ReviewAutoinflammation and autoimmunity: Bridging the divide
Highlights
► AIDs are characterized by chronic activation of immune system (innate immunity). ► ADs are characterized by chronic activation of immune system (innate and adaptive). ► Inflammasome related genes are involved in the pathogenesis of AIDs and, probably, of ADs. ► AIDs and ADs are systemic diseases, frequently affecting skin, gut and musculoskeletal system. ► New biological therapies have reduced disease morbidities and improved prognosis of AIDs and ADs.
Introduction
Autoinflammatory diseases (AIDs), also called periodic fever syndromes, refer to a group of rare, hereditary, recurrent, unprovoked inflammatory disorders which occur in the absence of infection [1], [2], [3]. These diseases primarily include familial Mediterranean fever (FMF), tumor necrosis factor (TNF) receptor-associated periodic fever syndrome (TRAPS), hyperimmunoglobulinemia D and periodic fever syndrome (HIDS), cryopyrin-associated periodic syndrome (CAPS) including familial cold autoinflammatory syndrome (FCAS), Muckle–Wells syndrome (MWS) and neonatal onset multi-system inflammatory disease (NOMID)/chronic infantile neurological cutaneous and articular syndrome (CINCA).
Some other diseases characterized by episodes of acute, apparently inexplicable inflammation have recently been classified in this group, including pyogenic disorders (pyogenic arthritis, pyoderma gangrenosum and acne syndrome (PAPA), chronic recurrent multifocal osteomyelitis syndrome (CRMO), Majeed's syndrome), immune-mediated granulomatous diseases (Blau's syndrome, Crohn's disease), and idiopathic febrile syndromes (systemic-onset juvenile idiopathic arthritis (sJIA), periodic fever with aphthous stomatitis, pharyngitis, and cervical adenopathy syndrome (PFAPA), and Behçet's syndrome), as shown in Table 1.
As soon as AIDs emerged as new entities, they were linked to the well known world of autoimmunity.
A preliminary observation is that these two types of diseases, AIDs and autoimmune diseases (ADs), share some characteristics: they start with the prefix “auto” to define a pathological process directed against self; they are systemic diseases, frequently involving skin and musculoskeletal system; they include monogenic and polygenic diseases.
From the pathogenetic point of view, they are characterized by a chronic activation of the immune system, which eventually leads to tissue inflammation in genetically predisposed individuals.
Nevertheless, the specific effectors of damage are different in the two groups of diseases: in AIDs the innate immune system directly causes tissue inflammation, whereas in ADs the innate immune system activates the adaptive immune system which, in turn, is responsible for the inflammatory process (Fig. 1) [4].
ADs exhibit distinct major histocompatibility (MHC)-associated haplotype susceptibility [4], whereas AIDs do not have associations with MHC class II haplotypes.
Patients affected with AIDs compared to those with ADs do not have autoantibodies or autoreactive antigen-specific T cells driving the disease process; in AIDs monocyte–macrophages rather than T and B cells are responsible for inflammation and damage [4].
Section snippets
Innate and adaptive immune effectors involved in autoinflammatory and autoimmune diseases
Innate immunity represents the first barrier in host immune defense; it identifies pathogens or other harmful triggers inducing an inflammatory process with the aim of blocking their diffusion, and activates adaptive immunity.
The effector cells of innate immunity are phagocytes, including macrophages, dendritic cells and other antigens presenting cells (APC) [4]. Innate immunity acts through pattern recognition receptors (PRR) which bind to highly conserved structures expressed by pathogens
Conclusions
AIDs and ADs are due to an alteration in the homeostasis of the immune system, the former of the innate immunity and the latter of both innate and adaptive immunity.
In AIDs, innate immune cells, including macrophages and neutrophils, induce an inflammatory process which results in target tissue damage. In ADs, effectors of innate and adaptive immunity contribute to the break of tolerance towards native antigens and to the development of autoantibodies which are eventually responsible for tissue
References (107)
- et al.
Autoinflammatory diseases
Best Pract Res Clin Rheumatol
(2008) - et al.
Sunburned skin activates inflammasomes
Trends Cell Biol
(2008) - et al.
Critical regulation of early Th17 cell differentiation by interleukin-1 signaling
Immunity
(2009) - et al.
Immune dysregulation, polyendocrinopathy, enteropathy, X-linked: forkhead box protein 3 mutations and lack of regulatory T cells
J Allergy Clin Immunol
(2007) - et al.
The inflammasome: a danger sensing complex triggering innate immunity
Curr Opin Immunol
(2007) - et al.
Exploring the complex relationships between infections and autoimmunity
Autoimmun Rev
(2008) - et al.
‘ASIA’ — autoimmune/inflammatory syndrome induced by adjuvants
J Autoimmun
(2011) - et al.
Autoinflammatory disease reloaded: a clinical perspective
Cell
(2010) - et al.
Inflammation and accelerated atherosclerosis: basic mechanisms
Rheum Dis Clin North Am
(2005) - et al.
