Immunoreceptors such as the high affinity IgE receptor, Fc⑀RI, and T-cell receptor-associated proteins share a common motif, the immunoreceptor tyrosine-based activation motif (ITAM). We used the yeast tribrid system to identify downstream effectors of the phosphorylated Fc⑀RI ITAM-containing subunits  and ␥. One novel cDNA was isolated that encodes a protein that is phosphorylated on tyrosine, contains a Src-homology 2 (SH2) domain, inositolpolyphosphate 5-phosphatase activity, three NXXY motifs, several proline-rich regions, and is called SHIP. Mutation of the conserved tyrosine or leucine residues within the Fc⑀RI  or ␥ ITAMs eliminates SHIP binding and indicates that the SHIP-ITAM interaction is specific. SHIP also binds to ITAMs from the CD3 complex and T cell receptor chain in vitro. SHIP protein possesses both phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase and inositol-1,3,4,5-tetrakisphosphate 5-phosphatase activity. Phosphorylation of SHIP by a protein-tyrosine kinase, Lck, results in a reduction in enzyme activity. Fc⑀RI activation induces the association of several tyrosine phosphoproteins with SHIP. SHIP is constitutively tyrosine-phosphorylated and associated with Shc and Grb2. These data suggest that SHIP may serve as a multifunctional linker protein in receptor activation.The aggregation of immunoreceptors by antigen initiates a complex response leading to cellular activation (1). Receptors on T-, B-, and mast cells each contain subunits with similar primary amino acid sequence within their cytosolic domains, comprising the immunoreceptor-based tyrosine activation motif (ITAM), 1 whose consensus is (D/E)X 2 YXX(L/I)X 6 -8 YXX(L/I) (2, 3). Both tyrosine residues within the ITAM are rapidly phosphorylated by protein kinases after receptor aggregation. The bisphosphorylated ITAM then binds directly to cytosolic tyrosine kinases such as Syk in B-cells and mast cells and ZAP70 in T-cells, thereby activating their tyrosine kinase activity (4, 5). In mast cells, the Fc⑀RI subunits  and ␥ each possess a single ITAM, which, when bisphosphorylated on tyrosine, binds to Syk (6 -8).We have used a novel genetic approach, the yeast tribrid system (8), to isolate cDNAs that encode proteins that interact with the tyrosine-phosphorylated Fc⑀RI ␥ ITAM. The yeast two-hybrid system facilitates the study of protein-protein interactions but is limited to the investigation of proteins that are properly expressed and modified in the host, Saccharomyces cerevisiae. S. cerevisiae does not employ tyrosine phosphorylation as a major regulatory modification of proteins (9, 10). This limits the utility of the two-hybrid system, especially in the area of signal transduction, where tyrosine phosphorylation is a critical component of the process. In order to study protein-protein interactions that are dependent on tyrosine phosphorylation or on other post-translational or allosteric modifications, the yeast tribrid system was developed (8, 11).In the yeast tribrid system, a third plasmid is introduced, which directs th...
Objectives Pain is commonly reported in people living with myositis. This study assesses the presence of pain in the subtypes of myositis as well frequency of opioid and non-opioid pain medication use. Methods A survey was developed and distributed by Myositis Support and Understanding, a patient-led advocacy organization, to members of its group. Multivariate logistic regression analysis and chi-squared tests were performed. Results A total of 468 participants completed the survey. 423 participants (dermatomyositis n = 183, polymyositis n = 109, and inclusion body myositis n = 131) were included, based on reported diagnosis, for final analysis. 91.5% of myositis participants reported current or past pain with 99% attributing their pain to myositis. There was a lower likelihood of pain in participants age over 60 years (OR 0.2, 95%CI : 0.1–0.6, p= 0.003). The percentage of participants reporting pain was statistically different based on myositis type (DM 97.2%, IBM 80.9%, and PM 94.5%, p< 0.001) with a higher likelihood of pain in DM compared with IBM (OR 3.7, 95%CI : 1.3–10.2, p= 0.011). There was a lower likelihood of pain in participants aged over 60 years (OR 0.2, 95%CI : 0.1–0.6, p= 0.003). Of the 387 participants reporting pain, 335 reported using pain medications (69% prescribed opioids). Male sex, age over 60 years, and myositis subtype were not associated with likelihood of non-opioid use. Conclusion Pain is a commonly reported symptom in myositis with variable treatment strategies, including opioid medications. This study highlights the importance of addressing pain as part of myositis treatment as well as the need for future studies understanding treatment effectiveness.
BackgroundIdiopathic inflammatory myopathies (IIMs) often lead to severe impairments in quality-of-life related to physical and emotional burdens. While the healthcare delivery burden in patients with specific types of IIMs has been explored[1], little is known about caregivers‘ burden, especially in rare diseses.[2]ObjectivesMyositis Support and Understanding (MSU), a non-profit patient-led advocacy organization for IIMs, distributed a survey to its members to better understand caregiver burden. The aim of this study was to evaluate the association between caregiver burden by IIM subtype and factors that impact caregiver wellbeing.MethodsData Source:An anonymous survey was distributed via RedCAP to MSU members worldwide. A total of 120 caregivers (age range: 30-89) responded to the survey over the course of 4 weeks.Survey: Demographic, diagnostic information, and disease duration data was collected from participants and their caregivers. The Zarit Burden Interview (ZBI), a validated instrument for a diverse range of patients and caregivers, was used to determine caregiver burden, testing domains including health, mental well-being, personal relationships, physical overload, social support, and home environment[3].Statistical analysis: Pearson chi-square test was performed to assess the association between duration of caregiving, myositis type, and caregiver age on the social well-being of caregivers. Regression analysis was also conducted to identify risk factors for increased caregiver burden. Significance was set at p<0.05.ResultsMost of the caregivers in this study were responsible for the care of participants with inclusion body myositis (IBM, 64%) followed by dermatomyositis (DM, 22%).Caregivers reported that 74% of IIM patients under their care had moderate to severe difficulties with mobility and required help some or most of the time. A total of 102 caregivers completed the ZBI: reported burden was mild to moderate in 44%, moderate to severe in 25%, and severe in 4% of caregivers. There was a high degree of at least moderate severity burden in IBM (33%), DM (25%), and polymyositis (25%).ConclusionCaregivers face a high degree of burden, most evident in IBM. Burden positively correlated with disease duration with an inflection time of 6 years, thereafter caregivers reported increased burden. The domains that were most impacted include personal strain, social and family life, role strain, and loss of control over one‘s life. Insights from this study can help create specific emotional coping strategies for myositis patients and their caregivers.References[1]Christopher-Stine L, Wan GJ, Kelly W, McGowan M, Bostic R, Reed ML. Patient-reported dermatomyositis and polymyositis flare symptoms are associated with disability, productivity loss, and healthcare resource use. J Manag Care Spec Pharm. 2020 Nov;26(11):1424-1433.[2]Yang, G., Cintina, I., Pariser, A.et al.The national economic burden of a rare disease in the United States in 2019.Orphanet J Rare Dis17, 163 (2022).https://doi.org/10.1186/s13023-022-02299-5[3]Bachner, Y. G., & O’Rourke, N. (2007). Reliability generalization of responses by care providers to the Zarit Burden Interview,Aging & Mental Health, 11(6), 678-685. DOI: 10.1080/13607860701529965Acknowledgements:NIL.Disclosure of InterestsNone Declared.
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