Card9/neutrophil signalling axis promotes IL-17A-mediated ankylosing spondylitis.

Objective: Polymorphisms in the antifungal signalling molecule are associated with ankylosing spondylitis (AS). Here, we investigated the cellular mechanism by which CARD9 controls pathogenic Th17 responses and the onset of disease in both experimental murine AS and patients.

Methods: Experiments in SKG, Card9SKG, neutrophil-deplete SKG mice along with murine, neutrophil and CD4 T cell cocultures examined Card9 function in neutrophil activation, Th17 induction and arthritis in experimental AS.

The innate immune receptor Nlrp12 suppresses autoimmunity to the retina.

Background: Nod-like receptors (NLRs) are critical to innate immune activation and induction of adaptive T cell responses. Yet, their role in autoinflammatory diseases of the central nervous system (CNS) remains incompletely defined. The NLR, Nlrp12, has been reported to both inhibit and promote neuroinflammation in an animal model of multiple sclerosis (experimental autoimmune encephalomyelitis, EAE), where its T cell-specific role has been investigated.

Orientia tsutsugamushi selectively stimulates the C-type lectin receptor Mincle and type 1-skewed proinflammatory immune responses.

Orientia tsutsugamushi is an obligately intracellular bacterium and the etiological agent of scrub typhus. The lung is a major target organ of infection, displaying type 1-skewed proinflammatory responses. Lung injury and acute respiratory distress syndrome are common complications of severe scrub typhus; yet, their underlying mechanisms remain unclear.

T cell-intrinsic role for Nod2 in protection against Th17-mediated uveitis.

Mutations in nucleotide-binding oligomerization domain-containing protein 2 (NOD2) cause Blau syndrome, an inflammatory disorder characterized by uveitis. The antimicrobial functions of Nod2 are well-established, yet the cellular mechanisms by which dysregulated Nod2 causes uveitis remain unknown. Here, we report a non-conventional, T cell-intrinsic function for Nod2 in suppression of Th17 immunity and experimental uveitis.

Nod2 Deficiency Augments Th17 Responses and Exacerbates Autoimmune Arthritis.

Arthritis in a genetically susceptible SKG strain of mice models a theoretical paradigm wherein autoimmune arthritis arises because of interplay between preexisting autoreactive T cells and environmental stimuli. SKG mice have a point mutation in ZAP-70 that results in attenuated TCR signaling, altered thymic selection, and spontaneous production of autoreactive T cells that cause arthritis following exposure to microbial β-glucans. In this study, we identify Nod2, an innate immune receptor, as a critical suppressor of arthritis in SKG mice.

Mincle Activation and the Syk/Card9 Signaling Axis Are Central to the Development of Autoimmune Disease of the Eye.

Uveitis, which occurs in association with systemic immunological diseases, presents a considerable medical challenge because of incomplete understanding of its pathogenesis. The signals that initiate T cells to target the eye, which may be of infectious or noninfectious origin, are poorly understood. Experimental autoimmune uveoretinitis (EAU) develops in mice immunized with the endogenous retinal protein interphotoreceptor retinoid binding protein in the presence of the adjuvant CFA.

Investigation of the relationship between the onset of arthritis and uveitis in genetically predisposed SKG mice.

Introduction: Systemic rheumatic conditions are often accompanied by intraocular inflammatory disease (termed uveitis). Despite the frequent manifestation of uveitis with arthritis, very little is understood of the underlying mechanisms that mediate the eye's susceptibility to disease. The genetically susceptible SKG mouse strain develops arthritis that arises from an inherent mutation that disrupts T-cell antigen receptor signal transduction and thymic selection.

Blau syndrome-associated Nod2 mutation alters expression of full-length NOD2 and limits responses to muramyl dipeptide in knock-in mice.

The biochemical mechanism by which mutations in nucleotide-binding oligomerization domain containing 2 (NOD2) cause Blau syndrome is unknown. Several studies have examined the effect of mutations associated with Blau syndrome in vitro, but none has looked at the implication of the mutations in vivo. To test the hypothesis that mutated NOD2 causes alterations in signaling pathways downstream of NOD2, we created a Nod2 knock-in mouse carrying the most common mutation seen in Blau syndrome, R314Q (corresponding to R334Q in humans).

Aberrant interleukin-1 signalling does not increase susceptibility of mice to NOD2-dependent uveitis.

Background: NOD2 is the genetic cause of Blau syndrome, an autoinflammatory disease that manifests as coincident uveitis and arthritis. Since dysregulation of IL-1 signalling is considered a pathogenic mechanism in a number of related autoinflammatory conditions, we examined the extent to which unimpeded interleukin (IL)-1 signalling influences NOD2-dependent inflammation of the eye versus the joint.

