Natural killer cell-mediated contact dermatitis-like reaction induced by treatment with TLR3 ligand poly(I:C).

INTRODUCTION: Poly(I:C) is recognised by endosomal Toll-like receptor 3 (TLR3) and activates cytotoxic CD8(+) lymphocytes and natural killer (NK) cells. It has been shown that the viral TLR3 agonist induces robust and long-lasting T-cell-mediated responses. In addition, TLR3 modulates the contact hypersensitivity reaction. OBJECTIVE: This study aimed to determine whether poly(I:C) injection can induce NK-mediated hapten reactivity in mice. METHODS: Mice were treated with poly(I:C), and their response to dinitrofluorobenzene hapten was measured by assessing ear swelling and serum interferon gamma (IFN-γ) production. Adoptive cell transfer and cell sorting were used to investigate the mechanism of the reaction, and the phenotype of poly(I:C)-activated liver NK cells was determined by flow cytometry analysis. RESULTS: The results showed that poly(I:C) administration increased ear swelling, serum IFN-γ levels and the response to hapten in both immunocompetent and T- and B-cell-deficient mice. Only liver poly(I:C)-activated DX5(+) NK cells were able to transfer reactivity to hapten into a naive recipient. Induction of liver NK cells after poly(I:C) administration was TLR3/TRIF- and IFN-γ-dependent, interleukin 12-independent, and not modulated by MyD88. CONCLUSION: This study provides new insights into how poly(I:C) stimulates NK-mediated reactivity to hapten and suggests that liver NK cells may modulate the immune response to non-pathogenic factors during viral infection.

Critical role for the chemokine receptor CXCR6 in NK cell-mediated antigen-specific memory of haptens and viruses.

Hepatic natural killer (NK) cells mediate antigen-specific contact hypersensitivity (CHS) in mice deficient in T cells and B cells. We report here that hepatic NK cells, but not splenic or naive NK cells, also developed specific memory of vaccines containing antigens from influenza, vesicular stomatitis virus (VSV) or human immunodeficiency virus type 1 (HIV-1). Adoptive transfer of virus-sensitized NK cells into naive recipient mice enhanced the survival of the mice after lethal challenge with the sensitizing virus but not after lethal challenge with a different virus. NK cell memory of haptens and viruses depended on CXCR6, a chemokine receptor on hepatic NK cells that was required for the persistence of memory NK cells but not for antigen recognition. Thus, hepatic NK cells can develop adaptive immunity to structurally diverse antigens, an activity that requires NK cell-expressed CXCR6.

Obesity aggravates contact hypersensitivity reaction in mice.

BACKGROUND: Obesity is associated with chronic, low-grade inflammation in tissues and predisposes to various complications, including inflammatory skin diseases. However, the link between obesity and contact hypersensitivity (CHS) is not fully understood. OBJECTIVES: We sought to determine the influence of obesity on T helper 1 (Th1)-mediated CHS. METHODS: The activity/phenotype/cytokine profile of the immune cells was tested in vivo and in vitro. Using quantitative polymerase chain reaction (qPCR) and fecal microbiota transplantation (FMT), we tested the role of a high-fat diet (HFD)-induced gut microbiota (GM) dysbiosis in increasing the effects of CHS. RESULTS: Exacerbated CHS correlates with an increased inflammation-inducing GM in obese mice. We showed a proinflammatory milieu in the subcutaneous adipose tissue of obese mice, accompanied by proinflammatory CD4+ T cells and dendritic cells in skin draining lymph nodes and spleen. Obese interleukin (IL)-17A-/-B6 mice are protected from CHS aggravation, suggesting the importance of IL-17A in CHS aggravation in obesity. CONCLUSIONS: Obesity creates a milieu that induces more potent CHS-effector cells but does not have effects on already activated CHS-effector cells. IL-17A is essential for the pathogenesis of enhanced CHS during obesity. Our study provides novel knowledge about antigen-specific responses in obesity, which may help with the improvement of existing treatment and/or in designing novel treatment for obesity-associated skin disorders.

Diet-induced obesity aggravates NK cell-mediated contact hypersensitivity reaction in Rag1-/- mice.

