|Year : 2020 | Volume
| Issue : 5 | Page : 13-18
Human leukocyte antigen - HLA B*27: Unraveling the link to pathogenesis
Sakir Ahmed, Ramnath Misra
Department of Clinical Immunology and Rheumatology, Kalinga Institute of Medical Sciences, KIIT University, Bhubaneswar, Odisha, India
|Date of Web Publication||23-May-2020|
Prof. Ramnath Misra
Department of Clinical Immunology and Rheumatology, Kalinga Institute of Medical Sciences, KIIT University, Bhubaneswar - 751 024, Odisha
Source of Support: None, Conflict of Interest: None
The association of spondyloarthritis (SpA) with human leukocyte antigen-B*27 (HLA-B*27) is one of the strongest known for a non-monogenic disease. How HLA-B*27 determines the aetiopathogenesis of SpA and disposes toward this group of disease has perplexed rheumatologists for decades. We searched through contemporary bibliographic databases for literature on the link between HLA-B*27 and different SpA, with special emphasis on ankylosing spondylitis. In this review, the structure and function relationship and subtypes of HLA-B*27 are discussed in the context. Then, three hypotheses on the pathological role of HLA-B*27 are presented. The first arthritogenic peptide hypothesis is based on molecular mimicry between the parts of the HLA-B*27 and epitopes of pathogenic Enterobacteriaceae. The second hypothesis is about the misfolding of the HLA-B*27 major chain, leading to endoplasmic reticulum (ER) stress and initiation of inflammation through the unfolded protein response. The third hypothesis deals with the formation of homodimers of the HLA-B*27 major chain on the cell surface, leading to the activation of natural-killer cells through the killer immunoglobulin-like receptors. Furthermore, discussed in the review are the epistatic factors such as ER-associated peptidase-1, role of microbiota, and the concept of autoinflammation in relation to HLA-B*27.
Keywords: Genetics, human leukocyte antigen, human leukocyte antigen-B*27, major histocompatibility complex, pathogenesis, spondyloarthritis
|How to cite this article:|
Ahmed S, Misra R. Human leukocyte antigen - HLA B*27: Unraveling the link to pathogenesis. Indian J Rheumatol 2020;15, Suppl S1:13-8
| Introduction|| |
The human leukocyte antigen (HLA) genes are encoded in the chromosome 6p2.3. Since they encode the HLA proteins that provide a scaffold for antigen presentation by various antigen-presenting cells, they have very important implications in different diseases, both infectious and autoimmune. The polymorphisms in these genes are associated with different diseases. Among all known associations, the strongest is the association of the HLA-B*27 with the spondyloarthritis (SpA).
In case of ankylosing spondylitis (AS), 80%–90% are associated with HLA-B*27. In case of nonradiographic SpA, the prevalence of HLA-B*27 is around 40%–70%. In reactive arthritis, it ranges from 40% to 80% depending on which region of the world it is reported from. The association is found in lesser (20%–50%) proportions in psoriatic arthritis and in inflammatory bowel-associated arthritis. However, even these are still stronger than most other known associations between the diseases and various genes. It is also associated with recurrent anterior uveitis (20%–88% depending on the population studied) and Behcet's disease. Since the first report of the association of HLA-B*27 with AS in 1972, it has been increasingly reported in a number of ocular and systemic diseases. This very strong association hints at a possible role of HLA-B*27 in the pathogenesis of this disease. This has also been proven in genome wide-association studies.
About 8% of Caucasians, 4% of North Africans, 2%–9% of Chinese, and 0.1%–0.5% of persons of Japanese descent possess HLA-B*27. HLA-B*27 positivity leads to a 20-fold increase in the chances of developing SpA. Conversely, <5% of HLA-B*27-positive people develop AS. HLA-B*27-positive individuals are less susceptible to HIV or hepatitis C infection. The low prevalence of HLA-B*27 in tropical regions is hypothesized to be due to higher mortality in malaria since there is a higher incidence of malaria in these regions. A study in American veterans had shown an association of HLA-B*27 positivity with increased mortality.
Thus, the role of HLA-B*27 in human health and disease maybe much broader than merely encompassing the spectrum of SpA. Keeping in view the topic of this supplement, we reviewed the available evidence on the role of HLA-B*27 in the pathogenesis of SpA. We have attempted to set this in the context to provide a picture of our current understanding of the role of B27 in SpA. This will help identify the therapeutic targets for the near future, as well as summarize the gap in knowledge.
| Search Strategy|| |
MEDLINE (via PubMed) and SCOPUS were searched with the terms related to “HLA-B27,” “pathogenesis,” “ankylosing spondylitis,” and “spondyloarthritis.” Relevant articles were screened and their bibliography scanned for further pertinent references. Preference has been given to the articles published in the past 10 years. Although based on available evidence, the review presents the authors' interpretation and personal opinions also.
