First Association of Interleukin 12 Receptor Beta 1 Deficiency with Sjogren's Syndrome.
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ABSTRACT:
SUBMITTER: Sogkas G
PROVIDER: S-EPMC5532512 | biostudies-other | 2017
REPOSITORIES: biostudies-other
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Project description:Interleukin (IL)‑12 modulates the generation and function of various immune cells and plays a vital role in the pathogenesis of Sjögren's syndrome (SS). Myeloid‑derived suppressor cells (MDSCs) are involved in autoimmune diseases by regulating various immune responses. However, it has not been confirmed whether inflammatory IL‑12 participates in the progression of SS via regulating MSDCs. In the present study, the plasma levels of IL‑12 were detected by ELISA in SS‑like non‑obese diabetic (NOD) mice. The mice were treated by intraperitoneal injection of IL‑12 and anti‑IL‑12 antibody, respectively, and then the salivary flow rate was detected. The pathology of submandibular glands was evaluated in tissue sections stained with hematoxylin and eosin. The proportion of MDSCs was assessed by flow cytometry. The results showed that plasma IL‑12 was significantly increased in the SS‑like NOD mice comparing with that noted in the control mice. The exogenous IL‑12 exacerbated SS‑like symptoms of NOD mice and promoted the generation of both bone marrow (BM) and splenic MDSCs in the SS‑like NOD mice. Of note, anti‑IL‑12 alleviated SS‑like symptoms of NOD mice and inhibited the generation of BM and splenic MDSCs. Moreover, the generation of MDSCs was crippled in the IL‑12‑deficient C57BL/6 (Il‑12‑/‑ B6) mice. Our findings suggest that aggravation of SS‑like symptoms by IL‑12 in NOD mice may be attributed to its promotion of MDSC development.
| S-EPMC6625410 | biostudies-literature
Project description:In Sjögren's Syndrome (SS), inherent glandular defects, autoimmunity, and mononuclear cell infiltration within the salivary glands cause reduced salivation leading to xerostomia. Excessive production of type I interferons (IFN), triggered by environmental and genetic factors, is considered pathogenic in this disorder. However, whether type I IFN production is causative or an outcome of the disease process is not known. To address this question, we introduced a deficiency of interferon alpha receptor 1 (Ifnar1) into B6.Aec1Aec2 mice, which are known to have the genetic loci necessary for developing a SS-like disorder. This new mouse strain, B6.Aec1Aec2Ifnar1 (-/-), lacking type I IFN-mediated signaling, was characterized for pilocarpine-induced salivation, the presence of serum autoantibodies, sialoadenitis, and dacryoadenitis. Compared with the B6.Aec1Aec2Ifnar1 (+/+) (wild-type) mice, the B6.Aec1Aec2Ifnar1 (-/-) (knockout) mice had significantly lower mononuclear cell infiltration in the salivary and lacrimal glands. The knockout mice were completely protected from salivary gland dysfunction. Surprisingly, they had a robust autoantibody response comparable with that of the wild-type mice. These findings demonstrate that, in the absence of type I IFN-mediated signaling, systemic autoantibody responses can be dissociated from glandular pathology. Our study suggests that, in genetically susceptible individuals, the type I IFN pathway can instigate certain features of SS.
