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Leukaemias
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2014
Based on the notion of immunological involvement in the pathogenesis of MDS, there has been a historical interest in testing a variety of immunosuppressive therapies, in particular antithymocyte globulin (ATG) and cyclosporine A (CSA), primarily in patients with ‘lower-risk’ disease.202 Early observations suggested a trend for better responses in those cases with hypocellular MDS or those with an HLA-DR15 class II phenotype.203 Overall, roughly a third of unselected patients respond to treatment with ATG. In a multivariate analysis of variables associated with response to ATG in patients treated at the National Institutes of Health, age emerged as the most powerful accompanied by duration of RBC transfusion dependence, and HLA-DR15.204 Recent studies have identified biomarkers that may offer more precision in identifying those patients responsive to immunosuppressive therapy. Zou and colleagues found that a CD4:CD8 ratio < 2.0, is highly predictive of response to equine ATG; this finding was subsequently validated in a prospective study using rabbit ATG in MDS patients.205 The ELN MDS 2013 guidelines recommend immunosuppressive therapy with ATG and CSA to be considered in patients below 60 years of age, with less than 5% marrow blasts, normal karyotype, and transfusion dependency who are not candidates for treatment with or for whom a therapeutic trial with HGFs has failed.191
Vasculitis
Published in Philip T. Cagle, Timothy C. Allen, Mary Beth Beasley, Diagnostic Pulmonary Pathology, 2008
Anti-GBM disease or GPS is associated with ANCA. In approximately 25% of patients with anti-GBM antibodies, a positive ANCA titer, mostly anti-MPO (P-ANCA), is seen (20). The primary target of anti-GBM antibody is a component of type IV collagen, and the pathogenic epitope is in noncollagenous 1 (NC1) domain of the α-3 chain of type IV collagen. Interestingly, the pathogenic antigen in the lungs is only exposed to the anti-GBM antibody when there is an underlying injury to the endothelial cells, such as smoking or lung infection, since the alveolar endothelial cells lack fenestrations. There is a strong human leukocyte antigen (HLA) association, with greater than 80% of the patients with anti-GBM disease carrying HLA-DR15 and DR4 alleles, while the DR7 locus seems to have a protective character (21). This suggests a possible role for T cells in the pathogenesis of autoimmune response in anti-GBM disease.
Pediatric Sleep Disorders
Published in Mark A. Richardson, Norman R. Friedman, Clinician’s Guide to Pediatric Sleep Disorders, 2016
Excessive daytime sleepiness may be caused by problems other than OSA. Increasingly, narcolepsy is diagnosed in children. Patients as young as seven to eight years of age are being identified. Narcolepsy is caused by a deficiency of hypocretin. It usually presents as excessive daytime sleepiness in children, but may not have the typical tetrad of cataplexy, hypnogogic hallucinations, and sleep paralysis that is characteristic in adults (47,48). Children rarely present with a primary complaint of cataplexy or sleep paralysis. Some degree of sleep disturbance including restlessness is more common. Children may snore, but OSA is not necessarily present. OSAS needs to be ruled out by PSG. Often a family history of narcolepsy or excessive daytime sleepiness is present. Narcolepsy has a strong inherited component related to HLA-DR15 (DR2). In children with excessive daytime sleepiness that cannot be explained by obstructive apnea or poor sleep hygiene, overnight PSG as well as a mean latency sleep test (MSLT) should be obtained (49). If the PSG is normal, patients undergo an MSLT, in which they are allowed to take four or five 20-minute naps. A diagnosis of narcolepsy is made when patients fall asleep quickly (mean sleep latency of under five minutes) and have sleep onset REM on at least two of the five naps (50). An increasing number of children are now diagnosed with narcolepsy. This trend is likely related to the easy access to pediatric sleep labs and the availability of genetic testing (51). The patients who fall asleep quickly but do not have sleep onset REM may have idiopathic hypersomnia, a mild form of daytime sleepiness, which may not be associated with cataplexy and hypnogogic hallucinations.
Differential Diagnosis of Vitritis in Adult Patients
Published in Ocular Immunology and Inflammation, 2021
Sarah Touhami, Mathilde Leclercq, Dinu Stanescu-Segall, Valérie Touitou, Bahram Bodaghi
While present in all age groups, intermediate uveitis seems to affect predominantly children and young adults during their third or fourth decade.6,11–13 There is also an important finding regarding gender distribution. Male predominance has been reported in many studies, especially in childhood uveitis cases,13 while others reported female predominance in adult cases. Familial associations are not the rule but have been noted in Asian families, and in identical twins.14,15 Associations with specific HLA (human leukocyte antigen) phenotypes have been reported, namely in HLA-DR15 and HLA-A28 patients, corroborating the hypothesis of at least a partial genetic component in intermediate uveitis.16,17 HLA-DR15-positive IU patients have been described to feature other HLA-DR15-related disorders including multiple sclerosis, optic neuritis, and narcolepsy.16,17
The small molecule antibody mimic SH7139 targets a family of HLA-DRs expressed by B-cell lymphomas and other solid cancers
Published in Journal of Drug Targeting, 2020
Rod Balhorn, Monique Cosman Balhorn, Karuppiah Balakrishnan, Robert B. Rebhun
The docking experiments conducted with HLA-DR11 and HLA-DR15 provided results similar to those obtained with HLA-DR10 except that all three ligands were more promiscuous with respect to the sites where they were predicted to bind (Figure 5(A)). For HLA-DR15, several Ct conformers were predicted to bind inside the antigen-binding cavity to all three sites. A similar result was obtained with the Cb ligand, which was also predicted to bind to all three sites. Most of the conformers of Dv docked to HLA-DR15 were predicted to bind to Site 2 as in HLA-DR10, but a few also bound in or near Site 1. In the experiments conducted with HLA-DR11, all three ligands were predicted to bind to Site 1, Dv and Cb were predicted to bind to Site 2, and Ct and Cb conformers were predicted to bind to Site 3. While the predicted binding of each ligand to multiple sites suggest the structures or surface properties of the cavities in HLA-DR15 and HLA-DR11 must differ sufficiently from those in HLA-DR10 to reduce the selectivity of the ligand’s binding to a single specific site (Figure 5(A)), these results also indicate SH7129 should be fully capable of binding to the antigen-binding pockets of HLA-DR15 and HLA-DR11 when the three ligands are linked together.
Intermediate Uveitis: A Review
Published in Ocular Immunology and Inflammation, 2023
Andrea York Tiang Teo, Bjorn Kaijun Betzler, Keith Low Qie Hua, Elizabeth Jiahui Chen, Vishali Gupta, Rupesh Agrawal
Regarding genetic determinants, while the familial occurrence of IU is rare, associations between human leukocyte antigen (HLA) haplotypes and the disease suggest a possible heritable cause. HLA-DR15, coding for one of the two HLA-DR2 subtypes, has been demonstrated to have an association with IU.47,70 It was further reported that some IU patients with HLA-DR15 positivity also had co-existing multiple sclerosis, optic neuritis, and/or narcolepsy.70 Other associations include HLA-A28, HLA-B8, HLA-B51, and HLA-B27.4,47,71–73 Some studies have also noted several instances of familial clustering of IU.74–76