BACKGROUND: Previous studies showed that natural killer (NK) cells mediate contact hypersensitivity (CHS) reaction. Many reports are showing that obesity promotes several inflammatory diseases. It was shown that diet-induced obesity (DIO) aggravates classical T cell-mediated CHS in mice. OBJECTIVES: To determine whether the high-fat diet (HFD)-induced obesity modulates antigen-specific NK cell-mediated response. METHODS: We evaluated the effect of DIO on NK cell-mediated CHS reaction using a model of dinitrofluorobenzene (DNFB)-induced CHS in Rag1-/- mice. RESULTS: Rag1-/- mice fed HFD for 8 but not for 4 weeks developed aggravated CHS reaction determined by ear swelling measurement when compared to animals kept on normal diet (ND) prior to DNFB sensitization. The obese Rag1-/- mice presented the adipose tissue inflammation. Furthermore, in vitro analysis showed that feeding with HFD significantly increases interferon γ (IFN-γ) and interleukin (IL)-12p70 and decreases adiponectin concentration in liver mononuclear cell (LMNC) culture supernatants. The flow cytometry analysis of LMNC revealed that HFD treatment prior to DNFB sensitization increases the percentage of NK1.1+ IFN-γ+ cell population and affects the development and maturation of NK1.1+ cells. CONCLUSIONS: In summary, current results suggest that the DIO significantly modulates the local and systemic inflammatory response, contributing to exacerbation of the CHS response mediated by liver NK cells.

Regulation of contact sensitivity in non-obese diabetic (NOD) mice by innate immunity.

BACKGROUND: Genetic background influences allergic immune responses to environmental stimuli. Non-obese diabetic (NOD) mice are highly susceptible to environmental stimuli. Little is known about the interaction of autoimmune genetic factors with innate immunity in allergies, especially skin hypersensitivity. OBJECTIVES: To study the interplay of innate immunity and autoimmune genetic factors in contact hypersensitivity (CHS) by using various innate immunity-deficient NOD mice. METHODS: Toll-like receptor (TLR) 2-deficient, TLR9-deficient and MyD88-deficient NOD mice were used to investigate CHS. The cellular mechanism was determined by flow cytometry in vitro and adoptive cell transfer in vivo. To investigate the role of MyD88 in dendritic cells (DCs) in CHS, we also used CD11cMyD88+ MyD88-/- NOD mice, in which MyD88 is expressed only in CD11c+ cells. RESULTS: We found that innate immunity negatively regulates CHS, as innate immunity-deficient NOD mice developed exacerbated CHS accompanied by increased numbers of skin-migrating CD11c+ DCs expressing higher levels of major histocompatibility complex II and CD80. Moreover, MyD88-/- NOD mice had increased numbers of CD11c+ CD207- CD103+ DCs and activated T effector cells in the skin-draining lymph nodes. Strikingly, re-expression of MyD88 in CD11c+ DCs (CD11cMyD88+ MyD88-/- NOD mice) restored hyper-CHS to a normal level in MyD88-/- NOD mice. CONCLUSION: Our results suggest that the autoimmune-prone NOD genetic background aggravates CHS regulated by innate immunity, through DCs and T effector cells.

Broad spectrum antibiotic enrofloxacin modulates contact sensitivity through gut microbiota in a murine model.

