Elsevier

Clinical Immunology

Volume 165, April 2016, Pages 21-28
Clinical Immunology

Review article
Shaping the spectrum — From autoinflammation to autoimmunity

https://doi.org/10.1016/j.clim.2016.03.002Get rights and content

Highlights

  • Inflammatory responses are exerted by components of the innate and the adaptive immune system.

  • Autoimmune-inflammatory disorders can be placed within an “immunological spectrum”.

  • Recent observations further establish manifold interconnections between innate and adaptive immune responses.

  • Deciphering innate and adaptive mechanisms in autoimmune-inflammatory disorders will allow target-directed treatment.

Abstract

Historically, autoimmune-inflammatory disorders were subdivided into autoinflammatory vs. autoimmune diseases. About a decade ago, an immunological continuum was proposed, placing “classical” autoinflammatory disorders, characterized by systemic inflammation in the absence of high-titer autoantibodies or autoreactive T lymphocytes, at the one end, and autoimmune disorders at the other end. We provide an overview of recent developments and observations, filling in some of the gaps and showing strong interconnections between innate and adaptive immune mechanisms, indicating that disorders from both ends of the immunological spectrum indeed share key pathomechanisms. We focus on three exemplary disorders: i) systemic juvenile idiopathic arthritis representing “classical” autoinflammatory disorders; ii) psoriasis, a mixed pattern disease; and iii) systemic lupus erythematosus, a prototypical autoimmune disease. We summarize scientific observations suggesting that, depending on disease stages and/or duration, individualized treatment targeting innate or adaptive immune mechanisms in disorders from either end of the immunological spectrum may control disease activity.

Introduction

Under physiological conditions, immune responses are induced by pathogens or other danger signals and conducted by immune and/or sometimes epithelial cells. The immune system can be subdivided into two parts, the developmentally more ancient innate immune system, and the evolutionarily younger adaptive or acquired immune system [1], [2], [3], [4], [5].

The innate immune system comprises a number of non-specific defense mechanism, constituting the “first line of defense” against pathogens. Innate mechanisms include both cellular and humoral components, which are involved in the detection and elimination of danger signals. Targets of the innate immune system can be of microbial origin (pathogen-associated molecular patterns, PAMPs) but also host molecules (danger-associated molecular patterns, DAMPs) [1], [2], [6]. Innate immune mechanisms are manifold and our understanding of their molecular composition and function is continuously expanding. Central molecules of innate immune mechanisms include Toll-like receptors (TLRs), Nod-like receptors (NLRs), scaffolding proteins, such as the caspase recruitment domain (CARD) family of proteins, and cytosolic DNA-sensing molecules, inflammatory multi-protein complexes, referred to as inflammasomes, the complement system, and others. Cellular components of the innate immune system comprise monocytes and macrophages, neutrophilic granulocytes, natural killer (NK) cells, and dendritic cells (DC). However, also non-immune cells, e.g. epithelial cells, express molecules that are considered part of the innate system, including TLR4/5, CARD family proteins, and inflammasome components [1], [2], [3], [4], [5], [6], [7].

The adaptive immune system is evolutionary younger and exclusive to vertebrates. Adaptive immune mechanisms create the immunological memory to pathogens in response to an initial contact. This results in a rapid and enhanced response to subsequent exposures. In contrast to inflammation mediated by the innate immune system, acquired immune responses are highly specific and can provide long-lasting protection from pathogens. Specificity to pathogens, spatiotemporal or regional control, and the limitation of inflammatory responses is necessary to prevent tissue damage, and is mediated by cells of the adaptive immune system (B and T cells), which provide humoral and cellular immune responses to “intruders” [8], [9], [10], [11].

