Gut microbiota facilitate chronic spontaneous urticaria.

Chronic spontaneous urticaria (CSU) comes with gut dysbiosis, but its relevance remains elusive. Here we use metagenomics sequencing and short-chain fatty acids metabolomics and assess the effects of human CSU fecal microbial transplantation, Klebsiella pneumoniae, Roseburia hominis, and metabolites in vivo. CSU gut microbiota displays low diversity and short-chain fatty acids production, but high gut Klebsiella pneumoniae levels, negatively correlates with blood short-chain fatty acids levels and links to high disease activity. Blood lipopolysaccharide levels are elevated, link to rapid disease relapse, and high gut levels of conditional pathogenic bacteria. CSU microbiome transfer and Klebsiella pneumoniae transplantation facilitate IgE-mediated mast cell(MC)-driven skin inflammatory responses and increase intestinal permeability and blood lipopolysaccharide accumulation in recipient mice. Transplantation of Roseburia hominis and caproate administration protect recipient mice from MC-driven skin inflammation. Here, we show gut microbiome alterations, in CSU, may reduce short-chain fatty acids and increase lipopolysaccharide levels, respectively, and facilitate MC-driven skin inflammation.

[Mastocytosis-a frequently unrecognized disease]. / Mastozytose ­ eine häufig unerkannte Erkrankung.

Mastocytosis is a rare disease characterized by clonal expansion and accumulation of mast cells (MC) in various organs. Mastocytosis results from an activating mutation of the KIT surface receptor leading to an increased proliferation of MC. There are significant differences between children and adult patients with mastocytosis. Children mainly present the cutaneous form, whereas adults more often exhibit the systemic form of mastocytosis. Patients with mastocytosis may be asymptomatic or affected by a variety of symptoms. Treatment is primarily supportive and aims at symptom control. New approved targeted therapies such as midostaurin and avapritinib changed the treatment paradigm in advanced forms of the disease, and next-generation inhibitors currently in clinical trials are expected in the near future.

How Infection and Vaccination Are Linked to Acute and Chronic Urticaria: A Special Focus on COVID-19.

Since more than a century ago, there has been awareness of the connection between viral infections and the onset and exacerbation of urticaria. Our knowledge about the role of viral infection and vaccination in acute and chronic urticaria improved as a result of the COVID-19 pandemic but it has also highlighted knowledge gaps. Viral infections, especially respiratory tract infections like COVID-19, can trigger the onset of acute urticaria (AU) and the exacerbation of chronic urticaria (CU). Less frequently, vaccination against viruses including SARS-CoV-2 can also lead to new onset urticaria as well as worsening of CU in minority. Here, with a particular focus on COVID-19, we review what is known about the role of viral infections and vaccinations as triggers and causes of acute and chronic urticaria. We also discuss possible mechanistic pathways and outline the unmet needs in our knowledge. Although the underlying mechanisms are not clearly understood, it is believed that viral signals, medications, and stress can activate skin mast cells (MCs). Further studies are needed to fully understand the relevance of viral infections and vaccinations in acute and chronic urticaria and to better clarify causal pathways.

Gut Microbiome Composition in Patients with Chronic Urticaria: A Review of Current Evidence and Data.

Recent studies have linked gut microorganism composition and chronic urticaria (CU); however, the underlying mechanisms responsible for this connection are unknown. Since the human immune system is in homeostasis with microbiota, and the composition of the microbiome regulates the development and function of the immune system, it is likely that an alteration of microbiota components (a dysbiosis) could influence the course of chronic spontaneous urticaria (CSU), including disease severity, patient quality of life and treatment outcome. To date, several studies have identified changes in the gut microbiota composition of patients with CSU, though only a few have exhibited metabolic abnormalities associated with gut dysbiosis. The studies on CSU patients predominantly showed that the relative abundance of beneficial bacteria was decreased (Firmicutes and Bacteroides), while that of opportunistic bacteria was increased (Enterobacteria and Proteobacteria). In addition, serum metabolome analysis revealed that gut microbiota-associated alterations in unsaturated fatty acids and the butanoate metabolism pathway may play a role in CSU. These findings are potentially associated with inflammation mediated by the imbalance of Th1/Th2/Th17 cytokines, which might contribute to CSU pathogenesis. Further research in this field could improve clinical, diagnostic, and therapeutic approaches to patients with CSU. By applying new knowledge on gut microbial communities and metabolomics, future CSU therapies could modify the microbiota composition using agents such as probiotics or other similar agents, which, in combination with current standard therapies, could hopefully lead to a reduction in symptoms and an improved quality of life for CSU patients.

