COMMENTARY COMMENTARY Autoinflammation and in systemic juvenile idiopathic

Peter A. Nigrovica,b,1 resulting from divergent genetic back- aDivision of , Immunology, and Allergy, Department of Medicine, Brigham and grounds, Ombrello et al. (1) show that sJIA Women’s Hospital, Harvard Medical School, Boston, MA 02115; and bDivision of Immunology, ’ is linked to a specific MHC II haplotype. In Department of Medicine, Boston Children s Hospital, Harvard Medical School, Boston, MA 02115 particular, the authors identify a strong association with two specific alleles of HLA- DRB1*11 (odds ratio 2.3). Using an impu- Juvenile idiopathic arthritis (JIA) encompasses immune tolerance is intact. and rashes tation strategy pioneered by Raychaudhuri et al. a range of phenotypes of joint are common presenting features and the most (2), Ombrello et al. (1) implicate a specific that begin in childhood. The most distinctive severe forms present early in life, reflecting amino acid, glutamate 68 (glut68), as the most and potentially most severe of these is systemic the fundamental impact of defective immune important carrier of risk, although they JIA (sJIA), an intensely inflammatory disease “brakes.” In many autoinflammatory condi- are unable to exclude a role for closely characterized by high spiking fevers and eva- tions, IL-1 antagonism results in dramatic im- linked amino acids. nescent rashes that sometimes progresses to provement, whereas such treatment is at best On its face, this finding throws a monkey a devastating chronic polyarthritis. In PNAS, modestly effective in autoimmune diseases. wrench into the characterization of sJIA as Ombrello et al. establish an unequivocal genetic So where does sJIA fit on this spectrum? an autoinflammatory disease. MHC linkage association between sJIA and the major histo- Most rheumatologic diseases are more prev- implies a role for T cells, because pre- compatibility (MHC) region, in particular with alent in females, but sJIA affects boys ap- + senting antigen to CD4 T cells is after all the class II allele HLA-DRB1*11 (1). This is a proximately as often as girls. Autoantibodies what MHC II does for a living. What are we big deal. Let’sconsiderwhy. Ombrello et al. establish to make of the fact that sJIA looks in so Autoinflammation and Autoimmunity many ways like an autoinflammatory dis- Over the last 15 y, it has become evident that an unequivocal genetic ease, and yet is clearly linked to the MHC? ’ there are multiple ways that the immune association between The answer is likely complicated, and it s ’ system can misfire to cause disease. The best sJIA and the major his- safe to say that we don tknowyet.Ombrello recognized of these is termed “autoimmunity,” et al. (1) raise the interesting hypothesis that the wherein the immune system errantly targets tocompatibility (MHC) MHC may act not as an antigen-presenting self-antigens as though they were foreign. region, in particular molecule but as a direct activator of macrophages, However, in some cases no autoantigen is with the class II allele dendritic cells, and other MHC II-expressing involved, and the immune system initiates lineages. This hypothesis preserves sJIA as a an inflammatory response because of a HLA-DRB1*11. pure autoinflammatory disease, with no role for antigen-specific T cells. Indeed, it is in- defect in normal self-inhibitory mecha- have not been identified. sJIA is the only triguing that—unlike rheumatoid arthritis- nisms. This family of disorders is termed form of childhood arthritis to occur with any “ ” associated MHC II amino acids—glut68 is autoinflammatory and is exemplified by frequency in the first year of life. Fevers and situated outside the antigen binding groove. diseases such as familial Mediterranean . rashes are florid. Finally, sJIA can respond This localization should exclude glut68 from a At a first approximation, autoimmune dis- dramatically to blockade of IL-1 (and IL-6, direct role in antigen selection, although it eases can be thought of as errors of adaptive which is both induced by and induces IL-1). could presumably still alter the spatial confor- immunity (mistakes by antigen-specific T In common with some autoinflammatory and B cells), whereas autoinflammatory dis- mation of the groove or otherwise modulate conditions, circulating levels of IL-18 can be the interaction between the MHC and the eases arise through defects in hard-wired path- extreme. It is therefore not surprising that ways typically associated with innate immunity. T-cell receptor. Furthermore, close linkage sJIA is often grouped with the autoinflam- raises the possibility that amino acids in the These two broad categories of immune- matory diseases. mediated disease exhibit characteristic hall- antigen-presenting groove may still play marks. Autoimmune diseases are usually more sJIA and the MHC key roles. However, as Ombrello et al. (1) prevalent in females, feature circulating auto- Enter Ombrello et al. (1). The association of point out, there is well-established precedent for , and display genetic linkage to spe- sJIA with the MHC has been explored pre- cific MHC I and II alleles required for antigen viously, but the small size of earlier series and Author contributions: P.A.N. wrote the paper. presentation. Fever, if it occurs, is rarely a the inconsistency of their results have left Conflict of interest statement: P.A.N. is supported by the dominant feature of the presentation. Auto- the impression that—like any self-respecting Rheumatology Research Foundation, the National Institute of — Arthritis, Musculoskeletal and Skin Disease (NIAMS), investigator- immunity in its usual polygenic forms is also autoinflammatory disease sJIA is free of initiated research grants from Novartis, Inc., and Sobi, Inc., and rare in the first year of life. In contrast, auto- MHC linkage. The present investigators the Fundación Bechara. He has received consulting fees from inflammatory diseases typically exhibit an even demonstrate otherwise. Gathering together Alkermes, Genentech, Novartis, Novo Nordisk, and Sobi. ratio of males to females and are free of auto- almost 1,000 cases and over 8,000 controls, See companion article on page 15970. antibodies or MHC I/II associations because and using strict criteria to avoid artifacts 1Email: [email protected].