Following the definition suggested by Kastner et al., autoinflammatory disorders are characterized by seemingly unprovoked systemic inflammation in the absence of high-titer autoantibodies and autoreactive T lymphocytes [12], [13]. More recently, however, the definition was expanded by the observation that external factors, including the environment, infections, temperature, etc., may promote flares, alter the phenotypes, and/or directly contribute to pathogenesis [1], [3], [4], [14]. Thus, historically autoinflammatory disorders used to be strictly separated from autoimmune disorders, in which adaptive immune cells (B and/or T lymphocytes) largely contribute to the pathophysiology. About a decade ago, McDermott and McGonagle proposed a classification of immunological diseases with prototypical, mostly monogenic autoinflammatory disorders at the one end, and classical autoimmune disorders at the other end of an immunological spectrum [13]. Over the recent years, a number of monogenic and polygenic common and rare disorders have been identified, providing advanced insight into the pathophysiology of autoinflammatory and autoimmune disorders, further establishing the interplay between the two “parts” of the immune system in complex systems (such as the human body) [4], [14], [15]. Furthermore, genome-wide association studies, molecular imaging techniques, gene function studies, and the identification of tissue-specific factors in some disorders provided insights into the relative contribution of innate and adaptive immune mechanisms to some non-infectious immunological disorders, aided in gaining a better understanding of autoimmune/inflammatory conditions, and scientifically verified the hypotheses of McGonagle et al. Here, we provide an update on molecular pathomechanisms contributing to the immunological continuum, focusing on three exemplary disorders: i) the “classical” autoinflammatory disease systemic juvenile idiopathic arthritis (sJIA), ii) the mixed-pattern disorder psoriasis, and iii) the prototypical autoimmune disease systemic lupus erythematosus [16] and what we learned from rare monogenic disorders. The goal of this manuscript is not to deliver an all-embracing review of molecular pathomechanisms of single disorders, however, to provide an overview of recent developments in three “model disorders”, focusing on proposed or established interconnections between innate and adaptive immune mechanisms in autoimmune-inflammatory disorders.

Section snippets

Classical autoinflammatory disorders: sJIA

The systemic form of juvenile idiopathic arthritis (sJIA) is a prototypical autoinflammatory disorder [17], [18]. During its early and highly acute phase it is characterized by clinical signs of inflammation including fevers, skin rash, lymphadenopathy, hepatosplenomegaly, and/or serositis [17], [19], [20], [21]. Particularly in this early inflammatory stage, sJIA is characterized by the absence of autoreactive T cells and high-titer autoantibodies, thus following the “traditional” definition

Mixed pattern disorders: psoriasis

Psoriasis is an immunologically mediated disease that covers a range of subtypes or disease-stages representing mixed patterns of dysregulated innate and/or adaptive immune responses (Fig. 1) [38], [39], [40]. Early psoriasis but also highly active disease during flares sometimes presents with pustulous lesions, which entail dermal infiltrates with innate immune cells, including neutrophilic granulocytes, monocytes/macrophages, activated mast cells, as well as classical dendritic and

“Classical” autoimmune disorders: systemic lupus erythematosus

Systemic lupus erythematosus [16] is a prototypical autoimmune disorder, characterized by the presence of autoantibodies, the formation of immune complexes, and self-reactive B- and T lymphocytes [52], [53]. As a result of severe immune dysregulation, affected individuals present with systemic inflammation and variable organ damage. The molecular pathology of SLE is highly complex and only incompletely understood. It is known to involve both genetic and environmental factors. While most genetic

Conclusions

Over the past decade, the identification of disease-causing mutations in single genes and the association of polymorphisms in disease-associated gene loci contributed to a deeper understanding of the pathophysiology of various autoimmune-inflammatory disorders. Recent observations underscore the significance and relevance of a previously proposed immunological continuum, ranging from monogenetic autoinflammatory disorders at the one end to autoimmune diseases at the other end [13]. Scientific

Acknowledgments

C.M.H. actively participated in advisory boards of Novartis pharmaceuticals. The author declares no conflict of interest concerning this manuscript. C.M.H.'s research is supported by the Fritz-Thyssen-Foundation (10.15.1.019MN) and the MeDDrive intramural program of the University of Technology Dresden (60.364). C.M.H. wishes to thank Susanne Abraham for helpful discussion and clinical images, Sigrun Hofmann and Angela-Rösen-Wolff for helpful discussion.

References (77)

  • C.T. Jordan et al.

    Rare and common variants in CARD14, encoding an epidermal regulator of NF-kappaB, in psoriasis

    Am. J. Hum. Genet.

    (2012)
  • C.T. Jordan et al.

