Disruption of Intestinal Homeostasis and Intestinal Microbiota During Experimental Autoimmune Uveitis.

Purpose: We determine the changes in intestinal microbiota and/or disruptions in intestinal homeostasis during uveitis. Methods: Experimental autoimmune uveitis (EAU) was induced in B10.RIII mice with coadministration of interphotoreceptor retinoid-binding protein peptide (IRBP) and killed mycobacterial antigen (MTB) as an adjuvant. Using 16S rRNA gene sequencing, we looked at intestinal microbial differences during the course of uveitis, as well as intestinal morphologic changes, changes in intestinal permeability by FITC-dextran leakage, antimicrobial peptide expression in the gastrointstinal tract, and T lymphocyte prevalence before and at peak intraocular inflammation. Results: We demonstrate that increased intestinal permeability and antimicrobial peptide expression in the intestinal tract coincide in timing with increased effector T cells in the mesenteric lymph nodes, during the early stages of uveitis, before peak inflammation. Morphologic changes in the intestine were most prominent during this phase, but also occurred with adjuvant MTB alone, whereas increased intestinal permeability was found only in IRBP-immunized mice that develop uveitis. We also demonstrate that the intestinal microbiota were altered during the course of uveitis, and that some of these changes are specific to uveitic animals, whereas others are influenced by adjuvant MTB alone. Intestinal permeability peaked at 2 weeks, coincident with an increase in intestinal bacterial strain differences, peak lipocalin production, and peak uveitis. Conclusions: An intestinal dysbiosis accompanies a disruption in intestinal homeostasis in autoimmune uveitis, although adjuvant MTB alone promotes intestinal disruption as well. This may indicate a novel axis for future therapeutic targeting experimentally or clinically.

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. METHODS: The eyes of IL-1Ra-deficient BALB/c mice were monitored histologically and by intravital videomicroscopy to determine if uveitis developed along with the expected spontaneous arthritis in ankles and knees. Expression levels of IL-1R and its negative regulators (IL-1Ra, IL-1RII, IL-1RAcP and single Ig IL-1R-related molecule) in eye and joint tissues were compared. Differences in uveitis induced by intraocular injection of lipopolysaccharide (LPS) in mice lacking IL-1R or IL-1Ra were assessed. RESULTS: Deficiency in IL-1Ra predisposes to spontaneous arthritis, which is exacerbated by previous systemic LPS exposure. The eye, however, does not develop inflammatory disease despite the progressive arthritis or LPS exposure. Organ-specific expression patterns for IL-1Ra and negative regulators of IL-1 activity were observed that appear to predict predisposition to inflammation in each location in IL-1Ra knockout mice. The eye is extremely sensitive to locally administered LPS, and IL-1Ra deficiency markedly exacerbates the resulting uveitis. CONCLUSION: This study demonstrates that IL-1Ra plays an important role in suppressing local responses in eyes injected with LPS and that there is discordance between murine eyes and joints in the extent to which IL-1Ra protects against spontaneous inflammation.

Future for biological therapy for uveitis.

PURPOSE OF REVIEW: To review biological therapies as they pertain to the treatment of inflammatory eye diseases, especially uveitis. RECENT FINDINGS: Biological therapies including antibodies, soluble receptors, and cytokines are being tested increasingly for a variety of ocular inflammations. As a class, tumor necrosis factor inhibitors have arguably been the most widely employed and have emerged as a successful approach to treat Behçet's disease. Alpha interferon has demonstrated efficacy in the treatment of Behçet's disease and other forms of posterior uveitis. Additional cytokines, cell surface markers, adhesion molecules, and accessory molecules are targets of biological therapy, but the relevance of these targets in eye inflammation is sometimes just theoretical. And any disruption of the immune response entails potential risk. SUMMARY: Biological therapies offer tremendous potential in the treatment of ocular inflammation, but their study to date has been limited and both the efficacy and the risk are incompletely known for most of the available interventions.

The NOD2 defect in Blau syndrome does not result in excess interleukin-1 activity.

OBJECTIVE: Blau syndrome is a rare, autosomal-dominant, autoinflammatory disorder characterized by granulomatous arthritis, uveitis, and dermatitis. Genetics studies have shown that the disease is caused by single nonsynonymous substitutions in NOD-2, a member of the NOD-like receptor or NACHT-leucine-rich repeat (NLR) family of intracellular proteins. Several NLRs function in the innate immune system as sensors of pathogen components and participate in immune-mediated cellular responses via the caspase 1 inflammasome. Mutations in a gene related to NOD-2, NLRP3, are responsible for excess caspase 1-dependent interleukin-1beta (IL-1beta) in cryopyrinopathies such as Muckle-Wells syndrome. Furthermore, functional studies demonstrate that caspase 1-mediated release of IL-1beta also involves NOD-2. The aim of this study was to test the hypothesis that IL-1beta may mediate the inflammation seen in patients with Blau syndrome. METHODS: IL-1beta release was measured in peripheral blood mononuclear cells cultured in vitro, obtained from 5 Blau syndrome individuals with a NOD2 (CARD15) mutation. RESULTS: We observed no evidence for increased IL-1beta production in cells obtained from subjects with Blau syndrome compared with healthy control subjects. Furthermore, we presented 2 cases of Blau syndrome in which recombinant human IL-1 receptor antagonist (anakinra) was ineffective treatment. CONCLUSION: Taken together, these data suggest that in contrast to related IL-1beta-dependent autoinflammatory cryopyrinopathies, Blau syndrome is not mediated by excess IL-1beta or other IL-1 activity.

