Autoinflammation, Antibody Deficiency, And Immune Dysregulation, Plcg2-Associated

A number sign (#) is used with this entry because autoinflammation and PLCG2-associated antibody deficiency and immune dysregulation (APLAID) is caused by heterozygous mutation in the PLCG2 gene (600220) on chromosome 16q.

See also PLAID (614468), an allelic disorder with some overlapping features.

Description

Autoinflammation and PLCG2-associated antibody deficiency and immune dysregulation (APLAID) is an autosomal dominant systemic disorder characterized by recurrent blistering skin lesions with a dense inflammatory infiltrate and variable involvement of other tissues, including joints, the eye, and the gastrointestinal tract. Affected individuals have a mild humoral immune deficiency associated with recurrent sinopulmonary infections, but no evidence of circulating autoantibodies (summary by Zhou et al., 2012).

Clinical Features

Zhou et al. (2012) reported a father and daughter with a systemic autoinflammatory disorder characterized by early-onset recurrent blistering skin lesions, nonspecific interstitial pneumonitis with respiratory bronchiolitis (NSIP), arthralgia, eye inflammation, enterocolitis, cellulitis, and recurrent sinopulmonary infections. Both individuals developed a full-body epidermolysis bullosa-like eruption in infancy, but this later evolved to recurrent erythematous plaques and vesiculopustular lesions that worsened with heat and sun exposure. Biopsy of open skin lesions revealed a dense infiltrate of neutrophils, eosinophils, histiocytes, and lymphocytes. In addition, the daughter developed corneal blisters at age 6 months and ulcerative colitis at age 2 years. Laboratory studies showed a decrease in circulating IgM and IgA antibodies, decreased numbers of class-switched memory B cells, and decreased numbers of NK T cells. Neither patient had autoantibodies. The symptoms were partially responsive to an IL1 (147760) inhibitor and high-dose corticosteroids.

Inheritance

The transmission pattern in the family with APLAID reported by Zhou et al. (2012) was consistent with autosomal dominant inheritance.

Molecular Genetics

In a father and daughter with APLAID, Zhou et al. (2012) identified a heterozygous missense mutation in the PLCG2 gene (600220.0004). The mutation was identified by exome sequencing and was shown to result in a gain of function.

Animal Model

Yu et al. (2005) identified a dominant mouse mutant, Ali5, with a point mutation (D993G) in the Plcg2 gene. The mice developed spontaneous swollen and inflamed paws, with dermatitis in the skin of the paws and ears. The skin infiltrate included granulocytes, macrophages, lymphocytes, eosinophils, and mast cells. The chronic inflammation led to bone involvement and destruction and arthritis. Some also developed signs of glomerulonephritis and keratitis. The disease had an autoimmune component mediated by autoantibody immune complexes, as well as B and T cell-independent inflammation. The mutation enhanced the ability of the Plcg2 protein to remain at the cytoplasmic membrane, which enhanced or prolonged its activity postactivation. The underlying mechanism was a gain of function leading to hyperreactive external calcium entry in B cells and expansion of innate inflammatory cells. The study identified Plcg2 as a key regulator in an autoimmune and inflammatory disease mediated by B cells and non-B, non-T hematopoietic cells. Everett et al. (2009) identified a second mouse mutant, Ali14, with a gain-of-function Y495C mutation in the spPH domain of the Plcg2 gene. The mutant protein showed enhanced activation in response to EGF stimulation and constitutive activation, likely by compromising autoinhibition.