The epidemiology of autoimmune diseases
Autoimmun Rev
(2003)
Neurolupus is associated with anti-ribosomal P protein antibodies: an inception cohort study
J Autoimmun
Periodic fever, aphthous stomatitis, pharyngitis and adenopathy syndrome: clinical characteristic and outcome
J Pediatr
Amyloidosis in autoinflammatory syndromes
Autoimm Rev
Antinucleosome antibodies in SLE: a two-year follow-up study of 101 patients
J Autoimmun
Commercial blot assays in the diagnosis of systemic rheumatic diseases
Autoimmun Rev
Diagnostic tests for antiribosomal P protein antibodies: a comparative evaluation of immunoblotting and ELISA assays
J Autoimmun
Anti-annexins autoantibodies: their role as biomarkers of autoimmune diseases
Autoimmun Rev
Autoantibodies in lupus: culprits or passive bystanders?
Autoimmun Rev
The kaleidoscope of glucorticoid effects on immune system
Autoimmun Rev
SLE diagnosis and treatment: when early is early
Autoimmun Rev
Mycophenolate mofetil: what is its place in the treatment of autoimmune rheumatic diseases?
Autoimmun Rev
Autoinflammatory syndromes
Clin Exp Rheumatol
Autoinflammatory diseases. Clinical and genetic advances
Arch Dermatol
Sensors of the innate immune system: their link to rheumatic diseases
Nat Rev Rheumatol
The inflammasomes: guardians of the body
Annu Rev Immunol
The NLR network and the immunological disease continuum of adaptive and innate immune-mediated inflammation
Semin Immunopathol
Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors
Nature
Recognition of nucleic acids by pattern-recognition receptors and its relevance in autoimmunity
Immunol Rev
Cryopyrin-associated periodic syndromes and autoinflammation
Clin Exp Dermatol
The clinical continuum of cryopyrinopathies: novel CIAS1 mutations in North American patients and a new cryopyrin model
Arthritis Rheum
Deregulated inflammasome signaling in disease
Immunol Rev
The IL-1 family: regulators of immunity
Nat Rev Immunol
Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory diseases
Annu Rev Immunol
An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist
N Engl J Med
Genetics and pathogenesis of inflammatory bowel disease
Nature
Blood leukocyte microarrays to diagnose systemic onset juvenile idiopathic arthritis and follow the response to IL-1 blockade
J Exp Med
Behçet's disease as an autoinflammatory disorder
Curr Drug Targets Inflamm Allergy
A clinical review of 105 patients with PFAPA (a periodic fever syndrome)
Acta Paediatr
Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy: known and novel aspects of the syndrome
Ann N Y Acad Sci
Autoimmune lymphoproliferative syndrome: molecular basis of disease and clinical phenotype
Br J Haematol
Genomics and the multifactorial nature of human autoimmune disease
N Engl J Med
Polimorphisms in inflammasome genes are involved in the predisposition to systemic lupus erythematosus
Autoimmunity
Infections and autoimmunity: the multifaceted relationship
J Leukoc Biol
Vaccines and autoimmunity
Nat Rev Rheumatol
Induction of the ‘ASIA’ syndrome in NZB/NZWF1 mice after injection of complete Freund's adjuvant (CFA)
Lupus
Autoimmunity anti-TNFα agents
Ann N Y Acad Sci
Environment and systemic lupus erythematosus: an overview
Autoimmunity
Stress and autoimmunity
Autoimmun Rev
Long-term clinical profile of children with the low-penetrance R92Q mutation of the TNFRSF1A gene
Arthritis Rheum
Factors and comorbidities associated with first neuropsychiatric event in systemic lupus erythematosus: does a risk profile exist? A large multicentre retrospective cross-sectional study on 959 Italian patients
Rheumatology
Cited by (176)
Clinical utility of measuring CD4<sup>+</sup> T follicular cells in patients with immune dysregulation
2023, Journal of AutoimmunityCo-occurrence of familial Mediterranean fever with systemic lupus erythematosus in South Asian population
2023, Reumatologia ClinicaCitation Excerpt :This acts as a catalyst for NLR activation and auto-antibody formation. This pathophysiology is described by Doria et al. in her study, in addition to a link between single nucleotide polymorphisms (SNPs) with SLE.23 As compared to the prevalence in the Mediterranean region, FMF is a rare disease in South Asia.24
Cytokine storm in COVID-19 and other diseases: emerging therapeutic interventions
2023, Stem Cells: an Alternative Therapy for COVID-19 and Cytokine StormThe immunopsychiatry of early-onset psychosis
2023, Adolescent Psychosis: Clinical and Scientific PerspectivesTreatment of refractory Yao syndrome with canakinumab
2022, JAAD Case ReportsCitation Excerpt :In contrast with classic autoimmune disorders, autoinflammatory conditions lack identifiable autoantibodies but rather comprise periodic fever syndromes with evanescent urticarial papules, plaques, figurate erythema, erysipelas-like eruptions, and sterile pustules, typically in association with. fever Elevated acute phase reactants, rash, serositis, arthritis, and lymphadenopathy are present in both autoinflammatory and autoimmune conditions.10 Yao et al2 developed a 6-gene panel to screen for periodic fever syndromes that may mimic YAOS (Table I).