Eating Increases and Exercise Decreases Disease Activity in Patients With Symptomatic Dermographism.

BACKGROUND: Eating can increase disease activity in patients with symptomatic dermographism , the most common subtype of chronic inducible urticaria, but it is unclear how common this is. The effects of exercising on symptomatic dermographism disease activity have also not yet been determined. OBJECTIVE: To assess the impact of exercise and nonspecific carbohydrate-rich food intake on the severity and intensity of symptomatic dermographism after exercise and nonspecific carbohydrate-rich food intake. METHODS: We assessed disease activity by FricTest provocation testing in 75 symptomatic dermographism patients before and after eating, exercising, or both. We determined the rates of food-dependent (FD) symptomatic dermographism and food-exacerbated (FE) symptomatic dermographism. By comparing post- and pre-exercise FricTest scores, we identified complete responders: that is, patients with a negative FricTest response after exercising and partial responders. Finally, we evaluated whether exercise protects patients with FD-symptomatic dermographism or FE-symptomatic dermographism from eating-induced worsening of symptomatic dermographism. RESULTS: Of 64 symptomatic dermographism patients, eight had FD-symptomatic dermographism (13%), 42 had FE-symptomatic dermographism (66%), and 14 patients showed no negative impact of eating on disease activity (21%). Physical exercise reduced FricTest skin provocation test responses in 83% of 58 patients. Exercising protected patients with FD/FE-symptomatic dermographism from worsening of symptomatic dermographism owing to eating in half of cases, with higher rates for exercise after eating (67%) compared with exercise before eating (35%). CONCLUSIONS: Our study shows that eating often worsen symptomatic dermographism symptoms, and exercise often improves it. Our findings might aid patients in controlling symptoms better.

Virus-infected mast cells activate virus-specific CD8+ T cells.

Efficient anti-viral responses of CD8+ T cells require signals that promote their effector cell differentiation, that are mainly provided by dendritic cells (DCs). Mast cells (MCs) are key drivers of DC maturation, but also influence their migration and antigen presenting properties and therefore indirectly mediate CD8+ T cell activation. MCs initiate innate immune responses at pathogen entry sites, promote the development of adaptive immune responses after infection, and release mediators including chemokines that recruit and activate immune cells including T cells during viral infections. However, whether MCs can directly activate virus-specific CD8+ T cells remains largely unknown. Here, we used an in vitro viral infection model with lymphocytic choriomeningitis virus (LCMV)-infected MCs or DCs co-cultured with either LCMV-specific CD8+ T cells or with WT (unspecific) CD8+ T cells. Similar to LCMV-infected DCs, LCMV-infected MCs clustered with virus-specific CD8+ T cells and induced their activation and production of antiviral cytokines. In addition, the co-stimulatory molecules CD86 and OX40L, but not CD80, were upregulated on MCs and an increased production of IL-6 and type I interferons after LCMV infection was shown. Our findings suggest that MCs can promote CD8+ T cell activation during viral infections. MC-mediated CD8+ T cell activation might be especially important within infected tissues where direct cellular interaction can take place. A better understanding of anti-viral functions of MCs may help developing new strategies to better treat viral infections.

Autoimmune chronic spontaneous urticaria.

