Editorial: Immunology of liver disease.
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Autoimmune Diseases↗
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Increased serum thyroid hormone binding and decreased free hormone in chronic active liver disease.
To determine whether chronic inflammatory disease of the liver increases serum thyroid hormone binding, we measured tri-iodothyronine resin binding ratios in nine patient with primary biliary cirrhosis and in nine with chronic active hepatitis. In each group, the average binding ratio was about 50 per cent higher than in control subjects. Thyroxinebinding globulin, measured by immunoassay in three patients, was elevated. Although average total thyroxine and tri-iodothyronine were increased slightly, the corresponding free hormone concentrations were lower than controls, probably because of decreased thyroid function associated with the high incidence of autoimmune thyroiditis in nonalcoholic (autoimmune) liver disease. Thyroid autoantibodies were found in 13 patients. Impaired hepatic thyroxine-to -tri-iodothyronine conversion may have contributed to the low free tri-iodothyronine. Thyrotropin was elevated in four patients. Because of increased serum thyroid hormone binding in these patients total thyroxine and tri-iodothyronine concentration can be normal despite hypothyroidism.
Autoantibodies↗
Smooth muscle autoantibodies and autoantigens.
Smooth muscle autoantibody (SMA) was first found in the sera of patients with chronic active hepatitis and subsequently in the sera of patients with other autoimmune liver diseases, viral infections, certain cancers, heroin addicts and female infertility. SMA from patients with chronic active hepatitis reacts with many muscle and 'non-muscle' tissues while SMA from patients with other diseases usually reacts only with smooth muscle. These differences in immunofluorescent staining reactions suggest that SMA is a heterogeneous group of autoantibodies reactive with different smooth muscle autoantigens. As further evidence for this are findings that broad-reacting SMA can be absorbed out by actin, whereas autoantibodies reactive only with smooth muscle cannot, and that different SMAs give different immunofluorescent staining patterns using fibroblasts in tissue culture. Such staining patterns correspond to reactivity with either microfilaments, microtubules or intermediate filaments, ubiquitous cytoplasmic structures which make up the 'cytoskeleton'. Autoantibodies to actin-like microfilaments appear specific for chronic active hepatitis, autoantibodies to microtubules occur in infectious mononucleosis whereas autoantibodies to intermediate filaments occur in infectious hepatitis, chickenpox, measles and mumps. Predictably, future studies will show that presence of SMA with specificities for other proteins in the three types of cytoplasmic filaments, and given more information on antigenicity of the proteins and pathogenicity of the corresponding autoantibodies.
Actins↗
Label-Free Urinary Proteomics Uncovers Immune-Related Non-Invasive Biomarkers for Primary Biliary Cholangitis.
Diagnosis of primary biliary cholangitis (PBC) currently depends on invasive liver biopsy or serum markers with inadequate diagnostic performance. This study aimed to identify non-invasive urinary protein biomarkers for PBC detection. Urine specimens from biopsy-verified PBC patients and healthy controls were processed through ultracentrifugation-based protein extraction, enzymatic digestion, and HPLC-ESI-IT/MS proteomic profiling; protein quantification was completed using Spectronaut v14.8. We identified 194 differentially expressed urinary proteins (109 upregulated, 85 downregulated) and screened 10 immune-related candidates through GO and KEGG enrichment. Pearson correlation further filtered three core proteins, osteopontin (SPP1/OPN), RAMP3 and S100A8, that correlated significantly with key PBC biochemical indices (ALP, GGT, AST, ALT, IgM, p < 0.05). Elevated urinary concentrations of OPN, RAMP3 and S100A8 were validated by ELISA in an independent cohort containing 30 PBC patients and 20 healthy volunteers. In summary, urinary OPN, RAMP3 and S100A8 are markedly increased in PBC patients and hold promise as non-invasive diagnostic biomarkers for PBC; however, their diagnostic specificity against other cholestatic and autoimmune liver diseases remains to be evaluated, and further confirmation in larger multicenter cohorts with disease control groups is warranted.
Humans↗
Occurrence and significance of antibody to liver-specific membrane lipoprotein by double-antibody immunoprecipitation method in sera of patients with acute and chronic liver diseases.
