Immunodeficiency, Common Variable, 8, With Autoimmunity

A number sign (#) is used with this entry because of evidence that common variable immunodeficiency-8 (CVID8) with autoimmunity is caused by homozygous mutation in the LRBA gene (606453) on chromosome 4q31.

Description

Common variable immunodeficiency-8 with autoimmunity is an autosomal recessive disorder of immune dysregulation. Affected individuals have early childhood onset of recurrent infections, particularly respiratory infections, and also develop variable autoimmune disorders, including idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, and inflammatory bowel disease. The presentation and phenotype are highly variable, even within families (summary by Lopez-Herrera et al., 2012 and Alangari et al., 2012). Immunologic findings are also variable and may include decreased B cells, hypogammaglobulinemia, and deficiency of CD4+ T regulatory (Treg) cells (Charbonnier et al., 2015).

For a general description and a discussion of genetic heterogeneity of common variable immunodeficiency, see CVID1 (607594).

Clinical Features

Lopez-Herrera et al. (2012) reported 5 patients from 4 unrelated consanguineous families with early-childhood onset of humoral immune deficiency and autoimmunity. In an Arabian family, 2 sibs presented in infancy with idiopathic thrombocytopenic purpura (ITP) followed by recurrent respiratory infections or otitis media. They both developed chronic lung disease and bronchiectasis. One had early-onset asthma and steroid-responsive monoarthritis, whereas the other developed a cerebral mass suggestive of a granuloma. Both showed poor overall growth. Laboratory studies showed low immunoglobulin levels, consistent with a diagnosis of CVID. A Sicilian boy presented with recurrent warts and perineal molluscum contagiosum at age 12 years. He later developed recurrent severe respiratory infections with interstitial pneumonitis and bronchiectasis, ITP, autoimmune hemolytic anemia, atrophic gastritis due to autoantibodies against intrinsic factor, a submaxillary abscess, and colitis. Laboratory studies showed low IgG and complete IgA deficiency with normal neutrophil count. Hilar and mediastinal lymph node biopsies showed lymphoid follicular hyperplasia with the absence of the follicular mantle zone. He also developed a brain tumor of the right temporal lobe which was shown to be a granulomatous infiltration with T cells, plasma cells, and macrophages, but few B cells. An Iranian boy presented at age 2 years with recurrent respiratory infections, autoimmune hemolytic anemia, and ITP. He developed finger clubbing due to chronic lung disease, hepatosplenomegaly, and failure to thrive. During 10 years' follow-up, he developed Crohn disease, cor pulmonale with right heart failure, and recurrent conjunctivitis. The fifth patient was an Iranian women who died at age 19 years after respiratory failure. She also had allergic dermatitis, recurrent diarrhea, recurrent upper respiratory infections, hypothyroidism, and myasthenia gravis. All homozygous individuals with LRBA deficiency showed reduced counts of switched-memory B cells, consistent with CVID. Two patients lacked marginal-zone-like B cells, and 1 had reduced counts of total B cells. Two patients had low natural killer (NK) cells, and 1 had low T-cell levels.

Alangari et al. (2012) reported 5 patients from 2 branches of a consanguineous Saudi family with an inherited disorder of immune dysregulation. One branch of the family contained 3 sisters ranging in age from 15 to 22 years. Two of the sisters presented in the first years of life with chronic nonbloody diarrhea, whereas the third presented with recurrent respiratory infections from age 4 years and developed diarrhea at age 18 years. Large-bowel biopsies of 2 patients showed mucosal inflammation and lymphocytic infiltration, and duodenal biopsy of 1 showed villous atrophy. One sister developed autoimmune thrombocytopenia and autoimmune hemolytic anemia. Two sisters had no history of recurrent infections. Immunologic workup showed low serum IgA and IgG with normal numbers of T and NK cells but markedly decreased T-cell proliferative responses. Two of the sisters had decreased numbers of B cells. The findings were consistent with a diagnosis of combined immunodeficiency. Two sibs from the other branch of the family presented with chronic diarrhea in childhood. Duodenal biopsies showed villous blunting and lymphocytic infiltration. One patient developed pancytopenia that responded to intravenous Ig and steroids; he also had Epstein-Barr virus (EBV)-induced lymphoproliferative disease. Neither of these sibs had a history of recurrent infections, and immunologic workup showed normal Ig levels, normal B, T, and NK cells, normal T-cell proliferative responses, and normal antibody production in response to vaccination. However, Alangari et al. (2012) noted that the phenotype in these patients was consistent with immune dysregulation, and that the patients could develop more apparent immunologic abnormalities with age. The variability in the phenotype within this family was ascribed to other genetic, epigenetic, and environmental factors.

