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Bridging autoinflammatory and autoimmune diseases

Abstract

Background

Autoimmunity is used to cause by impairment of adaptive immunity alone, whereas autoinflammatory was originally defined as a consequence of unregulated innate immunity. So, the pathogenetic mechanisms of autoimmune diseases were well-thought-out to be mediated by B and T lymphocytes. Whereas, autoinflammatory diseases were defined as unprovoked times of inflammation with the absence of a high titre of autoantibodies.

Main body of the abstract

Autoimmune and autoinflammatory diseases were split into two groups, but considering the similarities, it can be considered as only one group of diseases with a large immune pathological and clinical spectrum which involves at one end pure autoimmune diseases and the other pure autoinflammatory diseases.

Conclusions

We can safely conclude that there is bridging between autoinflammatory and autoimmune diseases.

Background

Autoinflammatory diseases are a novel and growing group of self-directed inflammatory disorders, not only described as episodic fever syndrome but also with periods of acute inexpressible inflammation involving the innate immune system [1]. They are characterized by inflammatory episodes at disease-prone sites, in the absence of autoreactive T cells and elevation of autoantibody level [2].

Autoimmune diseases are defined as an impairment of the immune system result in loss of immune tolerance against self-tissues, by the existence of autoreactive T and B cells, and by a complex mechanism of multifactorial etiology, whereas genetics and environmental factors are responsible for the onset of disease. Autoimmune disorders may be systemic, as in the case of systemic lupus erythematosus, or tissue-specific, as in the case of multiple sclerosis (against myelin) or type 1 diabetes (against pancreatic beta cells) [3].

Autoinflammatory and autoimmune diseases result from abnormal changes in innate and adaptive immunity that may result in the primary inflammatory state to an organ-specific injury. These disorders have heterogeneity in to affected organs and clinical phenotypes. But despite the variances in etiology and phenotypic changes, they share genetic basis, clinical presentation, and treatment results. The mechanisms of initiation remain poorly understood; however, the presence of similarities between autoimmune and autoinflammatory disorders designates variable degrees of interaction between them [4].

Autoimmune and autoinflammatory disorders are divided into two groups, but if similarities are taken into consideration, they might be considered as one group of diseases with a large immune pathological and clinical spectrum which contains at one end pure autoimmune diseases and the other pure autoinflammatory diseases. Despite the variances in primary players, autoinflammatory diseases share common features with autoimmune diseases, such as self-tissue-directed inflammation without observable infectious trigger or injury. While in autoinflammatory diseases the innate immunity directly results in tissue inflammation, in autoimmune disease the innate immune system triggers the adaptive system, and this activates the inflammatory process [5].

Main text

Autoinflammatory diseases

Autoinflammatory diseases are a group of monogenic and multifactorial (polygenic) disorders characterized by frequent inflammatory episodes whose heterogeneous symptoms are recurrently associated with fever (Tables 1 and 2). The important pathogenetic mechanism in autoinflammatory diseases is the direct and indirect dysregulation of inflammasomes; the multiprotein cytoplasmic complexes are relevant to innate immunity and inflammatory responses. The main components of inflammasomes are members of the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family, a class of pattern recognition receptors. When activated by pro-inflammatory triggers such as the stimuli transmitted by pathogens or damaged cells, NLRs detect pathogen-associated or damage-associated molecular patterns and begin inflammasome assembly, which induces the proteolytic activation of caspases and turning of pro-interleukin (IL)-1 into active (IL)-1, a key molecule of inflammation and innate immunity [6].

Table 1 Summary of monogenic autoinflammatory diseases [7]

Autoimmune diseases

The term “autoimmunity” is common to be referred to as a state associated with the impairment of adaptive immunity alone. So, the pathogenesis of autoimmune diseases was exclusively mediated by B and T lymphocytes whose B and T cell receptors recognized specific antigens, started the inflammatory response against autoantigens, and activated B cell-mediated autoantibody production [8].

The existence of autoantibodies is a common character of autoimmune diseases, and a big number of serum antibodies are guided against functional structures of the cell (nucleic acids, nuclear molecules, receptors, or other functional cell components). They not only play an important role in diagnosis and classification but may also be tangled in tissue damage. One of the best well-known pathogenic effects of autoantibodies is the cytotoxic damage of cells by cell surface binding and lysis. In this process, complement activation and/or antibody dependent cell-mediated cytotoxicity are the most common pathways of destruction [9]. Although autoimmune diseases are still considered adaptive immunity-mediated disorders, there is increasing confirmation that innate immunity and inflammasomes are also included [10].

