The Clinical Significance of Hepatic CD69+ CD103+ CD8+ Resident-Memory T Cells in Autoimmune Hepatitis.

BACKGROUND AND AIMS: The diverse inflammatory response found in the liver of patients with autoimmune hepatitis (AIH) is well established, but identification of potentially pathogenic subpopulations has proven enigmatic. APPROACH AND RESULTS: We report herein that CD69+ CD103+ CD8+ tissue-resident memory T cells (TRM ) are significantly increased in the liver of patients with AIH compared to chronic hepatitis B, NAFLD, and healthy control tissues. In addition, there was a significant statistical correlation between elevation of CD8+ TRM cells and AIH disease severity. Indeed, in patients with successful responses to immunosuppression, the frequencies of such hepatic CD8+ TRM cells decreased significantly. CD69+ CD8+ and CD69+ CD103+ CD8+ T cells, also known as CD8+ TRM cells, reflect tissue residency and are well known to provide intense immune antigenic responses. Hence, it was particularly interesting that patients with AIH also manifest an elevated expression of IL-15 and TGF-ß on inflammatory cells, and extensive hepatic expression of E-cadherin; these factors likely contribute to the development and localization of CD8+ TRM cells. Based on these data and, in particular, the relationships between disease severity and CD8+ TRM cells, we studied the mechanisms involved with glucocorticoid (GC) modulation of CD8+ TRM cell expansion. Our data reflect that GCs in vitro inhibit the expansion of CD8+ TRM cells induced by IL-15 and TGF-ß and with direct down-regulation of the nuclear factor Blimp1 of CD8+ TRM cells. CONCLUSIONS: Our data suggest that CD8+ TRM cells play a critical role in the pathogenesis of AIH, and GCs attenuate hepatic inflammation through direct inhibition of CD8+ TRM cell expansion.

FoxO1 suppresses IL-10 producing B cell differentiation via negatively regulating Blimp-1 expression and contributes to allergic asthma progression.

IL-10-producing B cells (B10) are involved in the prevention of autoimmune and allergic responses but its mechanisms remain poorly understood. We took advantage of the ovalbumin-induced asthma mouse model to demonstrate that the activity of FoxO1 is upregulated in lung B cells and correlates inversely with B10 cells, while showing decreased activity in ex vivo and in vitro induced B10 cells. We further observed that FoxO1 deficiency leads to increased frequency of B10 cells. These observations have in vivo clinical evidence, as B cell specific FoxO1 deficiency leads to reduced lung eosinophils and asthma remission in mice, and there are reduced regulatory B cells and increased FoxO1 activity in B cells of asthma patients. Single cell RNA-sequencing data demonstrated a negative correlation between the expression of Foxo1 and Il10 in B cells from the mouse spleen and lung and the human lung. For a biological mechanism, FoxO1 inhibits the expression of Prdm1, which encodes Blimp-1, a transcription factor of B10 cells. Our experimental evidence in both murine and human asthma demonstrates that FoxO1 is a negative regulator of B10 cell differentiation via negatively regulating Prdm1 and its expression in B cells contributes to allergic asthma disease.

The Immunologic Paradoxes of IgG4-Related Disease.

IgG4-related disease (IgG4-RD), which usually occurs in middle-aged and elderly men, is a newly recognized fibroinflammatory condition characterized by swelling and sclerosis of involved organs, increased IgG4-positive plasma cell infiltration in lesions, and elevated IgG4 concentration in serum. Despite growing interest in the research, the pathophysiological mechanism remains elusive. Most IgG4-RD patients respond well to steroid therapy initially, but recurrent and refractory cases are common, especially in advanced fibrotic stage. Recent studies have documented the heterogeneity of the B cell lineages, which suggests their multiple functions in IgG4-RD beyond IgG4 production, such as cytokine secretion, antigen presentation, autoantibody production, and modulation of T and B cell interactions. Thus, a critical balance exists between pathogenic and regulatory B subsets to prevent immunopathology. A prompt response to B cell depletion therapy reported in recent cases strongly suggests the imbalance within B cell lineages in IgG4-RD. A more precise understanding of the pathogenesis of IgG4-RD will open up new perspectives for therapeutic strategy. With a particular emphasis on the novel B cell-targeted therapeutic strategies, this review highlights the immunologic features of IgG4-RD and the possible roles of B cell lineages in the pathogenesis of IgG4-RD.

Mold and Human Health: a Reality Check.

There are possibly millions of mold species on earth. The vast majority of these mold spores live in harmony with humans, rarely causing disease. The rare species that does cause disease does so by triggering allergies or asthma, or may be involved in hypersensitivity diseases such as allergic bronchopulmonary aspergillosis or allergic fungal sinusitis. Other hypersensitivity diseases include those related to occupational or domiciliary exposures to certain mold species, as in the case of Pigeon Breeder's disease, Farmer's lung, or humidifier fever. The final proven category of fungal diseases is through infection, as in the case of onchomycosis or coccidiomycosis. These diseases can be treated using anti-fungal agents. Molds and fungi can also be particularly important in infections that occur in immunocompromised patients. Systemic candidiasis does not occur unless the individual is immunodeficient. Previous reports of "toxic mold syndrome" or "toxic black mold" have been shown to be no more than media hype and mass hysteria, partly stemming from the misinterpreted concept of the "sick building syndrome." There is no scientific evidence that exposure to visible black mold in apartments and buildings can lead to the vague and subjective symptoms of memory loss, inability to focus, fatigue, and headaches that were reported by people who erroneously believed that they were suffering from "mycotoxicosis." Similarly, a causal relationship between cases of infant pulmonary hemorrhage and exposure to "black mold" has never been proven. Finally, there is no evidence of a link between autoimmune disease and mold exposure.

