scholarly journals OR07-01 Identification of the First Case of Acquired Autoimmune Parathyroid Hormone (PTH) Resistance Due to PTH1 Receptor (PTH1R) Autoantibodies

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Adel Mandl ◽  
Peter D Burbelo ◽  
Giovanni DiPasquale ◽  
James Welch ◽  
William F Simonds ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Autoimmune Diseases ◽  
Elevated Serum ◽  
American Woman ◽  
Dependent Manner ◽  
Hormone Resistance ◽  
First Case ◽  
Symptomatic Hypocalcemia ◽  
Pth Resistance ◽  
Autoimmune Etiology

Abstract Background: Here we describe a patient who presented with symptomatic hypocalcemia and a biochemical picture suggestive of PTH resistance. PTH resistance is a hallmark of pseudohypoparathyroidism, a heterogeneous group of rare disorders caused by genetic or epigenetic alterations of PTH/PTHrP signaling. However, PTH receptor-related autoimmune etiology has not been identified as the underlying mechanism for PTH resistance. Here we describe the first case of acquired autoimmune PTH resistance that is secondary to PTH1R autoantibodies. Clinical Case: A 60-year-old African-American woman, who previously had normal calcium homeostasis, presented with acute, symptomatic hypocalcemia, hyperphosphatemia and markedly elevated serum PTH, consistent with parathyroid hormone resistance. She did not have other hormone resistance or a clinical phenotype suggestive of pseudohypoparathyroidism. Whole-exome sequencing and GNAS methylation analysis revealed no genetic or epigenetic defects of the PTH/PTHrP signaling pathway. Treatment with Calcitriol and Calcium supplements was initiated with good clinical response. Within 10 years of follow-up, the patient developed autoimmune hypothyroidism, alopecia and an unusual form of membranous glomerulonephritis, raising the suspicion for an autoimmune etiology for PTH resistance. Luciferase immunoprecipitation system assay identified antibodies against PTH1R with mapping to the N-terminal extracellular ligand-binding domain (amino acids 1- 178). Using an in vitro biological assay in GP-2.3 cells, we found that the antibodies derived from the patient’s serum blocked PTH downstream signaling via Gsalpha/cAMP/protein kinase A pathway in a concentration-dependent manner. The patient’s autoantibody profile led to the diagnosis of additional autoimmune diseases, including atrophic gastritis and Sjogren syndrome. Lymphocyte immunophenotyping using flow cytometry revealed an overall normal B and T cell profile, but with decreased frequencies and numbers of switched and non-switched memory B cell subsets and an increased frequency and number of the CD8+ naïve cell population. Genes associated with autoimmune inflammatory disorders were sequenced but no pathologic changes were detected. Conclusions: Identification of the first case of autoimmune PTH resistance secondary to PTH1R autoantibodies extends the etiologic spectrum of hypoparathyroidism and should be considered when a patient presents with findings consistent with pseudohypoparathyroidism, especially in the presence of additional autoimmune diseases.

Congenital Hypoparathyroidism Associated With Elevated Circulating Nonfunctional Parathyroid Hormone Due to Novel PTH Mutation

2020 ◽  
Vol 105 (7) ◽  
pp. 2408-2412
Author(s):  
Matti L Gild ◽  
Martyn Bullock ◽  
Catherine Luxford ◽  
Michael Field ◽  
Roderick J Clifton-Bligh
Keyword(s):  
Parathyroid Hormone ◽  
Elevated Serum ◽  
Gene Mutations ◽  
Homozygosity Mapping ◽  
Case Description ◽  
Biochemical Phenotype ◽  
Upper Limit ◽  
Codon Change ◽  
Serum Pth ◽  
Pth Resistance

Abstract Context Familial hypoparathyroidism has a heterogeneous presentation where patients usually have low parathyroid hormone (PTH) levels due to impaired production or secretion. This contrasts with pseudohypoparathyroidism, in which PTH resistance is usually associated with an elevated serum PTH. High levels of circulating PTH can also be due to bioinactive PTH, which is difficult to distinguish from pseudohypoparathyroidism on biochemical grounds. Case Description We report on 2 sisters from consanguineous parents who presented with tetany at birth and were diagnosed with congenital hypocalcemia. Serum PTH levels were normal for many years, but progressively increased in midadulthood to greater than 100x the upper limit of normal on multiple assays. Homozygosity mapping was performed on 1 sister that demonstrated loss of heterozygosity (LOH) around PTH. Sequencing revealed a previously unreported variant, c.94T>C, predicting a codon change of p.Ser32Pro that is biologically inactive. Conclusions This case report shows a previously unreported unusual biochemical phenotype of a rising PTH in the context of a novel PTH mutation. This expands the evolving genotypes associated with hypoparathyroidism without established gene mutations.

