In drug-induced, immune-mediated hepatitis, interleukin-33 reduces hepatitis and improves survival independently and as a consequence of FoxP3+ T-cell activity.

Immune-mediated, drug-induced hepatitis is a rare complication of halogenated volatile anesthetic administration. IL-4-regulated Th2-polarized reactions initiate this type and other types of hepatitis, while the mechanisms that regulate the severity remain elusive. IL-33 is an innate, IL-4-inducing, Th2-polarizing cytokine that has been detected in patients with liver failure and has been associated with upregulated ST2+Foxp3+CD4+CD25+ T cells; however, roles for IL-33 in drug-induced hepatitis are unclear.

Evolving Trends in Female to Male Incidence and Male Mortality of Primary Biliary Cholangitis.

Primary biliary cholangitis (PBC) has been regarded as female-predominant without evidence of gender difference in survival. We aimed to compare the overall survival, incidence and prevalence of PBC in two well defined population-based studies over a recent decade, considering also sex ratios and mortality. We have taken advantage of population-wide records, during 2000-2009, in Lombardia, Northern Italy, and Denmark.

Chemokine (C-X-C motif) ligand 13 promotes intrahepatic chemokine (C-X-C motif) receptor 5+ lymphocyte homing and aberrant B-cell immune responses in primary biliary cirrhosis.

Unlabelled: The serological hallmark of primary biliary cirrhosis (PBC) is the presence of high titer and specific antimitochondrial antibodies (AMAs). Although there is no global immune defect in patients with PBC, there is widespread dysregulated B-cell function, including increased sera levels of immunoglobulin M and enhanced B-cell responses to cytosine-phosphate-guanine stimulation. The mechanisms involved in this B-cell dysfunction have remained unknown.

Ongoing activation of autoantigen-specific B cells in primary biliary cirrhosis.

Unlabelled: The serologic hallmark of primary biliary cirrhosis (PBC), the antimitochondrial response to the E2 component of the pyruvate dehydrogenase complex (PDC-E2), has unique features, including continuous high titers of immunoglobulin M (IgM) and IgG reactivity throughout all stages of disease, capable not only of target enzyme inhibition, but also crossreactive with chemical xenobiotics that share molecular homology with the inner lipoyl domain of PDC-E2; such chemicals have been proposed as potential etiological agents. We used flow cytometry and enzyme-linked immunospot assay (ELISPOT) to examine B-cell subsets in 59 subjects, including 28 with PBC, 13 with primary sclerosing cholangitis (PSC), and 18 healthy controls. Strikingly, in PBC, although there were no significant differences in B-cell phenotype subpopulations, 10% of the total IgG and IgA plasmablast population and 23% of the IgM plasmablast population were uniquely reactive with PDC-E2, detected in the CXCR7+ CCR10low plasmablast population.

Cofactor-dependent conformational heterogeneity of GAD65 and its role in autoimmunity and neurotransmitter homeostasis.

The human neuroendocrine enzyme glutamate decarboxylase (GAD) catalyses the synthesis of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) using pyridoxal 5'-phosphate as a cofactor. GAD exists as two isoforms named according to their respective molecular weights: GAD65 and GAD67. Although cytosolic GAD67 is typically saturated with the cofactor (holoGAD67) and constitutively active to produce basal levels of GABA, the membrane-associated GAD65 exists mainly as the inactive apo form.

Fashioning the immunological self: the biological individuality of F. Macfarlane Burnet.

During the 1940s and 1950s, the Australian microbiologist F. Macfarlane Burnet sought a biologically plausible explanation of antibody production. In this essay, we seek to recover the conceptual pathways that Burnet followed in his immunological theorizing.

Autoimmune hepatitis: what must be said.

Autoimmune hepatitis (AIH) was first studied under its earlier name of "chronic active hepatitis" (CAH) from the 1950s, coincident with a renaissance of interest in autoimmunity. The definition of autoimmune serum reactants in disease, including CAH, gave new insights into chronic hepatitis and liver cirrhosis, and led to refinements of Burnet's clonal selection theory of acquired immunity, 1957-59. Various discoveries including serological reactants in CAH prompted its designation in 1965 as autoimmune hepatitis, and treatment with immunosuppressive drug regimens transformed outcomes and survival.

BAFF/BLyS inhibitors: A new prospect for treatment of systemic lupus erythematosus.

In November 2009, Human Genome Sciences and Glaxo-Smith Kline [HGS (Rockville, Maryland) and GSK, respectively] announced that Belimumab, a neutralizing antibody to the tumour necrosis factor (TNF)-like ligand, B-cell activating factor (BAFF belonging to the TNF family, also named BLyS), met the primary endpoints in two phase III clinical trials in systemic lupus erythematosus (SLE, lupus). In March 2011, Belimumab was approved by the US Federal Drug Agency for treatment of SLE patients; this was followed in May with approval by the European Medicines Agency for use in the European Union. This is an exciting development as it is the first successful late-stage clinical trial in SLE in over 40 years.