| S-EPMC3627507 | biostudies-literature
Project description:BackgroundInterleukin 12R?1 (IL-12R?1)-deficient patients are prone to clinical disease caused by mycobacteria, Salmonella, and other intramacrophagic pathogens, probably because of impaired interleukin 12-dependent interferon ? production. About 25% of patients also display mucocutaneous candidiasis, probably owing to impaired interleukin 23-dependent interleukin 17 immunity. The clinical features and outcome of candidiasis in these patients have not been described before, to our knowledge. We report here the clinical signs of candidiasis in 35 patients with IL-12R?1 deficiency.ResultsMost (n = 71) of the 76 episodes of candidiasis were mucocutaneous. Isolated oropharyngeal candidiasis (OPC) was the most common presentation (59 episodes, 34 patients) and was recurrent or persistent in 26 patients. Esophageal candidiasis (n = 7) was associated with proven OPC in 2 episodes, and cutaneous candidiasis (n = 2) with OPC in 1 patient, whereas isolated vulvovaginal candidiasis (VVC; n = 3) was not. Five episodes of proven invasive candidiasis were documented in 4 patients; 1 of these episodes was community acquired in the absence of any other comorbid condition. The first episode of candidiasis occurred earlier in life (median age±standard deviation, 1.5 ± 7.87 years) than infections with environmental mycobacteria (4.29 ± 11.9 years), Mycobacterium tuberculosis (4 ± 3.12 years), or Salmonella species (4.58 ± 4.17 years) or other rare infections (3 ± 11.67 years). Candidiasis was the first documented infection in 19 of the 35 patients, despite the vaccination of 10 of these 19 patients with live bacille Calmette-Guérin.ConclusionsPatients who are deficient in IL-12R?1 may have candidiasis, usually mucocutaneous, which is frequently recurrent or persistent. Candidiasis may be the first clinical manifestation in these patients.
| S-EPMC3871796 | biostudies-literature
Project description:We have identified a cDNA from a human phytohemagglutinin-activated lymphoblast library encoding a protein that binds 125I-labeled human interleukin 12 (125I-huIL-12) with a Kd of about 5 nM when expressed in COS-7 cells. When coexpressed in COS-7 cells with the previously identified IL-12 beta receptor (IL-12R beta) protein, two classes of 125I-huIL-12 binding sites were measured with Kds of about 55 pM and 8 nM, corresponding to the high- and low-affinity binding sites seen on phytohemagglutinin-activated lymphoblasts. This newly identified huIL-12R subunit is a member of the cytokine receptor superfamily, with closest resemblance to the beta-type cytokine receptor gp130 and the receptors for leukemia inhibitory factor and granulocyte colony-stimulating factor. Consequently, we have reclassified the previously identified IL-12R beta subunit as huIL-12R beta 1 and designated the newly identified subunit as huIL-12R beta 2. huIL-12R beta 2 is an 862-amino acid type I transmembrane protein with a 595-amino-acid-long extracellular domain and a cytoplasmic tail of 216 amino acids that contains three tyrosine residues. A cDNA encoding the mouse homolog of the huIL12R beta 2 protein has also been isolated. Human and mouse IL-12R beta 2 proteins show a 68% amino acid sequence identity. When expressed in COS-7 cells, huIL-12R beta 2 exists as a disulfide-linked oligomer with an apparent monomeric molecular weight of 130 kDa. Coexpression of the two identified IL-12R subunits in Ba/F3 cells conferred IL-12 responsiveness, and clones of these cotransfected Ba/F3 cells that grew continuously in the presence of IL-12 were isolated and designated LJM-1 cells. LJM-1 cells exhibited dose-dependent proliferation in response to huIL-12, with an ED50 of about 1 pM huIL-12. Interestingly, Ba/F3 cells transfected with IL-12R beta 2 alone proliferated in response to huIL-12 with an ED50 of about 50 pM, although a role for endogenous mouse IL-12R beta 1 in IL-12 signal transduction in these transfectants cannot be ruled out. These results demonstrate that the functional high-affinity IL-12R is composed of at least two beta-type cytokine receptor subunits, each independently exhibiting a low affinity for IL-12.