BACKGROUND: Medical advances in the field of infection therapy have led to an increasing use of antibiotics, which, apart from eliminating pathogens, also partially eliminate naturally existing commensal bacteria. It has become increasingly clear that less exposure to microbiota early in life may contribute to the observed rise in "immune-mediated" diseases, including autoimmunity and allergy. OBJECTIVE: We sought to test whether the change of gut microbiota with the broad spectrum antibiotic enrofloxacin will modulate contact sensitivity (CS) in mice. METHODS: Natural gut microbiota were modified by oral treatment with enrofloxacin prior to sensitization with trinitrophenyl chloride followed by CS testing. Finally, adoptive cell transfers were performed to characterize the regulatory cells that are induced by microbiota modification. RESULTS: Oral treatment with enrofloxacin suppresses CS and production of anti-trinitrophenyl chloride IgG1 antibodies. Adoptive transfer experiments show that antibiotic administration favors induction of regulatory cells that suppress CS. Flow cytometry and adoptive transfer of purified cells show that antibiotic-induced suppression of CS is mediated by TCR αß+CD4+CD25+FoxP3+ Treg, CD19+B220+CD5+ IL-10+, IL-10+ Tr1, and IL-10+ TCR γδ+ cells. Treatment with the antibiotic induces dysbiosis characterized by increased proportion of Clostridium coccoides (cluster XIVa), C coccoides-Eubacterium rectale (cluster XIVab), Bacteroidetes, and Bifidobacterium spp, but decreased segmented filamentous bacteria. Transfer of antibiotic-modified gut microbiota inhibits CS, but this response can be restored through oral transfer of control gut bacteria to antibiotic-treated animals. CONCLUSIONS: Oral treatment with a broad spectrum antibiotic modifies gut microbiota composition and promotes anti-inflammatory response, suggesting that manipulation of gut microbiota can be a powerful tool to modulate the course of CS.

The Effect of Surgical Stress on Postoperative Tαß and Tγδ Cell Distribution.

BACKGROUND: It was previously shown that appropriate distribution of immune cells between different tissues and organs of the body is required for proper function of the immune system. Our previous experiments demonstrated that surgical trauma in mice induces Tγδ lymphocyte migration from peripheral blood to peritoneal lymphoid organs. Tγδ cells have regulatory activity as they suppress the cell-mediated immune response in vitro via TGF-ß. In the current study, we aim to evaluate the influence of surgery on both Taß and Tγδ lymphocyte distribution in patients that underwent operation. MATERIALS AND METHODS: We investigated the percentage of Tαß and Tγδ cells in peripheral blood of patients undergoing standard surgical procedures (gastric resection, colorectal resection, cholecystectomy, and strumectomy) before and 3 days after operation. The percentage of Tαß and Tγδ cells was evaluated by FACS Canto II cytofluorimeter. RESULTS: We showed that only major surgery located in the peritoneal cavity (gastric and colorectal surgery) decreases the percentage of Tγδ cells in peripheral blood as opposed to less traumatic surgery (strumectomy and cholecystectomy) which does not have such effect. However, significant reduction of Tγδ cells after operation was only observed in a group of patients that underwent gastrectomy. Additionally, we found that gastrectomy results in significant reduction of cumulative Tγδ CD4 and Tγδ CD25 lymphocyte counts. CONCLUSION: Surgery results in decreased percentage of Tγδ lymphocytes in peripheral human blood, and this correlates with the severity and location of the surgical trauma. This observation may help to predict postoperative recovery after gastroabdominal surgery.

Epicutaneous immunization with ovalbumin and CpG induces TH1/TH17 cytokines, which regulate IgE and IgG2a production.

BACKGROUND: Subcutaneous allergen-specific immunotherapy is a standard route for the immunotherapy of allergic diseases. It modulates the course of allergy and can generate long-term remission. However, subcutaneous allergen-specific immunotherapy can also induce anaphylaxis in some patients, and therefore additional routes of administration should be investigated to improve the safety and tolerability of immunotherapy. OBJECTIVE: We sought to determine whether epicutaneous treatment with antigen in the presence of a Toll-like receptor 9 agonist can suppress TH2-mediated responses in an antigen-specific manner. METHODS: Epicutaneous immunization was performed by applying a skin patch soaked with ovalbumin (OVA) plus CpG, and its suppressor activity was determined by using the mouse model of atopic dermatitis. Finally, adoptive cell transfers were implemented to characterize the regulatory cells that are induced by epicutaneous immunization. RESULTS: Epicutaneous immunization with OVA and CpG reduces the production of OVA-specific IgE and increases the synthesis of OVA-specific IgG2a antibodies in an antigen-specific manner. Moreover, eosinophil peroxidase activity in the skin and production of IL-4, IL-5, IL-10, and IL-13 are suppressed. The observed reduction of IgE synthesis is transferable with T-cell receptor (TCR) αß(+)CD4(+)CD25(-) cells, whereas IgG2a production is dependent on both TCRαß(+) and TCRγδ(+) T cells. Further experiments show that the described phenomenon is myeloid differentiation primary response 88, IFN-γ, and IL-17A dependent. Finally, the results suggest that epicutaneous immunization with OVA and CpG decreases the synthesis of OVA-specific IgE and skin eosinophil peroxidase activity in mice with ongoing skin allergy. CONCLUSION: Epicutaneous application of protein antigen in the presence of adjuvant could be an attractive needle-free and self-administered immunotherapy for allergic diseases.

