of colonic inflammation in mPGES-1−/− mice. In WT mice, the colonic expression of mPGES-1 was highly induced on both mRNA and protein levels and colonic PGE2 increased significantly after DSS administration. Additionally, mPGES-1 protein was localized in the colonic mucosal epithelium and infiltrated inflammatory cells in underlying connective tissues and the lamina propria. The abnormalities consistent with colitis in mPGES-1−/− mice were associated with higher expression of colonic T-helper (Th)17 and Th1 cytokines, including interleukin 17A and interferon-γ. Furthermore, lack of mPGES-1 increased the numbers of Th17 and Th1 cells in the lamina propria mononuclear cells within the colon, even though the number of suppressive regulatory T cells also increased. CD4+ T cell depletion effectively reduced symptoms of colitis as well as colonic expression of Th17 and Th1 cytokines in mPGES-1−/− mice, suggesting the requirement of CD4+ T cells in the exacerbation of DSS-induced colitis under mPGES-1 deficiency. Conclusions These results demonstrate that mPGES-1 is the main enzyme responsible for colonic PGE2 production and deficiency of mPGES-1 facilitates the development of colitis by affecting the development of colonic T cell–mediated immunity. mPGES-1 might therefore impact both the intestinal inflammation and T cell–mediated immunity associated with IBD.

Influence of intestinal microbiota on the immunopathogenesis of atopic dermatitis in children

Particular attention is paid to atopic dermatitis (AD) as one of the earliest and most frequent clinical manifestations of allergy in children. AD is a multifactorial disease, the development of which is closely related to genetic defects in the immune response and adverse environmental influences. It was found that the action of these factors determines the rate of development of AD, especially in young children. One of these factors is a violation of the intestinal microbiota, which plays an essential role in the development of the child's immune system and has a protective effect in the formation of atopy. It has been shown that 80-95% of patients with AD have intestinal dysbiosis, while, along with a deficiency of lactobacilli and bifidobacteria, there is an excessive growth of Staphilococcus. The use of modern molecular genetics technologies made it possible to obtain a fairly complete understanding of the number, genetic heterogeneity and complexity of the bacterial components of the intestinal microbiota, while clinical studies have shown the importance of its interactions with the host organism in the formation of various forms of pathology. It has been established that the human intestinal microbiota is an evolutionary set of microorganisms that exists as a balanced microecological system in which the symbiotic microflora is in dynamic equilibrium, forms microbial associations that occupy a certain ecological niche in it, and is one of the most important factors affecting human health. The gut microbiota plays an important role in the pathogenesis of atopic dermatitis, which causes immunosuppression, but the exact mechanism of its action is still unclear. It is widely known that probiotics act on the immune system. These are living microorganisms with immunomodulatory effects that stimulate Th1 cytokines and suppress Th2 responses, which are being investigated for the treatment of several diseases. The most commonly used probiotics are part of the intestinal microflora such as lactobacilli, bifidobacteria and enterococci. The purpose of this article: to systematize the information available today on the influence of the composition of the intestinal microflora on the immunopathogenesis of atopic dermatitis.

Liver- and Spleen-Specific Immune Responses in Experimental Leishmania martiniquensis Infection in BALB/c Mice

Leishmania martiniquensis is a neglected cause of an emerging leishmaniasis in many countries, including France, Germany, Switzerland, the United States of America, Myanmar, and Thailand, with different clinical manifestations ranging from asymptomatic, cutaneous (CL), visceral (VL), and atypically disseminated CL and VL. The persistence of parasites and the recurrence of the disease after treatment are challenges in controlling the disease. To explore efficient prophylaxis and therapy, this study aimed to investigate infection outcome and organ-specific immune responses after inoculation with L. martiniquensis (MHOM/TH/2011/PG; 5 x 106 promastigotes) in BALB/c mice via intravenous and intraperitoneal routes. A quantitative PCR technique, targeting L. martiniquensis ITS1, was primarily established to estimate the parasite burden. We found that the infection in the liver resolved; however, persistent infection was observed in the spleen. Histopathology with Leishmania-specific immunostaining revealed efficient hepatic granuloma formation, while splenic disorganization with parasitized macrophages at different locations was demonstrated. The mRNA expression of Th1 cytokines (IFN-γ, TNF-α, IL-12p40) and iNOS in the liver and spleen was upregulated. In addition, high expression of IL-10 was observed in the spleen in the chronic phase, revealing a significant moderate correlation with the parasite persistence [r(12) = 0.72, P = 0.009]. Further clarification of the mechanisms of persistent infection and experimental infection in immunosuppressed murine models are warranted.

