How a Liver Autoantigen Puzzles Scientists
Imagine a protein so essential to life that its core structure has remained virtually unchanged from simple worms to humans over millions of years of evolution. Yet, this very same protein becomes the unintended target of a mysterious autoimmune attack in a rare liver disease. This is the fascinating story of the SLA/LP autoantigen—a molecule that embodies one of immunology's most intriguing puzzles: why does our immune system, designed to protect us, sometimes turn against our own essential cellular components?
The SLA/LP molecule plays a critical role in our cellular machinery, yet it's also the specific target of autoantibodies in a form of autoimmune hepatitis (AIH) 5 . Through studying this molecule across different species—from humans to mice, fish, flies, and worms—scientists are unraveling clues about both its vital biological function and its unexpected role in autoimmune disease.
SLA/LP stands for Soluble Liver Antigen/Liver Pancreas, an autoantigen targeted by the immune system in approximately 20-30% of patients with autoimmune hepatitis 5 . Autoimmune hepatitis is a chronic progressive liver disease characterized by ongoing inflammation and necrosis of liver cells, and SLA/LP autoantibodies serve as highly specific markers for diagnosing this condition 4 5 .
Beyond its clinical significance, SLA/LP has been identified as O-phosphoserine (Sep)-tRNA:selenocysteine (Sec)-tRNA synthase (SepSecS) 9 , an enzyme crucial for the production of selenoproteins—proteins that incorporate the rare amino acid selenocysteine. Selenoproteins play vital roles in antioxidant defense, thyroid hormone metabolism, and preventing cellular damage.
Final step in selenocysteine synthesis 8
The SLA/LP molecule is associated with the UGA tRNASec complex that facilitates the co-translational incorporation of selenocysteine into proteins 1 . Essentially, it helps convert a specific tRNA charged with serine into one charged with selenocysteine—the final step in selenocysteine synthesis 8 . Without this enzyme, our cells couldn't produce critical selenoproteins that protect against oxidative damage.
One of the most remarkable aspects of the SLA/LP story is its extraordinary evolutionary conservation. When researchers used computational biology to characterize SLA/LP genes across different species, they discovered that this molecule has been meticulously preserved throughout evolutionary history 1 3 .
| Species | Protein Identity (Compared to Human) | Genomic Organization | Key Findings |
|---|---|---|---|
| Human | 100% (reference) | 11 exons, ~39 kb on chromosome 4p15.2 | Two splice variants differing at amino-terminal residues |
| Mouse | 85% identical | 11 exons, ~28.5 kb on chromosome 5qC1 | Similar splice variants predicted |
| Zebrafish | 69% identical | Partial sequence available | High conservation in functional domains |
| Fruit Fly | 42% identical | Two isoforms identified | Potentially incomplete annotation |
| Worm | Homolog identified | Not fully characterized | Conservation confirmed |
"The SLA/LP molecule and its functionally relevant residues have been highly conserved throughout evolution, suggesting an indispensable function of the molecule" 3 .
The team began with known human SLA/LP mRNA sequences and used them to identify the corresponding gene in human genomic databases 1 .
Using BLAST algorithms, they queried the human SLA/LP protein sequence against protein databases of multiple species to identify homologous sequences 1 .
For each identified homolog, researchers mapped the exon/intron structure by comparing mRNA sequences to genomic DNA sequences 1 .
They used multiple algorithms including ClustalW for sequence alignment and various tools for domain identification 1 .
| Feature | Details | Biological Significance |
|---|---|---|
| Chromosomal Location | 4p15.2 | Mapped to specific human chromosomal region |
| Genomic Span | ~39 kilobases | Relatively compact gene size |
| Exon Organization | 11 exons | 10-11 translated depending on splice variant |
| Splice Variants | Two known variants | Differ by inclusion/exclusion of exon 2 |
The research revealed that the only domain of the human SLA/LP sequence that lacks significant homology with other species is the major antigenic epitope recognized by autoantibodies from AIH patients 1 3 8 . This finding suggests that SLA/LP autoimmunity is autoantigen-driven rather than being triggered by molecular mimicry of foreign pathogens.
The detection of anti-SLA/LP autoantibodies has become a valuable diagnostic tool in clinical practice. These autoantibodies are highly specific for AIH, with some studies reporting specificity up to 99% 5 9 . Approximately 20-30% of AIH patients test positive for anti-SLA/LP, and in about 8% of cases, these may be the only detectable autoantibodies 4 5 .
of AIH patients test positive for anti-SLA/LP
specificity for autoimmune hepatitis
Anti-SLA/LP positive patients may show quicker initial response to treatment, but long-term outcomes are similar to other AIH patients .
Despite evidence for autoantigen-driven autoimmunity, the molecular mimicry hypothesis persists as a potential trigger for SLA/LP autoimmunity. A fascinating 2013 in silico study revealed statistically significant structural similarity between the immunodominant region of SLA/LP and a surface antigen (PS 120) from Rickettsia species 8 .
The research predicted that both the SLA/LP autoepitope and the Rickettsia protein could bind to HLA-DRB1*03:01—a key genetic susceptibility factor for AIH—in a similar manner and with comparable affinity 8 .
CD4+ T cells primed against Rickettsia antigens might cross-react with self-SLA/LP, potentially initiating the autoimmune response.
Rickettsia Antigen
Cross-reaction
Liver Autoimmunity
The story of SLA/LP beautifully illustrates how evolution conserves what's essential while sometimes setting the stage for disease. The same molecular features that make SLA/LP indispensable for cellular function—its conserved active sites, its critical role in selenoprotein synthesis—may also contribute to its becoming an autoimmune target.
SLA/LP research represents a perfect marriage of basic biological inquiry and clinical relevance, advancing both our understanding of fundamental cellular processes and autoimmune disease mechanisms.
As research continues, each piece of this molecular puzzle brings us closer to understanding the delicate balance between biological fidelity and immunological identity—a balance that, when disrupted, can have profound consequences for human health.