Autoimmune Lymphoproliferative Syndrome Due to Ctla4 Haploinsuffiency D81.4

Immune dysregulation with autoimmunity, immunodeficiency and lymphoproliferation, in shortIDAIL, is a rare autosomal dominant complex immunodeficiency syndrome (see below Immune deficiencies primary/immune dysregulation) caused by a heterozygous mutation in the CTLA4 gene (123890; chromosome 2q33). The clinical picture is characterized by highly variable phenotypes. Constant features include recurrent infections, often combined with hypogammaglobulinemia.

Furthermore, the clinical picture is characterized by autoimmune features such as autoimmune cytopenias and abnormal lymphocytic infiltration of non-lymphoid organs, including the lungs, brain, and gastrointestinal tract, leading to enteropathy.

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).These results demonstrate that full expression of CTLA4 is required for T- and B-cell lymphocyte homeostasis and that a reduction in CTLA4 expression contributes to loss of immune tolerance and causes infiltrative autoimmune disease.

Schubert et al (2014) identified 6 different heterozygous mutations in the CTLA4 gene in 11 patients from 6 unrelated families with ALPS5 (see, e.g., 123890,0006-123890,0008).

In 133 patients from 54 unrelated families with IDAIL, Schwab et al. (2018) identified 45 different heterozygous mutations in the CTLA4 gene, including 28 novel mutations. CTLA4 expression in stimulated Treg cells was reduced in all CTLA4 mutation carriers tested. Functional studies showed that transendocytosis in CTLA4+ cells of

Le Coz C et al (2018) described two unrelated patients with coexisting CD28 and CTLA4 haploinsufficiency due to heterozygous chromosome 2q microdeletions. Their clinical phenotype, an inflammatory multiorgan disease, differed only insignificantly from patients with CTLA4 haploinsufficiency of autoimmune lymphoproliferative syndrome type V. (ALPS5). In contrast to the T cells of ALPS5 patients, which hyperproliferate and infiltrate organs upon T cell receptor-mediated activation, the T cells of these patients were hypoproliferative and did not infiltrate organs. Evidence included a significant increase in circulating innate lymphoid cell type 3 (ILC3) and ILC3 cytokines interleukin 22 and interleukin-17A. D

Laboratory tests often show lymphopenia and abnormal T- and B-cell series. The variable features are the result of impaired function of Treg cells, which play a role in immune homeostasis (Kuehn et al. 2014; Schwab et al. 2018, Lopez-Nevado et al. 2021).

The disease has overlap with autoimmune lymphoproliferative syndrome (ALPS-OMIM:601859).

Kuehn et al (2014) reported on six patients from four families with a complex immune disorder they termed "CTLA4 haploinsufficiency with autoimmune infiltration (CHAI)." In one family, a 22-year-old woman developed autoimmune thrombocytopenia in early childhood and lymphocytic infiltrates in the brain, gastrointestinal tract, and lungs. She had chronic lymphocytic enteropathy and diarrhea. Peripheral blood tests showed hypogammaglobulinemia and lymphopenia affecting mainly T cells. Immunosuppressive treatment resulted in some clinical improvement. Her father presented at age 40 years with inflammatory lung changes and lymphocytic enteropathy. He also had hypogammaglobulinemia and clonally expanded gamma/delta-CD8+ T cells (large granular lymphocytes) with bone marrow suppression. He died of infection.

Four additional patients from three 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, lung, and brain. Other symptoms in this cohort included:

Symptoms of generalized variable immunodeficiency with recurrent childhood infections,

Psoriasis

Food allergies

Extensive verrucae vulgares on the hands.

Schubert et al (2014) reported 11 patients from 6 unrelated families with immune dysregulation disorder. The age of onset and disease presentation varied, but most patients developed symptoms between the end of the first decade and the third decade. Seven patients met the diagnosis of common variable immunodeficiency (CVID). The main common clinical features included diarrhea 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. Inconsistent features included psoriasis, autoimmune thyroiditis, and autoimmune arthritis. Laboratory studies showed increased T-cell activation with decreased levels of CD4+CD45RA+ naïve T cells, a progressive decrease in circulating memory B cells, and hypogammaglobulinemia.

Schwab et al (2018) studied the characteristics of 133 patients from 54 unrelated families with CTLA4 deficiency confirmed by genetic analysis. The presenting symptoms and phenotypic manifestations varied widely. The median age at disease onset was 11 years (1-59 years); the mortality rate of affected mutation carriers was 16%. Symptoms included autoimmune cytopenia (33%), respiratory manifestations (21%), enteropathy (17%), type 1 diabetes (8%), neurologic symptoms such as seizures and headache (6%), thyroid disease (5%), arthritis (3%), growth retardation, fever or night sweats, atopic dermatitis or alopecia (2% each), and primary biliary cirrhosis, Addison's disease, or a wound healing disorder in one affected mutation carrier each.

Eight affected mutation carriers developed lymphoma, and 3 developed carcinoma of the stomach. Six of these malignancies were associated with EBV infection. Laboratory studies revealed lymphopenia in 39% of affected mutation carriers, and the absolute number of CD3+ T cells was reduced in 20%.

1. Kuehn HS et al. (2014) Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4. Science 345: 1623-1627.
2. Le Coz C et al. (2018) Cytotoxic T-lymphocyte-associated protein 4 haploinsufficiency-associated inflammation can occur independently of T-cell hyperproliferation. Front Immunol 9:1715.
3. Lopez-Nevado M et al (2021) Primary immune regulatory disorders with an autoimmune lymphoproliferative syndrome-like phenotype: immunologic evaluation, early diagnosis and management. Front. Immun. 12: 671755.
4. Schubert D et al. (2014) Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Nature Med. 20: 1410-1416.
5. Schwab C et al. (2018) Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4-insufficient subjects. J Allergy Clin Immun 142: 1932-1946.
6. Waterhouse P et al (1995) Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science 270: 985-988.