Primary biliary cirrhosis: What do autoantibodies tell us?

Table 1 Autoantibodies in primary biliary cirrhosis that are closely related to other autoimmune diseases

No.	Autoantibody	Autoantigen properties	Prevalence in PBC (%)	Clinical associations	Ref.
ANA
1	Anti-chromatin	Chromatin	8.9-25.0	Anti-chromatin antibodies are reported to be associated with disease activity in AIH, but their roles in PBC remains to be investigated	[99,127-129]
2	Anti-dsDNA	Double-stranded deoxyribonucleic acid	17.0-22.0	Anti-dsDNA antibodies are one of important criteria for the diagnosis of SLE. Co-existence of AMA and anti-dsDNA autoantibodies can be considered the serological profile of AIH/PBC overlap syndrome	[76,127,128,130,131]
3	Anti-ssDNA	Single-stranded deoxyribonucleic acid	59.0-71.0	Anti-ssDNA antibodies can be detected in many diseases	[132,133]
4	Anti-histone	Histone	43.6	Anti-histone antibodies are generally considered to be related to drug-induced lupus, though it can be detected in many autoimmune diseases including PBC	[132,134]
5	Anti-scl-70	Topoisomerase-1	3.0-24.0	Anti-scl-70 antibody serve as a specific maker for diffuse SSc and presents in 30%-60% of subjects with diffuse SSc	[127,132]
6	Anti-Sm	Proteins of 28/29, 16, 16.5, 18, and 12, 11, 6 kDa which participate in pre-messenger RNA processing into spliced mature mRNA	7.0-34.0	Anti-Sm autoantibodies are highly specific for SLE	[76,127,132,135]
7	Anti-SSA	Intracellular ribonucleoproteins of 60 and 52 kDa that are associated with small RNAs	5.0-30.0	Anti-Ro(SS-A) and anti-La(SS-B) antibodies are more frequently seen in SS and SLE. Their presence in PBC suggests that PBC often overlaps with SS	[76,127,132,135,136]
8	Anti-SSB	An intracellular ribonucleoprotein of 47 kDa that are associated with small RNAs	2.0-21.0
9	Anti-RNP	Ribonucleoprotein	5.0	More frequently seen in SLE	[76,127]
10	Anti-Jo-1	Histidyl tRNA synthetase	26.0	Anti-Jo-1 antibodies are predominantly detected in patients with myositis	[135]
11	Anti-U1RNP	U1snRNPs that contain specific proteins of 70, 33 and 20 kDa	3.1-5.0	Anti-U1snRNP antibodies predominantly present in SLE, and can be detected in PBC patients. The clinical significance of anti-U1snRNP antibodies in PBC is unknown	[137,138]
Other liver diseases-associated autoantibodies
12	Anti-SMA	A variety of target antigens including F-actin, G-actin, myosin, tropomyosin, troponin, desmin, vimentin, keratin, etc.	8.0-25.0	Anti-SMAs present mainly in AIH-I, and can also be detected in chronic active hepatitis. The presences of anti-SMAs in PBC are potential indicators of AIH/PBC overlap syndrome	[131,139]
13	Anti-SLA	SLA and liver and pancreas antigen	2.0-3.9	Anti-SLAs are autoantibodies seen in AIH-III.The presences of SLA autoantibodies in PBC indicate secondary autoimmune hepatitis	[9,140,141]
14	Anti-LKM	Liver kidney microsomal antigen	0.7	Anti-LKM antibodies occur preferentially in AIH-II. Anti-LKM autoantibodies can be seen in 21.4% of HCV-infected PBC patients, which suggests a close association between LKM and HCV-infected PBC	[142]
15	Anti-ASGPR	Asialoglycoprotein receptor	22.0-23.0	Anti-ASGPR antibodies mainly present in AIH and PBC. The autoimmune responses against ASGPR have been implicated in the development of AIH and PBC	[143-146]
16	Anti-LCM	Liver cell membrane specific antigen	42.0	Anti-LCM antibodies are detected predominantly in patients with HBsAg-negative chronic active hepatitis, but are also found in other liver diseases such as PBC	[147-149]
17	Anti-LSP	Liver specific protein	48.5	Anti-LSP antibodies present in viral hepatitis and autoimmune liver disease, and are found to correlate with severity of periportal inflammation and piecemeal necrosis in PBC	[144,150]