A double-antibody immunoprecipitation method was developed for detecting antibody to liver-specific membrane lipoprotein (anti-LSP) in sera of patients with various liver diseases and primary nonhepatic autoimmune diseases. Liver-specific membrane lipoprotein prepared from normal rat livers was labeled with 125I (chloramine-T) and monospecific antibody raised in rabbits. Cross-reactivity and absorption studies demonstrated that the assay used was highly specific. The frequency and titer of anti-LSP were similar for HBsAg-positive and -negative patients with both acute and chronic liver diseases. Patients with chronic active hepatitis had the highest frequenzy (25 of 44 cases, 57%) when compared with those with chronic persistent hepatitis (5 of 23 cases, 22%) and nonalcoholic cirrhosis (8 of 21 cases, 38%). Of the anti-LSP positive cases, the mean titer in patients with chronic active hepatitis tended to be the highest. In patients recovered from acute viral hepatitis, anti-LSP was transiently positive (7 of 20 cases, 35%) in the acute phase. In those who progressed to chronic hepatitis, a late rise as well as an early rise occurred in 6 of 10 patients before the diagnosis was made. Two of 6 patients with primary biliary cirrhosis had anti-LSP, but none of 41 patients with other nonviral liver diseases and none of 60 patients with primary nonhepatic autoimmune diseases. These data indicate that an autoimmune reaction directed against LSP can be initiated during the acute phase of viral hepatitis and it may persist in chronic hepatitis in both HBsAg-positive and -negative cases.
Acute Disease↗
Network proximity analysis as a theoretical model for identifying potential novel therapies in primary sclerosing cholangitis.
Primary Sclerosing Cholangitis (PSC) is a progressive cholestatic liver disease with no licensed therapies. Previous Genome Wide Association Studies (GWAS) have identified genes that correlate significantly with PSC, and these were identified by systematic review. Here we use novel Network Proximity Analysis (NPA) methods to identify already licensed candidate drugs that may have an effect on the genetically coded aspects of PSC pathophysiology.Over 2000 agents were identified as significantly linked to genes implicated in PSC by this method. The most significant results include previously researched agents such as metronidazole, as well as biological agents such as basiliximab, abatacept and belatacept. This in silico analysis could potentially serve as a basis for developing novel clinical trials in this rare disease.
Cholangitis, Sclerosing↗
A new pattern of non-organ- and non-species-specific anti-organelle antibody detected by immunofluorescence: the mitochondrial antibody number 5.
About 0.1% of the sera in human pathology produce a peculiar, cytoplasmic, non-organ- and non-species-specific fluorescence. This may easily be differentiated from the already described anti-organelle antibodies and, more particularly, from the mitochondrial antibodies of primary biliary cirrhosis. Should rat tissues be used in the immunofluorescence test, fluorescence predominates over the first two portions of the renal proximal tubules (P1 and P2) and the mucous neck cells of the stomach. This pattern may be atrributed to mitochondria, and in particular to their inner membranes by fluorescent staining of the ellipsoid region of the rods and cones of the eyes, and by absorption with purified organelles. To distinguish this antibody from the already described mitochondrial antibodies, this one will be called mitochondrial antibody number 5 (M5). The seven carriers of this antibody suffer from systemic lupus erythematosus or autoimmune haemolytic anaemia. In these cases no diseases of the liver were observed, contrary to other classical mitochondrial antibodies.
Adult↗
Identifying a therapeutic window of opportunity for people living with primary sclerosing cholangitis: Embryology and the overlap of inflammatory bowel disease with immune-mediated liver injury.
Primary sclerosing cholangitis (PSC) is a variably progressive, fibrosis-causing autoimmune disorder of the intrahepatic and extrahepatic bile ducts of unclear etiology. PSC is commonly (in 60%-90% of cases) associated with an inflammatory bowel disease (IBD) like PSC-IBD and less commonly with an autoimmune hepatitis (AIH) like PSC-AIH or AIH-overlap disorder. Hepatologists and Gastroenterologists often consider these combined conditions as distinctly different from the classical forms in isolation. Here, we review recent epidemiologic observations and highlight that PSC-IBD and PSC-AIH overlap appear to represent aspects of a common PSC clinico-pathological pathway and manifest in an age-of-presentation-dependent manner. Particularly from the pediatric experience, we hypothesize that all cases of PSC likely originate from a complex "Early PSC"-"IBD"-"AIH" overlap in which PSC defines the uniquely and variably associated "AIH" and "IBD" components along an individualized lifetime continuum. We speculate that a distinctly unique, "diverticular autoimmunity" against the embryonic cecal- and hepatic diverticulum-derived tissues may be the origin of this combined syndrome, where "AIH" and "IBD" variably commence then variably fade while PSC progresses with age. Our hypothesis provides an explanation for the age-dependent variation in the presentation and progression of PSC. This is critical for the optimal targeting of studies into PSC etiopathogenesis and emphasizes the concept of a "developmental window of opportunity for therapeutic mitigation" in what is currently recognized as an irreversible disease process. The discovery of such a window would be critically important for the targeting of interventions, both the administration of current therapies and therapeutic trial planning.
