Protein Kinase Cδ Deficiency Causes Mendelian Systemic Lupus Erythematosus With B Cell‐Defective Apoptosis and Hyperproliferation

Abstract

Objective Systemic lupus erythematosus (SLE) is a prototype autoimmune disease that is assumed to occur via a complex interplay of environmental and genetic factors. Rare causes of monogenic SLE have been described, providing unique insights into fundamental mechanisms of immune tolerance. The aim of this study was to identify the cause of an autosomal-recessive form of SLE. Methods We studied 3 siblings with juvenile-onset SLE from 1 consanguineous kindred and used next-generation sequencing to identify mutations in the disease-associated gene. We performed extensive biochemical, immunologic, and functional assays to assess the impact of the identified mutations on B cell biology. Results We identified a homozygous missense mutation in PRKCD, encoding protein kinase δ (PKCδ), in all 3 affected siblings. Mutation of PRKCD resulted in reduced expression and activity of the encoded protein PKCδ (involved in the deletion of autoreactive B cells), leading to resistance to B cell receptor– and calcium-dependent apoptosis and increased B cell proliferation. Thus, as for mice deficient in PKCδ, which exhibit an SLE phenotype and B cell expansion, we observed an increased number of immature B cells in the affected family members and a developmental shift toward naive B cells with an immature phenotype. Conclusion Our findings indicate that PKCδ is crucial in regulating B cell tolerance and preventing self-reactivity in humans, and that PKCδ deficiency represents a novel genetic defect of apoptosis leading to SLE.

Protein Kinase Cδ Promotes Transitional B Cell-Negative Selection and Limits Proximal B Cell Receptor Signaling To Enforce Tolerance

“…Indeed, this key difference explains the distinct outcomes for tolerance induction in these different mutant strains in the context of the sHEL/IgHEL system: while mutations of the Lyn/CD22/SHP-1 pathway turn anergy into deletion in the double-transgenic mice, PKC␦ deficiency does not enhance deletion but rather allows the B cells to develop and subsequently leads to loss of anergy. The requirement for PKC␦ for coupling the BCR to apoptosis in T1 cells can be at least partially attributed to its role in activating proapoptotic Ca 2ϩ -dependent Erk signaling (3,26,35). In addition, tonic signaling from the BCR is also enhanced in PKC␦ Ϫ/Ϫ transitional B cells, and the recent finding that the BAFFr acts at least in part by coopting the BCR signaling machinery (24) implies that PKC␦ deficiency may mimic at least some features of BAFF stimulation by enhancing tonic BCR signaling.…”

“…PKC␦ Ϫ/Ϫ mice represent a lupus mouse model in which this checkpoint is severely impaired, and its relevance in human disease is underscored by three recent reports of human patients with mutations in PKC␦ that underlie juvenile-onset SLE, autoimmune lymphoproliferative syndrome (ALPS), and B cell deficiency with autoimmunity, with some of these patients displaying defective B cell apoptosis and hyperpro- liferation of transitional B cells (3)(4)(5). The striking resemblance of the disease in these patients to the phenotypes we have characterized in the PKC␦ Ϫ/Ϫ mice highlights the relevance of these mice as a model of human disease that warrants further investigation.…”

“…PKC␦-deficient mice develop a severe autoimmune disease characterized by autoantibody production, glomerulonephritis, and robust B cell lymphoproliferation leading to splenomegaly and lymphadenopathy (1,2). Several recent reports have identified mutations in PKC␦ that appear to underlie autoimmune pathology in humans (3)(4)(5), supporting the notion that PKC␦ Ϫ/Ϫ mice represent a valuable mouse model of human disease. Although PKC␦ clearly has a vital function in suppressing autoimmune disease in both mice and humans, the mechanisms by which PKC␦ deficiency causes autoimmunity remain poorly defined.…”

Mosaic Tetrasomy 9p: A Mendelian Condition Associated With Pediatric-Onset Overlap Myositis

“…She had normal weight, height (+1 SD), and cranial perimeter growth. Accepted for publication May 6, 2015 Her standard karyotype, performed after her parents' informed consent, was mos47,XX,+i(9)(p10)[33]/46,XX [17]. Confirmation of isochromosome 9p was performed by interphase fluorescence in situ hybridization (FISH) by using commercial chromosome 9 centromeric probes.…”

“…1,2 To date, 3 major molecular pathways have been involved in the development of monogenic SLE: (1) a disturbed clearance of apoptotic material in complement deficiencies, leading to lupus in association with a predisposition to infections 15 ; (2) an upregulated production of type I IFN in type I interferonopathies, including Aicardi-Goutières syndrome, ACP5 gene mutations causing SLE associated with a skeletal dysplasia, mutations in DNASE1L3 associated with lupus nephritis, and STING (Stimulator of interferon genes)-associated vasculopathy with onset in infancy (SAVI) 3,16 ; and (3) defective T-cell apoptosis coupled with dysregulated B-cell proliferation, which results from protein kinase Cd deficiency, leading to Mendelian lupus in association with lymphoproliferative syndrome due to increased B-cell proliferation. 17 Until now, ACP5 gene mutation was the only known monogenic condition associated with the development of IM. 18 The present report suggests that mosaic tetrasomy of 9p might also predispose to this disease.…”