1 BACKGROUND

Autoantibodies (AAbs) are abnormal antibodies produced by pathogenic B cells against individual's own tissues. They are characteristics of various types of autoimmune diseases. Many AAbs have become specific serum biomarkers of autoimmune disease [1], with essential reference values for clinical diagnosis. Based on etiology, chronic liver disease (CLD) can be roughly classified into specific diseases, including autoimmune liver disease (AILD), viral hepatitis, alcoholic liver disease (ALD), and non-alcoholic fatty liver disease. AILD is a group of inflammatory lesions of the hepatobiliary system caused by autoimmune damage. It mainly includes autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC) [2]. In recent years, with the development of AAb detection technology, AAbs have become an indispensable part of diagnosing AILD. However, AAbs can also be present in patients with non-AILDs, such as viral hepatitis and ALD, which causes difficulty with the differential diagnosis and official diagnosis of liver diseases. At the same time, the significance and pathogenic mechanisms of AAbs in non-AILDs are unclear. This article summarizes the current literature on AAbs in several CLDs, such as AILD, viral hepatitis, and ALD, to provide an overview of the distribution of AAbs in CLDs.

2 AUTOANTIBODIES ASSOCIATED WITH AUTOIMMUNE HEPATITIS

AIH is an immunoinflammatory CLD [3] in which the humoral immune response plays an important role in pathogenesis. Its serological manifestations are elevated immunoglobulin G levels and positive serum AAbs [4]; immunoglobulin G can be used as a marker for diagnosis and disease activity. AIH can be divided into AIH-I and AIH-II subtypes based on the presence of different types of AAbs. AIH-I tends to occur in middle-aged and older patients, and is associated with the familiar AAbs, antinuclear antibody (ANA), anti-smooth muscle antibody (anti-SMA), and/or anti-soluble liver antigen/liver pancreas antibody (anti-SLA/LP). AIH-II mainly occurs in young and middle-aged patients, and is commonly associated with anti-liver kidney microsomal antibody (anti-LKM-1) and anti-liver cytosol antigen type 1 antibody (anti-LC-1) [5]. The presence of AIH-related AAbs can contribute to the diagnosis of AIH, but most AAbs have relatively low specificity. AAbs can also be found in individuals with acute or chronic hepatitis without AIH etiology and even in healthy individuals [6]. AAbs are undetectable in the serum of approximately 10%–15% of patients with AIH and can arise after an acute attack.

Indirect immunofluorescence (IIF) is the standard method for AAb detection in laboratory. IIF was first proposed in the 1950s by Coons, Kaplan, and Weller, at which time cryopreserved rodent tissue sections were used as the main substrate. Human tissue culture cells were not developed until the mid-1970s, after which human laryngeal cancer epithelial cells (Hep-2) cells have been used for IIF detection [7]. Hep-2 cells have large nuclei, which can help to identify ANA karyotypes [8, 9]. When ANAs are detected in Hep-2 cells, it is necessary to further identify specific AAbs such as anti-ds-DNA and anti-ENA antibodies. With technological developments, multi-analyte techniques such as enzyme-linked immunosorbent assays (ELISAs), chemiluminescence immunoassay and western blotting have become common methods for detecting ANA-specific AAbs in laboratories. In recent years, high-throughput chip technologies have also become popular. However, these technologies still have limitations and defects, and AAb detection methodologies must be improved to better facilitate clinical application, diagnosis, and treatment. These research directions will be of great interest in the future.

3 AUTOANTIBODIES ASSOCIATED WITH PRIMARY BILIARY CHOLANGITIS

PBC is a rare cholestatic liver disease that occurs most frequently in women [19, 20]. It is often clinically characterized by fatigue and pruritus, among other symptoms. PBC is often accompanied by other autoimmune diseases, such as rheumatoid arthritis and Hashimoto's thyroiditis. The diagnosis of PBC is mainly based on AAb detection.

Anti-mitochondrial antibody (AMA) can be found in more than 95% of PBC patients [21], and the specificity of AMA-M2 for PBC can reach 95%. However, about 5% of PBC patients are AMA-negative. PBC specific antinuclear AAbs, such as antibodies against sp100 and gp210, can be used to diagnose the disease in these cases, with specificity that can reach 90%. AMA is a specific antibody for the diagnosis of PBC, and the positive rate of AMA in PBC can reach 90%–95%. However, about 5% of PBC patients are AMA negative; antinuclear AAbs such as sp100 and gp210 can be used for the diagnosis of the disease by this time, and the specificity can reach 90%.

