Elsevier

Autoimmunity Reviews

Volume 12, Issue 1, November 2012, Pages 22-30
Autoimmunity Reviews

Review
Autoinflammation and autoimmunity: Bridging the divide

https://doi.org/10.1016/j.autrev.2012.07.018Get rights and content

Abstract

As soon as autoinflammatory diseases (AIDs) emerged as new entities, they have been linked to the well known world of autoimmunity. In fact, AIDs and systemic 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 musculoskeletal system; both include monogenic and polygenic diseases. From the pathogenetic point of view, they are characterized by a chronic activation of immune system, which eventually leads to tissue inflammation in genetically predisposed individuals. Nevertheless, the specific effectors of the 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.

Mutations in inflammasome-related proteins, particularly in NOD-like receptor (NLR) genes, have been strongly associated to the occurrence of AIDs, whereas the link between inflammasome and ADs is less clear. However, a role for this multiprotein-complex in some ADs can be postulated, since a wide spectrum of endogenous danger signals can activate NLRs and inflammasome products, including IL-1ß, can activate adaptive immunity. An association between single nucleotide polymorphisms (SNPs) localized in the inflammasome gene NLRP1 and systemic lupus erythematosus has recently been reported.

AIDs and ADs are currently subdivided into two different groups, but looking at their similarities they might be considered as a single group of diseases with a large immune pathological and clinical spectrum which includes at one end pure ADs and at the other end pure AIDs.

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)

  • C. Briani et al.

    Neurolupus is associated with anti-ribosomal P protein antibodies: an inception cohort study

    J Autoimmun

    (2009)
  • S. Padeh et al.

    Periodic fever, aphthous stomatitis, pharyngitis and adenopathy syndrome: clinical characteristic and outcome

    J Pediatr

    (1999)
  • L. Obici et al.

    Amyloidosis in autoinflammatory syndromes

    Autoimm Rev

    (2012)
  • A. Ghirardello et al.

    Antinucleosome antibodies in SLE: a two-year follow-up study of 101 patients

    J Autoimmun

    (2004)
  • A. Ghirardello et al.

    Commercial blot assays in the diagnosis of systemic rheumatic diseases

    Autoimmun Rev

    (2009)
  • A. Ghirardello et al.

    Diagnostic tests for antiribosomal P protein antibodies: a comparative evaluation of immunoblotting and ELISA assays

    J Autoimmun

    (2002)
  • L. Iaccarino et al.

    Anti-annexins autoantibodies: their role as biomarkers of autoimmune diseases

    Autoimmun Rev

    (2011)
  • O.P. Rekvig et al.

    Autoantibodies in lupus: culprits or passive bystanders?

    Autoimmun Rev

    (2012)
  • M. Zen et al.

    The kaleidoscope of glucorticoid effects on immune system

    Autoimmun Rev

    (2011)
  • A. Doria et al.

    SLE diagnosis and treatment: when early is early

    Autoimmun Rev

    (2010)
  • L. Iaccarino et al.

    Mycophenolate mofetil: what is its place in the treatment of autoimmune rheumatic diseases?

    Autoimmun Rev

    (2007)
  • M. Galeazzi et al.

    Autoinflammatory syndromes

    Clin Exp Rheumatol

    (2006)
  • S. Farasat et al.

    Autoinflammatory diseases. Clinical and genetic advances

    Arch Dermatol

    (2008)
  • A.N. Theofilopoulos et al.

    Sensors of the innate immune system: their link to rheumatic diseases

    Nat Rev Rheumatol

    (2010)
  • F. Martinon et al.

    The inflammasomes: guardians of the body

    Annu Rev Immunol

    (2009)
  • D. McGonagle et al.

    The NLR network and the immunological disease continuum of adaptive and innate immune-mediated inflammation

    Semin Immunopathol

    (2007)
  • E.A. Leadbetter et al.

    Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors

    Nature

    (2002)
  • T. Kawasaki et al.

    Recognition of nucleic acids by pattern-recognition receptors and its relevance in autoimmunity

    Immunol Rev

    (2011)
  • K. Shinkai et al.

    Cryopyrin-associated periodic syndromes and autoinflammation

    Clin Exp Dermatol

    (2008)
  • I Aksentijevich et al.

    The clinical continuum of cryopyrinopathies: novel CIAS1 mutations in North American patients and a new cryopyrin model

    Arthritis Rheum

    (2007)
  • M. Lamkanfi et al.

    Deregulated inflammasome signaling in disease

    Immunol Rev

    (2011)
  • J.E. Sims et al.

    The IL-1 family: regulators of immunity

    Nat Rev Immunol

    (2010)
  • S.L. Masters et al.

    Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory diseases

    Annu Rev Immunol

    (2009)
  • I. Aksentijevich et al.

    An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist

    N Engl J Med

    (2009)
  • B. Khor et al.

    Genetics and pathogenesis of inflammatory bowel disease

    Nature

    (2011)
  • F. Allantaz et al.

    Blood leukocyte microarrays to diagnose systemic onset juvenile idiopathic arthritis and follow the response to IL-1 blockade

    J Exp Med

    (2007)
  • A. Gül

    Behçet's disease as an autoinflammatory disorder

    Curr Drug Targets Inflamm Allergy

    (2005)
  • H.M. Feder et al.

    A clinical review of 105 patients with PFAPA (a periodic fever syndrome)

    Acta Paediatr

    (2010)
  • K. Kisand et al.

    Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy: known and novel aspects of the syndrome

    Ann N Y Acad Sci

    (2011)
  • A. Worth et al.

    Autoimmune lymphoproliferative syndrome: molecular basis of disease and clinical phenotype

    Br J Haematol

    (2006)
  • J.H. Cho et al.

    Genomics and the multifactorial nature of human autoimmune disease

    N Engl J Med

    (2011)
  • A. Pontillo et al.

    Polimorphisms in inflammasome genes are involved in the predisposition to systemic lupus erythematosus

    Autoimmunity

    (2012)
  • P. Sfriso et al.

    Infections and autoimmunity: the multifaceted relationship

    J Leukoc Biol

    (2010)
  • N. Agmon-Levin et al.

    Vaccines and autoimmunity

    Nat Rev Rheumatol

    (2009)
  • N. Bassi et al.

    Induction of the ‘ASIA’ syndrome in NZB/NZWF1 mice after injection of complete Freund's adjuvant (CFA)

    Lupus

    (2012)
  • F. Atzeni et al.

    Autoimmunity anti-TNFα agents

    Ann N Y Acad Sci

    (2005)
  • P. Sarzi-Puttini et al.

    Environment and systemic lupus erythematosus: an overview

    Autoimmunity

    (2005)
  • L. Stojanovich

    Stress and autoimmunity

    Autoimmun Rev

    (2010)
  • M.A. Pelagatti et al.

    Long-term clinical profile of children with the low-penetrance R92Q mutation of the TNFRSF1A gene

    Arthritis Rheum

    (2011)
  • M. Govoni et al.

    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

    (2012)
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