18	Anti-calreticulin	Calreticulin	20.0	Anti-calreticulin antibodies present in autoimmune liver disorder and IBD. They are not specific for PBC	[151,152]
19	Anti-FH	Fumarate hydratase	19.4	Anti-FH antibodies are found to be present predominantly in AIH. It can also be detected in PBC and other liver disease. The prevalence and clinic significance of anti-FH in PBC need further study	[153]
20	Anti-PGAM-B	Phosphoglycerate mutase isozyme B	16.7	Anti-PGAM-B antibodies are found to be present in 70.0% of AIH and 16.7% of PBC. It is also present in about 10% of viral hepatitis and 3.7% of healthy control. The clinical significance of anti-FH needs further study	[154]
21	Anti-p97/VCP	P97/valosin-containing protein	12.5	Anti-p97/VCP antibodies predominantly present in PBC, and can be detected in about 9.7% of AIH. The presence of anti-p97/VCP antibodies in PBC suggests less progressive disease course and benign prognosis	[155-157]
22	Anti-GSTA1-1	Glutathione S-transferase	10.0	Anti-GST autoantibodies are detected in 16.0% of AIH and 10.0% of PBC. Patients of AIH with positive anti-GST have severe diseases and poor prognosis	[158]
23	Anti-ASL	Argininosuccinate lyase	23.0	Anti-argininosuccinate lyase is a newly identified autoantibody in liver disease and its clinical relevance remains unknown	[159]
24	Anti-calmodulin	Calmodulin	IgM 50.0	Anti-calmodulin autoantibodies neither associate with anti-SMA, ANA and AMA, nor with hyperglobulinemia. The clinic significant of anti-calmodulin is unclear	[160]
			IgA 42.9
Gastroenteropathy-associated autoantibodies
25	ASCA	Baker's yeast saccharomyces cerevisiae	24.2	ASCA serves as a serological marker of Crohn’s disease, and has also been detected in other autoimmune disorders and in 5%-6.3% of blood donors. The prevalence of ASCA in AIH is 20%-30%, in AMA-negative PBC 44%. ASCA is common in PBC patients and correlates with higher level of circulating IgA. The prevalence of ASCA in PBC may be an indirect sign of enhanced mucosal immunity, but does not necessarily indicate concomitant inflammatory bowel disease	[161-163]
26	Anti-Galectin-3	Galectin-3, a member of -galactoside-binding lectins	30.0	Anti-Galectin-3 autoantibodies are primarily associated with Crohn's disease, and correlate negatively with disease activity. The significance of anti-Galectin-3 IgG autoantibodies in patients with PBC is unknown	[164]
27	Anti-tTG	Tissue transglutaminase	10.0-26.7	Anti-tTG autoantibody is mainly found in celiac disease. The prevalence of anti-tTG in PBC varies due to different types of substrate utilized in detection	[127,165,166]
28	AGA	Gliadin	16.0-21.0	Anti-gliadin antibodies are considered as the most reliable serological markers for celiac disease. They are also frequently seen in PBC, and IgA subclass of anti-gliadin antibodies are more pronounced in patients with Scheuer's stage III-IV disease	[166,167]
Vasculitis-associated autoantibodies
29	ANCA	Antigens including proteinase 3, myeloperoxidase, bactericidal/permeability-increasing protein, lactoferrin,human leukocyte elastase, cathepsin G, lysozyme, azurocidin, etc.	2-26	ANCAs are primarily associated with systemic vasculitides such as Wegener’s granulomatosis, microscopic polyangiitis and Churg-Strauss syndrome	[76,131,168]
30	Anti-MPO	Myeloperoxidase	9.0	Predominantly in microscopic polyangiitis, necrotizing and crescentic glomerulonephritis, Churg-Strauss syndrome	[169]
31	Anti-PR3	Proteinase 3	3.0	Predominantly in Wegener’s granulomatosis, and also detectable in microscopic polyangiitis, necrotizing and crescentic glomerulonephritis	[127]