Autoimmune diseases were expressed to be rare but, through accurate epidemiological studies, have been shown to affect 3–5% of the population, with autoimmune thyroid disease and type 1 diabetes being the most common among other autoimmune diseases. Despite this, there are approximately a hundred distinct autoimmune diseases, various of which are organ-specific like primary biliary cirrhosis and some of which including multiple organs like systemic lupus erythematosus [11].

Bridging autoinflammatory and autoimmune diseases

The autoinflammatory–autoimmune diseases continuum

Autoimmune and autoinflammatory diseases have a lot of similarities in pathogenesis and clinical presentations, involving genetic predisposition and repeated systemic inflammatory attacks [12]. Autoinflammation was considered as a disorder of innate immunity (in clear difference to autoimmunity), where self-directed inflammation, induced by limited factors at sites that lead innate immune cells activated and target tissue injury will happen. For example, disturbed homeostasis of cytokine cascades (as in the periodic fever disorders), unusual bacterial sensing (as in Crohn’s disease), and tissue microdamage predispose to local inflammation that is independent of adaptive immune responses. This led to the appearance of the immunological disease continuum classification of inflammation against self and too in the classical autoimmune diseases there is tolerance failure in the primary and secondary lymphoid organs with normal tissue being later exposed to an immunological storm [13].

Some diseases defined as classical autoimmune were then recognized to have a primary autoinflammatory beginning with secondary T cell-mediated target tissue autoimmune reactions that led to another category of diseases mediated between autoimmunity and autoinflammation also called (major histocompatibility complex MHC)-I associated disorders (Fig. 1) [14].

Fig. 1
figure 1

The immunological disease continuum with pure autoimmunity and pure autoinflammation or innate immunopathology at opposites [14]. FMF familial Mediterranean fever, TRAPS tumor necrosis factor receptor-associated periodic syndrome; HIDS hyperimmunoglobulinemia D syndrome; PAPA pyogenic arthritis pyoderma gangrenosum and acne syndrome; IBD inflammatory bowel disease; GCA giant cell arteritis; PsA psoriatic arthritis; PBS primary biliary cirrhosis; AAV ANCA-associated vasculitis; T1DM type 1 diabetes mellitus; SSc systemic sclerosis; SLE systemic lupus erythematosus; ATD autoimmune thyroid disorder; DM dermatomyositis; PM polymyositis; ALPS autoimmune lympho-proliferative syndrome; IPEX immune dysregulation polyendocrinopathy enteropathy x-linked syndrome; APECED autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy; GWAS genome-wide association studies; ERAP-1 endoplasmic reticulum aminopeptidase 1; SNP single-nucleotide polymorphism

The similarities between autoimmune and autoinflammatory diseases

Autoinflammatory diseases are a set of monogenic and multifactorial (polygenic) disorders characterized by frequent inflammatory episodes whose heterogeneous symptoms are recurrently associated with fever. The significant pathogenetic mechanism in autoinflammation is direct and indirect dysregulation of inflammasomes, the multiprotein cytoplasmic complexes specific to innate immunity and inflammatory attacks. Although autoimmune diseases are known as disorders mediated by adaptive immunity, there is growing proof that innate immunity and inflammasomes are also tangled. It seems obvious that despite the contrast in the system primarily tangled, autoinflammatory, and autoimmune disease have common features as the activation against self, with subsequent systemic inflammation, and without any external causal factors trigger these attacks [15].

Table 2 Summary of multifactorial autoinflammatory diseases [16]

The association between autoimmunity and autoinflammation that can illuminate similarities between two systems is interleukin (IL-1β), which is vital in linking the innate immune response due to nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) activation and the adaptive immune responses of T and B cells. IL-1 has also a role in the activation of interferon (IFN-γ) in memory T cells, T cell proliferation (which is also mediated by IL-2 and its receptor), increased B cell proliferation, and increased antibody synthesis, thus connecting the inflammasome-driven responses to the adaptive immune system in response to exogenous and endogenous signals [17].

Other evidence of the similarity between autoimmunity and autoinflammation regard nucleotide-binding oligomerization domain-containing protein 2 (NOD2), a member of a family of pattern recognition molecules with N-terminal caspase activation and recruitment domains (CARDS) that is also called the nucleotide-binding domain and leucine-rich repeat (LRR)-containing family. Autoinflammatory granulomatous diseases as Blau syndrome and early-onset sarcoidosis are result from NOD2 mutations in NACHT domains. At the same time, Crohn’s disease results from polymorphisms in LRRs [18].