| S-EPMC19484 | biostudies-literature
Project description:Descriptive and retrospective studies without control groups have suggested a possible association between primary Sjögren's syndrome (pSS) and vitamin B12 (B12) deficiency. This is of importance because several mucosal and neurological features are common to these two conditions and could be prevented or reversed in case of B12 deficiency. We aimed to evaluate the association between pSS and B12 deficiency. We prospectively assessed the B12 status of 490 patients hospitalized in an internal medicine department over a 15-week period. Patients with pernicious anemia were excluded. We extracted patients with pSS and paired them with controls according to age and sex, with a 1:5 ratio. Twenty-one pSS patients were paired with 105 control patients. The median age was 70 years old (51-75) and 95.2% of patients were women. The plasma B12 level was lower in pSS patients (329 (293-521) ng/L vs. 456 (341-587) ng/L, p < 0.0001). B12 deficiency was associated with pSS (42.9% among pSS patients vs. 11.4% among controls), even after adjustment for other causes of B12 deficiency (OR 6.45 (95%CI: 2.08-20.0)). In conclusion, pSS appeared to be associated with B12 deficiency, even after the exclusion of pernicious anemia. This justifies screening and treating B12 deficiency in pSS patients.
| S-EPMC7765802 | biostudies-literature
Project description:Patients with interleukin 12 (IL-12)p40 or IL-12 receptor ?1 (IL12R?1) deficiencies are prone to develop infections caused by mycobacteria and salmonella; other infections have only been rarely observed. In this report we describe 2 unrelated patients with complete autosomal recessive IL12R?1 deficiency who suffered from sepsis attributable to Klebsiella pneumoniae. A Mexican boy suffered from disseminated bacille Calmette-Guérin disease and infections caused by K pneumoniae and Candida albicans and had a fatal outcome. A Turkish girl living in France suffered from disseminated Nocardia nova infection and K pneumoniae sepsis. Therefore, Klebsiella infections should be considered in patients with IL12R?1 deficiency. Conversely, IL12R?1 deficiency should be considered in patients with unexplained klebsiellosis.
| S-EPMC3005354 | biostudies-literature
Project description:A patient with leukocyte adhesion deficiency type 1 (LAD1) had severe periodontitis and an intractable, deep, nonhealing sacral wound. We had previously found a dominant interleukin-23-interleukin-17 signature at inflamed sites in humans with LAD1 and in mouse models of the disorder. Blockade of this pathway in mouse models has resulted in resolution of the immunopathologic condition. We treated our patient with ustekinumab, an antibody that binds the p40 subunit of interleukin-23 and interleukin-12 and thereby blocks the activity of these cytokines, inhibiting interleukin-23-dependent production of interleukin-17. After 1 year of therapy, our patient had resolution of his inflammatory lesions without serious infections or adverse reactions. Inhibition of interleukin-23 and interleukin-17 may have a role in the management of LAD1. (Funded by the National Institute of Allergy and Infectious Diseases and others.).
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Project description:Sjögren's syndrome (SS) is a systemic autoimmune disease with no efficient treatment, and it is associated with dysregulated immune cells and impaired interleukin (IL)-2 signaling. IL-2 is critical for the development and maintenance of Treg cells. The use of low dose of IL-2 (LDIL-2) in the treatment of autoimmune diseases is promising, but the efficacy and mechanism in SS therapy are still to be confirmed. This study aims to investigate the therapeutic effect of LDIL-2 on SS in NOD (non-obese diabetic) mice. NOD mice (female, 8 weeks old) were randomly assigned into three groups (n = 8). Low dose of IL-2 (LDIL-2), high dose of IL-2 (HDIL-2), and isometric sterile water (control) were administered subcutaneously daily from week 8 to week 16. LDIL-2 administration significantly recovered the reduction in saliva flow and suppressed lymphocyte inflammation of the submandibular glands (SMGs) when compared with those treated with sterile water as controls (p < 0.05). SS related biomarkers including ANA, Anti-SSA/Ro, and Anti-SSB/La also declined (p < 0.05). In the low dose of IL-2 treated group, the proportion of CD4+CD25+Foxp3+Tregs in both spleen and cervical-lymph-node were higher than control mice (p < 0.05). Furthermore, CD4+Bcl-6+PD-1+CXCR5+Tfh cells, CD4+IFN-γ+Th1 cells, and CD4+IL-17A+Th17 cells were significantly reduced in LDIL-2 group (p < 0.05). Analysis of the SMGs biopsies showed significantly decreased inflammation scores after LDIL-2 administration and an increase of Tregs with immunohistochemical staining. Our findings provide in vivo evidence that LDIL-2 was an effective therapeutic intervention for SS observed in NOD mice and may restore immune balance through the promotion of Treg and suppression of germinal center (GC) B cells and effector T cells.
