|Ahead of print publication
Immunopathogenesis of spondyloarthropathies – Concept of major histocompatibility locus-I-opathy
Amlan Kusum Datta1, Uddalak Chakraborty1, Swati Kumar1, Atanu Chandra2
1 Department of Neurology, Bangur Institute of Neuroscience, Institute of Post Graduate Medical Education and Research, Kolkata, West Bengal, India
2 Department of Internal Medicine, R.G. Kar Medical College and Hospital, Kolkata, West Bengal, India
|Date of Submission||20-Oct-2020|
|Date of Acceptance||18-Mar-2021|
|Date of Web Publication||18-Nov-2021|
Amlan Kusum Datta,
Bangur Institute of Neurosciences, 52 1/A Sambhu Nath Pandit Road, Bhowanipore, Kolkata - 700 020, West Bengal
Source of Support: None, Conflict of Interest: None
Spondyloarthropathies (SpA) are a group of overlapping disorders sharing certain common clinical features and genetic associations. Historically, most of the research into the pathogenesis of SpA and other types of chronic arthritis have conventionally focused on the adaptive immune system. However, recently, the pendulum has shifted in favor of innate immunity. With an aim to explore bridging concept of major histocompatibility locus (MHC)-I-opathy in context of immunopathogenesis of SpA, MEDLINE and PubMed (2000-2019) databases were searched for English language articles using keywords “MHC-I-opathy” and “spondyloarthropathy.” We reviewed papers which addressed the concept of overlap between innate and adaptive immunity and interplay between local tissue factors and innate cellular responses in the pathogenesis of SpA. The term “MHC-I-opathy” encompasses of a group of diseases which exhibit interaction between tissue-specific factors and innate immune cells. Further studies are needed for understanding of its therapeutic implication in such diseases.
Keywords: Arthritis, axial spondyloarthropathies, human leucocyte antigen B27, immunology, major histocompatibility locus
| Introduction|| |
Spondyloarthropathies (SpA) comprises a group of disorders characterized by inflammatory arthritis, spondylitis, enthesitis, and extra-articular complications involving the skin, eyes, heart, and gut; the different subtypes appear to share important clinical, genetic, and pathologic features., They include following diseases:
- Axial spondyloarthritis (axSpA): Nonradiographic and radiographic
- Psoriatic arthritis and spondylitis
- Reactive arthritis
- Enteropathic arthritis and spondylitis
- Juvenile-onset spondylarthritis
- Undifferentiated spondyloarthritidies.
The immune system can be broadly divided into the innate immune system, which performs prompt recognition of pathogens and triggers a short lasting, rapid immune response; and the adaptive immune system, capable of antigen-specific responses, and long-term memory. Under current nomenclature, inflammatory diseases caused by aberrant adaptive immune elements are referred to as autoimmune, while those mediated by the innate immune system are considered autoinflammatory. Major histocompatibility locus (MHC)-I-opathy refers to diseases which exhibit interaction between tissue-specific factors and innate immunity. A comparison between a commonly encountered entity in rheumatology, autoimmune diseases, and MHC-I-opathy is depicted in [Table 1]. Interest in the ability of adaptive immune system to cause autoimmunity dates back over 100 years, to Paul Ehlrich's coining of the term “horror autotoxicus,” referring to potential harmful effects of antibodies. Burnet's clonal selection theory also cemented the concept of disease caused by aberrant immune regulation. In contrast, research in the innate immune system began relatively recently, following the discovery of microbial pattern-recognition molecules, such as the toll-like receptors (TLRs), and their downstream pathways.,
|Table 1: Comparison between major histocompatibility complex-I-opathies and autoimmune diseases|
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| Bridging Concept-Major Histocompatibility Locus I-Opathy|| |
The concept of MHC-I-opathy is immunopathologically linked to Bechet's disease and SpAs. The argument derives from three major groups of evidence:
- Genetic associations indicating common immunopathogenic mechanisms in relation to MHC-I associated adaptive immunity in Bechet's disease and SpAs,
- Local and tissue specific factors such as breakdown of barrier tissues (gut and skin), and microdamage to nonbarrier tissues such as uvea and enthesis, cause release of sequestered antigens and proinflammatory signals which herald secondary adaptive immune responses in SpA and Bechet's disease,
- Observations implicating a definite role of unconventional lymphocytes in “lymphoid stress surveillance” via the Interleukin-23 (IL-23)–IL-17 pathway at such tissue-specific sites.
| Genetic Associations – Role of Human Leukocyte Antigen-B27|| |
Human leukocyte antigen (HLA) B-27 is an allele of the HLA-B locus of HLA class I antigen, which is coded by a MHC, located on chromosome 6p. HLA molecules are formed inside endoplasmic reticulum (ER) and are transferred to cell surface after proper assembly.