The differences between autoinflammatory and autoimmune diseases

Rheumatic diseases can be classified as autoimmune and autoinflammatory disorders. Although some autoinflammatory disorders can resemble autoimmune diseases and sometimes serve as a prelude to autoimmunity the underlying pathogenesis is mostly distinct. Autoinflammatory diseases are innate immune disorders triggered by exogenous or endogenous factors and are marked by systemic inflammation. By contrast, autoimmune diseases are derived from abnormal responses to self-tissues mediated by both innate and adaptive immune cells; activation of autoreactive T and B cells ultimately causes the failure of immune tolerance, leading to chronic inflammation and local tissue destruction (Table 3) [19].

Table 3 The differences between autoinflammatory and autoimmune diseases

Intermediate diseases between autoinflammation and autoimmunity: (major histocompatibility complex (MHC)-I associated disorders

This group of clinically overlapping disorders termed the spondyloarthropathies (SPA) are mainly autoantibody negative and include psoriasis, psoriatic arthritis, Behcet’s disease, ankylosing spondylitis, Crohn’s disease, ulcerative colitis and uveitis, and other related disorders. Historically, these have been hard to know the relation that connects these diseases with autoinflammation and autoimmunity (Table 4). Several monogenic autoinflammatory syndromes appear to be closely related to these conditions, involving the deficiency of IL-36 receptor antagonist, Majeed’s syndrome and pyogenic arthritis, pyoderma gangrenosum, and acne syndrome [20].

Table 4 The main differences between autoimmune, monogenic autoinflammatory disorders and (major histocompatibility complex)-I associated disorders [20]

Autoimmunity–autoinflammatory overlap

The phenotype of both dystematic juvenile idiopathic arthritis (SJIA) in children and adult-onset still disease (AOSD) is viewed as part of the autoinflammatory spectrum. This is reinforced by evidence for an IL-1 transcriptional signature and responses to anti-IL-1 treatment. Poorly well-defined, or what was historically called “atypical AOSD”, is now considered as an autoinflammatory or unclassified systemic autoinflammatory disease. While SJIA has a rare monogenic variant documented in Arab populations, the typical cases of AOSD have a major histocompatibility complex-II association that related to autoimmunity, this can prove the presence of overlap between autoinflammation and autoimmunity [21].

The systemic lupus erythematosus (SLE) (the best example of bridging between autoinflammatory and autoimmune diseases)

The immunological disease continuum set Systemic lupus erythematosus toward the side of autoimmunity but even in 2006, it was known that soluble innate immunity, or the complement system, was connected to various SLE features with a decrease in C2, 3, and c4 that lead to the presence of SLE phenotypes (Fig. 2). Hence, SLE is placed to the side of the adaptive boundary or self-directed inflammation. But innate immunity might also be involved. Despite, beyond complement, Mendelian diseases collectively called “the interferonopathies”, due to impaired metabolism of self-nucleic acids, with elevated levels of type I IFN also lead to autoantibody associated SLE [22].

Fig. 2
figure 2

SLE is a one of the best examples in which the immunological continuum model can be applied showing the diversity of clinical manifestation according the involvement of different genetic and immune system components. SLE systemic lupus erythematosus; ALPS autoimmune lympho-proliferative syndrome; TREX1 three prime repair exonuclease1

Clinical approach to differentiate autoinflammation from autoimmunity:

Clinical investigations

The approach to differentiate autoinflammation from autoimmunity starts with good medical and family history, physical examination, laboratory tests involving complete blood count, level of complement and immunoglobulin in serum, general biochemistry, inflammatory biomarkers, and relevant autoantibodies. By the time autoinflammation is considered as a diagnosis, most patients will already have had a total workup involving assessment of infectious disease with blood cultures, viral, and bacteriological serologic studies [23].

Molecular investigations

The best test for the diagnosis of autoinflammatory disorders is an initial screen of genes known to be associated with monogenic autoinflammatory diseases. Patients tend to be sporadic rather than familial in hospitals. The difficulty of the genetic analysis is elevating, for example, the recognition that heterozygous mutations in the MEFV gene may be connected to Familial Mediterranean fever or other inflammatory phenotypes. While homozygous mutations are needed for autoimmune or autoinflammatory phenotypes in animal models, e.g., for CTLA4 or TNFAIP3, heterozygous mutations are associated with the presence of a Behcet’s disease-like phenotype. Unpopular types of NOD2 or TNFR1 are not infrequently present in patients with autoinflammatory disease clinics and their full meaning waits to be illuminated [24].

