|Ahead of print publication
Autoinflammation and autoimmunity: More to what meets the eye
Anu Balakrishnan1, Pankti Mehta2, Parikshit Sen3, Vikas Gupta4, Latika Gupta5
1 Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
2 Department of Clinical Immunology and Rheumatology, King George's Medical University, Lucknow, Uttar Pradesh, India
3 Maulana Azad Medical College, Delhi, India
4 Department of Clinical Immunology and Rheumatology, Dayanand Medical College and Hospital, Ludhiana, Punjab, India
5 Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences; Department of Rheumatology, Royal Wolverhampton Hospitals NHS Trust, Wolverhampton; City Hospital, Sandwell and West Birmingham Hospitals NHS Trust, Birmingham; Division of Musculoskeletal and Dermatological Sciences, Centre for Musculoskeletal Research, School of Biological Sciences, The University of Manchester, Manchester, UK
|Date of Submission||10-Apr-2022|
|Date of Acceptance||31-May-2022|
|Date of Web Publication||07-Oct-2022|
Department of Rheumatology, Royal Wolverhampton Hospitals NHS Trust, Wolverhampton WV10 0QP
Source of Support: None, Conflict of Interest: None
| Introduction|| |
Autoimmune and autoinflammatory disorders are both characterized by excessive undue activation of the immune system with autoimmune disorders primarily involving the adaptive immune arm of the immune system, whereas a dysregulated innate immune response is predominantly observed in autoinflammatory diseases.
Autoimmunity involves loss of immune tolerance against specific self-antigens with reactive T- and B-lymphocytes and production of autoantibodies; the prototype autoimmune diseases being rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Conversely, autoinflammatory diseases are dominated by inflammation triggered by various environmental factors such as infections, temperature changes, and even mechanical stimuli on a fertile background of genetic predisposition. The classic autoinflammatory syndrome, familial Mediterranean fever (FMF), was first described in 1945 by Siega as a periodic fever with “benign paroxysmal peritonitis.” The MEFV gene mutation was identified in 1997, paving the way for active research in the field of autoinflammatory syndromes and innate immunity. With further research, the classification of autoinflammatory diseases has evolved, based on the operative dominant inflammatory pathways.
However, attributing autoinflammation only to dysregulated innate immunity, and similarly asserting that adaptive immune involvement is the sole determinant of autoimmunity, is an oversimplification of the underlying pathophysiology. The innate and adaptive immune responses do not exist in isolation and mutual exclusion but instead act in conjunction. The innate immune system forms the first line of defense against danger signals and further activates the adaptive immune system. Similarly, autoinflammation and autoimmunity cannot be divided into absolute black and white, and an understanding of the various shades of gray is increasingly emerging.
It is now being recognized that apart from exclusive autoinflammatory disorders like periodic fever, the inflammasome-mediated mechanisms also play a role in diseases such as systemic-onset juvenile idiopathic arthritis (sJIA), gout, diabetes mellitus, and atherosclerosis as well as in autoimmune diseases such as RA and SLE., Diseases such as spondyloarthritis (SpA) and inflammatory bowel disease (IBD) share features of both autoinflammatory and autoimmune disorders, and thus, the broad classification of autoinflammatory and autoimmune diseases often overlooks the mechanistic overlap between the two. Thus, the concept of “immunological disease continuum” was conceived.
| Classification continuum|| |
The categorization of immunological diseases as a continuum was proposed by McDermott and McGonagle in 2006 on the principle that the disease phenotype depends on disturbances in the immune cells at the target site of inflammation rather than the immune system per se. This continuum consists of monogenic autoinflammatory diseases at one end typified by dysfunction of the innate immune system (neutrophils and monocytes), monogenic autoimmune diseases at the other end characterized by dysfunction of the adaptive immune system (T- and B-cells), and a mixed pattern of diseases in the center [Figure 1].
Autoinflammatory diseases at the far-left end of the spectrum are genetically determined and characterized by the rarity of occurrence and the absence of gender predilection. Whereas autoimmune disorders are characterized by polygenic etiology, female predominance and a progressive course with a rare occurrence of single gene defects. However, some diseases do not strictly follow these principles and lie at the center of this spectrum forming the classification continuum. There are polygenic autoinflammatory syndromes such as gout and adult-onset Still's disease which are characterized by episodic course, fever, arthritis, and a good response to interleukin (IL)-1 inhibition. At the extreme right, there are a group of monogenic autoimmune disorders such as immune dysregulation, polyendocrinopathy, and X-linked (IPEX) and autoimmune polyendocrinopathy, chronic candidiasis, and ectodermal dysplasia which have genetic defects in immune tolerance. At the center are diseases which show features of both autoinflammation and autoimmunity and are called mixed pattern diseases or “MHC-1-opathies.”
