Immunodeficiency 41 With Lymphoproliferation And Autoimmunity

A number sign (#) is used with this entry because of evidence that immunodeficiency-41 (IMD41) with lymphoproliferation and autoimmunity is caused by homozygous or compound heterozygous mutation in the IL2RA gene (147730) on chromosome 10p15.

Description

Immunodeficiency-41 is an autosomal recessive complex disorder of immune dysregulation. Affected individuals present in infancy with recurrent viral, fungal, and bacterial infections, lymphadenopathy, and variable autoimmune features, such as autoimmune enteropathy and eczematous skin lesions. Immunologic studies show a defect in T-cell regulation (summary by Goudy et al., 2013).

Clinical Features

Sharfe et al. (1997) described a novel human immune aberration arising from a truncation mutation of the interleukin-2 receptor alpha chain (CD25), a subunit of the tripartite high-affinity receptor for interleukin-2. This immunodeficiency was characterized by decreased numbers of peripheral T cells displaying abnormal proliferation but normal B-cell development. Extensive lymphocytic infiltration of tissues, including lung, liver, gut, and bone, was observed, accompanied by tissue atrophy and inflammation. Although mature T cells were present, the absence of CD25 affected the differentiation of thymocytes. While displaying normal development of CD2 (186990), CD3 (186790), CD4 (186940), and CD8 (186910) expression, CD25-deficient cortical thymocytes did not express CD1 (188370); furthermore, they failed to downregulate levels of antiapoptotic protein BCL2 (151430). The patient was a male child of first-cousin parents with a history of increased susceptibility to viral, bacterial, and fungal infections. He presented at the age of 6 months with cytomegalovirus (CMV) pneumonitis, persistent oral thrush, and Candida esophagitis. He also had adenovirus gastroenteritis, developed chronic diarrhea, and failed to thrive. From the age of 8 months, lymphadenopathy and hepatosplenomegaly became increasingly apparent, with no significant abnormality of liver function, however. He subsequently required hospitalization for recurrent exacerbation of lung disease. By the age of 3 years he had developed gingivitis, iron deficiency anemia with no evidence of hemolytic anemia, chronic inflammation of the mandible, and chronic lung disease involving the right upper lobe. Severe immunologic dysfunction was proven by the patient's inability to reject an allogeneic skin graft. Consequently the patient underwent an allogeneic bone marrow transplant following cytoreduction. Engraftment was rapid and a complete resolution of symptoms ensued.

Roifman (2000) performed additional studies on thymic tissue from the patient reported by Sharfe et al. (1997). They found that the markedly reduced apoptosis in the thymus resulted in expansion of autoreactive clones in multiple tissues.

Caudy et al. (2007) reported an 8-year-old boy with a complex immunologic disorder. He presented at age 6 weeks with diarrhea, insulin-dependent diabetes mellitus, and respiratory insufficiency due to CMV infection. During childhood, he developed autoimmune enteropathy with villous atrophy, eczema, lymphadenopathy, hepatosplenomegaly, hypothyroidism, autoimmune hemolytic anemia, and autoimmune granulocytopenia. He had recurrent infections, including Epstein-Barr virus (EBV) infection. The clinical features were reminiscent of IPEX (304790), but FOXP3 (300292) expression was normal on patient CD4+ T lymphocytes. Immunologic studies showed that the patient's cells failed to express detectable IL10 (124092) in response to IL2 (147680), suggesting a defect in the IL2 receptor. Caudy et al. (2007) noted that since IL10 is able to inhibit naive T-cell proliferation, absence of IL10 as seen in this patient was consistent with the complex features of immune dysregulation.

Goudy et al. (2013) reported an 8-year-old girl, born of consanguineous Italian parents, with early-onset recurrent viral, bacterial, and fungal infections, CMV infection, lymphadenopathy, and various autoimmune disorders, including autoimmune enteropathy, autoimmune thyroiditis, eczema, psoriasiform dermatitis, and alopecia. Skin biopsy showed an infiltration of CD8+ T lymphocytes. Immunologic studies showed alterations of the peripheral T-cell compartment, with a skew toward increased CD8+ T cells over CD4+ T cells and expansion of memory T cells. There were also low levels of NK and B cells. In vitro studies showed poor T-cell proliferative responses to polyclonal mitogens, fungi, and viruses. The findings were consistent with a lack of effective antigen-specific T-cell responses combined with cytokine-driven polyclonal T-cell proliferation and activation that mediated tissue damage.

Bezrodnik et al. (2014) reported a 5-year-old adopted girl from Argentina who presented in the first week of life with severe atopic dermatitis, chronic diarrhea, and severe respiratory infections. She later developed alopecia, severe varicella infection, and chronic pneumonia necessitating permanent oxygen therapy. At age 4, she had severely compromised lung parenchyma with follicular bronchiolitis and lymphocyte hyperplasia on lung biopsy. Immunologic workup showed hypergammaglobulinemia, absent IgG4, and impaired specific polysaccharide response. Regulatory T cells were extremely low, memory B cells were decreased, and activated CD4+ T cells showed no CD25 upregulation. Antinuclear antibodies were also present, but the patient did not have significant features of autoimmune disorders.

Inheritance

The transmission pattern of IMD41 in the families reported by Caudy et al. (2007) and Goudy et al. (2013) was consistent with autosomal recessive inheritance.

Molecular Genetics

In a patient with IL2RA deficiency, Sharfe et al. (1997) identified a homozygous 4-bp deletion in the CD25 gene, resulting in a frameshift in protein translation (147730.0001).

In an 8-year-old Caucasian boy with IMD41, Caudy et al. (2007) identified compound heterozygous truncating mutations in the IL2RA gene (147730.0004 and 147730.0005). Each unaffected parent was heterozygous for 1 of the mutations.

In an 8-year-old girl, born of consanguineous Italian parents, with IMD41, Goudy et al. (2013) identified a homozygous missense mutation in the IL2RA gene (S166N; 147730.0006). Each unaffected parent was heterozygous for the mutation. Patient CD4+ T cells showed absence of surface IL2RA expression, consistent with a loss of function. However, IL2RA was detected within the cytoplasm of the patient's T cells, suggesting that the mutation inhibits membrane expression. Additional functional studies of the variant were not performed.

In an adopted 5-year-old girl from Argentina with IMD41, Bezrodnik et al. (2014) identified a homozygous missense mutation in the IL2RA gene (Y41S; 147730.0007). Functional studies of the variant were not performed, but patient CD4+ T lymphocytes did not show upregulation of IL2RA upon activation.