Introduction: Evolution of inflammatory arthritis from innate to adaptive immune mechanisms.

Abstract

Inflammatory arthritis (IA) refers to arthritis in which an inflammatory process is a key player in the pathophysiology, often excluding osteoarthritis (OA) despite accumulating evidence that inflammation also is important in the pathophysiology of OA. Inflammatory arthritides include rheumatologic conditions such as gout, rheumatoid arthritis (RA), and spondyloarthritis (SpA) as well as infectious arthritis that occurs from Borrelia burgdorferi and viral infections. While much research of rheumatologic arthritis historically focused upon genetic risk, adaptive immune responses to self-antigens and a loss of tolerance, an improved understanding of infectious arthritis and mucosal immunology is providing greater insight into the processes that initiate rheumatologic disease. In all forms of arthritis, including OA, there is mounting evidence of microbial interactions with the host resulting in immunologic changes relevant to the disease. Then, as suggested in RA and juvenile idiopathic arthritis (JIA) as well as some infectious forms of arthritis, the mucosal immune response becomes systemic, although why the joint becomes specifically targeted remains unclear. In the case of RA, genetics as well as strong evidence for an evolving immune response toward post-translationally modified self-antigens partly explains how a mucosal response may become systemic. In SpA, however, innate immune mechanisms triggered by microbes or mechanical stress of joint structures in the setting of genetic predispositions for IL-23 production lead to local inflammation in the joint. The different types of arthritis described in this issue highlight the interplay between microbes, genetics, and dysregulated immunity that result in disease (Figure 1). In the first chapter, Stoll et al. describe how early life events such as mode of neonate delivery, feeding, and antibiotic exposure affect risk for the development of JIA. Although there is weak support for Cesarean delivery increasing the risk of JIA, stronger data show a protective effect of breastfeeding and a negative effect correlating with antibiotic use. As all of these factors also contribute to microbial colonization of an infant, and as microbial colonization affects immunologic maturation, the authors propose that this is a window of opportunity to affect immunity that may protect or predispose to the development of JIA. Indeed, multiple studies of the microbiome from children with JIA have demonstrated alterations in Faecalibacterium, Ruminococcus, and Bacteroides genera, but geographic differences prevail when combining data sets. Finally, therapeutic potential, in theory, exists within manipulation of the microbiome. However, selective depletion of the microbiota with antibiotics has been ineffective as a treatment for other forms of non-infectious arthritis and is likely to give rise to antibiotic-resistant organisms. In addition, probiotics or dietary changes also have been ineffective for ameliorating JIA. In the next chapter, McGonagle et al. connect the IL-23/IL-17 axis to enthesitis, the site of inflammation in SpA. The enthesis is comprised of fibrocartilage connecting tendons and ligaments to bone. As such, it must be able to tolerate a high degree of mechanical stress without activating the usual inflammatory pathways associated with microinjury. The fibrocartilage itself is avascular and without resident immune cells but surrounded by a synovio-enthesial complex with resident macrophages as well as vascularized tissues of tendon and bone into which the fibrocartilage inserts. Early inflammation of the enthesis originates from these adjacent vascularized tissues. Genetic polymorphisms of the IL-23/IL-17 pathway are associated with SpA, and CD14+ cells from healthy human enthesis as well as peripheral monocytes from patients with enthesitis are able to produce IL-23 when stimulated. Stimuli for IL-23 production have yet to be demonstrated in SpA, but may come from many factors such as TLR signaling, the genetically associated HLA B27, which is prone to misfolding, causing ER stress responses, IL-36 signaling and/or lack of IL-38 regulation, and prostaglandin synthesis. Then, within the enthesial complex, IL-23 acts upon IL-23R+ γδ T cells that are the key producers of the cytokine IL-17A. Although IL-17A contributes to bone remodeling typical of SpA, the precise mechanisms are incompletely understood. Intriguingly, blockade of IL-23 for the treatment of SpA has been effective for treatment of peripheral joint inflammation but not spinal disease, suggesting that the biology of the enthesis may differ between anatomic locations. Continuing the discussion of links between innate immunity and arthritic disease, in “Inflammasomes contributing to inflammation in arthritis,” Fabio Martinon and Lotte Spel address the role of distinct inflammasome complexes (eg, the NLRP3, NLRP1, NLRC4, pyrin, and AIM2 inflammasomes) in the pathogenesis of different inflammatory arthritides including ankylosing spondylitis, JIA, gout, and RA. The authors detail mechanisms that elicit inflammasome activation, including both microbial- and host-derived signals such as disruption of the trans-Golgi network that can occur in response to various stimuli, the cell types in which inflammasomes function, and the consequences of inflammasome activation to cells and tissues. In addition, the authors describe gain-of-function mutations in NLRs, as well as polymorphisms in regulators of inflammasome activity such as CARD8, that are associated with increased risk of arthritic disease. Finally, the authors review ongoing efforts to develop therapeutics against inflammasome complex components such as caspase-1 and NLRs, as well as products of inflammasome