Methods: Mice deficient for IL-1R antagonist (IL-1Ra) were administered the NOD2 agonist muramyl dipeptide (MDP) by systemic (intraperitoneal) or local (intraocular and/or intra-articular) injections.

Investigation of the peptidoglycan sensing molecule, PGLYRP-2, in murine inflammatory uveitis.

Background/aim: Peptidoglycan (PGN) recognition proteins (PGLYRPs) are innate immune molecules that recognise bacterial cell wall PGN, and participate in several inflammatory diseases such as arthritis. We sought to elucidate the contribution of PGLYRPs in murine uveitis (intraocular inflammatory disease) elicited by PGN, and the extent to which systemically administered PGN alters uveitis compared with arthritis versus locally triggered ocular responses.

Methods: Mice deficient for PGLYRP-2, PGLYRP-3 or PGLYRP-4 were administered PGN by an intraperitoneal or intraocular injection.

Spondyloarthritis: the eyes have it: uveitis in patients with spondyloarthritis.

Although systemic lupus erythematosus is the prototype multisystem disease, many other inflammatory diseases are also promiscuous, with symptoms manifesting in many organs. Now, new data emphasize the extra-articular involvement in spondyloarthritis, predominantly affecting the eye; however, the factors that account for the observed organ involvement remain unknown.

Neutralization of IL-17 ameliorates uveitis but damages photoreceptors in a murine model of spondyloarthritis.

Introduction: Uveitis, or intraocular inflammatory disease, is a frequent extra-articular manifestation of several forms of arthritis. Despite the frequent co-occurrence of uveitis and arthritis, little is understood of the eye's predisposition to this disease. We recently described a previously unreported uveitis in a murine model of spondyloarthropathy triggered by autoimmunity to aggrecan, a prominent proteoglycan (PG) macromolecule in cartilage.

Impact of IL-1 signalling on experimental uveitis and arthritis.

Background: Uveitis, or inflammatory eye disease, is a common extra-articular manifestation of many systemic autoinflammatory diseases involving the joints. Anakinra (recombinant interleukin (IL)-1 receptor antagonist (Ra)) is an effective therapy in several arthritic diseases; yet, few studies have investigated the extent to which IL-1 signalling or IL-1Ra influences the onset and/or severity of uveitis.

Objective: To seek possible links between arthritis and uveitis pathogenesis related to IL-1 signalling.

Interplay between innate and adaptive immunity in the development of non-infectious uveitis.

In vertebrates, the innate and adaptive immune systems have evolved seamlessly to protect the host by rapidly responding to danger signals, eliminating pathogens and creating immunological memory as well as immunological tolerance to self. The innate immune system harnesses receptors that recognize conserved pathogen patterns and alongside the more specific recognition systems and memory of adaptive immunity, their interplay is evidenced by respective roles during generation and regulation of immune responses. The hallmark of adaptive immunity which requires engagement of innate immunity is an ability to discriminate between self and non-self (and eventually between pathogen and symbiont) as well as peripheral control mechanisms maintaining immunological health and appropriate responses.

The NLRP3 inflammasome is active but not essential in endotoxin-induced uveitis.

Objective: The inflammasome complex involving caspase-1 and nucleotide-binding domain, leucine-rich repeat containing protein (NLRP)3, also known as NALP3 or cryopyrin is important for host responses to microbial pathogens and several autoinflammatory diseases. We investigated the extent to which NLRP3 and caspase-1 control ocular interleukin (IL)-1β production and severity of uveitis (intraocular inflammatory disease) in an established, acute inflammatory uveitis model, endotoxin-induced uveitis (EIU).

Methods: Expression of NLRP3, its adaptor molecule ASC, also known as PYCARD (PYD and CARD domain containing), and caspase-1 were examined by immunoblotting.

Interferon-γ regulates discordant mechanisms of uveitis versus joint and axial disease in a murine model resembling spondylarthritis.

Objective: The spondylarthritides (such as ankylosing spondylitis) are multisystem inflammatory diseases that frequently result in uveitis. Despite the common co-occurrence of uveitis with arthritis, there has been no explanation for the susceptibility of the eye to inflammation. Using an innovative intravital videomicroscopic approach, we discovered the coexistence of uveitis with axial and peripheral joint inflammation in mice immunized with cartilage proteoglycan (PG).

Investigation of the differential potentials of TLR agonists to elicit uveitis in mice.

TLRs are critical for host defense and innate immunity. Emerging evidence also supports a role for TLRs in many chronic inflammatory diseases, including inflammatory eye disease, known as uveitis. The activation of TLR4 by endotoxin induces a standard model of murine uveitis.