Chronic spontaneous urticaria (CSU) is a debilitating mast cell-driven disease characterized by recurrent wheals and/or angioedema. Substantial progress has been made in dissecting the 2 main autoimmune mechanisms that drive the pathogenesis of CSU. Type I autoimmune (autoallergic) CSU is associated with IgE antibodies against autoantigens, for example, thyroid peroxidase and IL-24. Type IIb autoimmune CSU is mediated by autoantibodies that activate mast cells, for example, via IgE and FcεRI, and is present in less than 10% of patients with CSU when strict criteria are used, that is, triple positivity of autologous serum skin test, immunoassays for IgG autoantibodies, and basophil activation tests. A subpopulation of patients with CSU has both types. Type IIb autoimmune CSU is characterized by higher disease severity, concomitant autoimmune diseases, low levels of total IgE, elevated levels of IgG-anti-thyroid peroxidase, basopenia, eosinopenia, poor response to antihistamines and to omalizumab, and a good response to cyclosporine. Novel targeted therapies for CSU are under development such as ligelizumab, an anti-IgE, fenebrutinib and remibrutinib, Bruton's tyrosine kinase inhibitors, and dupilumab, an anti-IL-4Rα. Further studies should investigate the overlap between autoallergic and type IIb autoimmune CSU, optimize the diagnosis of both autoimmune endotypes using easy-to-perform, noninvasive, and inexpensive markers, and assess differences in response to therapy.

Food-dependent and food-exacerbated symptomatic dermographism: New variants of symptomatic dermographism.

BACKGROUND: Symptomatic dermographism (SD) is the most common form of chronic inducible urticaria. The criterion standard for diagnosing SD and disease activity assessment in SD is provocation testing. As of now, if and what cofactors have an impact on provocation test results is unknown. OBJECTIVE: We sought to determine whether the induction of signs and symptoms of SD is affected by the intake of food. METHODS: We performed standardized skin provocation testing with a dermographometer (FricTest) before and after the intake of food. Patients were off antihistamine treatment for at least 3 days before testing. In total, 17 patients were tested after not having eaten for at least 4 hours (preprandial) on one volar forearm and 60 minutes after a carbohydrate-rich meal (postprandial) on the other. FricTest responses (wheals, itch) at trigger thresholds were assessed at 5 and 30 seconds as well as at 1, 2, 5, and 10 minutes. RESULTS: We identified 7 patients with SD who showed faster onset of FricTest-induced whealing and/or lower trigger thresholds after the intake of food, that is, food-exacerbated SD. In 5 other patients, FricTest provocation testing resulted in a positive response only after the intake of food, but not before. Three of these 5 patients with food-dependent SD had comorbid chronic spontaneous urticaria and 1 had cholinergic urticaria. CONCLUSIONS: We describe 2 previously unknown subtypes of SD, food-exacerbated SD and food-dependent SD. The prevalence and underlying pathomechanisms of food-exacerbated SD and food-dependent SD need to be investigated, and the impact of food intake on other forms of chronic inducible urticaria should be explored.

Mast Cells Modulate Antigen-Specific CD8+ T Cell Activation During LCMV Infection.

Mast cells (MCs), strategically localized at mucosal surfaces, provide first-line defense against pathogens and shape innate and adaptive immune responses. Recent studies have shown that MCs are involved in pathogenic responses to several viruses including herpes simplex viruses, dengue virus, vaccinia virus and influenza virus. However, the underlying mechanisms of MCs in the activation of CD8+ T cells during viral infections are not fully understood. Therefore, we investigate the role of MCs in the development of virus-specific CD8+ T cell responses using the well-characterized murine lymphocytic choriomeningitis virus (LCMV) model and the transgenic MasTRECK mice that contain the human diphtheria toxin receptor as an inducible MC-deficient model. Here, we report that MCs are essential for the activation and expansion of virus-specific CD8+ T cells. After MC depletion and subsequent intradermal LCMV infection, the CD8 + T cell effector phenotype and antiviral cytokine production were impaired at the peak of infection (day 8 p.i.). Importantly, MC-deficient mice were unable to control the infection and exhibited significantly higher viral loads in the spleen and in the ear draining lymph nodes compared to that of wild type control mice. In the absence of MCs, dendritic cell (DC) activation was impaired upon LCMV infection. In addition, type-I interferon (IFN) levels in the serum and in the spleen of MC-deficient mice were reduced during the first days of infection. Interestingly, depletion of MCs after intradermal LCMV infection did not impair virus-specific CD8+ T cell expansion, activation or antiviral cytokine production. In summary, our results indicate that MCs play a pivotal role in the activation and antiviral functions of CD8+ T cells through proper DC activation. A better understanding of the impact of MCs on CD8+ T cell responses is mandatory to improve antiviral immune responses.