Expression of activation-induced cytidine deaminase enhances the clearance of pneumococcal pneumonia: evidence of a subpopulation of protective anti-pneumococcal B1a cells.

We describe a protective early acquired immune response to pneumococcal pneumonia that is mediated by a subset of B1a cells. Mice deficient in B1 cells (xid), or activation-induced cytidine deaminase (AID(-/-) ), or invariant natural killer T (iNKT) cells (Jα18(-/-) ), or interleukin-13 (IL-13(-/-) ) had impaired early clearance of pneumococci in the lung, compared with wild-type mice. In contrast, AID(-/-) mice adoptively transferred with AID(+/+) B1a cells, significantly cleared bacteria from the lungs as early as 3 days post infection. We show that this early bacterial clearance corresponds to an allergic contact sensitivity-like cutaneous response, probably due to a subpopulation of initiating B1a cells. In the pneumonia model, these B1a cells were found to secrete higher affinity antigen-specific IgM. In addition, as in contact sensitivity, iNKT cells were required for the anti-pneumococcal B1a cell initiating response, probably through early production of IL-13, given that IL-13(-/-) mice also failed to clear infection. Our study is the first to demonstrate the importance of AID in generating an appropriate B1a cell response to pathogenic bacteria. Given the antibody affinity and pneumonia resistance data, natural IgM produced by conventional B1a cells are not responsible for pneumonia clearance compared with the AID-dependent subset.

[Skin as a place of immunomodulation].

The skin is the largest organ of the human body which plays a key role not only in physiological processes such as thermoregulation and the maintenance of the correct water and electrolyte balance, but also forms an effective barrier against microorganisms, protecting the organism against harmful external factors. Moreover, the skin is an important organ involved in immune mechanisms. The skin is a place of drug application to treat various local and systemic diseases. Those drugs are proteins and peptides sensitive to digestion in gastrointestinal tract, or chemical molecules metabolized in the liver. Epicutaneous immunization (EC) is a new therapeutic method used to treat immunological disorders. The phenomenom of immunomodulation has already been exploited to treat allergic diseases and is called allergen specific immunotherapy. The authors describe the current state of knowledge of the immune regulatory mechanisms that allow to use the EC method to treat immunological diseases mediated by Th1, Tc1 or Th2 lymphocytes. The new aspect of this immunotherapy is immunopotentiation that involves components of the innate immune system, working via the TLRs. The first clinical trials give promising outcomes of the use of EC method in the treatment of multiple sclerosis and respiratory allergic diseases.

Epicutaneous Immunization with Collagen Induces TCRαß Suppressor T Cells That Inhibit Collagen-Induced Arthritis.

BACKGROUND: We have shown previously, in an animal model of multiple sclerosis and in TNBS-induced colitis, that epicutaneous (EC) immunization with protein antigen induces T suppressor cells that strongly inhibit the inflammatory response in contact hypersensitivity reactions. METHODS: EC immunization was performed by applying to the shaved skin of the mouse dorsum a gauze patch soaked with a solution containing various amounts of type II collagen (COLL II) in a volume of 100 µl of PBS on days 0 and 4. On day 7 the patches were removed and mice were intradermally (i.d.) immunized with COLL II to induce collagen-induced arthritis (CIA). RESULTS: Our study shows that EC immunization with 100 or 30 µg of COLL II reduces disease severity, whereas lower doses (10 or 3 µg) do not affect CIA. Decreased disease severity observed after EC immunization with COLL II correlates with reduced myeloperoxidase activity in joint tissue and with reduced production of anti-citrullinated protein and anti-COLL II IgG2a antibodies. Transfer experiments show that EC immunization with COLL II induces suppressor cells that belong to the population of TCRαß lymphocytes and that EC-induced suppression declines with time. Both in vitro and in vivo experiments show that IL-17A plays an important role in EC-induced suppression of CIA. EC application of COLL II at the first signs of CIA also results in disease suppression. CONCLUSIONS: The suppression of inflammatory responses by T suppressor cells induced through EC immunization of a protein antigen may become an attractive noninvasive therapeutic method for a variety of clinical situations.