NLRs in immune privileged sites.

Innate immune receptors such as the nucleotide-binding domain, leucine-rich repeat-containing (NBD-LRR) receptors, referred to as NLRs, are known to serve as a critical component of host defense. However, their participation in inflammatory responses within immune privileged sites such as the brain and eye is less understood. The potential importance of NLRs in regulation of inflammation within these particular sites is further underscored by their association with autoinflammatory disorders, wherein localized inflammation can occur within the brain or eye as neuroinflammation or uveitis, respectively.

Contrasting ocular effects of local versus systemic endotoxin.

PURPOSE. A marked cellular infiltrate has been observed when endotoxin (lipopolysaccharide [LPS]) is injected into the mouse eye, but systemically injected LPS does not produce a comparable effect. Several hypotheses were tested to reconcile this discordance.

Dectin-1 and NOD2 mediate cathepsin activation in zymosan-induced arthritis in mice.

Objective: Activation of pattern recognition receptors (PRR) may contribute to arthritis. Here, we elucidated the role of NOD2, a genetic cause of inflammatory arthritis, and several other PRR in a murine model of inflammatory arthritis.

Methods: The roles of CR3, TLR2, MyD88, NOD1, NOD2, Dectin-1 and Dectin-2 were tested in vivo in arthritis elicited by intra-articular injections of zymosan, the fungal cell wall components curdlan, laminarin and mannan, and the bacterial cell wall peptidoglycan.

NOD2 deficiency results in increased susceptibility to peptidoglycan-induced uveitis in mice.

Purpose: The innate immune receptor NOD2 is a genetic cause of uveitis (Blau syndrome). Intriguingly, in the intestine where polymorphisms of NOD2 predispose to Crohn's disease, NOD2 reportedly suppresses inflammation triggered by the bacterial cell wall component, peptidoglycan (PGN). Whether NOD2 exerts a similar capacity in the regulation of ocular inflammation to PGN has not been explored.

Nucleotide-binding oligomerization domain 2 and Toll-like receptor 2 function independently in a murine model of arthritis triggered by intraarticular peptidoglycan.

Objective: Blau syndrome is an autoinflammatory disease resulting from mutations in the NOD2 gene, wherein granulomatous arthritis, uveitis, and dermatitis develop. The mechanisms by which aberrant NOD2 causes joint inflammation are poorly understood. Indeed, very few studies have addressed the function of nucleotide-binding oligomerization domain 2 (NOD-2) in the joint.

Nucleotide oligomerization domain-2 interacts with 2'-5'-oligoadenylate synthetase type 2 and enhances RNase-L function in THP-1 cells.

Nucleotide-binding and oligomerization domain-2 (NOD2) is an intracellular protein involved in innate immunity and linked to chronic inflammatory diseases in humans. Further characterization of the full spectrum of proteins capable of binding to NOD2 may provide new insights into its normal functioning as well as the mechanisms by which mutated forms cause disease. Using a proteomics approach to study human THP-1 cells, we have identified 2'-5'-oligoadenylate synthetase type 2 (OAS2), a dsRNA binding protein involved in the pathway that activates RNase-L, as a new binding partner for NOD2.

BALB/c mice genetically susceptible to proteoglycan-induced arthritis and spondylitis show colony-dependent differences in disease penetrance.

Introduction: The major histocompatibility complex (H-2d) and non-major histocompatibility complex genetic backgrounds make the BALB/c strain highly susceptible to inflammatory arthritis and spondylitis. Although different BALB/c colonies develop proteoglycan-induced arthritis and proteoglycan-induced spondylitis in response to immunization with human cartilage proteoglycan, they show significant differences in disease penetrance despite being maintained by the same vendor at either the same or a different location.

Methods: BALB/c female mice (24 to 26 weeks old after 4 weeks of acclimatization) were immunized with a suboptimal dose of cartilage proteoglycan to explore even minute differences among 11 subcolonies purchased from five different vendors.

Nucleotide oligomerization domain-2 (NOD2)-induced uveitis: dependence on IFN-gamma.

Purpose: Nucleotide oligomerization domain-2 (NOD2) plays an important role in innate immunity to sense muramyl dipeptide (MDP), a component of bacterial cell walls. Notably, NOD2 is linked to eye inflammation because mutations in NOD2 cause a granulomatous type of uveitis called Blau syndrome. A mouse model of NOD2-dependent ocular inflammation was employed to test the role of a cytokine strongly implicated in granuloma formation, IFN-gamma, in order to gain insight into downstream functional consequences of NOD2 activation within the eye triggering uveitis.