Reprogramming Intestinal Epithelial Cell Polarity by Interleukin-22.

Background: Interleukin-22 (IL-22) impacts the integrity of intestinal epithelia and has been associated with the development of colitis-associated cancer and inflammatory bowel diseases (IBD). Previous data suggest that IL-22 protects the mucosal barrier and promotes wound healing and barrier defect. We hypothesized, that IL-22 modulates cell polarity of intestinal epithelial cells (IECs) acting on tight junction assembly. The aim of the study was to investigate IL-22-dependent mechanisms in the reprogramming of intestinal epithelia. Methods: IECs were exposed to IL-22 at various concentrations. IECs in Matrigel® were grown to 3-dimensional cysts in the presence or absence of IL-22 and morphology and expression of polarity proteins were analyzed by confocal microscopy. Epithelial cell barrier (TER and sandwich assay) and TJ assembly analysis (calcium-switch assay) were performed. TJ and cell polarity protein expression were assessed by western blotting and confocal microscopy. Cell migration and invasion assays were performed. Induction of epithelial-mesenchymal transition (EMT) was assessed by RT-qPCR analysis and western blotting. Signaling pathway analyses were performed by phosphoblotting and functional assays after blocking STAT3 and ERK signaling pathways. Using the toxoplasma-model of terminal ileitis, IL-22-knock-out mice were compared to wild-type littermates, analyzed for barrier function using one-path-impedance-analysis and macromolecular flux (H3-mannitol, Ussing-chambers). Results: IECs exhibited a barrier defect after IL-22 exposure. TJ protein distribution and expression were severely impaired. Delayed recovery in the calcium-switch assay was observed suggesting a defect in TJ assembly. Analyzing the 3D-cyst model, IL-22 induced multi-lumen and aberrant cysts, and altered the localization of cell polarity proteins. Cell migration and invasion was caused by IL-22 as well as induction of EMT. Interestingly, only inhibition of the MAPK pathway, rescued the TJal barrier defect, while blocking STAT3 was relevant for cell survival. In addition, ileal mucosa of IL-22 deficient mice was protected from the barrier defect seen in Toxoplasma gondii-induced ileitis in wild type mice shown by significantly higher Re values and correspondingly lower macromolecule fluxes. Conclusion: IL-22 impairs intestinal epithelial cell barrier by inducing EMT, causing defects in epithelial cell polarity and increasing cell motility and cell invasion. IL-22 modulates TJ protein expression and mediates tight junctional (TJal) barrier defects via ERK pathway.

Th2 cells lacking T-bet suppress naive and memory T cell responses via IL-10.

Exacerbated immune responses and loss of self-tolerance lead to the development of autoimmunity and immunopathology. Novel therapies to target autoreactive T cells are still needed. Here, we report that Th2-polarized T cells lacking the transcription factor T-bet harbor strong immunomodulatory potential and suppress antigen-specific CD8+ T cells via IL-10. Tbx21-/- Th2 cells protected mice against virus-induced type 1 diabetes development and suppressed not only naive but also memory CD8+ T cell responses. IL-10-producing, but not IL-10-deficient Tbx21-/- Th2 cells down-regulated costimulatory molecules on dendritic cells and reduced their IL-12 production after lymphocytic choriomeningitis virus infection. Impaired dendritic cell activation hindered effector and cytotoxic CD8+ T cell development after infection. These findings indicate that Tbx21-/- Th2 cells strongly suppress proinflammatory responses of naive and memory T cells via IL-10. Thus, in vivo IL-10-secreting Th2 cells could harbor a therapeutic potential for the treatment of T cell-mediated inflammatory disorders.

New treatments for chronic urticaria.