Humans↗
[Experimental study of amino acid metabolism in the course of an autoimmune process induced by exposure to the gamma isomer of hexachlorocyclohexane].
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Amino Acids↗
[Autoimmune hepatitis (current state of research)].
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Antibody-Dependent Cell Cytotoxicity↗
Multilevel Exploration of Shared Genetic Architecture Between Primary Biliary Cholangitis and Four Autoimmune Diseases.
INTRODUCTION: Primary Biliary Cholangitis (PBC) frequently coexists with various autoimmune diseases, such as Multiple Sclerosis (MS), Psoriasis (PS), Rheumatoid Arthritis (RA), and Sjögren's Syndrome (SS). Understanding the genetic associations between these diseases is crucial for providing deeper insights into their shared pathogenic mechanisms and comorbidity patterns. METHODS: This study utilized genome-wide association study summary data of PBC and four autoimmune diseases (MS, PS, RA, and SS). A multi-stage analytical pipeline was employed to systematically investigate the genetic associations between the diseases. The analytical approach consisted of three stages: first, linkage disequilibrium score regression and high-definition likelihood methods were applied to estimate overall genetic correlations between the diseases; second, local genetic correlation analysis was conducted to pinpoint genetic signals in specific chromosomal regions; third, conditional/conjunctional false discovery rate (cond/conjFDR) algorithms were used to quantitatively assess genetic overlap and identify shared susceptibility loci. RESULTS: Genome-wide analysis revealed significant genetic associations between PBC and the four autoimmune diseases (MS, PS, RA, and SS). Regional analysis showed local genetic correlations across various chromosomal segments. cond/conjFDR analysis confirmed genetic intersections among the diseases and identified several critical genetic polymorphic loci that influence disease susceptibility. DISCUSSION: This study comprehensively delineates the shared genetic architecture underlying PBC and four autoimmune diseases through integrative analyses of multiple genome-wide approaches. The results highlight strong genetic correlations, particularly between PBC and MS, PS, RA, and SS, and identify key shared susceptibility genes, including CLEC16A, CD58, CD86, STAT4, IRF5, TYK2, and TNFAIP3, which collectively mediate immune dysregulation through autophagy, cytokine signaling, and NF-κB pathways. These findings not only extend current understanding of the molecular mechanisms driving autoimmune comorbidity but also provide potential genetic targets for future functional validation and therapeutic exploration. CONCLUSION: This study provides comprehensive genomic evidence for the genetic connections between PBC and the four autoimmune diseases (MS, PS, RA, and SS), offering valuable insights into the shared pathological mechanisms underlying their comorbidities.
Humans↗
Genetic factors in the development of chronic active hepatitis.
In 14 of 16 patients with chronic active hepatitis (C.A.H.) who did not have HLA antigens B8 and/or B12 an external triggering factor (drug or virus) could be demonstrated at onset of symptoms. In contrast external factors were involved in only 11 of 25 cases of C.A.H. in patients with HLA-B8 and/or B12. In the latter group antinuclear antibodies were less common in cases possible triggered by external agents compared with cases in which no such factor was demonstrated. The results suggest that there are at least two pathogenetically different types of C.A.H.---one genetically determined type in which no external factor is involved and in which autoimmune phenomena are common, and another type triggered by environmental agents and not involving predisposing genetic factors.
Autoantibodies↗
[Hepatic reaction in ulcerative colitis and Crohn's disease (author's transl)].