[Immunological mechanisms involved in obesity and their role in metabolic syndrome]. / Mechanizmy immunologiczne towarzyszace otylosci i ich rola w zaburzeniach metabolizmu.

In the past 50 years, the occurrence of human obesity has risen dramatically across the globe. The WHO reported that at least 1.9 billion (1.9 × 10(9)) adults are overweight and 600 million are obese, and the numbers are expected to rise dramatically in the future without intervention. The recent increase in human obesity is caused by increased energy intake and reduced energy expenditure that results in a massive increase in adipose tissue, which is generally harmful to our health. Indeed, the increase in human obesity is strongly associated with an increase in many diseases such as type 2 diabetes (T2D), biliary disease, cardiovascular disease, hepatic steatosis, airway disease, neurodegeneration and certain cancers. The metabolic and immune systems are closely linked and functionally dependent. As a result, excessive nutrient consumption associated with obesity can be recognized as a harmful, stress-inducing biological event by innate pattern recognition receptors (PRRs). This activates inflammatory and stress responses in various metabolic tissues, leading to the chronic low-grade inflammation called metabolic inflammation or "metainflammation". Adipose tissue is mainly composed of adipocytes, although other cell types contribute to its growth and function, including pre-adipocytes, macrophages, lymphocytes, fibroblasts and vascular cells. Obesity can result in profound changes in the cell composition of fat tissue and can lead to the modulation of individual cell phenotypes. Many factors are involved in development of metainflammation, including hypoxia of adipocytes, oxidative stress, endoplasmic reticulum stress, activation of inflammasomes, adipocyte death, activation of TLR and abnormal gut flora.

Epicutaneous immunization with TNP-Ig and Zymosan induces TCRαß+ CD4+ contrasuppressor cells that reverse skin-induced suppression via IL-17A.

BACKGROUND: Our previous work showed that epicutaneous (EC) immunization with protein antigen e.g. TNP-conjugated mouse immunoglobulin (TNP-Ig) in the form of a patch prior to hapten sensitization inhibits Th1-mediated contact hypersensitivity (CHS) in mice. We also found that suppression of CHS was mediated by TCRαß+ CD4+ CD8+ T suppressor cells producing TGF-ß. The aim of this study was to investigate the role of innate immunity in the suppression of CHS. METHODS: Mice were immunized by applying gauze patches containing protein antigen alone or in the presence of zymosan, and were then tested for the CHS response. Adoptive cell transfer experiments were used to study the mechanisms involved in the reversal of skin-induced suppression. The influence of EC immunization on cytokine production by lymph node cells was measured by ELISA. RESULTS: We found that EC immunization with TNP-Ig and zymosan before trinitrophenyl chloride sensitization reverses skin-induced suppression, demonstrated in vivo and in vitro. The reversal of skin-induced suppression was transferable by antigen-specific TCRαß+ CD4+ T contrasuppressor cells. Furthermore, we showed that the contrasuppression was IL-17A-dependent and TLR2- and MyD88-independent. CONCLUSIONS: Our work strongly suggests that EC immunization with protein antigen and zymosan reverses skin-induced suppression and that this approach may be a potential tool to increase the immunogenicity of weakly immunogenic antigens.

[Tc1-mediated contact sensitivity reaction, its mechanism and regulation]. / Reakcja nadwrazliwosci kontaktowej Tc1 zalezna, jej mechanizm i regulacja.