Ncf1 Governs Immune Niches in the Lung to Mediate Pulmonary Inflammation in Mice

Neutrophil cytosolic factor 1 (Ncf1) is a major genetic factor associated with autoimmune diseases and has been identified as a key player in autoimmune mediated inflammation. We addressed the role of Ncf1 in an antigen-induced pulmonary inflammation model, and found that the Ncf1m1j mutation, causing a deficient reactive oxygen species response, alleviated disease. The Ncf1m1j mutation was associated with a reduced inflammatory cell infiltration in airways, but had limited effect on mucus secretion, antibody production and lung fibrosis. The disease remission in the Ncf1 mutated mice was reversed when functional Ncf1 was transgenically expressed in alveolar macrophages, suggesting that the cellular inflammation was depended on functional Ncf1 in alveolar macrophages. By determining cytokine and chemokine profiles in lung and serum, we found that Ncf1 deficiency allowed an increased expression of Th1 cytokines, including TNF-α, IFN-γ and IL-12. Since also epithelial cytokines were found to be regulated by Ncf1, we tested the effect of Ncf1 in IL-33 and IL-25 induced lung inflammation models. Mice with the Ncf1m1j mutation showed less sensitivity to IL-33, but not IL-25, induced lung inflammation, in a macrophage independent manner. The mice with deficient Ncf1 showed a reduced eosinophil infiltration and group 2 innate lymphoid cell (ILC2) activation. The production of IFN-γ in CD4+ T cells was increased, whereas IL-5 and IL-13 in ILC2 were decreased. Importantly, anti-IFN-γ antibody treatment of Ncf1 deficient mice increased eosinophil infiltration and rescued ILC2 activation in the lung. We conclude that Ncf1 deficiency enhances Th1 response, deactivates ILC2, and protects against pulmonitis.

Th1/Th2 Cytokine Profiles Differentiating Tuberculous from Malignant Pleural Effusions: A Systematic Review and Meta-Analysis

To clarify which one has a different predominance of Th1 and Th2 immune responses in malignant and tuberculous pleural effusions. We did a meta-analysis of the results published previously to assess the levels of Th1/Th2 cytokines in two types of pleural effusion, and evaluated its ability to distinguish TPE from MPE. We queried the PubMed and Embase databases for studies indexed from 2000 up to March 2021. We included studies that (a) diagnosis of TPE and MPE by on culture, or pleural biopsy tissue provided; (b) compared levels of Th1/Th2 cytokines in pleural effusion between TPE and MPE. Pooled data by using a random-effects model or fixed-effects model, standardized mean differences (SMD) across studies comparing TPE and MPE. We also performed Egger test to assess of publication bias. Of 917 identified studies, a total of 42 studies were selected in the meta-analysis. Compared with malignant subjects, tuberculous subjects had a significant higher level of TNF-α [2.22, (1.60–2.84)], an elevated level of IFN-γ [3.30, (2.57–4.40)] in pleural effusion, a situation where the Th1 immune response dominates. Conversely, Interleukin-4 (IL-4) and IL-10 (Th2 cytokines) levels were higher in MPE than TPE. Besides, they were shown to be statistically insignificant tiny effects were [-0.15, (-0.94–0.63)], [-0.04, (-0.21–0.12)] respectively. We confirmed that pleural effusions caused by tuberculosis, a situation in which the Th1 cytokines are predominant. The slight preponderance of Th2 cytokines in malignant pleural effusions, which are not convincing enough to prove.

The immunomodulatory effects of long-term supplementation with Lactobacillus casei Shirota depend on ovalbumin presentation in BALB/c mice

Immunomodulation is an ability of several particular probiotics. However, it still remains unclear whether the immunomodulatory effects of specific probiotics vary for different antigen presentation models with the same antigen. To investigate this matter, six groups of BALB/c mice (n = 10) were exposed to one of two antigen presentation models: ovalbumin (OVA) by injection alone, or injection plus intranasal administration. Moreover, the mice were fed distilled water or Lactobacillus casei Shirota fermented beverage (LcSFB) at low (2.5 × 109 CFU/kg body weight) or high doses (5 × 109 CFU/kg body weight) by gavage for 8 weeks. LcSFB enhanced the proliferation of splenocytes, production of OVA-specific immunoglobulin (Ig)-G and IgA, and the ratio of T-helper (Th)-2/Th1 cytokines in mice injected with OVA. Conversely, in the mice treated with OVA by injection plus intranasal administration, LcSFB attenuated the immune responses against OVA by reducing the proliferation of splenocytes, levels of OVA-specific IgE, IgG, and IgM, and ratio of Th2/Th1 cytokines. Moreover, LcSFB increased the percentage of regulatory T cells in the injection plus intranasal administration group. Taken together, this work indicates the immunoregulatory effects of LcSFB depend on how the antigen is presented. Therefore, the use of probiotics to boost the immune system must be carefully considered.