32	Anti-LF	Lactoferrin	25.0-35.7	Are detected in several autoimmune disorders, such as Crohn's disease, SLE, systemic vasculitides. They are not specific markers for PBC	[170,171]
Thrombophilia-associated autoantibodies
33	Anti-β2GPI	β(2)-glycoprotein I	IgG 2-15	Represent specific features of patients with antiphospholipid syndrome. Their presence in PBC often indicates severe disease and worse prognosis	[127,172,173]
34	Acl	Cardiolipin	IgG 27.3
35	Anti-PS	Phosphatidylserine	IgM 75
36	Anti-PT	Prothrombin	IgG 7
37	Anti-PE	Phosphatydilethanolamine	IgG 5
Diabetes mellitus-associated autoantibodies
38	Anti-GAD	Glutamic acid decarboxylase	5.5	Anti-GAD occurs preferentially in the patients with type 1 diabetes. Clinical significance of Anti-GAD in PBC is unclear	[174]
39	Anti-SOX13	Transcriptional factor SOX13	18.0	SOX13 was initially identified in type 1 diabetes. The present of anti-SOX13 in PBC may merely indicate an immune response to products of damage to parenchymal tissue	[175]
Autoimmune thyroid diseases-associated autoantibodies
40	Anti-TG	Thyroglobulin	54.5	Anti-TG, anti-TPO and anti-TR are markers of autoimmune thyroid diseases. Their significances in PBC are unknown	[176]
41	Anti-TPO	Thyroid peroxidase	45.5
42	Anti-TR	TSH receptor	9.1
Others autoantibodies
43	Anti-CCP	Cyclic citrullinated peptide	2.7-4.0	Anti-CCP antibodies are highly specific for RA with sensitivity of 60%-70%. Presence of anti-CCP antibodies in PBC patients suggests RA overlap	[125,126,177]
44	Anti-ClpP	Microbial caseinolytic proteases P	30-47	ClpP is highly conserved among bacteria. Anti-ClpP in PBC suggests infection factors and molecular mimicry involved in the pathogenesis	[178,179]
45	Anti-β-subunit of bacterial RNA polymerase	β-subunit of bacterial RNA-polymerase	32.8	These autoantibodies in PBC, suggest bacterial triggers of PBC	[180]
46	Anti-EPO	Eosinophil peroxidase	52.5	PBC patients with positive anti-EPO antibodies have less peripheral eosinophils	[181]
47	Anti-p53	Nuclear protein of 53 kDa that regulates cell proliferation and apoptosis	8.0	Anti-p53 autoantibodies are commonly seen in malignancies and organ-specific autoimmune diseases such as type 1 diabetes, thyroid diseases, PBC and AIH	[182]
48	Anti-acetylcholine receptor	Nicotinic acetylcholine receptor	58.8-74.0	Anti-acetylcholine receptor antibodies are primarily associated with myasthenia gravis, though PBC patients with positive anti-acetylcholine receptor antibodies do not have clinical symptoms of myasthenia	[169,183,184]
49	Anti-CAII	Carbonic anhydrase II	18-31	Anti-CAII antibody is likely a nonspecific marker of autoimmunity. It has been detected in a variety of autoimmune diseases, including Graves’ disease, type 1 diabetes, SS, SLE, AIH and PBC. In cases of PBC, no significant correlation has been found between anti-CAII antibody and AMA	[185-189]
50	Anti-α enolase	α-enolase	28.6	Anti-α-enolase antibodies present in a variety of inflammatory and autoimmune disorders, such as SLE, IBD, RA and AIH, and are not likely to be specific markers for any disease. They might be involved in destruction of biliary epithelium and are associated with hepatic failure	[190-195]
51	Anti-HSP	Heat shock proteins	45.7	Enhanced biliary expression of heat shock protein is found in PBC. Anti-HSPs are common in PBC, and are related to titers of AMA. They might cross-react with the main mitochondrial antigens in PBC	[196-199]
52	Anti-FKBP12	FK506 binding protein 12	44.4	The significance of anti-FKBP12 antibodies in PBC is unclear	[200]

SLA: Soluble liver antigen; PBC: Primary biliary cirrhosis; AMA: Antimitochondrial antibodies; SLE: Systemic lupus erythematosus; SSc: Systemic sclerosis; ANA: Antinuclear antibodies.