Etiopathogenesis of primary biliary cirrhosis

Primary biliary cirrhosis(PBC) is an autoimmune disease of the liver characterized by progressive bile duct destruction eventually leading to cirrhosis and liver failure.The serological hallmark of the disease is the presence of circulating antimitochondrial antibodies(AMA).These reflect the presence of autoreactive T and B cells to the culprit antigens,the E2 subunits of mitochondrial 2-oxo-acid dehydrogenase enzymes,chiefly pyruvate dehydrogenase(PDC-E2).The disease results from a combination of genetic and environmental risk factors.Genetic predisposition is indicated by the higher familial incidence of the disease particularly among siblings and the high concordance rate among monozygotic twins.Environmental triggering events appear crucial to disrupt a pre-existing unstable immune tolerance of genetic origin allowing,after a long latency,the emergence of clinical disease.Initiating mimetopes of the vulnerable epitope of the PDC-E2 autoantigen can be derived from microbes that utilize the PDC enzyme or,alternatively,environmental xenobiotics/chemical compounds that modify the structure of native proteins to make them immunogenic.A further alternative as a source of antigen is PDC-E2 derived from apoptotic cells.In the effector phase the biliary ductular cell,by reason of itsproclivity to express the antigen PDC-E2 in the course of apoptosis,undergoes a multilineage immune attack comprised of CD4+ and CD8+ T cells and antibody.In this article,we critically review the available evidence on etiopathogenesis of PBC and present interpretations of complex data,new developments and theories,and nominate directions for future research.

The modulation of co-stimulatory molecules by circulating exosomes in primary biliary cirrhosis

Exosomes are nanoparticles of endocytic origin, secreted by a myriad of cell populations that are attracting increased attention by virtue of their ability to modulate cell-to-cell communications. They are also attracting attention in a variety of immunological issues, including autoimmunity and, in particular, their ability to regulate cytokine and chemokine activation. Primary biliary cirrhosis （PBC） is considered a model autoimmune disease, which has a highly focused cytotoxic response against biliary epithelial cells. We have isolated exosomes from plasma from 29 patients with PBC and 30 healthy controls （HCs）, and studied the effect of these exosomes on co-stimulatory molecule expression and cytokine production in mononuclear cell populations using an ex vivo system. We also identified the microRNA （miRNA） populations in PBC compared to HC exosomes. We report herein that although exosomes do not change cytokine production, they do significantly alter co-stimulatory molecule expression on antigen-presenting populations. Further, we demonstrated that CD86 up-regulated expression on CD14＋ monocytes, whereas CD40 up-regulated on CD11c＋ dendritic cells by exosomes from patients with PBC. In addition, there were differences of miRNA expression of circulating exosomes in patients with PBC. These data have significant importance based on observations that co-stimulatory molecules play a differential role in the regulation of T-cell activation. Our observation indicated that aberrant exosomes from PBC selectively induce expression of co-stimulatory molecules in different subset of antigen-presenting cells. These alterations may involve in pathogenesis of autoimmune liver disease.

Experimental evidence on the immunopathogenesis of primary biliary cirrhosis

Primary biliary cirrhosis(PBC)is a chronic cholestatic liver disease for which an autoimmune pathogenesis is supported by clinical and experimental data,including the presence of autoantibodies and autoreactive T cells.The etiology remains to be determined,yet data suggest that both a susceptible genetic background and unknown environmental factors determine disease onset.Multiple infectious and chemical candidates have been proposed to trigger the disease in a genetically susceptible host,mostly by molecular mimicry.Most recently,several murine models have been reported,including genetically determined models as well as models induced by immunization with xenobiotics and bacteria.

Guillain–Barré syndrome, transverse myelitis and infectious diseases

Guillain–Barrésyndrome(GBS)and transverse myelitis(TM)both represent immunologically mediated polyneuropathies of major clinical importance.Both are thought to have a genetic predisposition,but as of yet no specific genetic risk loci have been clearly defined.Both are considered autoimmune,but again the etiologies remain enigmatic.Both may be induced via molecular mimicry,particularly from infectious agents and vaccines,but clearly host factor and co-founding host responses will modulate disease susceptibility and natural history.GBS is an acute inflammatory immune-mediated polyradiculoneuropathy characterized by tingling,progressive weakness,autonomic dysfunction,and pain.Immune injury specifically takes place at the myelin sheath and related Schwann-cell components in acute inflammatory demyelinating polyneuropathy,whereas in acute motor axonal neuropathy membranes on the nerve axon(the axolemma)are the primary target for immune-related injury.Outbreaks of GBS have been reported,most frequently related to Campylobacter jejuni infection,however,other agents such as Zika Virus have been strongly associated.Patients with GBS related to infections frequently produce antibodies against human peripheral nerve gangliosides.In contrast,TM is an inflammatory disorder characterized by acute or subacute motor,sensory,and autonomic spinal cord dysfunction.There is interruption of ascending and descending neuroanatomical pathways on the transverse plane of the spinal cord similar to GBS.It has been suggested to be triggered by infectious agents and molecular mimicry.In this review,we will focus on the putative role of infectious agents as triggering factors of GBS and TM.

