Autoimmune Lymphoproliferative Syndrome, Type Iii

A number sign (#) is used with this entry because autoimmune lymphoproliferative syndrome type III (ALPS3) is caused by homozygous mutation in the PRKCD gene (176977) on chromosome 3p21.

Description

Autoimmune lymphoproliferative syndrome type III is an autosomal recessive disorder of immune dysregulation. The phenotype is variable, but most patients have significant lymphadenopathy associated with variable autoimmune manifestations. Some patients may have recurrent infections. Lymphocyte accumulation results from a combination of impaired apoptosis and excessive proliferation (summary by Oliveira, 2013).

For a general description and a discussion of genetic heterogeneity of ALPS, see 601859.

Clinical Features

Salzer et al. (2013) reported a 12-year-old boy, born of consanguineous Turkish parents, with a primary immune deficiency syndrome characterized by B-cell deficiency and severe autoimmunity. He had recurrent infections involving most systems (respiratory, urinary, gastrointestinal) beginning in the first year of life. At age 15 months, he developed autoimmune nephrotic syndrome; renal biopsy showed membranous glomerulonephritis with IgG and complement component deposits. By age 3 years, he had hepatosplenomegaly and generalized lymphadenopathy associated with low-grade herpes viremia. Additional autoimmune features included polychondritis and antiphospholipid syndrome, with antinuclear, anti-dsDNA, and anticardiolipin IgG antibodies. He was treated with IV IgG at age 4 years, which resulted in a decrease in infections, and with anti-CD20 therapy, but autoantibodies persisted. Initial immunologic workup showed low IgG with increased IgA and IgM. The formal criteria of CVID, which includes decreased levels of at least 2 classes of Ig were not met, but the phenotype was consistent with a CVID-like disorder. B-cell studies showed a reduction of CD19+ B cells, decreased memory B cells, and increased CD21(low) B cells. T-cell studies showed mildly decreased proliferative responses. The patient's father had Behcet disease and mild autoimmune thyroiditis at age 40 years, whereas his mother was asymptomatic. Oliveira (2013) noted that the patient reported by Salzer et al. (2013) had an autoimmune lymphoproliferative disorder that resembled ALPS without meeting the formal diagnostic criteria for it. Treatment with low-dose steroids and the immunosuppressive agent mycophenolate mofetil resulted in good disease control in this patient.

Andre et al. (2007) reported 3 sibs, born of consanguineous parents of European descent, with a childhood-onset autoinflammatory disorder. The most severely affected child presented at age 3 years with a lymphoproliferative syndrome with lymphadenopathy and hepatosplenomegaly. She had severe hemolytic anemia and later developed idiopathic thrombocytopenia purpura. She also had manifestations reminiscent of systemic lupus erythematosus (SLE; 152700), such as cutaneous erythema and glomerulonephritis arthralgias. Laboratory studies showed increased erythrocyte sedimentation rate, hypergammaglobulinemia, and autoantibodies. B cells were increased, but alpha/beta, CD4-/CD8- T cells were not detectable. The condition required vigorous immunosuppressive treatment. The patient's sister and brother presented at ages 10 and 6 years, respectively, with features of SLE, including rash, arthritis, and glomerulonephritis, but without a frank lymphoproliferative disorder. In vitro assays of patient lymphocytes showed impaired activation-induced apoptosis associated with increased levels of the antiapoptotic factor BCL2A1 (601056). In a follow-up of the patients reported by Andre et al. (2007), Belot et al. (2013) noted that none of them presented with features of early-onset immunodeficiency, although 1 died at age 13 years of septic shock. The patients had increased numbers of immature B cells and decreased numbers of memory B cells. B cells from 1 patient showed a hyperproliferative response to stimulation, and mutant lymphocytes were resistant to calcium-dependent apoptosis.

Kuehn et al. (2013) reported a Hispanic boy who had recurrent sinusitis and otitis in early childhood associated with generalized lymphadenopathy, hepatosplenomegaly, and recurrent fevers. He also had a facial rash and erythematous macules, but no renal disease. Laboratory studies showed several nonspecific autoantibodies, hypergammaglobulinemia, increased erythrocyte sedimentation rate and C-reactive protein, and B-cell lymphocytosis with the majority of cells expressing the immature marker CD5 (153340); class-switched memory B cells were decreased. Cultured B cells showed increased secretion of IL10 (124092). NK cells showed impaired function. The patient responded well to immunosuppressive therapy. Patient B cells were increased in number and showed hyperproliferation in response to stimulus; T cells did not show an increased rate of proliferation.

Inheritance

The transmission pattern of immune dysregulation in the families reported by Salzer et al. (2013) and Andre et al. (2007) was consistent with autosomal recessive inheritance.

Molecular Genetics

In a patient with ALPS3, Salzer et al. (2013) identified a homozygous splice site mutation in the PRKCD gene (176977.0001). The mutation was found by homozygosity mapping and exome sequencing and segregated with the disorder in the family. Western blot analysis showed absent expression of the PRKCD protein in patient cells and decreased expression in cells from the heterozygous father. Patient cells showed defective phosphorylation of MARCKS (177061), a downstream target of PRKCD, as well as increased IL6 (147620) production after stimulation. Genetic analysis also revealed a heterozygous variant (rs231775) in the CTLA4 gene (123890.0001) in the patient and his father, which may have acted as a disease modifier given its association with autoimmune disorders.

In 3 sibs with ALPS3, originally reported by Andre et al. (2007), Belot et al. (2013) identified a homozygous missense mutation in the PRKCD gene (G510S; 176977.0002). The mutation was found by a combination of linkage analysis and whole-exome sequencing.

In a Hispanic boy with ALPS3, Kuehn et al. (2013) identified a homozygous missense mutation in the PRKCD gene (R614W; 176977.0003). Western blot analysis showed low levels of mutant protein expression in patient cells, and immunohistochemical studies showed absent protein expression in the patient's lymph node. Knockdown of PRKCD by siRNA in control B cells caused an increase in B-cell proliferation without an increase in T-cell proliferation.

Animal Model

PRKCD is involved in B-cell signaling and in the regulation of growth, apoptosis, and differentiation of a variety of cell types. Prkcd is most abundant in B and T lymphocytes of lymphoid organs, cerebrum, and intestine of normal mice. By generating mice with a disruption in the Prkcd gene, Miyamoto et al. (2002) observed that the mice are viable up to 1 year but prone to autoimmune disease, with enlarged lymph nodes and spleens containing numerous germinal centers. Flow cytometric analysis showed increased numbers of bone marrow-derived B cells, but no change in CD5+ B cells or T cells. Transfer of B cells into Rag1 (179615) -/- mice resulted in greater numbers of splenic B cells and germinal centers in mice receiving Prkcd -/- cells. Prkcd-deficient B cells also mounted a stronger proliferative response than those from wildtype mice. RT-PCR analysis detected higher levels of IL6 (147620), but not other cytokines, in mutant than in wildtype B cells. EMSA analysis showed increased DNA-binding activity of NFIL6 (CEBPB; 189965) but not NFKB. Serum IgG1 and IgA, but not other isotype, concentrations were greater in Prkcd-deficient mice. Although Miyamoto et al. (2002) did not detect antinuclear antibodies, they did observe high levels of primarily IgG antibodies to chromatin in older mutant mice. Histologic analysis revealed evidence of glomerulonephritis with deposition of IgG and complement component C3. Miyamoto et al. (2002) noted that crosslinking of B-cell receptors leads to activation of both Prkcb (176970) and Prkcd, but that proliferation in mice deficient in these enzymes is reduced and enhanced, respectively, possibly allowing for fine regulation of the immune response.