The contact hypersensitivity reaction (CHS) to haptens is a classic example of cell-mediated immune response. In the effector phase, two stages can be distinguished: an early component, that appears only 2 hours after subsequent contact with the hapten, and the late component that develops approximately 24 hours later which is mediated by TCRαß+ cells. The effector lymphocytes may be CD4+ T helper 1 (Th1) cells or CD8+ T cytotoxic 1 (Tc1) cells, which depends on the employed hapten and/or mice strain. NKT lymphocytes play the crucial role in the CHS initiation, by supporting B1 cells in the antigen-specific IgM antibodies production. The development of an early component is essential for the recruitment of T effector (Teff) cells to the side of hapten deposition and for the complete expansion of inflammatory reaction. The CHS reaction is under T regulatory (Treg) cells control, both in the induction phase as well as in the effector phase. A new view of a negative regulation of the Tc1 mediated CHS response is based on the suppression induced by epicutaneous (EC) application of protein antigen. The DNP-BSA skin application, on a gauze patch, leads to a state of immunosuppression. This maneuver results in rising the population of Treg cells with TCRαß+CD4+CD25+Foxp3+ phenotype. The mechanism of suppression requires direct contact between Treg cells and Teff cells and the participation of CTLA-4 molecule is also necessary. The described method of evoking immune tolerance via EC immunization may contribute to elaborate a new method of allergic contact dermatitis therapy. This is because of its effectiveness, ease of induction and non-invasive protein antigen application.

Lack of TCRalphabeta+ CD8+ and TCRgammadelta+ lymphocytes ameliorates LPS induced orchitis in mice--preliminary histological observations.

The inflammation of the reproductive system can affect reproduction causing partial or complete infertility. It is well known that lipopolysaccharide (LPS) triggers an inflammatory response in the whole organism, including immunologically privileged organs, e.g. the testicles. Adult male TCRalpha-/-, TCRdelta-/-, CD1d-/- and beta2m-/- on B10.PL (H-2(u)) and B10.PL control mice were intraperitonealy (i.p.) injected with lipopolysaccharide (LPS). The animals were killed 24h and 10 days post LPS treatment and their gonads were prepared for microscopic examination. Histological changes in the testes after LPS injection were found only in control B10PL and CD1d-/- mice. The experiments revealed disturbances in Leydig's glands structure, blood vessel dilatation in the interstitial tissue as well as degeneration of seminal tubule epithelium, disruption ofspermatogenesis and subsequent decrease of sperm cell number in the tubule lumen. These changes were noticed mainly 10 days after LPS treatment. Lack of either TCRalphabeta+ CD8+ or TCRgammadelta+ lymphocytes diminishes the response of testicular macrophages to LPS whereas the absence of CD1d-dependent NKT cells does not affect macrophage reactivity.

Migraine and the microbiota. Can probiotics be beneficial in its prevention? - a narrative review.

Migraine is a recurrent disease of the central nervous system that affects an increasing number of people worldwide causing a continuous increase in the costs of treatment. The mechanisms underlying migraine are still unclear but recent reports show that people with migraine may have an altered composition of the intestinal microbiota. It is well established that the gut-brain axis is involved in many neurological diseases, and probiotic supplementation may be an interesting treatment option for these conditions. This review collects data on the gastrointestinal and oral microbiota in people suffering from migraine and the use of probiotics as a novel therapeutic approach in its treatment.

Intestinal permeability disturbances: causes, diseases and therapy.

Nowadays, a pathological increase in the permeability of the intestinal barrier (the so-called leaky gut) is increasingly being diagnosed. This condition can be caused by various factors, mainly from the external environment. Damage to the intestinal barrier entails a number of adverse phenomena: dysbiosis, translocation of microorganisms deep into the intestinal tissue, immune response, development of chronic inflammation. These phenomena can ultimately lead to a vicious cycle that promotes the development of inflammation and further damage to the barrier. Activated immune cells in mucosal tissues with broken barriers can migrate to other organs and negatively affect their functioning. Damaged intestinal barrier can facilitate the development of local diseases such as irritable bowel disease, inflammatory bowel disease or celiac disease, but also the development of systemic inflammatory diseases such as rheumatoid arthritis, ankylosing spondylitis, hepatitis, and lupus erythematosus, neurodegenerative or psychiatric conditions, or metabolic diseases such as diabetes or obesity. However, it must be emphasized that the causal links between a leaky gut barrier and the onset of certain diseases often remain unclear and require in-depth research. In light of recent research, it becomes crucial to prevent damage to the intestinal barrier, as well as to develop therapies for the barrier when it is damaged. This paper presents the current state of knowledge on the causes, health consequences and attempts to treat excessive permeability of the intestinal barrier.