The Pathogenic and Therapeutic Implications of Ceramide Abnormalities in Atopic Dermatitis

Ceramides play an essential role in forming a permeability barrier in the skin. Atopic dermatitis (AD) is a common chronic skin disease associated with skin barrier dysfunction and immunological abnormalities. In patients with AD, the amount and composition of ceramides in the stratum corneum are altered. This suggests that ceramide abnormalities are involved in the pathogenesis of AD. The mechanism underlying lipid abnormalities in AD has not yet been fully elucidated, but the involvement of Th2 and Th1 cytokines is implicated. Ceramide-dominant emollients have beneficial effects on skin barrier function; thus, they have been approved as an adjunctive barrier repair agent for AD. This review summarizes the current understanding of the mechanisms of ceramide abnormalities in AD. Furthermore, the potential therapeutic approaches for correcting ceramide abnormalities in AD are discussed.

Cryptococcus neoformans Δsgl1 Vaccination Requires Either CD4+ or CD8+ T Cells for Complete Host Protection

Cryptococcus neoformans is a fungal pathogen causing life-threatening meningoencephalitis in susceptible individuals. Fungal vaccine development has been hampered by the fact that cryptococcosis occurs during immunodeficiency. We previously reported that a C. neoformans mutant (Δsgl1) accumulating sterylglucosides (SGs) is avirulent and provides complete protection to WT challenge, even under CD4+ T cell depletion, an immunodeficient condition commonly associated with cryptococcosis. We found high levels of SGs in the lungs post-immunization with Δsgl1 that decreased upon fungal clearance. Th1 cytokines increased whereas Th2 cytokines concurrently decreased, coinciding with a large recruitment of leukocytes to the lungs. Depletion of B or CD8+ T cells did not affect either Δsgl1 clearance or protection from WT challenge. Although CD4+ T cell depletion affected clearance, mice were still protected indicating that clearance of the mutant was not necessary for host protection. Protection was lost only when both CD4+ and CD8+ T cells were depleted, highlighting a previously unexplored role of fungal-derived SGs as an immunoadjuvant for host protection against cryptococcosis.

Immunoregulatory Effects of Imuno TF® (transfer factors) on Th1/Th2/Th17/Treg Cytokines

Transfer factors are known since 1955 due to their activities on the immune system. Although the reports on the effects on diverse immune mechanisms, their role on Th1, Th2, Th17 and Treg responses was still not described. In this sense, the present work focused on the evaluation of such immune responses. For that, human lymphocytes, and mice thymic, splenic and Peyer’s cells were stimulated with Lipopolysaccharides and Concanavalin A, and then treated with isolated transfer factors (Imuno TF®). The culture medium was harvested and the quantification of Th1 cytokines (IL-2 and IFN-γ), Th2 cytokines (IL-4, IL-5, and IL-13), Th17 cytokine (IL-17), Treg cytokine (IL-35), inflammatory cytokines (IL-6 and TNF-α), and antiinflammatory cytokine (IL-10) was performed, as well as the quantification of mRNA levels. Imuno TF® positively regulated Th1 cytokines, while decreased Th2 cytokines. It also increased levels of mRNA and secretion of the anti-inflammatory cytokine IL-10, whereas it reduced levels of mRNA and the secretion of pro-inflammatory cytokines IL-6 and TNF-α. Finally, it reversed the hypersecretion of IL-17 and did not promote significant changes in IL-35 secretion. This highlights the role of Imuno TF® in the regulation of the immune responses.

Coordinate Induction of Humoral and Spike Specific T-Cell Response in a Cohort of Italian Health Care Workers Receiving BNT162b2 mRNA Vaccine

Vaccination is the main public health measure to reduce SARS-CoV-2 transmission and hospitalization, and a massive worldwide scientific effort resulted in the rapid development of effective vaccines. This work aimed to define the dynamics of humoral and cell-mediated immune response in a cohort of health care workers (HCWs) who received a two-dose BNT162b2-mRNA vaccination. The serological response was evaluated by quantifying the anti-RBD and neutralizing antibodies. The cell-mediated response was performed by a whole blood test quantifying Th1 cytokines (IFN-γ, TNF-α, IL-2), produced in response to spike peptides. The BNT162b2-mRNA vaccine induced both humoral and cell-mediated immune responses against spike peptides in virtually all HCWs without previous SARS-CoV-2 infection, with a moderate inverse relation with age in the anti-RBD response. Spike-specific T cells produced several Th1 cytokines (IFN-γ, TNF-α, and IL-2), which correlated with the specific-serological response. Overall, our study describes the ability of the BNT162b2 mRNA vaccine to elicit a coordinated neutralizing humoral and spike-specific T cell response in HCWs. Assessing the dynamics of these parameters by an easy immune monitoring protocol can allow for the evaluation of the persistence of the vaccine response in order to define the optimal vaccination strategy.