Inflammatory bowel disease: beyond the boundaries of the bowel.

Dysregulated inflammation in the gut, designated clinically as inflammatory bowel disease (IBD), is manifested by the prototypic phenotypes of an Arthus-like reaction restricted to the mucosa of the colon, as in ulcerative colitis, or a transmural granulomatous reaction, as in Crohn's disease, or an indeterminate form of the two polar types. That the inflammation of IBD can trespass the boundaries of the bowel has long been known, with articular, ophthalmologic, cutaneous, hepatobiliary or other complications/associations - some autoimmune and others not - affecting significant numbers of patients with IBD. Also notable is the frequency of diagnosis of IBD-type diseases on a background of systemic, (mostly myelo-hematological) disorders, associated with alterations of either (or both) innate or adaptive arms of the immune response.

A 50-year experience with autoimmune hepatitis: and where are we now?

Background: Autoimmune hepatitis (AIH) as chronic active hepatitis became recognized in the 1940s as a progressive hyperglobulinemic disease affecting younger women attributed to persisting virus infection of the liver: autoimmunity then was barely on the horizon.

Early Observations: The lupus erythematosus (LE) cell reported in 1948 signified the presence of antinuclear autoantibodies, promoting perceptions of autoimmunity in certain chronic diseases. Recognition of LE cells in chronic hepatitis led to the designation of 'lupoid hepatitis', with autoimmunity further substantiated by anti-cytoplasmic autoantibodies detected by complement fixation.

The autoimmunity of primary biliary cirrhosis and the clonal selection theory.

Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease in which an immune-mediated injury targets the small intrahepatic bile ducts. PBC is further characterized by highly specific serum antimitochondrial autoantibodies (AMAs) and autoreactive T cells, a striking female predominance, a strong genetic susceptibility and a plethora of candidate environmental factors to trigger the disease onset. For these reasons, PBC appears ideal to represent the developments of the clonal selection theory over the past decades.

Autoantibody heritability in thyroiditis: IgG subclass contributions.

Using a simple screening technique called regression of offspring on mid-parent (ROMP) to examine the role of IgG subclasses in affected and unaffected siblings of children and adolescents with autoimmune thyroid disease and their parents, both total-restricted and subclass-restricted autoantibodies to thyroglobulin (Tg) were assayed quantitatively for each of the IgG subclasses. There was a significant correlation of anti-Tg titer of probands with parental titers in thyrotoxicosis (TT), (R(2) = 0.569, p = 0.

The odd couple: a fresh look at autoimmunity and immunodeficiency.

The paradoxical relationship between immunodeficiency (under-responsiveness) and autoimmunity (over-responsiveness) affecting the immune system was debated at the Fourth AARDA Colloquium on cross-disciplinary issues in autoimmunity. Immunodeficiency disease and autoimmune disease, far from being mutually exclusive, share profound dysregulation of the immune system. Among the most keenly discussed issues were: i) the remarkably high number of molecularly identified primary immunodeficiencies with autoimmune expressions; ii) the homeostasis of immune function such that deficiency in any one given compartment can result in over activity in the same or another compartment; iii) whilst some immune deficiency states are essentially monogenic, each of them can exhibit striking variability in autoimmune outcome, indicative of epigenetic or environmental influences on phenotypic expression; iv) innate immunity, particularly complement defects, as well as adaptive immunity, is complicit in the immunodeficiency-autoimmunity axis; v) features of certain of the disorders discussed at the meeting forced a reappraisal of what actually is meant by 'autoimmune disease'.

What's in a name? Experimental encephalomyelitis: 'allergic' or 'autoimmune'.

New linguistic coinage can signify new practices and fresh perceptions in science: descriptors therefore are not trivial. Here, we consider the shifting valence of 'allergic' and 'autoimmune' in conceptions of experimental encephalomyelitis (EE). Ehrlich's dismissal of the relevance to disease of autoimmunity resulted in its 'long struggle for recognition' notwithstanding the convincing attribution in 1904 of the hemolysis of paroxysmal cold hemoglobinuria.

CX3CL1 (fractalkine): a signpost for biliary inflammation in primary biliary cirrhosis.

Unlabelled: Improvements in the treatment of primary biliary cirrhosis (PBC) may depend upon dissection of mechanisms that determine recruitment of mononuclear cells to intralobular bile ducts, including the role of the chemokine-adhesion molecule CX3CL1 (fractalkine). We submit that there are unique interactions between intrahepatic biliary epithelial cells (BECs), endothelial cells (ECs), liver sinusoidal endothelial cells (LSECs), and liver-infiltrating mononuclear cells (LMCs), and that such interactions will in part dictate the biliary-specific inflammatory response. To address this, we studied fresh explanted livers from pretransplantation patients with PBC and with inflammatory liver disease due to viral infection (disease controls) and biopsy material from patients with a discrete liver tumor (normal controls).