Burns et al. (2012) reported a Pakistani girl, born of consanguineous parents, who presented at age 4 years with generalized lymphadenopathy, splenomegaly, neutropenia, thrombocytopenia, and chronic diarrhea associated with autoimmune enteropathy. Initial immunologic workup showed increased serum IgG and low numbers of NK cells; T-cell number and function were normal. She showed growth defects and additional autoimmune features, and was treated with steroids and rituximab. Five years later, she developed severe recurrent infections and had new onset of an antibody deficiency with variable decreases in B cells. Exome sequencing identified a large homozygous deletion in the LRBA gene. Burns et al. (2012) noted that this disorder can present as an autoimmune syndrome with later development of a primary immunodeficiency.

Charbonnier et al. (2015) reported a boy, born of consanguineous Saudi parents, who presented in infancy with autoimmune enteropathy, type 1 diabetes mellitus, autoimmune hypothyroidism, autoimmune hemolytic anemia, and recurrent infections. Immunologic workup showed reduced T-cell proliferative responses, normal B-cell numbers, increased immunoglobulin levels, and increased autoantibodies. The phenotype was reminiscent of X-linked immunodysregulation, polyendocrinopathy, and enteropathy (IPEX; 304790), but the patient did not carry mutations in the FOXP3 gene (300292). Whole-exome sequencing identified a homozygous truncating mutation in the LRBA gene (606453.0006). Charbonnier et al. (2015) also reported 2 sibs from a consanguineous Lebanese family who had childhood onset of recurrent infections, as well as variable features of immune dysregulation, including generalized lymphadenopathy, fibrosing pneumonitis with granulomas, hepatosplenomegaly, and pancytopenia. Laboratory investigations of these 3 patients and of the 3 sisters reported by Alangari et al. (2012) showed severe decreases in the number of CD4+ Treg cells, as well as decreases in several Treg cell markers, such as FOXP3, IL2RA (147730), and CTLA4 (123890). In vitro studies showed that patient Treg cells had impaired suppression of T-cell proliferation, with a skewing in favor of memory T cells and intense autoantibody production, as well as marked expansion of T follicular helper (T-FH) cells and contraction of T follicular regulatory (T-FR) cells. Patient Treg cells showed increased apoptosis and metabolic dysfunction.

Lo et al. (2015) identified 9 patients with LRBA deficiency. Most patients were diagnosed in early childhood with CVID, and all patients experienced substantial inflammatory and/or autoimmune complications. LRBA deficiency was associated with type 1 diabetes mellitus in 3 patients, Burkitt lymphoma in 1, and exocrine pancreatic insufficiency in 1. Three patients experienced severe interstitial lung disease consisting of dense predominantly T-cell interstitial infiltrates that was refractory to multiple medications and led to progressive impairment of lung function. All patients had undergone corticosteroid therapy, and several had undergone various other immunosuppressive therapies prior to abatacept. Two underwent splenectomy.

Clinical Management

Lo et al. (2015) treated 9 CVID8 patients with abatacept, a CTLA4 (123890)-immunoglobin fusion drug. Interstitial lung disease and severe enteritis improved dramatically after treatment.

Inheritance

The transmission pattern of CVID8 in the families reported by Lopez-Herrera et al. (2012) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 5 patients from 4 unrelated consanguineous families with CVID8 with autoimmunity, Lopez-Herrera et al. (2012) identified 4 different homozygous mutations in the LRBA gene (606453.0001-606453.0004). The first mutation was found by linkage analysis followed by candidate gene sequencing. Heterozygous mutation carriers were unaffected. Cultured patient B cells showed a failure to proliferate, differentiate into plasma cells, or produce antibodies under inducible conditions. Patient cells also showed an increased susceptibility to apoptosis, most likely due to impaired autophagy and abnormal accumulation of cellular organelles. No LRBA mutations were found in 12 additional families with suspected autosomal recessive CVID.

In 5 affected individuals from 2 branches of a consanguineous Saudi family with CVID8 with autoimmunity, Alangari et al. (2012) identified a homozygous truncating mutation in the LRBA gene (606453.0005). The mutation, which was found by a combination of homozygosity mapping and exome sequencing in 2 patients, was confirmed by Sanger sequencing and segregated with the disorder in the family.

Charbonnier et al. (2015) identified 2 different homozygous truncating mutations in the LRBA gene (see, e.g., 606453.0006) in affected members of 2 unrelated consanguineous families with CVID8 with autoimmunity.

Lo et al. (2015) identified 9 patients with immune deficiency and/or autoimmunity from 8 unrelated kindreds with biallelic loss-of-function mutations in LRBA. All mutations decreased or abolished LRBA protein expression as assessed by immunoblotting and flow cytometry.