| Structure of Human Leukocyte Antigen-b*27|| |
Class I major histocompatibility (MHC) molecules include HLA-A, HLA-B, or HLA-C, and they are present on cell surfaces. Class I molecules present predominantly cytosolic peptides (e.g., viral particles) to cluster of differentiation (CD) 8 positive (cytotoxic) T-cells. Beyond the “classical” HLA-B*27 molecule found in the endoplasmic reticulum (ER) and expressed on the surface, a number of noncanonical forms have been described. These include dimers, heterotrimers, HLA-B*27 with 2 molecules of β2-microglobulin, and so forth.
| Function of Human Leukocyte Antigen-b*27|| |
For normal endogenous antigen presentation, proteasomes splice cytosolic proteins into peptides of up to 25 amino acid residues. Peptides of 8–16 amino acid lengths are preferentially taken up by transporter, ATP-binding cassette subfamily B member and carried to the ER. The ER amino-peptidase 1 (ERAP1) cleaves these peptides further into oligopeptides of 8–9 amino acids that is optimal to bind the antigen presentation groove of the HLAB27. Other ER aminopeptidases (NPEPPS, LNPEP, and ERAP2) have also been implicated in the pathogenesis of AS.
| Subtypes of Human Leukocyte Antigen-b*27|| |
As of October 23, 2019, there were 311 reported genotypes of HLA-B*27. However, a large number of these are null alleles and do not lead to protein synthesis. HLA-B*27:05 is the most frequent and has been reported in all races and ethnicities. HLA-B*27:05, contains 31 alleles, from HLA-B*27:05:02 to HLA-B*27:05:32. It predisposes to AS and is considered the ancestral subtype of HLA-B*27. HLA-B*27:09 is one of the most frequent subtypes in Africa and is not associated with AS despite being different from HLA-B*27:05 in only 1 amino acid. Similarly, HLA-B*27:06 is not associated with AS [Table 1].
|Table 1: Amino acid sequence of the common subtypes of human leukocyte antigen-B*27|
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| Evidence from Animal Models|| |
Rodent models of SpA have been produced by introducing the overexpression of HLA-B*27 in them. These include Lewis (21-H), F344 (33-3), and Lewis (21-3 × 283-2) rats that overexpress both HLA-B*27 molecules and the associated β2-microglobulin. The Lewis (21-H) has 150 copies of HLA-B*27 and 90 copies of β2-microglobulin, the F344 (33-3) 55 copies of HLA-B*27, and 66 copies of β2-microglobulin. The Lewis (21-3 × 283-2) F1 has 20 copies of HLA-B*27 and 50 copies of β2-microglobulin. It has been seen that rodents with the higher expression of HLA-B*27 have higher disease penetrance. This strengthens the belief that HLA-B*27 has a definitive role in the pathogenesis of the disease.
The ANKENT mice develops spontaneous ankylosing enthesitis. Furthermore, the mouse model lacking β2-microglobulin has been shown to cause spontaneous arthritis even in the absence of CD8+ T-cells. This is an argument against the arthritogenic peptide hypothesis (see next section).
| Hypotheses of Pathogenic Role of Human Leukocyte Antigen-b*27|| |
Three most important hypotheses regarding the role of HLA-B*27 are discussed below:
Arthritogenic peptide hypothesis
This is the classical hypothesis that there are aberrant antigen processing and presentation leading to immune activation. It is based on molecular mimicry between certain postulated Enterobacteriaceae and peptides found in joints [Figure 1]. This would imply that the disease pathogenesis is highly dependent on CD8+ cells. However, in the murine model, even after the depletion of CD8+ T-cell, there was still the development of arthritis or colitis.
|Figure 1: Arthritogenic peptide hypothesis: HLA-B27 on an APC presenting a peptide derived from enterobacteria (Klebsiella) to the CD8+ T-cells. HLA-B27 subtypes that differ in residues of peptide-binding groove may facilitate the generation of cytotoxic T-cells that mediate disease pathogenesis. APC: Antigen-presenting cells; CD: Cluster of differentiation; HLA: Human leukocyte antigen; TCR: T-cell receptor|
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This theory proposes that the HLA-B*27 molecule is intrinsically unstable in the ER, leading to misfolding [Figure 2]. The misfolded protein accumulates initiating the unfolded protein response (UPR), leading to the activation of autoinflammatory pathways and autophagy. This process upregulates interleukin (IL)-23 and IL-17 both of which have been implicated in the pathogenesis of AS. However, the upregulation of UPR in AS has not been shown to be consistent.