activation, namely the cytokines IL-1β and IL-18, for the treatment of IA and other inflammatory diseases. The next two chapters focus on IA triggered by infectious agents. In “A joint effort: the interplay between the innate and adaptive immune system in Lyme arthritis,” Joosten and colleagues review interactions between Borrelia burgdorferi spirochetes, the causative microbe of Lyme arthritis, and innate and adaptive immune responses of the host. As part of this, the authors highlight the key pathogenic versus protective roles of innate and adaptive immune responses, respectively, for Lyme arthritis. In addition, the authors address possible explanations for the persistence of arthritic symptoms in some Lyme patients. First, the authors discuss key steps in the initiation of Lyme arthritis, including mechanisms of spirochete dissemination to articular joint tissue and the innate immune responses that initiate inflammation and induce tissue injury at this site. Next, the authors review evidence suggesting that dysregulation of adaptive immune responses, including CD4+ Th1 and Th17 cell responses, may drive the development of persistent, antibody refractory Lyme arthritis that occurs in some patients. Next, in “Pathogenic Th1 responses in chikungunya virus-induced inflammation and their modulation upon Plasmodium parasites co-infection,” Ng and colleagues review another acute, and sometimes persistent, IA triggered by an infectious agent. In this article, the authors focus on chikungunya virus, one of the several mosquito-transmitted alphaviruses (including Mayaro, o’nyong nyong, Ross River, and Sindbis viruses) that cause acute and chronic IA. The authors discuss clinical and immunologic similarities between this viral arthritis and other forms of arthritis such as RA, including a key pathogenic role for CD4+ Th1 cells in joint inflammation and injury. The authors also describe events that trigger cellular infiltration of joint tissue during chikungunya virus infection, including roles for monocytes and macrophages, as the initial infiltrating cell types found in the chikungunya virus-infected joint, in promoting some aspects of the injurious response following activation by NK cells, and limiting others (eg, neutrophil infiltration of joint tissue). Finally, because chikungunya virus co-circulates in many regions of the world with Plasmodium protozoan parasites, the mosquito-transmitted causative agents of malaria, the authors describe their efforts to understand the impact to individuals co-infected with both pathogens. To date, the findings suggest that Plasmodium co-infection ameliorates the severity of chikungunya virus-induced IA, likely through immune modulation. As described by the authors, this provides a unique opportunity to define the protective mechanisms and perhaps exploit this knowledge for the development of new therapies. Continuing the discussion of triggers of IA, in “Urate-induced immune programming: consequences for gouty arthritis and hyperuricemia,” Joosten et al. provide an overview of mechanisms by which hyperuricemia (ie, excess urate in the blood) promotes systemic inflammation and IA, including intriguing evidence for urate-induced trained immunity, or reprogamming, of myeloid cells toward a maladaptive inflammatory state. The authors review what is known about urate metabolism and factors that influence it’s accumulation, as well as the evidence for urate-induced immune programming. In addition, the authors describe factors that trigger the formation of monosodium urate (MSU) crystals in the setting of high concentrations of urate, and discuss how these MSU crystals function as DAMP (danger-associated molecular pattern)-like molecules that elicit activation and inflammatory responses of innate immune cells, such as dendritic cells, via activation of the NLRP3 inflammasome. Finally, the authors detail how soluble urate can transcriptionally reprogram cells via epigenetic mechanisms, resulting in increased constitutive expression of proinflammatory genes and enhanced responsive to stimuli. Thus, this trained immunity may drive persistent inflammation in response to continuous urate exposure. For the last article in our subsection on triggers of IA, Darrah and colleagues review features of IA that can develop in patients receiving immune checkpoint inhibitor (ICI) therapy. As highlighted by the authors, the study of ICI-IA provides a unique opportunity to interrogate the development of IA during the earliest stages, as the triggering event is temporally defined. The authors review major immune checkpoints currently targeted by approved antibody-based therapies, namely the CTLA-4 and PD-1 checkpoints, and describe the known roles for each of these checkpoints in the development of IA in both animal models and patients with RA or SpA. Importantly, the authors also compare and contrast the clinical features and response to treatment across patients with ICI-IA, RA, and SpA. As discussed by the authors, the knowledge gained from these types of comparative analyses improves our understanding of the role of these immune checkpoints in both RA and SpA and may provide insight into the critical early events in the development of IA. Next, Demoruelle and colleagues discuss how environmental interactions in the lung contribute to the development of RA as well as become a target of autoimmunity itself. Up to 70% of individuals with RA have some form of lung disease from interstitial lung disease (ILD) to airways disease, often associated with older age, male sex, and smoking. Smoking and other inhalants cause alterations to the microbiome of the upper airways as well as localized inflammation, and in the setting of genetic risk for RA, such as that found with the HLA-DR4 shared epitope, result in the organization of tertiary lymphoid structures and