Complications of autoinflammatory disorders against autoimmune disorders

The intensity of autoinflammatory disorders ranges from very mild disease to dangerous forms resulting in elevation of rates of mortality. Patients can present with poorly defined autoinflammatory-driven shock and circulatory collapse which similar to septicemia. This really may be part of the autoinflammatory disease spectrum under the coverage of (macrophage activation syndrome) MAS. Indeed, MAS and severe sepsis resemble each other in the clinical, laboratory, pathological characters, involving an increase in ferritin level, various cytopenia, hepatic impairment with an elevation of liver enzymes, in particular, coagulopathy with a disseminated intravascular coagulation and tissue hemophagocytosis. In differences to autoinflammatory disorders, serious autoimmune diseases tend to exhibit a predominant attack of a single organ system and absence of the severe constitutional features with some exceptions involving dangerous anti-phospholipid syndrome, pulmonary involvement in anti-glomerular basement membrane syndrome, or severe autoimmune nephritis [25].

Therapeutic implications of autoinflammation and autoimmunity

Not only the autoimmunity and autoinflammation had common anatomical and genetic features but their useful therapeutic manipulation further represents immune pathogenesis and proper disease categorization. The emerging therapeutic results show an overarching concept but there are some therapeutic exceptions in these groups. For example, molecules that selectively target B cells (primarily anti-CD20 therapy with rituximab) are used in many of the classical autoantibody associated disorders. On the other side, predominantly autoinflammatory disorders often represent good results for anti-IL-1 therapy [26].

The non-autoantibody-mediated SpA-associated disorders commonly represent very good results to cytokine blockers and anti-TNFs. The “intermediate diseases” or “MHC-I-opathy” disorders express good results to therapies that block the IL-23/17 axis likely representing how local tissue factors ultimately arrange the so-called type 17 innate and adaptive lymphocytes to drive IL-17-associated pathology. Small molecules antagonize conventional T cells action over a large range of inflammatory diseases, but commonly less well than cytokine blockers. Steroids work through the entire spectrum of inflammatory disorders likely reflecting a lot of results on the immune system. Finally, the heterogeneity and difficulty of the immune system need to be well-known, reflecting the fact that some cytokine blockers, especially IL-6 antagonist, is useful in several adaptive immune disorders as well as innate/autoinflammatory disorders (Fig. 3) [14].

Fig. 3
figure 3

Autoimmunity and autoinflammation classification is reflected in differential therapeutic targeting. MMF mycophenolate mofetil; BAFF B cell activating factor; IL interleukin; IL-1R IL-1 receptor; IL-18BP IL-18 binding protein; TNF tumor necrosis factor; TNFI TNF inhibitor; JAKI Janus kinase inhibitor

Conclusions

Autoinflammatory and autoimmune disorders are marked by aberrant changes in innate and adaptive immunity that may lead to initial inflammatory action to an organ specific damage. These diseases have heterogeneity in terms of affected organs and clinical phenotypes. Despite the differences in etiology and phenotypic variations, they have common genetic associations, treatment responses, and clinical presentations, consequently, the presence of some similarities and differences between autoimmune and autoinflammatory disorders indicates variable degrees of bridging and overlapping between them.

Availability of data and materials

The datasets used during this review are available from the corresponding author.

Abbreviations

NOD:

Nucleotide-binding oligomerization domain

NLR:

Nucleotide-binding oligomerization domain (NOD)-like receptor

IL-1:

Interleukin

IFN:

Interferon

LRR:

Leucine-rich repeat

MHC:

Major histocompatibility complex

SPA:

Spondylo arthropathies

SJIA:

Systematic juvenile idiopathic arthritis

AOSD:

Adult onset still disease

SLE:

Systemic lupus erythematosus

CTLA4:

Cytotoxic T-lymphocyte antigen 4

TNFAIP3:

Tumor necrosis factor alpha-induced protein 3

MAS:

Macrophage activation syndrome

TNF:

Tumor necrosis factor

TNFR1:

Tumor necrosis factor receptor 1

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EE contributed to writing main text and conclusion of the manuscript. EZ contributed to tables and figure writing. SS gave the idea of the review and design of all parts of the manuscript. EH shared in all parts of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Eman S. Habib.

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El-Shebiny, E.M., Zahran, E.S., Shoeib, S.A. et al. Bridging autoinflammatory and autoimmune diseases. Egypt J Intern Med 33, 11 (2021). https://doi.org/10.1186/s43162-021-00040-5

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Keywords

  • Autoinflammatory
  • Autoimmune diseases
  • Bridging