OBJECTIVE: Chronic urticaria (CU) is a common, heterogeneous, and debilitating disease. Antihistamines and omalizumab are the mainstay therapies of CU. Additional treatment options are needed. Here, we review the off and beyond label use of licensed drugs, novel treatments that are currently under development, and promising new targets. DATA SOURCES: MEDLINE was searched for recent reports of the successful use of treatments in CU and promising targets for the development of novel treatment options. We also searched ClinicalTrials.gov for recent and ongoing randomized clinical trials in CU. STUDY SELECTIONS: Relevant articles were selected and reviewed. RESULTS: Omalizumab, the treatment of choice in patients with antihistamine-resistant chronic spontaneous urticaria (CSU), should be explored for use in chronic inducible urticaria in children younger than 12 years with CSU and at higher doses. The off-label use of dupilumab, reslizumab, mepolizumab, and benralizumab can be effective in CU. Ligelizumab and UB-221, 2 novel anti-IgE monoclonal antibodies, are in clinical trials for CU. Other promising drugs that are currently under development for CU are a chemoattractant receptor-homologous molecule expressed on TH2 cell antagonist, a monoclonal antibody to Siglec-8 (AK002), Bruton tyrosine kinase inhibitors (fenebrutinib and Lou064), a spleen tyrosine kinase inhibitor, and dupilumab. Promising targets of future therapies include the Mas-related G-protein-coupled receptor X2; the histamine4 receptor; C5a and its receptor; inhibitory mast cell receptors other than Siglec-8; interleukin 33, interleukin 25, and thymic stromal lymphopoietin, and stem cell factor. CONCLUSION: Novel and better treatments for CU are very much needed. Some agents are in clinical trials already (eg, ligelizumab), and additional ones should be developed, making use of the many promising targets recently identified and characterized.

Interleukin-22 induces interleukin-18 expression from epithelial cells during intestinal infection.

T helper 1 (Th1) cell-associated immunity exacerbates ileitis induced by oral Toxoplasma gondii infection. We show here that attenuated ileitis observed in interleukin-22 (IL-22)-deficient mice was associated with reduced production of Th1-cell-promoting IL-18. IL-22 not only augmented the expression of Il18 mRNA and inactive precursor protein (proIL-18) in intestinal epithelial cells after T. gondii or Citrobacter rodentium infection, but also maintained the homeostatic amount of proIL-18 in the ileum. IL-22, however, did not induce the processing to active IL-18, suggesting a two-step regulation of IL-18 in these cells. Although IL-18 exerted pathogenic functions during ileitis triggered by T. gondii, it was required for host defense against C. rodentium. Conversely, IL-18 was required for the expression of IL-22 in innate lymphoid cells (ILCs) upon T. gondii infection. Our results define IL-18 as an IL-22 target gene in epithelial cells and describe a complex mutual regulation of both cytokines during intestinal infection.

The IFN-γ-inducible GTPase, Irga6, protects mice against Toxoplasma gondii but not against Plasmodium berghei and some other intracellular pathogens.

Clearance of infection with intracellular pathogens in mice involves interferon-regulated GTPases of the IRG protein family. Experiments with mice genetically deficient in members of this family such as Irgm1(LRG-47), Irgm3(IGTP), and Irgd(IRG-47) has revealed a critical role in microbial clearance, especially for Toxoplasma gondii. The in vivo role of another member of this family, Irga6 (IIGP, IIGP1) has been studied in less detail. We investigated the susceptibility of two independently generated mouse strains deficient in Irga6 to in vivo infection with T. gondii, Mycobacterium tuberculosis, Leishmania mexicana, L. major, Listeria monocytogenes, Anaplasma phagocytophilum and Plasmodium berghei. Compared with wild-type mice, mice deficient in Irga6 showed increased susceptibility to oral and intraperitoneal infection with T. gondii but not to infection with the other organisms. Surprisingly, infection of Irga6-deficient mice with the related apicomplexan parasite, P. berghei, did not result in increased replication in the liver stage and no Irga6 (or any other IRG protein) was detected at the parasitophorous vacuole membrane in IFN-γ-induced wild-type cells infected with P. berghei in vitro. Susceptibility to infection with T. gondii was associated with increased mortality and reduced time to death, increased numbers of inflammatory foci in the brains and elevated parasite loads in brains of infected Irga6-deficient mice. In vitro, Irga6-deficient macrophages and fibroblasts stimulated with IFN-γ were defective in controlling parasite replication. Taken together, our results implicate Irga6 in the control of infection with T. gondii and further highlight the importance of the IRG system for resistance to this pathogen.