scholarly journals The Mutant Thyroid Hormone Receptor Beta R320P Causes Syndrome of Resistance to Thyroid Hormone

2018 ◽  
Vol 2018 ◽  
pp. 1-3 ◽  
Author(s):  
Tetsuya Kimura ◽  
Yoshitaka Hayashi ◽  
Yuka Tsukamoto ◽  
Yasuyuki Okamoto
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Hormone Receptor ◽  
Elevated Serum ◽  
Index Patient ◽  
Serum Levels ◽  
Heterozygous Mutation ◽  
Hormone Resistance ◽  
Thyroid Hormone Resistance ◽  
First Case ◽  
Thyroid Hormone Resistance Syndrome

A 31-year-old Japanese male patient with a history of atrial fibrillation showed elevated serum levels of free thyroxine and triiodothyronine and a normal level of thyrotropin. The same abnormal hormone pattern was also found in his son. These data indicated that the index patient and the son have thyroid hormone resistance syndrome. Exon sequencing using DNA from these two patients revealed that both patients harbored a heterozygous mutation in the THRB gene: G1244C in exon 9, which results in R320P substitution. Therefore, thyroid hormone resistance syndrome caused by THRB mutation (RTHβ) was diagnosed. The mutation of the 320th arginine to proline has not been found to date. In conclusion, herein, we have described the first case of RTHβ that is associated with R320P mutation.

A novel GNAS mutation inherited from probable maternal mosaicism causes two siblings with pseudohypoparathyroidism type 1A

2020 ◽  
Vol 33 (9) ◽  
pp. 1219-1224
Author(s):  
Qi Wang ◽  
Jiayi Xian ◽  
Pingjiao Chen ◽  
Jingying Wang ◽  
Yan Gao ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Maternal Inheritance ◽  
De Novo ◽  
Novel Mutation ◽  
Subcutaneous Tissue ◽  
Thyroid Stimulating Hormone ◽  
Hormone Resistance ◽  
Case Presentation ◽  
Pth Resistance ◽  
Gnas Mutation

AbstractObjectivesObjectives Pseudohypoparathyroidism type 1A (PHP1A) is caused by maternal inheritance of GNAS mutations. It is characterized by the resistance to several hormones, primarily the parathyroid hormone (PTH), and the features of Albright’s hereditary osteodystrophy.Case presentationHere, we present a family comprised two affected brothers with PHP1A and identify a novel mutation (c.277C>T) in the GNAS gene. The siblings developed a slightly different presentation in the same clinical condition. Although both patients presented with PTH resistance, which is the hallmark of PHP, the proband showed the thyroid-stimulating hormone resistance with the progression of heterotopic ossification from skin and subcutaneous tissue into deep connective tissue, while the younger brother with normocalcemia did not show the resistance to other hormones. The patients may inherit the mutation from their mother who presumably carries the mutation as a mosaicism.ConclusionsOur case highlights the significance of considering mosaicism as an explanation for apparent de novo cases of pseudohypoparathyroidism.

Abstract #615: Hypocalcemia Secondary to Parathyroid Hormone Resistance

2016 ◽  
Vol 22 ◽  
pp. 135
Author(s):  
Mitali Talsania ◽  
Ammara Aziz ◽  
Lauren LaBryer ◽  
Jonea Lim
Keyword(s):  
Parathyroid Hormone ◽  
Hormone Resistance

The coexistence of autoimmune pancreatitis and elevated serum IGG4 in autoimmune diseases