4 AUTOANTIBODIES ASSOCIATED WITH PRIMARY SCLEROSING CHOLANGITIS

PSC is a rare chronic cholestatic liver disease characterized by inflammatory destruction of the intrahepatic or extrahepatic bile ducts, leading to cholestasis, fibrosis and eventually progression to cirrhosis [34]. Most patients have no clinical symptoms at the time of diagnosis [35]. Therefore, when cholestasis is found during a routine health assessment or high-risk patient screening (such as that for patients with inflammatory bowel disease), PSC diagnostic tests should be performed. The diagnosis of PSC is mainly based on magnetic resonance cholangiopancreatography (MRCP), rather than endoscopic retrograde cholangiopancreatography (ERCP). Compared with ERCP, MRCP has higher sensitivity of 0.86 and specificity of 0.94. MRCP is sufficient for a diagnosis of PSC and the risks associated with ERCP can be avoided [36].

There are a variety of autoantibodies in patients with PSC, such as ANA and AMA, but they are nonspecific and have no definite diagnostic value [37, 38]. Anti-neutrophil cytoplasmic antibodies (ANCAs) are the most highly associated with PSC, they can be found in the serum of approximately 93% of PSC patients. The presence of serum perinuclear anti-neutrophil cytoplasmic antibody (p-ANCA) is closely related to a poor clinical outcome for patients [39]. P-ANCA has recently been associated with a distinct clinical phenotype. P-ANCA-positive patients are younger at onset than the average patient with PSC and have a lower risk of cholangiocarcinoma.

5 AUTOANTIBODIES ASSOCIATED WITH HEPATITIS B VIRUS

Hepatitis B virus (HBV) infection is a global public health problem. Despite effective vaccines and therapeutics, HBV infection still causes nearly 1 million deaths yearly, due to acute hepatitis, fulminant liver failure, chronic hepatitis, cirrhosis and hepatocellular carcinoma [40]. Some studies have detected a variety of AAbs in patients with HBV infection [41], including ANA, AMA, anti-SMA, and other non-organ-specific AAbs. In the HBV infection, ANA is mainly of low titer with a granular and homogeneous pattern.

Maya, Gershwin, and Shoenfeld [42] posited that an autoimmune reaction contributes to liver injury in patients with HBV infection. HBV infection can induce autoimmune phenomena, and HBV infection is more closely related to autoimmunity than other viruses [43]. The mechanisms of virus-induced autoimmunity may be as follows: (a) molecular mimicry of HBV antigen results in cross-reaction of viral antibodies with an individual's self-antigens; (b) after virus infection, host cellular antigens change and induce an autoimmune response; or (c) viral genes accompany host genes for transcription and translation in offspring cells, such that the structure of liver cells changes and the body eliminates liver cells as foreign bodies. Through these mechanisms, HBV could induce autoimmunity and produce AAbs, leading to the destruction of liver cells. HBV and AIH must be differentiated in clinical practice. Patients with either have an autoimmune phenomenon, but patients with AIH have higher AAb titers.

6 AUTOANTIBODIES ASSOCIATED WITH ALCOHOLIC LIVER DISEASE

The main characteristic of ALD is excessive alcohol intake. The pathogenesis of ALD mainly includes ethanol metabolism-related oxidative stress, intestinal endotoxin and Kupffer cell activation, and a Toll-like receptor signaling pathway [44]. Although adaptive immunity appears to play a critical role in the pathogenesis of ALD, it also indicates that autoimmunity participates in the pathogenesis of ALD.

Low titers of non-organ-specific AAbs, such as ANA, anti-SMA, and AMA, can be detected in the serum of patients with ALD. In addition, Min LIAN [44] found that high titers of antibodies were related to cirrhosis in ALD patients. They speculated that AAbs had a specific correlation with the disease stage.

7 CONCLUSION

CLDs are a public health problem worldwide, and the liver can, to an extent, reflect health status [45]. Therefore, a clinical focus on liver disease is warranted. The etiology of CLD varies in different geographic regions. According to etiology, CLD can be roughly divided into AILD, viral hepatitis, ALD, non-alcoholic fatty liver disease, and drug-induced liver injury. HBV infection and ALD are significant epidemics in China.

At the beginning of the twenty-first century, the clinical understanding of AILD was limited, and there was confusion around its diagnosis. However, with an increase in AAb detection modalities and improvements in detection technology, significant progress has been made in AILD diagnosis. AAbs have become one of the diagnostic criteria for AILD. In addition, the pathogenesis of HBV and ALD, which both reportedly involve autoimmune phenomena leading to liver injury, have aroused concern. The detection of AAbs in patients with viral hepatitis and ALD confirms the involvement of autoimmunity in the pathogenesis of both. Furthermore, many patients with AILD also have viral hepatitis, so clinical attention should be paid to differential diagnosis.

AUTHOR CONTRIBUTION

Jinyu Han contributed to conceptualization and writing the manuscript, and Jin Chen was responsible for consulting the literature. Yajie Wang contributes to the project administration.

CONFLICT OF INTEREST

Professor Yajie Wang is the member of the iLABMED Editorial Board. To minimize bias, she was excluded from all editorial decision-making related to the acceptance of this article for publication. The remaining authors declare no conflict of interest.

ETHICS STATEMENT

Not applicable.

INFORMED CONSENT

Not applicable.