Novel murine infection models provide deep insights into the "ménage à trois" of Campylobacter jejuni, microbiota and host innate immunity.

BACKGROUND: Although Campylobacter jejuni-infections have a high prevalence worldwide and represent a significant socioeconomic burden, it is still not well understood how C. jejuni causes intestinal inflammation. Detailed investigation of C. jejuni-mediated intestinal immunopathology is hampered by the lack of appropriate vertebrate models. In particular, mice display colonization resistance against this pathogen. METHODOLOGY/PRINCIPAL FINDINGS: To overcome these limitations we developed a novel C. jejuni-infection model using gnotobiotic mice in which the intestinal flora was eradicated by antibiotic treatment. These animals could then be permanently associated with a complete human (hfa) or murine (mfa) microbiota. After peroral infection C. jejuni colonized the gastrointestinal tract of gnotobiotic and hfa mice for six weeks, whereas mfa mice cleared the pathogen within two days. Strikingly, stable C. jejuni colonization was accompanied by a pro-inflammatory immune response indicated by increased numbers of T- and B-lymphocytes, regulatory T-cells, neutrophils and apoptotic cells, as well as increased concentrations of TNF-α, IL-6, and MCP-1 in the colon mucosa of hfa mice. Analysis of MyD88(-/-), TRIF(-/-), TLR4(-/-), and TLR9(-/-) mice revealed that TLR4- and TLR9-signaling was essential for immunopathology following C. jejuni-infection. Interestingly, C. jejuni-mutant strains deficient in formic acid metabolism and perception induced less intestinal immunopathology compared to the parental strain infection. In summary, the murine gut flora is essential for colonization resistance against C. jejuni and can be overcome by reconstitution of gnotobiotic mice with human flora. Detection of C. jejuni-LPS and -CpG-DNA by host TLR4 and TLR9, respectively, plays a key role in immunopathology. Finally, the host immune response is tightly coupled to bacterial formic acid metabolism and invasion fitness. CONCLUSION/SIGNIFICANCE: We conclude that gnotobiotic and "humanized" mice represent excellent novel C. jejuni-infection and -inflammation models and provide deep insights into the immunological and molecular interplays between C. jejuni, microbiota and innate immunity in human campylobacteriosis.

Immunology of Toxoplasma gondii.

Toxoplasma gondii is an obligate intracellular parasite. Following oral infection the parasite crosses the intestinal epithelial barrier to disseminate throughout the body and establish latent infection in central nervous tissues. The clinical presentation ranges from asymptomatic to severe neurological disorders in immunocompromised individuals. Since the clinical presentation is diverse and depends, among other factors, on the immune status of the host, in the present review, we introduce parasitological, epidemiological, clinical, and molecular biological aspects of infection with T. gondii to set the stage for an in-depth discussion of host immune responses. Since immune responses in humans have not been investigated in detail the present review is exclusively referring to immune responses in experimental models of infection. Systemic and local immune responses in different models of infection are discussed, and a separate chapter introduces commonly used animal models of infection.

Anti-inflammatory effects of resveratrol, curcumin and simvastatin in acute small intestinal inflammation.