The Presence of Lactobacillus spp. and its Effect on the Occurrence of Other Microorganisms in the Reproductive Tract of Polish Women.

Disorders of the vaginal microbiota can lead to many complications and affect fertility. This study evaluates the role of Lactobacillus in the vagina and its impact on the incidence of colonization by pathogenic microorganisms, analyzing the results of 1,039 women of reproductive age (18-49 years) who underwent a microbiological examination of the reproductive tract in 2020. Samples were examined by microscopy, culture, and NAAT. As the number of Lactobacillus increases, the chance of developing symptoms decreases. In fact, it has been shown that the higher the number of Lactobacillus spp. the less frequently Gardnerella vaginalis and Streptococcus group B are observed. As the concentration of Lactobacillus spp. increases by one category, the risk of G. vaginalis after adjustment to age and pH decreases by 80% (p < 0.001). Similarly, the correlation between Lactobacillus spp. and vaginal pH was shown. After adjustment to age, the odds of prevalence pH > 4.5 for people with Lactobacillus category higher 1 is 76% lower.

Proton pump inhibitor alters Th17/Treg balance and induces gut dysbiosis suppressing contact hypersensitivity reaction in mice.

Proton pump inhibitors (PPIs), such as omeprazole, are the most commonly prescribed drugs. Treatment with PPIs alters gut microbiota composition and reduces the production of reactive oxygen (ROS) and proinflammatory IL-1ß, IL-6, and TNF-α cytokines. Here, using the T cell-dependent contact hypersensitivity (CHS) response, an animal model of allergic contact dermatitis (ACD) that affects up to 30% of the population, we demonstrated that a two-week omeprazole treatment suppresses the development of CHS. Omeprazole treatment before CHS induction, reduced inflammatory response in ears measured by ear swelling, ear biopsy weight, MPO activity, and proinflammatory cytokine production. These changes were associated with reduced frequency of TCRαß+ CD4+ IL-17A+ and TCRαß+ CD8+ IL-17A+ T cells and increased frequency of TCRαß+ CD4+ CD25+ FoxP3+ Treg, and TCRαß+ CD4+ IL-10+ Tr1 cells in peripheral lymphoid organs. Omeprazole treatment decreased the production of ROS, TNF-α, and IL-6, which supported Th17 cell induction, and increased the frequency of Clostridium cluster XIVab and Lactobacillus, implicated in Treg cell induction. The fecal microbiota transplantation (FMT) experiment confirmed the role of omeprazole-induced changes in gut microbiota profile in CHS suppression. Our data suggests that omeprazole ameliorates inflammatory response mediated by T-cells.

Natural killer cell-mediated contact sensitivity develops rapidly and depends on interferon-α, interferon-γ and interleukin-12.

Natural killer (NK) cell-mediated contact sensitivity was recently described in mice. Here, we confirm NK cell-mediated contact sensitivity (CS) in SCID and RAG1(-/-) mice but not in SCIDbeige mice, which have non-functional NK cells that lack NK cell granules. NK cell-mediated CS was transferred by liver mononuclear cells and the DX5(+) fraction of liver cells, confirming that NK cells mediate CS in the absence of T and B cells. Participation of NKT cells and B-1 cells was ruled out using Jα18(-/-) and JH(-/-) mice, respectively. Remarkably, NK cell-mediated CS was observed just 1 hr after immunization and was detectable as early as 30 min after challenge. Further, we examined cytokine requirements for NK cell-mediated CS, and found that liver mononuclear cells from interleukin-12(-/-) , interferon-γ(-/-) and interferon-α receptor(-/-) donors fail to transfer NK cell-mediated CS to naive hosts. Our studies clearly show that dinitrofluorobenzene sensitized NK cells mediate very rapid, antigen-specific cell-mediated immunity, with features of both innate and acquired immune responses.