Comparative analysis of portal cell infiltrates in antimitochondrial autoantibody-positive versus antimitochondrial autoantibody-negative primary biliary cirrhosis.

First Hospital, University of Jilin, Changchun, China.
Hepatology (Impact Factor: 12). 12/2011; 55(5):1495-506. DOI: 10.1002/hep.25511
Source: PubMed

ABSTRACT Substantial evidence supports dysregulated B-cell immune responses in patients with primary biliary cirrhosis (PBC), including the presence of serum antimitochondrial antibodies (AMAs). However, recent reports from murine models of PBC suggest that B cells may also provide regulatory function, and indeed the absence of B cells in such models leads to exacerbation of disease. The vast majority of patients with PBC have readily detectable AMAs, but a minority (<5%) are AMA negative (AMA(-)), even with recombinant diagnostic technology. This issue prompted us to examine the nature of B-cell infiltrates surrounding the portal areas in AMA-positive (AMA(+)) and AMA(-) patients, because they display indistinguishable clinical features. Of importance was the finding that the degree of bile duct damage around the portal areas was significantly milder in AMA(+) PBC than those observed in AMA(-) PBC patients. The portal areas from AMA(-) patients had a significant increase of cluster of differentiation (CD)5(+) cells infiltrating the ductal regions, and the levels of B-cell infiltrates were worse in the early phase of bile duct damage. The frequency of positive portal areas and the magnitude of CD5(+) and CD20(+) cellular infiltrates within areas of ductal invasion is associated with the first evidence of damage of biliary duct epithelia, but becomes reduced in the ductopenia stage, with the exception of CD5(+) cells, which remain sustained and predominate over CD20(+) cells. CONCLUSION: Our data suggest a putative role of B-cell autoimmunity in regulating the portal destruction characteristic of PBC.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: 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 IgM and IgG reactivity throughout all stages of disease, capable not only of target enzyme inhibition, but also cross-reactive 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 have used flow cytometry and ELISPOT to examine B cell subsets in 59 subjects, including 28 with PBC, 13 with 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. In contrast, plasmablast reactivity to a control antigen, tetanus toxoid, was minimal and similar in all groups. Additionally, we isolated plasmablast-derived polyclonal antibodies and compared reactivity with plasma-derived antibodies and noted a distinct non-circulating tissue source of xenobiotic cross-reacting antibodies. The high levels of autoantigen specific peripheral plasmablasts indicate recent activation of naive or memory B cells and a continuous and robust activation. The presence of CXCR7+CCR10low PDC-E2-specific ASCs suggests a mechanistic basis for the migration of circulating antigen specific plasmablasts to the mucosal epithelial ligands CXCL12 and CCL28. In conclusion, our findings suggest a sustained rigorous B cell response in PBC, likely activated and perpetuated by cognate autoantigen. (Hepatology 2014;)
    Hepatology 07/2014; · 12.00 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: As rheumatologic diseases became understood to be autoimmune in nature, the drugs used to treat this group of conditions has evolved from herbal or plant derived anti-inflammatory agents, such as salicylates, quinine and colchicine to the many recently approved biological response modifiers. These new drugs, especially the anti-tumor necrosis factor agents, have shown remarkable efficacy in autoimmune diseases, and there are new agents under investigation that will provide additional treatment options. In between, the world was introduced to cortisone and all of its derivatives, as chemical synthesis led to better, more efficacious drugs with lesser side effects. Disease modifying anti-rheumatic agents have actually been around since the first half of the 20(th) century, but only began to be used in the treatment of autoimmune diseases in the 1970s and 1980s. One advantage is that they have been invaluable in their ability to offer "steroid sparing" to decrease the adverse effects of steroids. Research over the past decade has resulted in a new class of drugs that influence cytokine regulatory pathways such as the Janus associated kinase inihibitors. The promise of personalized medicine now permeates current research into new pharmacological agents for the treatment of autoimmune disease. The new appreciation for the gene-environment interaction in the pathogenesis of most diseases especially those as heterogeneous as autoimmune diseases, has led to our focus on targeted therapies. Add to that the new knowledge of epigenetics and how changes in DNA and histone structure affect expression of genes that can play a role in immune signaling, and we now have a new exciting frontier for cutting edge drug development. The history of treatment of autoimmune diseases is really only a little over a century, but so much has changed, leading to increasing lifespans and improved quality of life of those who suffer from these ailments.
    Autoimmunity reviews 01/2014; · 6.37 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: There is a paucity of information on extrahepatic autoimmune (EHA) conditions associated with primary biliary cirrhosis (PBC) and on the impact of EHA conditions on PBC patients' survival. Our goal was to assess the association between PBC and other autoimmune diseases and the impact of EHA conditions on the natural history of PBC. We took advantage of 361 consecutive PBC patients enrolled between 1975 and 2012 (22 males, 339 females; mean follow-up 8 ± 6.9 years). Any associated EHA conditions, PBC histological stage at diagnosis, biochemical data, physiological history, and extrahepatic malignancies developing during the follow-up were recorded. Survival was analyzed by means of Kaplan-Meier curves. Importantly, 221 patients (61.2 %) had at least one EHA conditions: 45 patients (20.4 %) had Hashimoto thyroiditis; 7 (3.2 %) had Graves' thyroiditis; 65 (29.4 %) had Raynaud's phenomenon; 124 (56.1 %) had Sjogren's syndrome; 8 (3.6 %) had systemic lupus erythematosus; 22 (9.9 %) had scleroderma; 22 (9.9 %) had rheumatoid arthritis; 18 (8.1 %) had cutaneous autoimmune diseases; 8 (3.6 %) had vasculitis; 5 (1.4 %) had celiac disease; and 25 (13.1 %) had other EHA conditions. The proportion of patients with associated EHA conditions enrolled during representative periods (1975-1980, 1981-1990, 1991-2000, 2001-2010, 2011-2012) remained stable. No differences emerged between patients with versus without EHA conditions in terms of mean age at PBC diagnosis, antimitochondrial antibody (AMA), or antinuclear antibody (ANA) positivity, histological stage at diagnosis, smoking habits, alcohol consumption, or BMI >25. Multiple logistic regression analysis showed that only female gender was significantly associated with positivity for EHA conditions (OR 4.8; 95 % CI 1.6-13.7, p = 0.004). The mean survival after the diagnosis of PBC was much the same in patients with and without EHA conditions. In conclusion, EHA conditions are often associated with PBC, especially in female patients, but they do not reduce patient survival.
    Clinical Reviews in Allergy & Immunology 05/2014; · 5.59 Impact Factor

Full-text (2 Sources)

Available from
May 27, 2014