The possibility of maladies in which the immune system turns against its host has long held a special fascination, dating back to the time of Paul Ehrlich and “Horror Autotoxicus
). Inherited illnesses, so-called “experiments of nature,” extend our understanding of genes and proteins we may have thought we understood while opening windows to the heretofore unimaginable. The publication of this review marks the tenth anniversary of the concept of systemic autoinflammatory diseases. The idea was initially proposed with the identification of ectodomain mutations in the p55 tumor necrosis factor (TNF) receptor in patients with a dominantly inherited syndrome of fever and widespread inflammation (the TNF receptor–associated periodic syndrome, TRAPS) (2
). This discovery followed close on the heels of the positional cloning of the gene for a similar recessively inherited illness, familial Mediterranean fever (FMF) (3
), and thereby raised the possibility that these disorders might be prototypes for an emerging family of inflammatory diseases. Both FMF and TRAPS are characterized by seemingly unprovoked, recurrent episodes of fever, serositis, arthritis, and cutaneous inflammation, but the usual hallmarks of autoimmunity, namely high-titer autoantibodies and antigen-specific T cells, are usually absent. The term autoinflammatory was coined to draw the distinction between this category of illnesses and the more classically recognized autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis, in which the hallmarks of adaptive immunity are more evident.
The following year witnessed the identification of the gene underlying yet another hereditary fever, the hyperimmunoglobulinemia D with periodic fever syndrome (HIDS) (5
), and the positional cloning of a dominantly inherited gene that causes a curious syndrome of fever, malaise, and hives-like rash upon generalized cold exposure (7
). Neither of these latter mendelian disorders fits under the rubric of classical autoimmunity, thus further kindling the notion that autoinflammation might serve as the basis for a new taxonomy of human diseases that are in a sense complementary to the established autoimmune diseases. Based more on their clinical presentation than on a detailed understanding of their molecular basis, several other categories were added to the autoinflammatory universe, including metabolic disorders such as gout and other crystalline arthropathies, complement diatheses such as hereditary angioedema, granulomatous diseases such as Blau syndrome (chronic granulomatous synovitis with uveitis and cranial neuropathy), storage diseases such as Gaucher’s disease and Hermansky-Pudlak syndrome, fibrosing disorders such as idiopathic pulmonary fibrosis, and vasculitic syndromes such as Behçet’s disease (8
). This formulation not only widened the phenotypic scope associated with autoinflammation but also extended the concept into the realm of genetically complex disease. Even more recently, several other classes of diseases have been placed under the autoinflammatory banner, including idiopathic febrile syndromes [systemic-onset juvenile idiopathic arthritis (SoJIA); adult Still’s disease; the syndrome of periodic fever with aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA)] (9
); pyogenic disorders such as the syndrome of pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) (11
); and the autoinflammatory bone diseases (12
). The notion that the inflammatory manifestations of these diseases are truly unprovoked is, of course, a relative matter, since we now know that a number of factors, including psychological stress, trauma, immunizations, cold exposure, and dietary indiscretion, may trigger some of these illnesses, but in all cases the autoinflammatory appellation implicitly posits a significant host predilection.
A truly useful disease nosology reflects not only clinical phenotype but also underlying biology, thereby suggesting previously unexpected relationships between/among illnesses, spawning new pathogenic hypotheses, and directing the clinician to novel therapeutic targets. At first in parallel and relatively independently, the biologic basis for autoinflammation was established with the recognition of innate immunity as a phylogenetically ancient, hardwired, rapid-response system distinct from but, in mammals, intertwined with adaptive immunity (13
). Over time, it became clear that the myeloid effector cells and germline molecules of innate immunity play a major role in the pathogenesis of many of the illnesses clinically classified as autoinflammatory, while the lymphoid cells and somatically plastic molecules of the adaptive immune system play a more significant role in the classic autoimmune diseases. A watershed in the convergence of the clinical concept of autoinflammatory disease with the biology of innate immunity came with the discovery that three well-established autoinflammatory diseases are all caused by activating, gain-of-function mutations in NLRP3
(originally denoted CIAS1
yndrome 1; also known as NALP3
, and CLR1.1
), encoding what was then a newly recognized molecular linchpin in the innate immune system (7
The discovery of disease-associated mutations in NLRP3
solidified the nexus between autoinflammatory disease and innate immunity for several reasons. First, the NLRP3
protein product, originally called cryopyrin, now officially denoted NLRP3, is a component of a macromolecular complex, the inflammasome, that senses various microbial products and endogenous “danger signals” (damage-associated molecular patterns, DAMPs) to activate caspase-1, thereby initiating IL-1β and IL-18 processing, a key step in the innate immune response (16
). Second, the NLRP3 inflammasome may directly or indirectly interact with proteins mutated in other putative autoinflammatory diseases, including pyrin (in FMF) (17
) and PSTPIP1 (in PAPA syndrome) (11
). Third, the inflammasome has now been implicated in the pathogenesis of a number of diseases, such as gout (18
) and pulmonary fibrosis (19
), included in the expanded definition of autoinflammation, thus providing molecular vindication for the clinical classification. Finally, NLRP3 is a prototype for a family of proteins, now known as the NLR family (22
), that is intimately involved in the innate immune system, and recent evidence implicates other members of this protein family in human disease.