Comparative clinical characteristics and natural history of three variants of sclerosing cholangitis: IgG4-related SC, PSC/AIH and PSC alone.

There is increased interest and recognition of the clinical variants of Sclerosing Cholangitis (SC) namely IgG4-SC, PSC/AIH overlap and PSC. For most Centers, the characteristic of IgG4-SC has not been thoroughly clinically compared with other sclerosing cholangitis variants. Further there are relatively few PSC/AIH overlap patients and the clinical outcome is not well characterized, especially for the PSC/AIH overlap syndrome. Our objective herein is to clarify the differences and similarities of the natural history of IgG4-SC, the PSC/AIH overlap and PSC alone. We also place in perspective the diagnostic value of serum IgG4 for IgG4-SC and investigate biomarkers for predicting the prognosis of sclerosing cholangitis. In this study, we took advantage of our large and well-defined patient cohort to perform a retrospective cohort study including 57 IgG4-SC, 36 PSC/AIH overlap patients, and 55 PSC patients. Firstly, as expected, we noted significant differences among immunoglobulin profiles and all patients exhibited similar cholestatic profiles at presentation. Cirrhotic events were found in 20 of total 57 IgG4-SC, 15 of 36 PSC/AIH overlap, and 18 of 55 PSC patients. Serum IgG4 was elevated in 92.65% of IgG4-SC patients with an 86% sensitivity and 98% specificity for diagnosis. IgG4-SC patients had a better treatment response at 6-month and 1-year than PSC/AIH patients, while the latter responded better with steroids than PSC patients. Importantly the adverse outcome-free survival of IgG4-SC patients was reduced, unlike earlier reports, and therefore similar to the PSC/AIH overlap syndrome. Serum IgG and total bilirubin were useful to predict long-term survival of IgG4-SC and PSC/AIH, respectively. In conclusion, serum IgG4≧1.25 ULN shows an excellent predictability to distinguish IgG4-SC among SC patients. IgG4-SC appears to be immune-mediated inflammatory process, while PSC/AIH overlap more tends to be cholestatic disease.

Adaptive immunity in the liver.

The anatomical architecture of the human liver and the diversity of its immune components endow the liver with its physiological function of immune competence. Adaptive immunity is a major arm of the immune system that is organized in a highly specialized and systematic manner, thus providing long-lasting protection with immunological memory. Adaptive immunity consists of humoral immunity and cellular immunity. Cellular immunity is known to have a crucial role in controlling infection, cancer and autoimmune disorders in the liver. In this article, we will focus on hepatic virus infections, hepatocellular carcinoma and autoimmune disorders as examples to illustrate the current understanding of the contribution of T cells to cellular immunity in these maladies. Cellular immune suppression is primarily responsible for chronic viral infections and cancer. However, an uncontrolled auto-reactive immune response accounts for autoimmunity. Consequently, these immune abnormalities are ascribed to the quantitative and functional changes in adaptive immune cells and their subsets, innate immunocytes, chemokines, cytokines and various surface receptors on immune cells. A greater understanding of the complex orchestration of the hepatic adaptive immune regulators during homeostasis and immune competence are much needed to identify relevant targets for clinical intervention to treat immunological disorders in the liver.

Diagnostic challenges in celiac disease and the role of the tissue transglutaminase-neo-epitope.

The diagnosis of celiac disease (CD) remains a clinical challenge based on the incomplete specificity and sensitivity rates of current non-invasive tests. Furthermore, histological assessments fail to identify all overt cases and, in particular, do not manifest pathognomonic alterations in silent cases. Accordingly, the majority of CD cases are diagnosed with great delay. Recent research into the pathogenesis of CD, allowed us to identify a neo-antigen that appears to be the most promising serological tool for the detection of anti-tissue transglutaminase as well as anti-gliadin antibodies.

The anti-inflammatory properties of cocoa flavanols.

Signs of chronic or acute inflammation have been demonstrated in most cardiovascular diseases of multifactorial pathogenesis, including atherosclerosis and chronic heart failure. The triggers and mechanisms leading to inflammation may vary between clinical conditions but they share many common mediators, including specific patterns of eicosanoid and cytokine production. Certain cocoa-based products can be rich in a subclass of flavonoids known as flavanols, some of which have been found in model systems to possess potential anti-inflammatory activity relevant to cardiovascular health. Indeed, experimental evidence demonstrates that some cocoa-derived flavanols can reduce the production and effect of pro-inflammatory mediators either directly or by acting on signaling pathways. However, it should be noted that the evidence for any beneficial effects of cocoa flavanols in providing a meaningful anti-inflammatory action has been gathered predominantly from in vitro experiments. Therefore, additional research in well-designed human clinical experiments, using cocoa properly characterized in terms of flavanol content, would be a welcome addition to the evidence base to determine unambiguously if this benefit does indeed exist. If so, then flavanol-rich cocoa could be a potential candidate for the treatment, or possibly prevention, of the broad array of chronic diseases that are linked to dysfunctional inflammatory responses.