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.

Proteomic analysis reveals distinctive protein profiles involved in CD8^(+) T cell-mediated murine autoimmune cholangitis

Autoimmune cholangitis arises from abnormal innate and adaptive immune responses in the liver,and T cells are critical drivers in this process.However,little is known about the regulation of their functional behavior during disease development.We previously reported that mice with T cell-restricted expression of a dominant negative form of transforming growth factor beta receptor type Ⅱ(dnTGFβ RII)spontaneously develop an autoimmune cholangitis that resembles human primary biliary cholangitis(PBC).Adoptive transfer of CD8^(+) but not CD4^(+) T cells into Rag1^(−/−)mice reproduced the disease,demonstrating a critical role for CD8^(+) T cells in PBC pathogenesis.Herein,we used SOMAscan technology to perform proteomic analysis of serum samples from dnTGFβRII and B6 control mice at different ages.In addition,we analyzed CD8 protein profiles after adoptive transfer of splenic CD8^(+) cells into Rag1^(−/−)recipients.The use of the unique SOMAscan aptamer technology revealed critical and distinct profiles of CD8 cells,which are key to biliary mediation.In total,254 proteins were significantly increased while 216 proteins were significantly decreased in recipient hepatic CD8^(+) cells compared to donor splenic CD8^(+) cells.In contrast to donor splenic CD8^(+) cells,recipient hepatic CD8^(+) cells expressed distinct profiles for proteins involved in chemokine signaling,focal adhesion,T cell receptor and natural killer cell-mediated cytotoxicity pathways.

Long noncoding RNA lncKdm2b: A critical player in the maintenance of group 3 innate lymphoid cells

Innate lymphoid cells(ILCs)represent a heterogeneous population,including both effectors and regulators of innate immunity,inflammation and tissue modeling.1 ILCs are categorized into three subgroups,ILC1s,ILC2s and ILC3s,based on similarities in phenotypic,ontogenetic and functional characteristics.2 ILC3s intrinsically require the transcription factor retinoic acid receptor-related orphan receptorγt(RORγt)for their development and function.3 In response to specific stimuli,ILC3s produce IL-17 and IL-22 and play a critical role in intestinal mucosal protection,inflammation and innate responses 4 accompanied by a series of pathophysiological changes involving large-scale genetic upregulation and downregulation.5,6 However,a key challenge remains in understanding the molecular mechanisms underlying the development and maintenance of ILC3s.

Comprehensive review of autoantibodies in patients with hyper-IgM syndrome

Hyper-immunoglobulin M syndrome is an X-linked primary immunodeficiency disease caused by mutations in the CD40 ligand gene.The CD40 ligand has been recently highlighted as playing a key role in the pathogenesis of primary biliary cholangitis.In the present study,we assessed an extensive set of serum autoantibodies in a series of well-defined patients with hyper-immunoglobulin M syndrome.Serum,liver-related and liver-not-related autoantibodies IgG,IgM and IgA were tested by ELISA and standard indirect immunofluorescence in HEp-2 cells in 13 Tunisian patients(8 males and 5 females,aged 1–12 years)with hyper-immunoglobulin M syndrome during 1995–2012 and,as controls,21 age-and gender-matched blood donors.The level of IgM antibody against MIT3 was significantly higher in patients than in controls(35.8 vs 10.7,P=0.002).Half of the hyperimmunoglobulin M syndrome patients were found to be anti-MIT3 IgM positive vs none of the controls(Po0.0001).Twenty-three percent of patients were found to be anti-sp100 antibody positive vs only 0.05%of controls.By immunofluorescence,92.3%of patients were MIT3 IgM positive vs none of the controls.In conclusion,the IgM class of anti-MIT3 antibodies was shown to be present by both ELISA and immunofluorescence in most of the patients with hyper-immunoglobulin M syndrome.The presence of the hallmark of primary biliary cholangitis,a disease where the CD40 ligand is a key player,in an immunodeficiency disease caused by mutations in the CD40 ligand gene is very intriguing and opens new scenarios in understanding the immune pathogenesis of primary biliary cholangitis.

