Discovery and characterization of cross-reactive intrahepatic antibodies in severe alcoholic hepatitis

Author:

Ahmadi Ali Reza1ORCID,Song Guang2ORCID,Gao Tianshun3ORCID,Ma Jing4,Han Xiaomei3,Hu Ming-Wen3,Cameron Andrew M1,Wesson Russell N1,Philosophe Benjamin1,Ottmann Shane1,King Elizabeth1,Gurakar Ahmet5,Qi Le1,Peiffer Brandon1ORCID,Burdick James1,Anders Robert6,Zhou Zhanxiang7,Lu Hongkun4,Feng Dechun4,Chen Chien-Sheng8ORCID,Qian Jiang3ORCID,Gao Bin4,Zhu Heng2ORCID,Sun Zhaoli1ORCID

Affiliation:

1. Department of Surgery, Johns Hopkins University School of Medicine

2. Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine

3. Department of Ophthalmology, Johns Hopkins University School of Medicine

4. Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH)

5. Department of Medicine, Johns Hopkins University School of Medicine

6. Department of Pathology, Johns Hopkins University School of Medicine

7. Center for Translational Biomedical Research and Department of Nutrition, University of North Carolina at Greensboro, North Carolina Research Campus

8. Department of Food Safety/Hygiene and Risk Management, National Cheng Kung University

Abstract

The pathogenesis of antibodies in severe alcoholic hepatitis (SAH) remains unknown. We analyzed immunoglobulins (Ig) in explanted livers from SAH patients (n=45) undergoing liver transplantation and tissues from corresponding healthy donors (HD, n=10) and found massive deposition of IgG and IgA isotype antibodies associated with complement fragment C3d and C4d staining in ballooned hepatocytes in SAH livers. Ig extracted from SAH livers, but not patient serum exhibited hepatocyte killing efficacy. Employing human and Escherichia coli K12 proteome arrays, we profiled the antibodies extracted from explanted SAH, livers with other diseases, and HD livers. Compared with their counterparts extracted from livers with other diseases and HD, antibodies of IgG and IgA isotypes were highly accumulated in SAH and recognized a unique set of human proteins and E. coli antigens. Further, both Ig- and E. coli-captured Ig from SAH livers recognized common autoantigens enriched in several cellular components including cytosol and cytoplasm (IgG and IgA), nucleus, mitochondrion, and focal adhesion (IgG). Except IgM from primary biliary cholangitis livers, no common autoantigen was recognized by Ig- and E. coli-captured Ig from livers with other diseases. These findings demonstrate the presence of cross-reacting anti-bacterial IgG and IgA autoantibodies in SAH livers.

Funder

National Institute on Alcohol Abuse and Alcoholism

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

Cited by 1 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

1. Alcohol-associated liver disease;Journal of Clinical Investigation;2024-02-01

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