|Figure 2: HLA-B27 molecule is intrinsically unstable molecule which in the endoplasmic reticulum elicits unfolded protein response resulting in stimulation of IL-17 and IL-23 proinflammatory cytokines important in the pathogenesis of AS. ATF6: Activating transcription factor 6; ER: Endoplasmic reticulum; IRE1: Inositol-requiring enzyme 1; PERK: Protein kinase R-like endoplasmic reticulum kinase; HLA: Human leukocyte antigen; IL: Interleukin|
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Human leukocyte antigen-B*27 heavy-chain homodimer formation hypothesis
As discussed above, there are many noncanonical forms of HLA-B*27 such as dimers and heterotrimers. When especially the heavy-chain homodimer gets expressed on the surface, it can activate innate receptors like killer immunoglobulin-like receptors (KIRs) like KIR3DL2 [Figure 3]. KIR genetic polymorphisms have been linked to AS in some populations. One criticism of this hypothesis is that homodimer formation is not unique to HLA-B*27.
|Figure 3: HLA-B27 has property to form homodimers that are dependent on residue Cys67 in their extracellular α1 domain. Cell surface B272 (homodimer) binds to innate immune receptors such as killer immunoglobulin receptors KIR3DL1, KIR3DL2, and leukocyte immunoglobulin-like receptor LILIRB2 on CD4 + T-cells, NK cells, and myeloid cells in humans. The KIR3DL2/B27 interaction has pro-inflammatory effects on both NK and T-cells and favors a Th17 phenotype in ankylosing spondylitis. CD: Cluster of differentiation; NK: Natural killer|
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| Epistasis and Modifier Genes|| |
Epistasis is the presence and effect of modifier genes that are non-allelic, but exert an effect on the outcome of a structurally different gene. The classic example is the role of ERAP1 in the presence of AS. The surface expression of aberrant forms of HLA-B27 on cell surface seems to be dependent on ERAP1. Epistasis between ERAP1 and HLA-B*27 was not observed in a large genetic study in the East Asian population with AS. However, this study was not powered to look at epistasis. In the 10%–15% of AS without HLA-B*27 (negative), there seems to be no role of ERAP1 polymorphisms either. Then, other epistatic factors have been reported like the HLA-B*60; the HLA-B*27+/HLA-B*60 + genotype leads to a very severe form of AS. Similarly, many other possible epistatic genes are being reported in AS.
| Human Leukocyte Antigen-b*27 and Microbiota|| |
It is well known that the gut microbiota has been implicated in the genesis and flares of SpA. The evidence is the strongest in case of reactive arthritis when there is a temporal association between a gut infection and initiation of arthritis. It has also been shown that the presence of HLA-B*27 influences the constitution of the microbiota. There was an increased prevalence of Prevotella spp. and decrease in the relative abundance of Rikenellaceae in HLA-B*27 transgenic animals compared to the wild types. The gut microbiota also depends on the genetic background beyond HLA, thus leading to the concept of a dysbiosis landscape. In this concept, it is not single or a small number of microbes, but rather groups of multiple microbes that lead to an aberrant immune response. It should be kept in mind that murine models of SpA do not develop arthritis if kept in a germ-free state.
| Concept of Major Histocompatibility-i-opathies|| |
Autoinflammation is the inflammation triggered by innate pathways independent of auto-antibodies or auto-reactive T-cells. Although the concept started in periodic fevers, it was soon realized that gout, Behcet disease, etc., have a predominant component of autoinflammation. This concept has spread into SpA with SpA involving more of innate pathways rather than acquired immunity pathways. The spectrum of disease related to HLA-class I molecules that predominantly involve innate inflammation have been grouped together as “MHC-I-opathies.” These include SpA, Behcet disease, Takayasu arteritis, and Birdshot chorioretinopathy. Unlike classical autoimmune diseases, these do not have female preponderance, occur in a younger age group, have a waxing and waning course, and is associated with barrier function perturbations (e.g., gut and mucosa). Joint disease in this group is more in lower limbs and entheses, implying the role of mechanotransduction in the pathogenesis.
| Avenues for Future Research|| |
Current research is working on how antigen presentation occurs with HLA-B*27, and what goes wrong to initiate autoinflammation. Other potential avenues include understanding the role of various epistatic genes. Less than 5% of people with HLA-B*27 positivity develop AS: the secret must thus lie within the epistatic factors and environmental factors. The story of gut microbiota needs to be tied up with the story of HLA-B*27. A role of ROR-γt+ CD3+ double-negative innate immune cells in the development of SpA has been described. Again, the connection to HLA-B*27 needs to be explained to complete the picture of pathogenesis of AS. Furthermore, it may be interesting to know if mechanotransduction can alter the antigen presentation through HLA-B*27.
| Conclusion|| |
The story of HLA-B*27 has grown from a marker in SpA to an integral player in its pathogenesis. It has also made us understand how epistasis takes place in rheumatic diseases. It has changed the concept of SpA from an autoimmune to an MHC-I dependent, predominantly autoinflammatory syndrome. How these help in the production of targeted therapy to possibly prevent SpA progression needs to be seen.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]