With the recognition that these inflammatory diseases without hallmarks of adaptive immunity are in fact disorders of the innate immune system, it is possible to propose a new schema based upon underlying molecular mechanisms (). It should be stated at the outset that, as noted by McGonagle & McDermott (25
), the spectrum of self-reactive immunological disease represents a continuum between autoimmune disorders based primarily on lesions of the adaptive immune system and autoinflammatory conditions rooted primarily in the innate immune system. Particularly for genetically complex disorders, multiple lesions of both branches of the immune system, with potentially self-amplifying loops, are quite possible. In keeping with the foregoing discussion, the first types of autoinflammatory disease enumerated in the Table are IL-1β inflammasomopathies, defined as disorders of macromolecular IL-1β-activating complexes, the prototypes of which are nucleated by NLRP3, but which may also include complexes of a number of related proteins. Intrinsic inflammasomopathies represent molecular lesions in the constituent proteins of the complex, while extrinsic inflammasomopathies denote disorders of various upstream or downstream regulatory elements.
Provisional molecular/functional classification of autoinflammatory disease
Although the IL-1β inflammasome represents a major conceptual advance in our understanding of innate immunity and related human disease, it is by no means the only molecular engine of innate immunity. In the Table, the proposed Type 2 autoinflammatory diseases, such as Crohn’s disease (CD) and Blau syndrome (BS), are caused in part by sequence variants in NOD2/CARD15
). While IL-1β undeniably plays a role in both illnesses, the NOD2/CARD15 protein plays a central role in NF-κB activation in response to intracellular microbial products. Emphasizing the interplay between innate and adaptive immunity, granulomas feature prominently in both disorders. In a third member of the proposed NF-κB activation disorders, Guadaloupe variant periodic fever syndrome, mutations occur in NLRP12
, encoding a regulator of NF-κB activation (29
A third group of autoinflammatory diseases is due to the biologic consequences of protein misfolding in cells of the innate immune system. The mendelian prototype of this process is TRAPS, in which missense substitutions in the p55 TNF receptor lead to misfolding (30
) and ligand-independent activation of kinases and aberrant cytokine production. Similarly, in the spondyloarthropathies, misfolding of HLA-B27 appears to trigger the unfolded protein response (UPR) in macrophages and consequently inappropriate cytokine secretion (31
Disorders of the complement system, long recognized as a key component of innate immunity, can lead to a host of immunologic disorders. In some cases, such as the deficiency of the fourth component of complement, abnormal clearance of immune complexes leads to a classical autoimmune lupus-like picture. Here we focus on those instances in which the deficiency of complement regulatory factors produces an autoinflammatory phenotype, such as age-related macular degeneration and atypical hemolytic uremic syndrome (Type 4 disease in the Table).
Cherubism, a relatively newly recognized autoinflammatory disorder of the bone, is caused by mutations in an SH3-binding protein (34
), which in animal models leads to heightened responsiveness to the cytokines M-CSF and RANKL, and increased osteoclastogenesis (35
). Given the importance of cytokine signaling in the innate immune response, additional examples of aberrant cytokine responses will likely be identified in other autoinflammatory diseases, and hence the proposal of Type 5 disorders.
Finally, macrophage activation is a common theme among a host of inflammatory diseases, and the genetics of familial hemophagocytic lymphohistiocytosis implicates loss-of-function lesions in the adaptive immune system as one cause of this (36
). Other mechanisms leading to activation of effector cells in the innate immune system and elaboration of a proinflammatory cytokine milieu also characterize Type 6 autoinflammatory disease, which possibly includes the leading cause of death in the Western world, atherosclerosis (38
There remain a number of human illnesses that are clearly autoinflammatory but do not fall neatly into any of the proposed categories. For some disorders, such as PFAPA, the molecular details are still too few to permit classification, whereas for other syndromes, such as SoJIA, multiple molecular mechanisms are emerging. In yet other instances, such as Behçet’s disease, lack of detail and heterogeneity appear paradoxically to go hand in hand. Undoubtedly, the six types of autoinflammatory disease enumerated in represent only a beginning but should serve not only to organize our thinking about existing data, but also to stimulate hypotheses about less well-understood phenotypes.