    PSORS2 is due to mutations in CARD14

    Am. J. Hum. Genet.

    (2012)
  • Q. Zhou et al.

    Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease

    Nat. Genet.

    (2016)
  • M. Diani et al.

    T cell responses in psoriasis and psoriatic arthritis

    Autoimmun. Rev.

    (2015)
  • H. Morbach et al.

    Autoinflammatory bone disorders

    Clin. Immunol.

    (2013)
  • A. Ablasser et al.

    Nucleic acid driven sterile inflammation

    Clin. Immunol.

    (2013)
  • Y. Yang et al.

    Gene copy-number variation and associated polymorphisms of complement component C4 in human systemic lupus erythematosus (SLE): low copy number is a risk factor for and high copy number is a protective factor against SLE susceptibility in European Americans

    Am. J. Hum. Genet.

    (2007)
  • Y.J. Crow

    Type I interferonopathies: mendelian type I interferon up-regulation

    Curr. Opin. Immunol.

    (2015)
  • K. Chen et al.

    Endocytosis of soluble immune complexes leads to their clearance by FcgammaRIIIB but induces neutrophil extracellular traps via FcgammaRIIA in vivo

    Blood

    (2012)
  • S.L. Masters

    Broadening the definition of autoinflammation

    Semin. Immunopathol.

    (2015)
  • G. Sarrabay et al.

    The autoinflammatory diseases: a fashion with blurred boundaries!

    Semin. Immunopathol.

    (2015)
  • S.L. Masters et al.

    Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease (*)

    Annu. Rev. Immunol.

    (2009)
  • A.K. Simon et al.

    Evolution of the immune system in humans from infancy to old age

    Proceedings Biological Sciences/The Royal Society

    (2015)
  • A. Davidson et al.

    Autoimmune diseases

    N. Engl. J. Med.

    (2001)
  • C.M. Hedrich et al.

    Cell type-specific regulation of IL-10 expression in inflammation and disease

    Immunol. Res.

    (2010)
  • D. McGonagle et al.

    A proposed classification of the immunological diseases

    PLoS Med.

    (2006)
  • S.W. Canna et al.

    New monogenic autoinflammatory diseases—a clinical overview

    Semin. Immunopathol.

    (2015)
  • I. Aksentijevich

    Update on genetics and pathogenesis of autoinflammatory diseases: the last 2 years

    Semin. Immunopathol.

    (2015)
  • G.S. Alarcon et al.

    Time to renal disease and end-stage renal disease in PROFILE: a multiethnic lupus cohort

    PLoS Med.

    (2006)
  • S. Brydges et al.

    The systemic autoinflammatory diseases: inborn errors of the innate immune system

    Curr. Top. Microbiol. Immunol.

    (2006)
  • E.M. Behrens et al.

    Evaluation of the presentation of systemic onset juvenile rheumatoid arthritis: data from the Pennsylvania Systemic Onset Juvenile Arthritis Registry (PASOJAR)

    J. Rheumatol.

    (2008)
  • C.K. Correll et al.

    Advances in the pathogenesis and treatment of systemic juvenile idiopathic arthritis

    Pediatr. Res.

    (2014)
  • C.M. Hedrich et al.

    Anakinra: a safe and effective first-line treatment in systemic onset juvenile idiopathic arthritis (SoJIA)

    Rheumatol. Int.

    (2012)
  • P.A. Nigrovic et al.

    Anakinra as first-line disease-modifying therapy in systemic juvenile idiopathic arthritis: report of forty-six patients from an international multicenter series

    Arthritis Rheum.

    (2011)
  • S.J. Vastert et al.

    Effectiveness of first-line treatment with recombinant interleukin-1 receptor antagonist in steroid-naive patients with new-onset systemic juvenile idiopathic arthritis: results of a prospective cohort study

    Arthritis Rheum.

    (2014)
  • R.E. Petty et al.

    International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001

    J. Rheumatol.

    (2004)
  • P.A. Nigrovic

    Review: is there a window of opportunity for treatment of systemic juvenile idiopathic arthritis?

    Arthritis Rheum.

    (2014)
  • F. De Benedetti et al.

    Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis

    N. Engl. J. Med.

    (2012)
  • Cited by (0)

    View full text