Immunodeficiency 63 with Lymphoproliferation and Autoimmunity D81.0

Immunodeficiency 63 with lymphoproliferation and autoimmunity is an autosomal recessive inherited disorder characterized by dysregulation of the immune system. Affected individuals show features of abnormal activation of certain immune signaling pathways in infancy, leading to lymphoproliferation, dermatitis, enteropathy, and hypergammaglobulinemia, as well as features of immunodeficiency, such as recurrent infections and increased susceptibility to viral infections, particularly CMV.

Laboratory studies show increased numbers of NK cells exhibiting impaired differentiation and abnormal T cell populations or responses.

Some patients may die in childhood; hematopoietic bone marrow transplantation is curative (Zhang et al. 2019).

Fernandez et al (2019) reported on two immunodeficient siblings born to consanguineous parents from Tajikistan. The first patient presented in early infancy with diarrhea and failure to thrive, which worsened after two months of vaccinations. Gastrointestinal biopsies revealed submucosal lymphoid hyperplasia of the esophagus, gastritis, duodenitis, and colitis. Disseminated CMV infection was noted. Other findings: Eczematous dermatitis, food allergies, lymphocytic interstitial pneumonitis, EBV viremia and a positive direct Coombs test. His younger affected sister had similar symptoms at birth, including CMV viremia and severe autoimmune hemolytic anemia, but no EBV infection. Detailed immunologic examination revealed increased numbers of NK cells, particularly less differentiated NK cells (CD56-bright), increased memory CD8+ T cells, decreased regulatory T cells, and increased numbers of memory B cells in association with increased IgG levels. Patients were treated with immunosuppression and hematopoietic stem cell transplantation. The older child was cured, the younger one died.

Etio: Evidence included homozygous 9-bp deletion (c.665_673del) in the IL2RB gene, resulting in in-frame deletion of 3 conserved residues in the extracellular motif (146710.0001). Analysis of patients' NK and T cells revealed significantly decreased surface expression of IL2RB compared with controls. Plasma levels of IL2 (147680) and IL15 (600554) were increased, indicating impaired receptor response, and this was associated with differentially increased levels of phosphorylated STAT5 (601511) in NK and T cells compared with controls. The results were consistent with impaired IL2/IL15 signaling and suggested immune cell-specific responses to the mutation.

Zhang et al (2019) reported on eight patients from four consanguineous families of South Asian, Middle Eastern, and Eastern European descent. Five patients from three families (families A, B, and C) presented in infancy or early childhood with features of autoimmunity and immunodeficiency. Clinical manifestations included diarrhea and failure to thrive due to enteropathy, eczematous dermatitis, pneumonitis, food allergies, lymphadenopathy, hepatosplenomegaly, autoimmune hemolytic anemia, and recurrent ear or urinary tract infections. All patients had either CMV or EBV infection. One 2-year-old suffered from thyrotoxicosis due to Graves' disease.

Laboratory tests revealed elevated circulating immunoglobulins, decreased regulatory T cells, variable positive autoantibodies, and increased levels of IL2 (147680) and IL15 (600554). NK cells were elevated. Detectable levels of the cytotoxic effector proteins perforin (170280) and granzyme B (123910) were high. Two patients had low numbers of CD8+ T cells, and one patient had impaired T-cell proliferative response. Three patients died in the first years of life; one survived after hematopoietic stem cell transplantation, and one was still alive at 5 years of age on rituximab therapy. In a fourth family, intrauterine growth retardation occurred with restricted fetal movements. Evidence included 3 different homozygous mutations in the IL2RB gene: a missense mutation (L77P; 146710. 0002) that caused a hypomorphic effect depending on the cell type; another missense mutation (S40L; 146710.0003) that impaired the response to IL2; and a nonsense mutation (Q96X; 146710.0004) that resulted in a complete loss of receptor function. CD4+ and CD8+ T cells from these patients showed different but specific impairments in downstream IL2 signaling with decreased STAT5 phosphorylation.

1. Fernandez IZ et al (2019) A novel human IL2RB mutation results in T and NK cell-driven immune dysregulation. J Exp Med 216: 1255-1267.
2. Suzuki H et al (1995) Deregulated T cell activation and autoimmunity in mice lacking interleukin-2 receptor beta. Science 268: 1472-1476.
3. Zhang Z et al (2019) Human interleukin-2 receptor beta mutations associated with defects in immunity and peripheral tolerance. J Exp Med 216: 1311-1327.