| Mixed pattern diseases or “MHC-1-opathies”|| |
Mixed pattern diseases or MHC-1-opathies is an umbrella term that includes psoriasis, Behcet's disease (BD), and SpA spectrum of disorders [Figure 2]. This concept is unified by an association with class I MHC molecules, early age of onset with equal sex predilection, and a waxing and waning course. Most of these diseases occur as a result of mucosal barrier dysfunction and failure of immune stress surveillance. SpA and BD are included in this group. Although Takayasu arteritis is also being suggested in this group, the exact pathophysiology is still unknown [Table 1].
|Figure 2: (a) MHC-1-opathies, (b) The model of danger theory, (c) Progression of systemic-onset juvenile idiopathic arthritis. PRR: Pattern recognition receptor, DAMPs: Damage-associated molecular patterns, APC: Antigen-presenting cell, ILC: Innate lymphoid cell, MAS: Macrophage activation syndrome, IL: Interleukin, TGF: Transforming growth factor|
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The immunology behind MHC-1-opathies is supported in wake of the danger model, which suggests that cellular injury and stress are more important determinants of immune system activation than the foreignness of the antigen [Figure 2]. Therefore, an immune response can be elicited by injured tissues by the release of certain “danger signals” even in the absence of an infectious agent. Each of the concerned MHC1 has a predilection to affect certain tissues and hence confers risk for certain specific manifestations. For instance, HLA-B27 confers a risk for spondylitis, enthesitis, arthritis, aortitis, and eye involvement. HLA-C06 is associated with skin involvement and HLA-B51 with eye, vessel, and skin involvement. The biomechanical stress, physical trauma as well as microorganisms can act as a trigger for the disease in these areas.
One of the pathogenetic mechanisms of HLA-B27 in ankylosing spondylitis is the formation of homodimers on cell surfaces owing to the unstable nature of HLA-B27. These homodimers then engage killer immunoglobulin-like receptors and leukocyte immunoglobulin-like receptors on natural killer cells and Th17 cells triggering activation of the innate and adaptive immune systems. Furthermore, the role of biomechanical stress has been exemplified by lower-limb predominant arthritis and enthesitis in humans, and this has been proven in animal studies. Multiple reports have recently shown elevated B-cells in the peripheral blood, peripheral joints as well as the presence of antibodies such as anti-CD74, anti-14-3-3 eta, and anti-citrullinated vimentin paving the way for greater exploration of the autoimmune basis of the disease. These are attributed to primary genetic defects in the B-cell-associated genes or as a result of chronic inflammation-induced break in peripheral tolerance.
Similarly, BD has a clinical profile similar to the SpA spectrum in the form of arthritis, skin involvement, oral ulcers, uveitis, and gastrointestinal involvement, which are indistinguishable from Crohn's disease. In a subset of patients with BD who had acne and arthritis, ultrasonography showed increased enthesopathy scores, suggesting that BD may be closely related to SpA. Genetic studies have suggested the role of both autoimmune and autoinflammatory pathways in the pathogenesis of BD., In a study from Turkey, the authors demonstrated an increased occurrence of SpA and BD in patients with FMF and their first-degree relatives. In another study from Israel, the authors assessed the presence of FMF mutations in MHC-1-opathies and other autoimmune conditions and found that FMF mutations were seen in 1.2% of patients with psoriasis and Crohn's disease.
Although MHC-1-opathies lack the classical features of autoimmunity, immunosuppressants, and anticytokine therapies form the cornerstone of therapy for these mixed pattern disorders. Colchicine has been effective for mucocutaneous BD, but more severe forms require immunosuppression. Thus, they classically fit into mixed pattern diseases with clinical features more akin to autoinflammatory diseases but pathology and treatment options such as autoimmune diseases.
| A few more gray areas|| |
Despite a majority of diseases being successfully placed along the continuum, many diseases have not yet found a place due to their indeterminate fluidic nature, as well as significant lacunae in the understanding of the disease pathophysiology that exist in the current scenario. At times, certain inflammatory disorders may exhibit a biphenotypic pattern, wherein the inciting inflammatory event is autoinflammatory, but a gradual breach of tolerance and epitope spreading (potentially) leads to a shift toward an autoimmune spectrum later in the disease course. sJIA and AOSD begin as autoinflammatory diseases typified by fever and other systemic features, with IL-1 blocking therapies being very effective in the acute phase with an innate immunity-driven pathogenesis. However, Th17-mediated responses take over in the later phase of the disease when systemic manifestations decline and erosive arthritis predominates. The chronic phase of the systemic JIA can be concluded as an evolution of the disease from an autoinflammatory to an autoimmune phenotype according to this study [Figure 2].