| S-EPMC9160330 | biostudies-literature
Project description:The clinical phenotype of interleukin 12 receptor beta1 chain (IL-12Rbeta1) deficiency and the function of human IL-12 in host defense remain largely unknown, due to the small number of patients reported. We now report 41 patients with complete IL-12Rbeta1 deficiency from 17 countries. The only opportunistic infections observed, in 34 patients, were of childhood onset and caused by weakly virulent Salmonella or Mycobacteria (Bacille Calmette-Guérin -BCG- and environmental Mycobacteria). Three patients had clinical tuberculosis, one of whom also had salmonellosis. Unlike salmonellosis, mycobacterial infections did not recur. BCG inoculation and BCG disease were both effective against subsequent environmental mycobacteriosis, but not against salmonellosis. Excluding the probands, seven of the 12 affected siblings have remained free of case-definition opportunistic infection. Finally, only five deaths occurred in childhood, and the remaining 36 patients are alive and well. Thus, a diagnosis of IL-12Rbeta1 deficiency should be considered in children with opportunistic mycobacteriosis or salmonellosis; healthy siblings of probands and selected cases of tuberculosis should also be investigated. The overall prognosis is good due to broad resistance to infection and the low penetrance and favorable outcome of infections. Unexpectedly, human IL-12 is redundant in protective immunity against most microorganisms other than Mycobacteria and Salmonella. Moreover, IL-12 is redundant for primary immunity to Mycobacteria and Salmonella in many individuals and for secondary immunity to Mycobacteria but not to Salmonella in most.
| S-EPMC2193866 | biostudies-literature
Project description:PurposeThe potential role of commensals as triggering factors that promote inflammation in dry eye disease has not been explored. The objective of this study was to evaluate whether ocular microbiota changes with the onset of dry eye disease in thrombospondin-1-deficient (TSP-1(-/-)) mice, a strain that develops Sjögren's syndrome-like disease.MethodsConjunctival swabs were collected from TSP-1(-/-) and C57BL/6 mice and analyzed for bacterial presence. Opsonophagocytosis of the bacterial conjunctival isolates derived from the aged TSP-1(-/-) mice by neutrophils derived from either TSP-1(-/-) or C57BL/6 bone marrow was evaluated. The bactericidal activities of TSP-1-derived peptide were examined.ResultsWe found that in TSP-1(-/-) mice, the conjunctival colonization with Staphylococcus aureus and coagulase negative staphylococci sp (CNS) species was significantly increased with aging and preceded that of the wild-type C57BL/6 control mice. This correlated with increased neutrophil infiltration into the conjunctiva of the TSP-1(-/-) mice, suggesting that TSP-1 plays a significant role in regulating immunity to commensals. Accordingly, the TSP-1(-/-) PMNs opsonophagocytozed the ocular commensals less efficiently than the TSP-1-sufficient neutrophils. Furthermore, a TSP-1-derived peptide, 4N1K, exhibited significant antimicrobial activity when compared to a control peptide against commensal sp.ConclusionThese studies illustrate that alterations in the commensal frequency occur in the early stages of development of Sjögren's-like pathology and suggest that interventions that limit commensal outgrowth such as the use of TSP-1-derived peptides could be used for treatment during the early stages of the disease to reduce the commensal burden and ensuing inflammation.
| S-EPMC4575514 | biostudies-literature