Immunodeficiency 43

A number sign (#) is used with this entry because of evidence that immunodeficiency-43 (IMD43) is caused by homozygous mutation in the B2M gene (109700) on chromosome 15q21.

Clinical Features

Waldmann et al. (1968), Waldmann (1969), and Waldmann and Terry (1990) investigated a 34-year-old woman and her 17-year-old brother, products of a first-cousin marriage, who had marked reduction in serum concentrations of immunoglobulin and albumin (ALB; 103600). The total circulating and body pools of IgG were less than 28% of normal, although the IgG synthetic rates were in the normal range. IgG survival was short, with a 5-fold increase in catabolic rate. There was proteinuria or abnormality of renal or liver function and no circulating antibodies directed against either immunoglobulin or albumin. Furthermore, Waldmann and Terry (1990) excluded excessive gastrointestinal protein loss by normal fecal (51)Cr-labeled albumin tests. The hypercatabolic hypoproteinemia was associated with chemical diabetes mellitus and a skeletal deformity, i.e., shortened ulnae and bowed radii. Ardeniz et al. (2015) stated that the female sib reported by Waldmann and Terry (1990) reportedly had purple-red spots and ulcerations on her legs after age 21 years, and died of sepsis and bleeding at age 40. Her brother was asymptomatic, but lost to follow-up.

Ardeniz et al. (2015) reported 2 sibs, born of consanguineous parents, with B2M deficiency. The proband was a 31-year-old woman with nasal perforation resulting from skin ulceration and diffuse ulcerated brown-violet-colored skin lesions on the extremities. The lesions appeared as subcutaneous nodules at 9 years of age during a flu-like infection and progressed slowly. She also had a history of recurrent lung infections resulting in bronchiectasis, and granulomatous dermatitis without identification of an infectious agent. Her 18-year-old brother was essentially asymptomatic, but had bronchiectasis associated with recurrent respiratory tract infections. Laboratory studies of both patients showed severe hypoproteinemia, decreased IgG with normal IgA and IgM, decreased alpha-beta CD8+ T cells, increased gamma-delta CD8+ T cells, and almost undetectable beta-2-microglobulin. Detailed in vitro studies of patient CD8+ T cells and NK cells showed defects in cytotoxic function. Family history included 3 sibs who died early in life and a sister who died at age 22 years with a diagnosis of 'cutaneous tuberculosis.' The findings were consistent with a complex immunodeficiency.

Inheritance

The transmission pattern of IMD43 in the family reported by Ardeniz et al. (2015) was consistent with autosomal recessive inheritance.

Molecular Genetics

In the 2 sibs reported by Waldmann (1969), Wani et al. (2006) identified a homozygous mutation in the B2M gene (109700.0001). Both sibs had B2M serum levels that were less than 1.0% of normal as well as soluble HLA levels that were less than 0.2% of normal. The neonatal Fc receptor (FcRn) (FCGRT; 601437) is a heterodimer of a nonclassical MHC class I alpha chain and B2M that binds the 2 most abundant serum proteins, IgG and albumin, after their constitutive cellular uptake. FcRn binds both proteins, thus acting as a salvage pathway, protecting them from lysosomal degradation and extending the catabolic half-lives of both proteins. In these sibs, deficiency of B2M and subsequent deficiency of FcRn resulted in increased catabolism of serum proteins.

In 2 Turkish sibs, born of consanguineous parents, with IMD43, Ardeniz et al. (2015) identified a homozygous loss-of-function mutation in the B2M gene (109700.0003). Patient lymphocytes showed no detectable B2M surface protein expression, and serum levels of B2M were undetectable. MHC-I was undetectable on the surface of patient cells, and there was intracellular accumulation of the MHC-I heavy chain (see HLA-A, 142800). Surface expression of CD1A (188370), CD1B (188360), and CD1C (188340) was absent on monocyte-derived dendritic cells, consistent with the notion that B2M also stabilizes the surface expression of these molecules. There was also functional inactivation of NK cells and lack of invariant natural killer T cells (iNKT). Absent FcRn surface expression led to low serum IgG and albumin (103600) in both sibs.