Similarly, palindromic rheumatism has been recognized as a relapsing–remitting variant of RA. It occurs as episodic and self-limiting arthritis involving one or more joints. Ultrasound studies have shown that palindromic rheumatism has a presence of periarthritis instead of active synovitis seen in RA. One Spanish study showed the presence of MEFV mutations in 12.3% of patients with palindromic rheumatism. These findings along with some success with colchicine favor it to be an autoinflammatory disorder. Similar involvement is also reported in intermittent hydrarthrosis, although the exact pathophysiology is largely understudied and poorly understood., Notably, the presence of autoantibodies and progression to RA in more than half of the patients with palindromic rheumatism makes it seem plausible that a subset was autoimmune to start with, Notably, a subset may have autoimmune origins as substantiated by the presence of autoantibodies and progression to RA in more than half of the patients. Further studies await a deeper understanding of the exact pathophysiologic origins in these cases at the crossroads of autoimmunity.
The COVID-19 pandemic has brought us to the crossroads of autoimmunity and autoinflammation. The spectrum of COVID-19 (other than direct infection) is broad. It ranges from autoinflammatory syndromes in the acute phase like COVID cytokine storm and macrophage activation syndrome and the subacute phase like multisystem inflammatory syndrome to the emergence of autoimmunity in the form of laboratory evidence of autoantibodies such as ANA and antiphospholipid antibodies, as well as clinical syndromes in predisposed individuals. These syndromes may be systemic or organ-specific, and both short- and long-lasting autoimmunities have been observed. This itself forms an autoinflammation–autoimmunity continuum.
Among autoinflammatory diseases, the most intriguing of all is the multisystem inflammatory syndrome – children/adults. Although it shares some clinical features with Kawasaki disease, it has more gastrointestinal and systemic features. Mechanistically, it is driven by IL-10 and tumor necrosis factor-alpha with a possible role of multiple autoantibodies again making it difficult to classify.,, The pathogenetic mechanisms of these are unclear. They are determined by factors such as age (with MIS-C being more common in children) and gender (myositis, arthritis, GBS, myelitis, and glomerulonephritis are reported mainly in men, whereas thyroiditis and pancreatitis occur more frequently in women). The most plausible mechanisms for induced autoimmunity and autoinflammation due to COVID-19 are a direct result of the viral trigger-molecular mimicry and bystander activation on the background of a genetic predisposition. Certain HLA-B and HLA-C alleles and a cluster on chromosome 3p21 are risk factors for severe COVID-19., There is a striking similarity between COVID-19 hyperinflammation and anti-MDA5 dermatomyositis (melanoma differentiation antigen) in terms of rapidly progressive respiratory disease with hyperferritinemia and rashes throwing light on a plausible commune pathogenetic pathway. MDA-5 is part of the viral sensing machinery of the cell triggering a type I interferon response which can be triggered by both viral infections and antibodies.,,,,
| Adding a third dimension?|| |
Many autoinflammatory syndromes such as deficiency of adenosine deaminase 2, LUBAC deficiency, and APLAID as well as autoimmune diseases such as CTLA4 haploinsufficiency, CVID, and RAG1/2 deficiency are associated with concurrent immune deficiency. The updated classification of inborn errors of immunity has defined a separate subgroup for those with inherent susceptibility to autoimmunity as well as autoinflammation. These include autoimmune lymphoproliferative syndrome that presents with autoimmune cytopenias, autoimmune polyendocrine syndrome with antibodies to IL-17 resulting in immune deficiency, syndromes causing very early-onset IBD (IPEX), IL-10 deficiency, IL-10 R deficiency, etc., and those with general autoimmunity (CTLA4 and LRBA defects). Further, there is a higher prevalence of immunodeficiencies involving complement components and B-cells in adult-onset autoimmune diseases like SLE in certain ethnicities like Persians due to the high rate of consanguineous marriages. This aspect holds translational value with regard to therapeutics and may need replacement of complement components using fresh frozen plasma, IVIG, or avoidance of B-cell depleting therapy for B-cell immunodeficiency. Low copy numbers of C4A in SLE a study from Mexico have also been linked to a greater risk of infections. Some inborn errors immunity form an important third dimension in addition to autoimmunity and autoinflammation that helps us define the positions of various diseases better along the continuum.,,,
Thus, in diseases other than monogenic diseases, innate and adaptive immune responses act in conjunction along a continuum, and not in mutual exclusion. This can be compared to the gene–environment continuum of characteristics of the human body, wherein some aspects like blood group are determined by a single set of genes, whereas skin complexion and eye color display a polygenic inheritance with environmental influence. [43, 44] A classification continuum based on these principles, representative of the underlying disease pathophysiology, would help classify many diseases in future.
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[Figure 1], [Figure 2]