www.pnas.org/cgi/doi/10.1073/pnas.1521837113 PNAS | December 29, 2015 | vol. 112 | no. 52 | 15785–15786 Downloaded by guest on October 4, 2021 cell activation via the MHC, and MHC II- The Biphasic Hypothesis effective cytokine blockade should dramatically mediated cell activation by staphylococcal How can we harmonize the findings of abrogate the development of chronic arthritis, a enterotoxins can exhibit allele specificity (3). Ombrello et al. (1) with these clinical and possibility suggested by observational series but However, the more straightforward inter- mechanistic observations? One potential solution not yet confirmed in clinical trials. It is im- pretation of an MHC II association runs is that mechanisms of disease onset may be portant to note that many sJIA patients have no through antigen presentation. This would seem distinct from mechanisms driving disease identified genetic defects in cell–cell killing, al- especially likely here because HLA-DRB1*11 chronicity (11). According to the so-called though functional impairment in cytotoxic cell is linked not only with sJIA but also two “biphasic hypothesis,” sJIA begins as a function is common, at least in the acute phase. other forms of childhood arthritis, oli- syndrome of immune dysregulation manifest- Some patients respond incompletely to IL-1 in goarticular and seronegative polyarticular JIA ing as elevated levels of cytokines, such as IL-1. early disease, whereas others exhibit excellent (4, 5). The plausibility of the T-cell alternative is This autoinflammatory-like cytokine milieu responses even years into the disease course. enhanced by several interesting aspects of the skews the T-cell effector/regulatory balance, These differences may well reflect pathogenic sJIA phenotype. First, familial sJIA is ex- promoting development of a population of heterogeneity, although the extent and impor- traordinarily rare. Second, whereas sJIA oc- pathogenic lymphocytes responsible for chronic tance of pathophysiological differences among curs in infancy, it is exceptionally rare in early arthritis. This hypothesis is suggested by the sJIA patients remain to be defined (14, 15). infancy (first 6 mo of life), unlike many other surprisingly central role of T cells (including γδ The findings of Ombrello et al. (1) are autoinflammatory syndromes. Third, as cells) in arthritis resulting from IL-1 receptor therefore a big deal because they force a re- Ombrello et al. (1) note, T-cell skewing to- agonist (IL-1ra) deficiency in mice (12, 13). examination of the increasingly prevalent ward Th17 cells has been observed in sJIA Genetic or acquired impairment in cell–cell assumption that sJIA is an autoinflammatory patients, whereas blockade of T-cell cos- killing, perhaps exposed by intercurrent in- disease. More clues will likely emerge as timulation is anecdotally of some therapeutic fection, could drive the initial inflammatory further results from the authors’ genome- value. Fourth, unlike other autoinflammatory episode. Hypothetically, defective killing might wide association study become available. diseases, sJIA is often self-limited. Between also set the stage for disease chronicity by More generally, the present study provides one-third and one-half of patients experi- impairing elimination of autoreactive T cells. an occasion to reflect on immune-mediated ence what is termed “monophasic sJIA,” In this way, impaired cytotoxicity could give pathology. The distinction between autoim- defined as a single episode of sJIA that re- rise to episodes of uncontrolled inflammation munity and autoinflammation is not black solves within 24 mo (6), a phenotype that and promote a T-cell–dependent chronic in- and white. For example, patients with familial could potentially reflect restoration of im- flammatory disease (although this latter step is Mediterranean fever show an enhanced mune tolerance. Finally, sJIA typically so far unsupported by clinical evidence and is prevalence and severity of many rheumato- − − evolves in phases. In many patients, overt not known to be required in IL-1ra / mice). logic diseases, potentially reflecting amplifi- systemic features (fevers and rashes) fade The biphasic hypothesis makes specific cation of inflammation originating with a over time, leaving behind a chronic and predictions. The most evident is that the MHC slip in immune tolerance. Indeed, many in- sometimes intractable arthritis. IL-1 blockade association should be stronger in sJIA pa- flammatory diseases are likely somewhere on is remarkably effective in the acute phase, tients who develop chronic arthritis than in the spectrum between purely autoimmune leading to complete remission in greater than those without, a possibility