HLA B27 is present in more than 90% of SpA patients and in <10% of the general population. Currently, three mechanisms are hypothesized which aim to explain this association [Figure 1].
|Figure 1: Different structures of human leucocyte antigen B27 and their participation in pathogenesis of arthritis. Human leucocyte antigen -B27 is first generated as a free heavy chain, which inside the cell becomes folded in association with β2-microglobulin (β2m) and antigenic peptide, and then becomes expressed on the cell surface as a trimolecular complex. Expression can occur on the cell surface as homodimers of heavy chains without β2m. Abbreviations: ER: endoplasmic reticulum; kIR: killer-cell immunoglobulin-like receptor, LILR: leukocyte immunoglobulin-like receptor, Nk: natural killer cells|
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The arthritogenic peptide hypothesis
This hypothesis is based on the classic structure and the canonical function of HLA B-alleles. HLA B27 molecules exist as a trimolecular complex of a polymorphic HLA class I heavy chain together with a monomorphic light chain (β2 microglobulin) and a single highly variable peptide. The peptides conform to a strict motif, usually with arginine as the second amino acid. The function of HLA B molecules is to present peptides derived from intracellular pathogens (e.g., Viruses) to CD8+ T lymphocytes to generate a protective adaptive immune response.
The arthritogenic peptide hypothesis postulates that in case of SpAs, there is a breakdown of tolerance to certain self-peptides, which is a consequence of mimicry between the self-peptides and certain pathogen-derived peptides.
Free heavy chain hypothesis
The hypothesis is based on the observation that HLA B27 molecules can exist on the cell surface as free heavy chains independent of β2m or peptides. Large number of these free heavy chains are found on surfaces of monocytes in patients with AS. These free chains are proficient in recognizing nontraditional allele-specific receptors on natural killer (NK) cells and T-lymphocytes. These receptors are KIRs (NK-cell immunoglobulin-like receptors) and LILRs (leukocyte immunoglobulin-like receptors). Engagement of these receptors and subsequent infiltration of heavy chain expressing monocytes in synovium initiate and propagate the disease process.
Unfolded protein response hypothesis
As discussed earlier, HLA-B27 heavy chains are synthesized linearly into a processing organelle inside the cell by ER. Initially, these molecules do not have any conformation and are described as “unfolded.” Then, they undergo a series of conformational changes through formation of complexes with ER chaperones. HLA-B27 molecules have more prolonged retention times inside ER and have propensity for existing in unfolded/misfolded forms. These unfolded forms induce an unfolded protein response (UPR), which in conjunction with activation by pattern recognition receptors such as those for lipopolysaccharides, would generate proinflammatory cytokines such as IL-23, to such a degree as to cause arthritis.,
| Role of Nonmajor Histocompatibility Locus Genes in Pathogenesis|| |
Apart from the classic HLA B27, other novel genes have recently been found to have strong disease association with SpAs. Two of them are endoplasmic reticulum aminopeptidase (ERAP) (discussed below) and IL-23R. Other gene associations include IL-1R2, ANTRX (which encodes for a protein, capillary morphogenesis protein 2), TRADD, TNFR1. Two other strong genetic associations are with STAT3 and CARD9.
| Endoplasmic Reticulum Aminopeptidase 1|| |
With regard to its role in pathogenesis of SpA, the most important nonMHC gene discovered till date is ERAP-1. The association of ERAP1 with ankylosing spondylitis has been replicated in multiple populations, including Caucasians and nonwhite ethnicities. ERAPs are metallo-proteinases which are responsible for “trimming” of peptides into shorter fragments so that they are compatible with the HLA B27 groove. As a consequence of ERAP polymorphism, abnormal peptide processing is inevitable leading to formation of unstable peptide-MHC complexes, susceptible to misfolding. These misfolded HLA B27 molecules accumulate inside ER and lead to ER stress culminating in, as previously described, a proinflammatory state called UPR. As discussed, generation of free heavy chain through peptide-MHC instability can generate aberrant immune responses by engaging LILRs and KIRs.
