Autoantibodies Against “Nuclear Dots” in Primary Biliary Cirrhosis

Abstract

Autoantibodies against nuclear proteins are not always but rather frequently present in sera of patients with primary biliary cirrhosis (PBC). The specificity and diagnostic value of these autoantibodies for PBC have only recently become clear through cloning of the cDNA of some of the corresponding autoantigens which allowed the establishment of immunological assays with recombinant autoantigens expressed in E. coli and eukaryotic cells. In this report we summarize primarily the knowledge on the structure and putative function of two nuclear autoantigens, the Sp100 and PML proteins, which are present in so-called nuclear dots (NDs) and against which autoantibodies are present in a subpopulation of PBC patients. Furthermore, the type of autoimmune response (epitope specificity and immunoglobulin class) against both the Sp100 and PML proteins and the specificity of the anti-Sp100 and anti-PML autoantibodies for PBC patients and patients with other autoimmune diseases is reviewed. Current knowledge clearly indicates that determination of anti-Sp100 and anti-PML autoantibodies substantially improves diagnosis of PBC as these autoantibodies are highly specific for this disease even when autoantibodies against mitochondrial antigens, a hallmark of most PBC patients, are not found. The type of autoimmune response against the Sp100 and PML proteins also provides some clues about possible mechanisms which lead to autoantigenicity of both proteins.

PML nuclear bodies: Assembly and oxidative stress-sensitive sumoylation

“…6,7 These structures were initially discovered by electron microscopy and subsequently reobserved by immunofluorescence where autoimmune sera of primary biliary cirrhosis patients marked SP100, a prototypic PML NB resident protein. [6][7][8] Yet, PML NBs drew real attention only decades after with the observation that they were disrupted, in a treatment-reversible manner, in cells from patients suffering from Acute Promyelocytic Leukemia (APL). [9][10][11] This leukemia is driven by the PML/RARA oncogenic fusion protein, which results from a chromosomal translocation.…”

Positive markers in AMA-negative PBC

“…The existence of ANAs specific for PBC is in contrast to autoimmune hepatitis type 1, a disease also characterized by the presence of ANA (alone or in association with antismooth muscle antibody) because in autoimmune hepatitis type 1, no disease-specific ANA has yet been identified. The PBC-specific ANAs give two distinct immunofluorescence patterns: the perinuclear (rimlike) (10) and the multiple nuclear dot pattern (11). Molecular targets associated with these two immunofluorescence appearances have been identified.…”

Presence of disease specific autoantibodies against liver sinusoidal cells in primary biliary cirrhosis

“…Additionally, in other studies, in addition to the intense staining of the apical surface of BECs, positive staining was observed in a subset of macrophages in portal lymph nodes [6] and in hepatocytes [7] . In addition to AMAs, which are the hallmark of PBC, antinuclear antibodies (ANAs) have also been detected in 30% of PBC patients [8][9][10] . Two PBC-specific ANA immunofluorescence patterns have been identified [11,12] : "multiple nuclear dots", corresponding to the antigens Sp100 and Sp140, promyelocytic leukemia (PML) nuclear body proteins and small ubiquitin-like modifiers (SUMOs) [13,14] , and "nuclear membrane" (rim), caused by anti-nuclear envelope antibodies (ANEAs), such as gp210 and nucleoporin p62 [15,16] .…”