not tested in the and purely autoinflammatory (16). The paper 50% of patients, but treatment efficacy is present work. T-cell skewing and other by Ombrello et al. (1) helps to situate sJIA in much more modest in chronic arthritis (7–9). features of autoimmunity (such as clonal ex- this continuum, and supports speculation A further wrinkle in the sJIA story arises pansion, and potentially even autoantibodies) that sJIA may exemplify a new mode of through the interesting association of sJIA with should characterize chronic arthritis more pathogenesis: an autoinflammatory process episodes of explosive inflammation, termed than new-onset disease. Most importantly, early begetting an . macrophage activation syndrome (MAS). MAS affects 10–20% of patients with sJIA, typically early in the disease course. Clinical 1 Ombrello MJ, et al. (2015) HLA-DRB1*11 and variants of the 9 Quartier P, et al. (2011) A multicentre, randomised, double-blind, features of this “cytokine storm” include per- MHC class II locus are strong risk factors for systemic juvenile placebo-controlled trial with the interleukin-1 receptor antagonist – sistent fever, disseminated intravascular idiopathic arthritis. Proc Natl Acad Sci USA 112:15970 15975. anakinra in patients with systemic-onset juvenile idiopathic arthritis 2 Raychaudhuri S, et al. (2012) Five amino acids in three HLA (ANAJIS trial). Ann Rheum Dis 70(5):747–754. coagulation, and multisystem end-organ dys- proteins explain most of the association between MHC and 10 Mellins ED, Macaubas C, Grom AA (2011) Pathogenesis of seropositive rheumatoid arthritis. Nat Genet 44(3):291–296. function; hemophagocytosis is often noted systemic juvenile idiopathic arthritis: Some answers, more questions. 3 Scholl PR, et al. (1990) Effect of isotypes and allelic polymorphism Nat Rev Rheumatol 7(7):416–426. on bone marrow biopsy. MAS mimics the on the binding of staphylococcal exotoxins to MHC class II molecules. 11 Nigrovic PA (2014) Review: Is there a window of opportunity for phenotype observed in patients with congenital J Immunol 144(1):226–230. – 4 Thomson W, et al.; British Paediatric Rheumatology Study Group treatment of systemic juvenile idiopathic arthritis? Arthritis defects in perforin/granzyme-mediated cell cell (2002) Juvenile idiopathic arthritis classified by the ILAR criteria: Rheumatol 66(6):1405–1413. killing, a group of diseases termed familial HLA associations in UK patients. Rheumatology (Oxford) 41(10): 12 Horai R, et al. (2004) TNF-alpha is crucial for the development of hemophagocytic lymphohistiocytosis (FHL). 1183–1189. autoimmune arthritis in IL-1 receptor antagonist-deficient mice. J Clin 5 Hollenbach JA, et al. (2010) Juvenile idiopathic arthritis and HLA Invest 114(11):1603–1611. Many patients with sJIA and MAS exhibit class I and class II interactions and age-at-onset effects. Arthritis 13 Akitsu A, et al. (2015) IL-1 receptor antagonist-deficient mice mutations in FHL-associated genes, implicat- Rheum 62(6):1781–1791. develop autoimmune arthritis due to intrinsic activation of IL-17- ing impaired cytotoxicity—involved both in 6 Singh-Grewal D, Schneider R, Bayer N, Feldman BM (2006) producing CCR2(+)Vγ6(+)γδ T cells. Nat Commun 6:7464. Predictors of disease course and remission in systemic juvenile 14 Gattorno M, et al. (2008) The pattern of response to anti- downregulating immune responses and in idiopathic arthritis: Significance of early clinical and laboratory interleukin-1 treatment distinguishes two subsets of patients with — features. Arthritis Rheum 54(5):1595–1601. combating viral infections in sJIA-associated systemic-onset juvenile idiopathic arthritis. Arthritis Rheum 58(5): 7 Nigrovic PA, et al. (2011) Anakinra as first-line disease-modifying – MAS. Indeed, impaired natural killer cell therapy in systemic juvenile idiopathic arthritis: report of forty-six patients 1505 1515. function and “subclinical MAS” are very from an international multicenter series. Arthritis Rheum 63(2):545–555. 15 Shimizu M, Nakagishi Y, Yachie A (2013) Distinct subsets of common in active sJIA, suggesting that related 8 Vastert SJ, et al. (2014) Effectiveness of first-line treatment with patients with systemic juvenile idiopathic arthritis based on their recombinant interleukin-1 receptor antagonist in steroid-naive patients cytokine profiles. Cytokine 61(2):345–348. control defects represent a broad underlying with new-onset systemic juvenile idiopathic arthritis: Results of a 16 McGonagle D, McDermott MF (2006) A proposed classification theme of sJIA pathogenesis (10). prospective cohort study. Arthritis Rheumatol 66(4):1034–1043. of the immunological diseases. PLoS Med 3(8):e297.

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