Within the framework of a prospective study on the course and prognosis of ulcerative colitis and Crohn's disease begun in 1968, serial blind needle biopsies of the liver were carried out for the early establishment of liver involvement. In 201 needle biopsies taken in 114 patients with ulcerative colitis, normal findings were observed in 51, fatty infiltration in 24, and accompanying inflammation in 23, fatty infiltration together with a mesenchymal reaction in 8, fatty liver in 6 and sclerosing cholangitis and granulomatous hepatitis in 1 patient each. Of 69 needle biopsies taken in 45 patients with Crohn's disease we established normal findings in 13, an insignificant accompanying inflammation in 19, fatty infiltration in 5, granulomatous hepatitis in 3, fatty liver in 2, fatty liver together with a mesenchymal reaction in 2 and serum hepatitis in 1. Laboratory tests (alkaline phosphatase, SGOT, SGPT, BSP excretion) are not particularly suitable as screening tests. The diagnostic yield of serial blind needle biopsies of the liver is low and, despite the low-risk nature of the method, often dispensable. Laparoscopy, or at least blind needle biopsy of the liver, should be retained for the further clarification of serious deviations of laboratory values from the normal range, or of suspicious palpation findings.
Adolescent↗
Occupational vitiligo induced by p-tert-butylphenol, a systemic disease?
Vitiligo, morphologically indistinguishable from true vitiligo, was detected in 54 of 198 men exposed to p-tert-butylphenol (P.T.B.P.) during its manufacture. There is evidence that P.T.B.P. caused vitiligo by a systemic mechanism and that the severity of the disease was related to the intensity of exposure. No association with autoimmune disease was found. Screening for other possible associated disorders revealed mildly abnormal liver-function tests in 6 workers: liver biopsy confirmed liver damage. Of the 144 men exposed to P.T.B.P. who did not have vitiligo, only 2 had any abnormal liver-function tests. It seems possible that the liver damage is related to P.T.B.P.
Chemical Industry↗
Antibody-dependent cell-mediated (K cell) cytotoxicity against isolated hepatocytes in chronic active hepatitis.
Lymphocytes from 12 of 17 patients with chronic active hepatitis were cytotoxic towards isolated hepatocytes in a microcytotoxicity assay. Enriched fractions of B cells, prepared by removal of E-rosetted cells, were cytotoxic in all 12 cases, whereas T-cell fractions, prepared by removal of erythrocyte-antibody-complement-rosetted cells, were cytotoxic in only 1 case (P less than 0-0005). HBsAg positive and negative cases reacted similarly. In 6 patients the addition of 5 mug aggregated IgG significantly reduced cytotoxicity from 54% +/- 15 to 13% +/- 15 (mean +/- 1S.D.) suggesting that K cells may be the effector cell in an antibody-dependent, cell-mediated reaction directed against a liver-specific membrane lipoprotein.
Adult↗
Peptides and autoimmune disease.
The use of derived and synthetic peptides has contributed greatly to our understanding of encephalitogenic determinants in the basic protein molecule. Peptides derived from BP by use of trypsin, pepsin, cathepsin D (brain and liver) and BNPS-skatole have proven most useful. Synthetic peptides have served to define the disease-inducing determinants with precision. A remarkable feature of these studies is that different antigenic determinants serve as encephalitogenic sites in different species. The encephalitogenic sites comprise short peptide domains of the BP polypeptide chain, only 8 residues (rat), 9 residues (guinea pig), and 10 residues (rabbit) in length. In view of the requirement for both haptenic and carrier specificity of an immunogenic molecule, it is impressive that these peptides themselves elicit the autoimmune disease, EAE. While less active than BP on a molar basis, they are nonetheless potent encephalitogens, producing clinical signs in rats and guinea pigs at less than 1 microgram dose. The data indicate that for most animal species (guinea pig, rat, monkey) there appears to be only one major encephalitogenic determinant, an unusual finding in view of the number of antigenic determinants for cell-mediated immunity existing in the BP molecule. Possibly a combination of genetic and anatomical factors may account for this phenomenon. A relationship may exist between multiple sclerosis and EAE as shown by peptide studies; lymphocytes are found in MS patients during exacerbation sensitized to the same region of BP active in the monkey. The major encephalitogenic sites are: Guinea Pig (9) Phe-Ser-Trp-Gly-Ala-Glu-Gly-Gln-Lys(Arg); Rabbit (10) Thr-Thr-His-Tyr-Gly-Ser-Leu-Pro-Gln-Lys; Rat (8) Ser-Gln-Arg-Ser-Gln-Asp-Glu-Asn; Monkey (14) Phe-Lys-Leu-Gly-Gly-Arg-Asp-Ser-Arg-Ser-Gly-Ser-Pro-Hser.
Amino Acid Sequence↗