2011 ◽  
Vol 49 (05) ◽  
Author(s):  
V Terzin ◽  
I Földesi ◽  
L Kovács ◽  
G Pokornyi ◽  
T Wittmann ◽  
...  
Keyword(s):  
Autoimmune Diseases ◽  
Autoimmune Pancreatitis ◽  
Elevated Serum ◽  
Serum Igg4

scholarly journals First Case of Autochthonous Equine Theileriosis in Austria

Pathogens ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 298
Author(s):  
Esther Dirks ◽  
Phebe de Heus ◽  
Anja Joachim ◽  
Jessika-M. V. Cavalleri ◽  
Ilse Schwendenwein ◽  
...  
Keyword(s):  
Developmental Stages ◽  
Elevated Serum ◽  
Clinical Signs ◽  
Dermacentor Reticulatus ◽  
Theileria Equi ◽  
Amyloid A ◽  
First Case ◽  
Blood Smears ◽  
Eastern Austria ◽  
Iatrogenic Transmission

A 23-year-old pregnant warmblood mare from Güssing, Eastern Austria, presented with apathy, anemia, fever, tachycardia and tachypnoea, and a severely elevated serum amyloid A concentration. The horse had a poor body condition and showed thoracic and pericardial effusions, and later dependent edema and icteric mucous membranes. Blood smear and molecular analyses revealed an infection with Theileria equi. Upon treatment with imidocarb diproprionate, the mare improved clinically, parasites were undetectable in blood smears, and 19 days after hospitalization the horse was discharged from hospital. However, 89 days after first hospitalization, the mare again presented to the hospital with an abortion, and the spleen of the aborted fetus was also PCR-positive for T. equi. On the pasture, where the horse had grazed, different developmental stages of Dermacentor reticulatus ticks were collected and subjected to PCR, and one engorged specimen was positive for T. equi. All three amplicon sequences were identical (T. equi genotype E). It is suspected that T. equi may repeatedly be transmitted in the area where the infected mare had grazed, and it could be shown that transmission to the fetus had occurred. Due to the chronic nature of equine theileriosis and the possible health implications of infection, it is advised to include this disease in the panel of differential diagnoses in horses with relevant clinical signs, including horses without travel disease, and to be aware of iatrogenic transmission from inapparent carrier animals.

scholarly journals AB0037 EXPRESSION OF NEGATIVE CHECKPOINT MOLECULES BTLA AND HVEM IS DYSREGULATED IN AUTOIMMUNE DISEASES

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1321.1-1321
Author(s):  
S. Nagpal ◽  
S. Cole ◽  
A. Floudas ◽  
M. Wechalekar ◽  
Q. Song ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Autoimmune Disease ◽  
Autoimmune Diseases ◽  
Immune Checkpoint ◽  
Peripheral Blood ◽  
Expression Patterns ◽  
Myeloid Cell ◽  
Dependent Manner ◽  
Research Support

Background:Immune checkpoint blockade with agents targeting CTLA4 and PD-1/PD-L1 alone or in combination has demonstrated exceptional efficacy in multiple cancer types by “unleashing” the cytotoxic action of quiescent, tumor-infiltrating T cells. However, the therapeutic action of these immunotherapies goes hand in hand with the loss of immune tolerance and appearance of immune-related adverse events such as colitis, arthralgia and inflammatory arthritis in responsive patients. Therefore, immune checkpoint molecules have been proposed as targets for the treatment of autoimmune diseases.Objectives:Herein, we interrogate the potential of BTLA/HVEM axis as a target for restoring immune homeostasis in rheumatoid arthritis (RA), Systemic Lupus Erythematosus (SLE) and Sjogren’s Syndrome (SjS) by examining their expression patterns in autoimmune disease tissues.Methods:Message and protein expression of BTLA and HVEM were examined in RA and SLE synovial tissues, SLE cutaneous lesions, SjS salivary glands and peripheral blood samples of autoimmune disease by RNA sequencing and flow cytometry.Results:Tissue dysregulation of the BTLA-HVEM axis was observed: Increased BTLA RNA level in RA synovium, SLE-affected skin, and SjS salivary gland samples, whereas HVEM level was affected only in the RA synovium when compared to unaffected tissues. Detailed immunophenotyping of B, T, and myeloid cell populations in RA, SLE, SjS and healthy control PBMCs revealed differential modulation of the BTLA+ or HVEM+ immune cell subsets in a disease-context dependent manner. SjS patients showed an overall decrease in memory B cells and most of the BTLA+ B cell subsets while a decrease in HVEM+ B cells was observed only in SLE PBMC samples and not RA and SLE samples. Immunophenotyping with a T cell panel exhibited decreased BTLA and HVEM expression on T cell subsets in SjS and SLE but not in RA patients. In addition, protein levels of HVEM were differentially decreased in SLE myeloid cell subsets. Finally, we demonstrate tissue-specific surface expression patterns of BTLA in RA and SLE samples: higher surface BTLA levels on RA and SLE PBMC B cells than matched tissue-derived B cells.Conclusion:Our results demonstrate a dysregulation of the BTLA/HVEM axis in either lesional tissue or peripheral blood in an autoimmune disease context-dependent manner. These results also indicate the potential of targeting BTLA-HVEM axis for the treatment of multiple autoimmune diseases.Disclosure of Interests:Sunil Nagpal Shareholder of: Janssen Pharmaceuticals, Employee of: Janssen Pharmaceuticals, Suzanne Cole Shareholder of: Janssen Research & Development employee, Employee of: Janssen Research & Development employee, Achilleas Floudas: None declared, Mihir Wechalekar Grant/research support from: Grant from Janssen Research & Development, Qingxuan Song Shareholder of: Employee of Janssen Research, Employee of: Employee of Janssen Research, Tom Gordon: None declared, Roberto Caricchio Grant/research support from: Financial grant from Janssen Research & Development, Douglas Veale: None declared, Ursula Fearon: None declared, Navin Rao Shareholder of: Janssen Pharmaceuticals, Employee of: Janssen Pharmaceuticals, Ling-Yang Hao Shareholder of: Employee of Janssen Research, Employee of: Employee of Janssen Research

