Autoimmune Lymphoproliferative Syndrome, Type V

A number sign (#) is used with this entry because autoimmune lymphoproliferative syndrome type V (ALPS5) is caused by heterozygous mutation in the CTLA4 gene (123890) on chromosome 2q33.

Description

Autoimmune lymphoproliferative syndrome type V is an autosomal dominant complex immune disorder characterized by autoimmune thrombocytopenias and abnormal lymphocytic infiltration of nonlymphoid organs, including the lungs, brain, and gastrointestinal tract, resulting in enteropathy. Some patients may show features of an immunodeficiency syndrome with recurrent infections, but immunosuppressive therapy often results in clinical improvement (summary by Kuehn et al., 2014).

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

Clinical Features

Kuehn et al. (2014) reported 6 patients from 4 families with a complex immune disorder they referred to as 'CTLA4 haploinsufficiency with autoimmune infiltration (CHAI).' In 1 family, a 22-year-old woman developed autoimmune thrombocytopenia as well as brain, gastrointestinal, and lung lymphocytic infiltrates in early childhood. She had chronic lymphocytic enteropathy and diarrhea. Peripheral blood studies showed hypogammaglobulinemia and lymphopenia mostly affecting T cells. Immunosuppressive treatment resulted in some clinical improvement. Her father presented at age 40 with inflammatory lung lesions and lymphocytic enteropathy. He also had hypogammaglobulinemia and clonally expanded gamma/delta-CD8+ T cells (large granular lymphocytes) that suppressed the bone marrow. He eventually died of central line infection. Four additional patients from 3 unrelated families were subsequently identified from a cohort of 23 patients with autoimmune cytopenias, hypogammaglobulinemia, CD4+ T-cell lymphopenia, and lymphocytic infiltration of nonlymphoid organs, including the gastrointestinal tract, lungs, and brain. In addition to these features, 1 patient had symptoms of a common variable immunodeficiency with occasional infections in childhood, another had a history of psoriasis, and a third had food allergies and extensive warts on his hands. Immunologic workup of the patients showed decreased numbers of circulating naive CD45RA+ T cells compared to controls; affected individuals also had variable progressive loss of circulating B cells. Patient regulatory T cells showed decreased FOXP3 (300292) and IL2RA (147730) expression compared to controls, and these regulatory T cells showed poor suppression of proliferation of cocultured T responder cells in vitro. Patients had increased frequency of autoreactive CD21(lo) B cells, which are considered anergic or exhausted, and these cells showed increased tendency for apoptosis as well as decreased ability to secrete immunoglobulin. These changes resulted in B-cell lymphopenia and were believed to be a result of regulatory T-cell dysfunction.

Schubert et al. (2014) reported 11 patients from 6 unrelated families with an immune system dysregulation disorder. The age at onset and presentation was variable, but most patients developed symptoms between late in the first decade and the third decade. Seven patients fulfilled the diagnosis of common variable immunodeficiency (CVID). The main common clinical features included diarrhea associated with lymphocytic enteropathy, recurrent respiratory infections, granulomatous lymphocytic interstitial lung disease, lymphocytic infiltration of organs, including bone marrow, kidney, brain, and liver, lymphadenopathy and splenomegaly, and autoimmune cytopenias. More variable features included psoriasis, autoimmune thyroiditis, and autoimmune arthritis. Affected tissues showed extensive CD4+ T-cell infiltration. Laboratory studies showed increased T-cell activation with decreased levels of CD4+CD45RA+ naive T cells, a progressive decline in circulating memory B cells, and hypogammaglobulinemia.

Inheritance

The transmission pattern of ALPS5 in the families reported by Kuehn et al. (2014) and Schubert et al. (2014) was consistent with autosomal dominant inheritance and incomplete penetrance.

Molecular Genetics

In 6 patients from 4 families with autoimmune lymphoproliferative syndrome type V, Kuehn et al. (2014) identified 4 different heterozygous loss-of-function mutations in the CTLA4 gene (see, e.g., 123890.0003-123890.0005). The mutation in the first family was found by whole-exome sequencing; mutations in subsequent families were found by direct screening of the CTLA4 gene in 23 unrelated probands with a similar phenotype. Knockdown of CTLA4 using siRNA in control mononuclear cells recapitulated the hyperproliferative T-cell phenotype observed in the patients. The findings demonstrated that full expression of CTLA4 is required to govern T- and B-cell lymphocyte homeostasis, and that reduction of CTLA4 expression contributes to loss of immune tolerance and causes infiltrative autoimmune disease.

In 11 patients from 6 unrelated families with ALPS5, Schubert et al. (2014) identified 6 different heterozygous mutations in the CTLA4 gene (see, e.g., 123890.0006-123890.0008). The mutation in the first family was found by whole-exome sequencing; mutations in subsequent families were found by direct screening of the CTLA4 gene in 71 unrelated probands with CVID and enteropathy or autoimmunity. Patient regulatory T cells showed decreased CTLA4 protein expression. In vitro studies showed impaired suppressive function of regulatory T cells and impaired ligand capture and transendocytosis of CD80 (112203).

Animal Model

Waterhouse et al. (1995) showed that homozygous Ctla4 gene-targeted mice accumulated T-cell blasts in their lymph nodes and spleens, which were enlarged 5 to 10 times normal. Ctla4-deficient mice had much higher serum immunoglobulin concentrations than normal, their B cells exhibited activation markers, and many of their tissues showed extensive lymphocyte proliferation. The Ctla4-knockout mice became moribund by 3 to 4 weeks of age and died of apparent myocardial failure due to lymphocytic infiltration. Although Ctla4-deficient T cells proliferated spontaneously and strongly when stimulated through the T-cell receptor, they were sensitive to cell death induced by cross-linking of the Fas receptor (134637) and by gamma irradiation. Through these and other findings, the authors concluded that CTLA4 plays an important inhibitory role in regulating lymphocyte expansion.