increased production of antibodies to citrulline modified peptides (ACPA) even in the absence of pulmonary disease. In the years preceding the development of joint swelling characteristic of RA, airway abnormalities and mucosal-derived IgA ACPA are often present in both the sputum and the serum, suggesting a link between the pulmonary mucosa and the development of RA. Given the centrality of ACPA to the diagnosis and pathogenesis of RA, much effort has been placed on identification of citrullinated self-antigens and understanding how they are generated. Andrade et al. provide a historical overview of how citrullinated proteins were identified as key targets of autoantibodies generated in RA. The authors then describe the techniques and challenges of characterizing the RA citrullinome through mass spectrometry. In spite of the challenges, major advancements include the demonstration that citrullination is not unique to RA, but occurs broadly across normal tissues in healthy individuals. However, the process of hypercitrullination is enriched in the affected joints in RA, which may represent altered immune pathways that are reviewed by the authors. ACPA are one type of autoantibody specific to RA and belong to a larger class of autoantibodies. The diversity and role of autoantibodies and B cells in RA are reviewed by van der Woude and colleagues in their article “Autoantibodies and B Cells: the ABC of rheumatoid arthritis pathophysiology.” The authors first summarize the classes of autoantibodies and the current state of knowledge regarding their role in the pathophysiology of disease. Given the role of ACPA and intense study over the past decade, much information is based on this class of autoantibodies, but newer classes such as autoantibodies targeting carbamylated and acetylated proteins are also included. Then, based on the success of targeting B cells for therapy in RA, they present the case for the centrality of these cells in the pathophysiology of disease, reviewing hypotheses from the generation of autoantigens through the development of autoreactive B cells. Finally, the authors summarize how T cells and HLA genetics contribute to the process of autoreactive B-cell development. To further elucidate the role of T cells in RA, Sakaguchi and colleagues developed a unique animal model of T cell–mediated inflammatory arthritis (SKG) due to a mutation in the Zap70 gene resulting in reduced T-cell receptor signal strength that affects thymic development and an increase in autoreactive T cells in the periphery. Similar results have been observed with other mutations in Zap70 and TCR signaling proteins. Interestingly, regulatory T cells are expanded in SKG mice, but demonstrate reduced suppressive function. The authors then discuss how additional host genetics in both mice and humans result in differing forms of autoimmunity. The result is a peripheral expansion of Th17 effector cells, stimulated through microbial products, which migrate to the joints where they coordinate with other immune cell types to create an inflammatory environment resulting in arthritis. In understanding the function of T cells in RA, it has become apparent that they are integral in driving synovial inflammation, and this is partly due to altered metabolism as reviewed by Weyand and Goronzy. In their article, they review how CD4+ T cells alter cellular metabolism from glycolysis to the pentose phosphate pathyway and generation of excess NAPDH. In doing so, T cells are prepared for proliferation, but bypass the G2/M checkpoint and demonstrate an aging phenotype with shortened telomeres and lack of mitochondrial DNA repair. These events lead to intracellular lipid storage. The authors also review the potential upstream factors of T-cell hypermetabolism in RA as well as data suggesting altered synovial macrophage metabolism contributing to disease pathogenesis. Finally, to conclude this issue, Raychaudhuri and colleagues provide a comprehensive historical review of the genetics of RA, a polygenic disease with numerous associated loci (that influence both innate and adaptive immunity) and few alleles of large effect size. The authors begin by reviewing early RA genetic studies, including MHC, linkage and genome-wide SNP association studies. Importantly, the authors discuss the difficulties encountered using these approaches for identifying associations with non-MHC loci, including a lack of power. Thus, some candidate gene associations identified during this early phase have been difficult to reproduce. Next, the authors review findings from large scale RA genetic studies that occurred following completion of the Human Genome Project, and discuss how this work revealed new genetic associations that in some cases were reproducible and provided genetic validation of RA drug targets (eg, TNF, IL-6, and NF-κB). In addition, because most of the disease-associated variants identified were located in noncoding sequences, the authors discuss efforts to understand how such variants influence the regulation of gene expression, including eQTL studies, and recent analyses indicating that variants can function in a cell-type-specific manner, implicating discrete cell subpopulations in the development and progression of RA. The authors also provide a detailed discussion of the issue of “missing heritability,” or incomplete measure of genetic heritability for complex polygenic diseases such as RA, and statistical approaches that can be used to overcome this issue and advance the development of polygenic risk scores for individuals. Finally, using HLA typing as an example, the authors highlight how the predominance of European populations in genetic studies hampers the development of diagnostic and treatment strategies for RA, and call for diversifying reference populations that are used in human genetics research.