BACKGROUND: The health beneficial effects of Resveratrol, Curcumin and Simvastatin have been demonstrated in various experimental models of inflammation. We investigated the potential anti-inflammatory and immunomodulatory mechanisms of the above mentioned compounds in a murine model of hyper-acute Th1-type ileitis following peroral infection with Toxoplasma gondii. METHODOLOGY/PRINCIPAL FINDINGS: Here we show that after peroral administration of Resveratrol, Curcumin or Simvastatin, mice were protected from ileitis development and survived the acute phase of inflammation whereas all Placebo treated controls died. In particular, Resveratrol treatment resulted in longer-term survival. Resveratrol, Curcumin or Simvastatin treated animals displayed significantly increased numbers of regulatory T cells and augmented intestinal epithelial cell proliferation/regeneration in the ileum mucosa compared to placebo control animals. In contrast, mucosal T lymphocyte and neutrophilic granulocyte numbers in treated mice were reduced. In addition, levels of the anti-inflammatory cytokine IL-10 in ileum, mesenteric lymph nodes and spleen were increased whereas pro-inflammatory cytokine expression (IL-23p19, IFN-γ, TNF-α, IL-6, MCP-1) was found to be significantly lower in the ileum of treated animals as compared to Placebo controls. Furthermore, treated animals displayed not only fewer pro-inflammatory enterobacteria and enterococci but also higher anti-inflammatory lactobacilli and bifidobacteria loads. Most importantly, treatment with all three compounds preserved intestinal barrier functions as indicated by reduced bacterial translocation rates into spleen, liver, kidney and blood. CONCLUSION/SIGNIFICANCE: Oral treatment with Resveratrol, Curcumin or Simvastatin ameliorates acute small intestinal inflammation by down-regulating Th1-type immune responses and prevents bacterial translocation by maintaining gut barrier function. These findings provide novel and potential prophylaxis and treatment options of patients with inflammatory bowel diseases.

Interleukin (IL)-23 mediates Toxoplasma gondii-induced immunopathology in the gut via matrixmetalloproteinase-2 and IL-22 but independent of IL-17.

Peroral infection with Toxoplasma gondii leads to the development of small intestinal inflammation dependent on Th1 cytokines. The role of Th17 cells in ileitis is unknown. We report interleukin (IL)-23-mediated gelatinase A (matrixmetalloproteinase [MMP]-2) up-regulation in the ileum of infected mice. MMP-2 deficiency as well as therapeutic or prophylactic selective gelatinase blockage protected mice from the development of T. gondii-induced immunopathology. Moreover, IL-23-dependent up-regulation of IL-22 was essential for the development of ileitis, whereas IL-17 was down-regulated and dispensable. CD4(+) T cells were the main source of IL-22 in the small intestinal lamina propria. Thus, IL-23 regulates small intestinal inflammation via IL-22 but independent of IL-17. Gelatinases may be useful targets for treatment of intestinal inflammation.

Polymorphisms in the myosin light chain kinase gene that confer risk of severe sepsis are associated with a lower risk of asthma.

BACKGROUND: Myosin light chain kinase (MYLK) is a multifunctional protein involved in regulation of airway hyperreactivity and other activities relevant to asthma. OBJECTIVE: To determine the role of MYLK gene variants in asthma among African Caribbean and African American populations. METHODS: We performed association tests between single nucleotide polymorphisms (SNPs) in the MYLK gene and asthma susceptibility and total serum IgE concentrations in 2 independent, family-based populations of African descent. Previously we identified variants/haplotypes in MYLK that confer risk for sepsis and acute lung injury; we compared findings from our asthma populations to findings in the African American sepsis and acute lung injury groups. RESULTS: Significant associations between MYLK SNPs and asthma and total serum IgE concentrations were observed in the African Caribbean families: a promoter SNP (rs936170) in the smooth muscle form gave the strongest association (P = .009). A haplotype including rs936170 corresponding to the actin-binding activity of the nonmuscle and smooth muscle forms was negatively associated with asthma (eg, decreased risk) in both the American (P = .005) and Caribbean families (P = .004), and was the same haplotype that conferred risk for severe sepsis (P = .002). RNA expression studies on PBMCs and rs936170 suggested a significant decrease in MYLK expression among patients with asthma with this variant (P = .025). CONCLUSION: MYLK polymorphisms may function as a common genetic factor in clinically distinct diseases involving bronchial smooth muscle contraction and inflammation. CLINICAL IMPLICATIONS: Genetic variants in MYLK are significantly associated with both asthma and sepsis in populations of African ancestry.