Altered host:pathogen interactions conferred by the Blau syndrome mutation of NOD2.

Blau syndrome (BS) is a rare familial granulomatous disease manifested by uveitis, arthritis and skin rash. BS has recently been found to be associated with a distinctive mutation in NOD2, which encodes an intracellular toll-like receptor. We have compared host cell interaction with bacterial challenge in U937 cells expressing wild type human NOD2 (NOD2(wt)), mutant NOD2 (NOD2(Blau)), or a vector control (VC). The cells were incubated with Salmonella typhimurium. Intracellular uptake was assessed by harvesting the cells at different time points following invasion and quantitating the CFU, recovered after gentamicin treatment to kill extracellular organisms. Expression of TNF-alpha, TLR2 and TLR4 was determined by semi-quantitative RT-PCR under resting conditions and after stimulation by bacteria. Invasion of target cells with S. typhimurium was diminished in the presence of NOD2(Blau). Expression of TNF-alpha mRNA was enhanced following bacterial invasion in all cell lines but NOD2(Blau) was associated with a more rapid decline in TNF-alpha expression. Kinetics of intracellular clearance of bacteria indicated a relative defect in NOD2(Blau) compared to controls. This clearance defect may be related to the lack of sustained TNF-alpha seen in the early stages. These events were not related to differential TLR2 or TLR4 expression since there were no significant differences seen between the cell lines after bacterial stimulation. Our findings indicate that the NOD2 mutation associated with this syndrome alters host:microbial interaction, and this may have relevance to triggering factors in the ocular and joint inflammation seen in BS.

Retisert (Bausch & Lomb/Control Delivery Systems).

Retisert (Envision TD), a sustained release intraocular implant containing fluocinolone acetonide, has been developed and launched in the US by Bausch & Lomb and Control Delivery Systems for the treatment of chronic non-infectious uveitis affecting the posterior segment of the eye.

Prevalent use of complementary and alternative medicine by patients with inflammatory eye disease.

AIM: To study complementary and alternative medicine (CAM) use in patients who suffer from inflammatory eye disease. METHODS: Current and previous use of CAM was determined by face-to-face interviews of consecutive patients attending a university-based tertiary-referral inflammatory eye disease clinic during a 3-month period. Additional sociodemographic and clinical information was obtained by review of clinical records. RESULTS: Of the 89 eligible patients who were interviewed, 37 (42%) reported using CAM for the specific purpose of improving their eye condition. Most commonly used CAM included vitamin preparations (n = 13), herbal medicines (n = 10), prayer (n = 15) and acupuncture (n = 9). Multiple forms of CAM were used by one third of patients. Female gender (p = 0.05), a higher rating of occupational prestige (p = 0.05) and the diagnosis of uveitis rather than another form of inflammatory eye disease (p = 0.04) were significantly associated with reporting of current or past use of CAM. Most patients who used CAM considered that these therapies were benefiting their ocular condition, and few adverse events were reported. Sixteen percent of patients cited physician resources as a source for therapeutic information about CAM. CONCLUSIONS: Use of CAM is common among patients with inflammatory eye diseases. Because CAM may influence the course of disease, cause adverse effects, and interact with conventional immunosuppressive treatment, physicians should routinely question patients with these diagnoses regarding the use of such therapies.

HLA-B27-associated uveitis: overview and current perspectives.

PURPOSE OF REVIEW: To review current knowledge about the pathogenesis, clinical presentation, and treatment of HLA-B27-associated uveitis, which is the most commonly identified cause of uveitis in community-based practice and an important cause of ocular morbidity. RECENT FINDINGS: Significant advances have been made in understanding the pathogenesis of HLA-B27-associated ocular and systemic disease, especially with regard to the genetic underpinning of these diseases. Increasing attention has also been focused on the use of alternative therapies in the treatment of HLA-B27-associated uveitis, with special attention to sulfa class antibiotics, historically have been used to treat the articular manifestations of the spondyloarthritides, and newer drugs that inhibit tumor necrosis factor-alpha. SUMMARY: The next several years promise to yield exciting new advances in understanding of the genetic epidemiology and treatment of HLA-B27-associated uveitis.