Protein Kinase C-Delta Defect in Autoimmune Lymphoproliferative Syndrome-Like Disease: First Case from the National Iranian Registry and Review of the Literature

Sharifinejad, Niusha; Azizi, Gholamreza; Behniafard, Nasrin; Zaki‐Dizaji, Majid; Jamee, Mahnaz; Yazdani, Reza; Abolhassani, Hassan; Aghamohammadi, Asghar

doi:10.1080/08820139.2020.1829638

Cited by 11 publications

(18 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…An elevation of double-negative T cells, CD8 + T cells, serum IgG level, as well as a reduction in NK cells, was observed in the patient. 7 In the literature review of the three PRKCD patients, all of them show an elevated TCRαβ + CD4/CD8 double-negative T cells (DNT). The early clinical onset of the disease and prominent autoimmunity in PRKCD deficiency was demonstrated to be associated with an abnormal B cell compartment, characterized by increased naive and diminished memory cells as well as high number of TCRαβ + CD4/CD8 double-negative T cells (DNT).…”

Section: Discussionmentioning

confidence: 99%

“…This population of cells is reported to be increased in Common Variable Immune Deficient (CVID) patients with autoimmunity and splenomegaly, particularly as a required criteria for ALPS, 5 and has also been observed previously for PRKCD deficiency. 6 , 7 However, treatment with sirolimus in PRKCD disorders had not been previously described, even the effect of sirolimus on PRKCD has not yet been fully elucidated, it is known to have immunomodulatory, anti-inflammatory, anti-proliferative, and photoprotective effects. 11 Recent data on the sirolimus mechanism revealed an immunomodulatory effect through inhibition of mTORC1 in CD4 + , CD8 + , DNT, and Teff (CD4+CD25 low ) cells thereby inducing rebalance of Treg, mTORC1 low expression, of these cells.…”

Section: Discussionmentioning

confidence: 99%

“… 6 Numerous studies in humans and mice have established that variation on PRKCD may affect B-cell signaling and autoimmunity, as well as regulation of growth, apoptosis, and differentiation of a variety of cell types. 7 – 10 Interestingly, clinical manifestations of the so far reported cases exhibit some of the signs of the ALPS-like disease, including autoimmunity, cytopenia, and increased B-cell numbers and proliferation. In this pedigree report, we describe the clinical and laboratory findings of homozygous PRKCD variant, presenting features of ALPS symptom with raised ratio of DNTs and a low percentage of Treg and Th17.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Sirolimus is effective in autoimmune lymphoproliferative syndrome-type III: A pedigree case report with homozygous variation PRKCD

Chen

et al. 2021

Int J Immunopathol Pharmacol

View full text Add to dashboard Cite

Autoimmune lymphoproliferative syndrome (ALPS) usually presents in childhood with fever, nonmalignant splenomegaly, and lymphadenopathy along with cytopenia, which is caused by mutations in the FAS apoptotic pathway. The TCRαβ + CD4/CD8 double-negative T cells (DNT), one of required criteria of ALPS, will rise markedly in ALPS. Human Protein kinase C delta (PRKCD) deficiency (OMIM # 615559) was recently identified to be causative for an ALPS-type III with significant B-cell proliferation particularly of immature B cells. We report a pedigree homozygous variation of PRKCD gene (c.36T>G, p. Y12X) which presented with refractory cytopenia, splenomegaly, and polarization of DNT/regulatory T cells (Treg) axis. After repeated recurrence, the patient was treated with mTOR inhibitor sirolimus, which had a safety mechanism and specifically rebalance the DNT/Treg axis. The patient’s hemoglobin and clinical condition improved gradually by the application of sirolimus (1.5 mg/m2, actual blood concentration 4.27–10.3 ng/l). Homozygous variation in PRKCD may lead to typical ALPS clinical manifestations. Targeting DNT/Treg axis, use of sirolimus in such patients may help to achieve good clinical control.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Sirolimus is effective in autoimmune lymphoproliferative syndrome-type III: A pedigree case report with homozygous variation PRKCD

Chen

et al. 2021

Int J Immunopathol Pharmacol

View full text Add to dashboard Cite

show abstract

“…Since 2013, 11 patients from 7 kindreds suffering from autosomal recessive (AR) PKCδ deficiency have been reported ( Kuehn et al, 2013 ; Belot et al, 2013 ; Kiykim et al, 2015 ; Salzer et al, 2013 ; Lei et al, 2018 ; Nanthapisal et al, 2017 ; Meyts et al, 2021 ; Sharifinejad et al, 2020 ). They manifested with a monogenic form of systemic lupus erythematosus (SLE) occurring before the age of 10 yr.…”

