Characterization of adult patients with IgG subclass deficiency and subnormal IgG2

Abstract

Background Adults with IgG subclass deficiency (IgGSD) with subnormal IgG2 are inadequately characterized. Methods We retrospectively analyzed observations in unrelated adults with IgGSD evaluated in a single hematology clinic (1991-2019) and selected those with subnormal serum IgG2 (<117 mg/dL (<1.2 g/L)) without corticosteroid therapy to describe: age; prevalence of women; upper/lower respiratory infection; autoimmune condition(s); atopy; other allergy; frequent or severe respiratory tract infection in first-degree relatives; IgG, IgG subclasses, IgA, and IgM; blood lymphocyte subpopulations; human leukocyte antigen (HLA)-A and-B types and haplotypes; and 23-valent pneumococcal polysaccharide vaccination (PPSV23) responses. We determined the prevalence of subnormal IgG2 among unrelated adults with IgGSD without corticosteroid therapy and compared general characteristics of those with and without subnormal IgG2. Results There were 18 patients (94.4% women) with subnormal IgG2. Mean age was 52 ± 11 y. Upper/lower respiratory infection occurred in 94.4%/74.8%, respectively. Autoimmune condition(s), atopy, other allergy, and frequent or severe respiratory infection in first-degree relatives occurred in 44.4%, 44.4%, 61.1%, and 22.2%, respectively. Median IgG2 was 105 mg/dL (83, 116). Subnormal IgG, IgG1, IgG3, IgG4, IgA, and IgM was observed in 66.7%, 50.0%, 100.0%, 5.6%, 33.3%, and 0%, respectively. Lymphocyte subpopulations were normal in most patients. HLA frequencies were similar in patients and controls. Three of 4 patients had no protective S. pneumoniae serotype-specific IgG levels before or after PPSV23. These 18 patients represent 7.6% of 236 adults with IgGSD. Prevalence of subnormal IgG, subnormal IgG3, and subnormal IgA was significantly greater in 18 adults with

Factors associated with IgG levels in adults with IgG subclass deficiency

“…In this study, there was a predominance of women in all IgGSD groups, consistent with other reports of IgGSD in adults [ 6 , 16 , 19 – 21 , 24 , 45 , 69 ]. The predominance of females among persons with IgGSD becomes evident at puberty [ 70 ].…”

“…Regressions on IgG revealed significant positive associations of IgG1, both in patients with subnormal IgG1 only and patients with combined subnormal IgG1/IgG3, after adjustment for other variables. In 12 adult patients with IgGSD and subnormal IgG2 and subnormal IgG, nine also had subnormal IgG1 [ 16 ]. These observations demonstrate that IgG1 is a major component of IgG in adults with IgGSD as it is in subjects unselected for subnormal IgG subclass levels [ 2 , 4 , 28 – 30 ].…”

“…Regressions on IgG revealed significant positive associations of IgG2 in both subnormal IgG1 subclass groups, after adjustment for other variables. In 12 adults with IgGSD selected for subnormal IgG2 levels who also had subnormal IgG, three had normal IgG1 [ 16 ]. These observations demonstrate that IgG2 is also a major component of IgG in adults with IgGSD as it is in normal subjects [ 1 , 2 , 4 , 28 – 30 ].…”

“…Mean IgG2 was significantly lower in patients with IgG < 7.00 g/L than IgG ≥ 7.00 g/L in this study, although the IgG2 level of each patient was within the reference limit. Subnormal IgG2 is associated with frequent or severe respiratory infection in some persons [ 13 – 16 ], whereas other persons with subnormal or absent IgG2 are healthy [ 30 , 40 , 41 , 47 , 48 ]. Thus, it is unknown whether quantitative differences in IgG2 levels in the present patients contributed to their frequent or severe respiratory tract infection.…”

POGZ modulates the DNA damage response in a HP1-dependent manner

“…Interestingly, we found that serum IgG2b levels were almost 50% lower in Pogz +/Δ mice compared to age-matched wild-type controls (Fig.5L), indicative of a defective antibody response. Importantly, patients with a selective IgG2 subclass deficiency usually suffer from recurrent upper and lower respiratory tract infections (Barton, Barton et al, 2020), which have also been reported in severe cases of WHSUS (Stessman et al, 2016). Altogether, our data indicate that Pogz haplo-insufficient mice present a developmental delay, a deficit in intellectual abilities, a hyperactive behaviour as well as a compromised humoral immune response, reminiscent of the clinical features reported in WHSUS patients.…”