scholarly journals AB0095 PRECLINICAL CHARACTERIZATION OF CJ-15314, A HIGHLY SELECTIVE JAK1 INHIBITOR, FOR THE TREATMENT OF AUTOIMMUNE DISEASES

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1347.2-1347
Author(s):  
S. Y. Ki ◽  
H. Shin ◽  
Y. Lee ◽  
H. R. Bak ◽  
H. Yu ◽  
...  
Keyword(s):  
Autoimmune Disease ◽  
Autoimmune Diseases ◽  
Whole Blood ◽  
Inflammatory Diseases ◽  
Selective Inhibition ◽  
Janus Kinase ◽  
Dependent Manner ◽  
Human Whole Blood

Background:Janus kinases (JAK1, JAK2, JAK3, and TYK2) play critical roles in mediating various cytokine signaling, and has been developed as a target for autoimmune diseases such as RA. Tofacitinib, oral Pan-JAK inhibitor, demonstrated efficacy in RA patients, but its widespread use is limited by safety issues. Baricitinib, JAK1/2 inhibitor, is also known to interfere with the hematopoiesis system, such as anemia and thrombocytopenia associated with suppression of JAK2 signals. Therefore, it is necessary to develop a new potent compound that selectively inhibits JAK1 over JAK2, 3Objectives:To identify the pharmacological characteristic based on efficacy of CJ-15314 as potent and selective JAK1 inhibitor for treatment of autoimmune disease.Methods:In vitro, cell-based, kinase panel, Kd value and human whole blood assay were performed to determine the inhibition potency and selectivity for JAK subfamily kinases. In vivo therapeutic potential was evaluated by RA model including rat Adjuvant-Induced Arthritis (AIA) and collagen-induced arthritic (CIA). To confirm the possibility of further expansion into the autoimmune disease, BioMAP® Diversity PLUS® Panel was performed by discoverX.Results:In vitro assay, CJ-15314 inhibited JAK kinase family in a concentration-dependent manner with IC50 values of 3.8 nM against JAK1, Selectivity for JAK1 over JAK2, 3 was approximately 18, 83 fold greater for CJ-15314. In 1mM ATP condition, CJ-15314 has been confirmed to have the highest JAK1 selectivity over competing drugs, under 1 mM ATP condition that reflects the physiological environment in the body. Similarly, Kd values has also confirmed the selectivity of JAK1, which is 10 fold higher than JAK2, 3. Accordingly, in human whole blood assays, CJ-15314 is 11 fold more potent against IL-6 induced pSTAT1 inhibition through JAK1 (IC50 value: 70 nM) than GM-CSF-induced pSTAT5 inhibition (JAK2) whereas baricitinib and filgotinib exhibited only 2 fold and 7 fold respectively.In vivo efficacy model, CJ-15314 inhibited disease severity scores in a dose dependent manner. In the rat AIA model, CJ-15314 at 30 mg/kg dose showed 95.3% decrease in arthritis activity score, 51.2% in figotinib at 30 mg/kg, 97.7% showed baricitinib at 10 mg/kg. CJ-15314 showed superior anti-arthritic efficacy than filgotinib. CJ-15314 also minimally affected anemia-related parameters but not bricitinib end of the 2-week treatment. In the rat CIA model, like 10 mg/kg of bricitinib, 30 mg/kg of CJ-15314 also has a similar effect, with a significant reduction in histopathological scores.In biomap diversity panel, CJ-15314 inhibited the expression of genes such as MCP-1, VCAM-1, IP-10, IL-8, IL-1, sTNF-α and HLA-DR confirming the possibility of expansion into other diseases beyond arthritis.Conclusion:CJ-15314 is a highly selective JAK1 inhibitor, demonstrates robust efficacy in RA animal model and is good candidate for further development for inflammatory diseases.