The effects of Spirulina on anemia and immune function in senior citizens

Anemia and immunological dysfunction(i.e.immunosenescence)are commonly found in older subjects and nutritional approaches are sought to counteract these phenomena.Spirulina is a filamentous and multicellular bule-green alga capable of reducing inflammation and also manifesting antioxidant effects.We hypothesized that Spirulina may ameliorate anemia and immunosenescence in senior citizens with a history of anemia.We enrolled 40 volunteers of both sexes with an age of 50 years or older who had no history of major chronic diseases.Participants took a Spirulina supplementation for 12 weeks and were administered comprehensive dietary questionnaires to determine their nutritional regimen during the study.Complete cell count(CCC)and indoleamine 2,3-dioxygenase(IDO)enzyme activity,as a sign of immune function,were determined at baseline and weeks 6 and 12 of supplementation.Thirty study participants completed the entire study and the data obtained were analyzed.Over the 12-week study period,there was a steady increase in average values of mean corpuscular hemoglobin in subjects of both sexes.In addition,mean corpuscular volume and mean corpuscular hemoglobin concentration also increased in male participants.Older women appeared to benefit more rapidly from Spirulina supplements.Similarly,the majority of subjects manifested increased IDO activity and white blood cell count at 6 and 12 weeks of Spirulina supplementation.Spirulina may ameliorate anemia and immunosenescence in older subjects.We encourage large human studies to determine whether this safe supplement could prove beneficial in randomized clinical trials.

AIM associated with the IgM pentamer: attackers on stand-by at aircraft carrier

Circulating immunoglobulin M(IgM)exists in a pentameric form,possessing a polyreactive nature that responds not only to foreign antigens but also to autoantigens;thus,it is involved in both beneficial and detrimental immune responses,including protection from infection and the progression of autoimmunity.On the other hand,IgM also behaves as a carrier of the apoptosis inhibitor of macrophage(AIM)protein,storing a large amount of the inactivated form of AIM in the blood through this association.Under different disease conditions,AIM can dissociate from IgM locally or systemically to exert its function,inducing the removal of various biological debris such as excess fat,bacteria,cancer cells or dead cell debris.Most typically,upon induction of acute kidney injury(AKI),IgM-free AIM is filtered by the glomerulus in the kidney,which stimulates the clearance of intraluminal dead cells debris at the obstructed proximal tubules,thereby facilitating the repair of kidney injury.Interestingly,cats exhibit a deficiency in AIM release from IgM,which may increase their susceptibility to renal failure.Conversely,association with AIM inhibits IgM binding to the Fcα/μreceptor on follicular dendritic cells at the splenic germinal center,thereby protecting the IgM immune complex from Fcα/μreceptor-mediated internalization,which supports IgM-dependent antigen presentation to B cells and stimulates high-affinity IgG antibody production.The regulation of AIM–IgM binding,resulting from the discovery of reciprocal actions between AIM and IgM,could lead to the development of novel therapies against different diseases.

In situ mass spectrometry of autoimmune liver diseases

Primary biliary cirrhosis(PBC),primary sclerosing cholangitis(PSC)and autoimmune hepatitis(AIH)are the major forms of autoimmune liver diseases each characterized by the destruction of a specific liver cell type and the presence of differing auto-antibodies.We took a proteomic approach utilizing in situ matrix-assisted laser desorption/ionization mass spectrometry(MALDI MS)to obtain profiles directly from liver samples of patients with PBC,PSC,AIH and controls.The ability to precisely localize the region for acquisition of MALDI MS allowed us to obtain profiles from bile ducts,inflammatory infiltrates and hepatocytes from each biopsy sample.Analysis tools developed to identify peaks and compare peaks across diseases and cell types were used to develop models to classify the samples.Using an initial set of testing samples from PBC patients and controls,we identified unique peaks present in bile ducts,inflammatory infiltrates and hepatocytes that could classify samples in a validation cohort with 88–91%accuracy.Interestingly,profiles of PSC and AIH did not differ significantly from PBC.Identification of proteins in these peaks may represent novel autoantigens or effector molecules.These findings illustrate the potential of a proteomic approach to autoimmune diseases with in situ MALDI MS.

Celiac disease:a model disease for gene-environment interaction

Celiac sprue remains a model autoimmune disease for dissection of genetic and environmental influences on disease progression.The 2010 Congress of Autoimmunity included several key sessions devoted to genetics and environment.Several papers from these symposia were selected for in-depth discussion and publication.This issue is devoted to this theme.The goal is not to discuss genetic and environmental interactions,but rather to focus on key elements of diagnosis,the inflammatory response and the mechanisms of autoimmunity.

Novel trends in celiac disease

Celiac disease(CD)is one of the most common food intolerances in developed world.It affects genetically susceptible individuals and has severe consequences if it remains undiagnosed.A disease known for more than a century,it is still the focus for experts from various fields of research and development.Geneticists,pathologists,immunologists,food engineers and dieticians share their knowledge and expertise to improve the conditions of CD patients.With new insights in the pathomechanism of gluten processing and antigen presentation in CD,it was possible to improve the diagnostic antigen mimicking the primary epitope in CD.These celiac neo-epitopes are comprised of a complex of gliadin peptides crosslinked with transglutaminase(tTg).They are an early diagnostic marker for CD which occurs up to 6 months earlier than classical markers known to miss a certain amount of CD patients.