Loss-of-function of the protein kinase C δ (PKCδ) causes a B-cell lymphoproliferative syndrome in humans

Abstract

• Mutations in PRKCD cause a syndrome characterized by chronic benign lymphadenopathy, positive autoantibodies, and NK dysfunction.• PRKCD deficiency disrupts control of B-cell proliferation and apoptosis and affects NK-cell cytolytic activity.Defective lymphocyte apoptosis results in chronic lymphadenopathy and/or splenomegaly associated with autoimmune phenomena. The prototype for human apoptosis disorders is the autoimmune lymphoproliferative syndrome (ALPS), which is caused by mutations in the FAS apoptotic pathway. Recently, patients with an ALPS-like disease called RAS-associated autoimmune leukoproliferative disorder, in which somatic mutations in NRAS or KRAS are found, also were described. Despite this progress, many patients with ALPS-like disease remain undefined genetically. We identified a homozygous, loss-of-function mutation in PRKCD (PKCd) in a patient who presented with chronic lymphadenopathy, splenomegaly, autoantibodies, elevated immunoglobulins and natural killer dysfunction associated with chronic, low-grade Epstein-Barr virus infection. This mutation markedly decreased protein expression and resulted in ex vivo B-cell hyperproliferation, a phenotype similar to that of the PKCd knockout mouse. Lymph nodes showed intense follicular hyperplasia, also mirroring the mouse model. Immunophenotyping of circulating lymphocytes demonstrated expansion of CD51CD201 B cells. Knockdown of PKCd in normal mononuclear cells recapitulated the B-cell hyperproliferative phenotype in vitro. Reconstitution of PKCd in patient-derived EBV-transformed B-cell lines partially restored phorbol-12-myristate-13-acetate-induced cell death. In summary, homozygous PRKCD mutation results in B-cell hyperproliferation and defective apoptosis with consequent lymphocyte accumulation and autoantibody production in humans, and disrupts natural killer cell function. (Blood. 2013;121(16):3117-3125)

B-cell tolerance regulates production of antibodies causing heparin-induced thrombocytopenia

“…Signaling molecule PKCd controls B-cell anergy and its deficiency impairs B-cell tolerance, leading to autoantibody production in humans and mice. 11,19,20 Unmanipulated PKCd-deficient mice spontaneously produced significantly higher levels of PF4/ heparin-specific IgMs than wild-type controls ( Figure 2B). A significantly higher number of unmanipulated PKCd-deficient mice also spontaneously produced elevated levels of PF4/heparin-specific IgGs relative to wild-type controls ( Figure 2C).…”

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

“…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.…”

Autoimmunity in Primary Antibody Deficiencies

“…PKC-δ-deficient mice represent elevation of a B-cell lineage-specific expansion, such as naïve and activated follicular mature B cells, and also show defective B-cell tolerance to self-antigens [121,122]. In humans, PKC-δ deficiency is known as a genetic defect leading to B-cell deficiency, impaired apoptosis, and consequently to SLE [123,124]. Salzer et al [125] reported a patient with a PKC-δ mutation who was suffering from recurrent infections and severe SLE as well as autoimmune disorders such as membranous glomerulonephritis and antiphospholipid syndrome.…”