Section: Introductionmentioning

confidence: 99%

“…These patients had small numbers of memory B cells (CD19 + /CD27 + ), very large numbers of naive (CD19 + /CD27 − ) and immature (CD19 + /CD21 − ) B cells, and an impaired Ig class switch ( Kuehn et al, 2013 ; Belot et al, 2013 ). High counts of circulating CD8 + T cells and double-negative (CD4 − /CD8 − ) T cells were observed in some cases, together with slightly low levels of T cell proliferation in vitro ( Kuehn et al, 2013 ; Sharifinejad et al, 2020 ; Kiykim et al, 2015 ). Intriguingly, these patients suffer not only from autoimmune disease, but also from recurrent and/or severe infections ( Kuehn et al, 2013 ; Belot et al, 2013 ; Kiykim et al, 2015 ; Salzer et al, 2013 ; Lei et al, 2018 ; Nanthapisal et al, 2017 ; Meyts et al, 2021 ; Sharifinejad et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Impaired respiratory burst contributes to infections in PKCδ-deficient patients

Neehus

Moriya

Lévy

et al. 2021

Journal of Experimental Medicine

Self Cite

View full text Add to dashboard Cite

Patients with autosomal recessive protein kinase C δ (PKCδ) deficiency suffer from childhood-onset autoimmunity, including systemic lupus erythematosus. They also suffer from recurrent infections that overlap with those seen in patients with chronic granulomatous disease (CGD), a disease caused by defects of the phagocyte NADPH oxidase and a lack of reactive oxygen species (ROS) production. We studied an international cohort of 17 PKCδ-deficient patients and found that their EBV-B cells and monocyte-derived phagocytes produced only small amounts of ROS and did not phosphorylate p40phox normally after PMA or opsonized Staphylococcus aureus stimulation. Moreover, the patients’ circulating phagocytes displayed abnormally low levels of ROS production and markedly reduced neutrophil extracellular trap formation, altogether suggesting a role for PKCδ in activation of the NADPH oxidase complex. Our findings thus show that patients with PKCδ deficiency have impaired NADPH oxidase activity in various myeloid subsets, which may contribute to their CGD-like infectious phenotype.

show abstract

Chronic Granulomatous Disease-Like Presentation of a Child with Autosomal Recessive PKCδ Deficiency

et al. 2022

View full text Add to dashboard Cite

Background Autosomal recessive (AR) PKCδ deficiency is a rare inborn error of immunity (IEI) characterized by autoimmunity and susceptibility to bacterial, fungal, and viral infections. PKCδ is involved in the intracellular production of reactive oxidative species (ROS). Material and Methods We studied a 5-year old girl presenting with a history of Burkholderia cepacia infection. She had no history of autoimmunity, lymphocyte counts were normal, and no auto-antibodies were detected in her plasma. We performed a targeted panel analysis of 407 immunity-related genes and immunological investigations of the underlying genetic condition in this patient. Results Consistent with a history suggestive of chronic granulomatous disease (CGD), oxidative burst impairment was observed in the patient’s circulating phagocytes in a dihydrorhodamine 123 (DHR) assay. However, targeted genetic panel analysis identified no candidate variants of known CGD-causing genes. Two heterozygous candidate variants were detected in PRKCD: c.285C > A (p.C95*) and c.376G > T (p.D126Y). The missense variant was also predicted to cause abnormal splicing, as it is located at the splice donor site of exon 5. TOPO-TA cloning confirmed that exon 5 was completely skipped, resulting in a truncated protein. No PKCδ protein was detected in the patient’s neutrophils and monocyte-derived macrophages. The monocyte-derived macrophages of the patient produced abnormally low levels of ROS, as shown in an Amplex Red assay. Conclusion PKCδ deficiency should be considered in young patients with CGD-like clinical manifestations and abnormal DHR assay results, even in the absence of clinical and biological manifestations of autoimmunity.

show abstract

Protein Kinase C-Delta Defect in Autoimmune Lymphoproliferative Syndrome-Like Disease: First Case from the National Iranian Registry and Review of the Literature

Cited by 11 publications

References 27 publications

Sirolimus is effective in autoimmune lymphoproliferative syndrome-type III: A pedigree case report with homozygous variation PRKCD

Sirolimus is effective in autoimmune lymphoproliferative syndrome-type III: A pedigree case report with homozygous variation PRKCD

Impaired respiratory burst contributes to infections in PKCδ-deficient patients

Chronic Granulomatous Disease-Like Presentation of a Child with Autosomal Recessive PKCδ Deficiency

Contact Info

Product

Resources

About