| Role of Tissue Factors|| |
Enthesitis and concept of synovio-entheseal complex
Enthesis are the sites of attachment of tendon, ligament, or joint capsule on the surface of bone. Enthesis form a functional unit along with synovium, together forming synovio-entheseal complex. Microdamage and chronic stress at these sites lead to secondary activation of cells of innate immune system, thereby setting up a proinflammatory cascade [Figure 2].,
|Figure 2: The synovio-entheseal complex in health and disease. Normally, the synovium is vital in the nourishment and lubrication of entheseal fibrocartilage. In the setting of disease, entheseal damage may trigger an inflammatory cascade instead of tissue repair seen in health|
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Role of gut microbiota
Proinflammatory events in SpAs may lead to disruption of intestinal mucosal barrier. Intestinal inflammation may also lead to alteration of in character of normal gut flora, as evidenced from mice models.
Leakage of microbial toxins into blood stream may result in priming of spondylitis-inducing immune cells, which subsequently migrate to periphery.
| The Interleukin-23/Interleukin-17 axis – the Missing Link between Adaptive and Innate Immunity|| |
Emerging evidence suggests that a growing family of unconventional lymphocytes participate in lymphoid stress surveillance at sites of barrier perturbation or mechanical stress via the IL-23/IL-17 pathway. This evidence suggests the dual importance of this pathway not only in adaptive immune responses but also in tissue specific immune responses at sites of involvement in SpAs (enthesis, cartilage, gut, eye, etc.) [Figure 3].
|Figure 3: The IL-23–IL-17 axis is linked to innate lymphoid stress surveillance in tissues. IL-23Rexpressing unconventional lymphocytes participate in homeostatic tissue repair at mucosal surfaces. Sitespecific innate immune reactions, in the setting of immune dysregulation, might enable these cells to prime adaptive immune responses. This response can manifest as a twocytokine attack from the IL-23–IL-17 axis. Abbreviations: ERAP1: endoplasmic reticulum aminopeptidase 1, IL-23R: IL-23 receptor, ILC: innate lymphoid cell, NKT: natural killer T, Tc17: IL-17 secreting CD8+ cytotoxic T cell|
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IL-23 is produced in high amounts by intraepithelial mucosal associated T-cells, which are located at sites of tissue stress, thus suggesting evidence of adaptive immune involvement. However, as reviewed by Abraham and Cho, IL-23R is present on cells of the innate immune system such as dendritic cell, macrophages, and NKT cells. Engagement of these cells lead to generation of a two-edged cytokine attack: first, manifesting as an unconventional lymphocyte deregulation and neutrophilic infiltration (innate immune response) and second, through production of IL-17, activation of TH17 and other aspects of adaptive immune system.
Recent studies have shown superior efficacy of IL-23 and IL-12 blockade with ustekinumab, and IL-17 by secukinumab and brodalumab in patients of psoriatic arthritis point toward genetic association between this pathway and adaptive CD8+ T cell responses that involve IL-17 effector mechanisms.
| Conclusion|| |
It is a now a consensus that SpAs (along with Bechet's disease and psoriasis) could collectively be viewed under the umbrella of MHC-I-opathies since interactions between local tissue factors and MHC-I alleles influence expression of these diseases. As both innate immune mechanisms and MHC-I-related T-cell responses are involved in the pathogenesis of these disorders, it is predicted that they might respond to therapies that target cytokines and T-cells. This postulate has proven true for psoriatic arthritis and some other SpAs as well as Bechet's disease, however, remains to be verified in axSpA. In reference to axSpAs, apart from conventional MHC reactions, abnormal peptide presentation and protein misfolding might also contribute to immunopathogenesis. Role of humoral immunity in these diseases is probably limited, if any, as the antibodies are believed to be a product of tissue damage rather than the cause of it. Irrespective of significant new insights into immunopathogenesis of SpAs and other rheumatological disorders, the genetic and clinical diversity of these individual diseases pose a daunting challenge to their understanding and management.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]