* CJ-15314 is currently conducting a phase I trial in south Korea.References:[1]Clark JD et al. Discovery and development of Janus kinase (JAK) inhibitors for inflammatory diseases. J Med Chem. 2014; 57(12):5023-38.[2]Burmester GR et al. Emerging cell and cytokine targets in rheumatoid arthritis. Nat Rev Rheumatol. 2014; 10(2):77-88[3]Jean-Baptiste Telliez et al. Discovery of a JAK3-selective inhibitor: functional differentiation of JAK3-selective inhibition over pan-JAK or JAK1-selective inhibition. ACS Chem. Biol., 2016; 11 (12):3442-3451Disclosure of Interests:so young Ki Employee of: CJ healthcare, hyunwoo shin Employee of: CJ healthcare, yelim lee Employee of: CJ healthcare, Hyoung rok Bak Employee of: CJ healthcare, hana yu Employee of: CJ healthcare, Seung Chan Kim Employee of: CJ healthcare, juhyun lee Employee of: CJ healthcare, donghyun kim Employee of: CJ healthcare, Dong-hyun Ko Employee of: CJ Healthcare, dongkyu kim Employee of: CJ healthcare

Direct effect of parathyroid hormone on insulin secretion from pancreatic islets

1990 ◽  
Vol 258 (6) ◽  
pp. E975-E984 ◽  
Author(s):  
G. Z. Fadda ◽  
M. Akmal ◽  
L. G. Lipson ◽  
S. G. Massry
Keyword(s):  
Insulin Secretion ◽  
Parathyroid Hormone ◽  
Pancreatic Islets ◽  
Insulin Release ◽  
Direct Effect ◽  
Indirect Evidence ◽  
Cytosolic Calcium ◽  
Dependent Manner ◽  
Stimulation Of

Indirect evidence indicates that parathyroid hormone (PTH) interacts with pancreatic islets and modulates their insulin secretion. This property of PTH has been implicated in the genesis of impaired insulin release in chronic renal failure. We examined the direct effect of PTH-(1-84) and PTH-(1-34) on insulin release using in vitro static incubation and dynamic perifusion of pancreatic islets from normal rats. Both moieties of the hormone stimulated in a dose-dependent manner glucose-induced insulin release but higher doses inhibited glucose-induced insulin release. This action of PTH was modulated by the calcium concentration in the media. The stimulatory effect of PTH was abolished by its inactivation and blocked by its antagonist [Tyr-34]bPTH-(7-34)NH2. PTH also augmented phorbol ester (TPA)-induced insulin release, stimulated adenosine 3',5'-cyclic monophosphate (cAMP) generation by pancreatic islets, and significantly increased (+50 +/- 2.7%, P less than 0.01) their cytosolic calcium. Verapamil inhibited the stimulatory effect of PTH on insulin release. The data show that 1) pancreatic islets are a PTH target and may have PTH receptors, 2) stimulation of glucose-induced insulin release by PTH is mediated by a rise in cytosolic calcium, 3) stimulation of cAMP production by PTH and a potential indirect activation of protein kinase C by PTH may also contribute to the stimulatory effect on glucose-induced insulin release, and 4) this action of PTH requires calcium in incubation or perifusion media.

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