Deficiency of Somatic Hypermutation of Immunoglobulin G Transcripts Is a Better Predictor of Severe Respiratory Tract Infections than Lack of Memory B Cells in Common Variable Immunodeficiency

Background. Common variable immunodeficiency (CVID) is a primary immunodeficiency disorder (PID) that typically presents with hypogammaglobulinemia and impaired antibody production. Objectives. This study aimed to promote the awareness of CVID, whose clinical spectrum is quite broad. Methods. The demographic, clinical, and laboratory characteristics of 12 children (seven males and five females) with CVID were analyzed retrospectively. The patients were diagnosed using the diagnostic criteria of the European Society for Primary Immunodeficiencies. Results. The median disease onset age was 7.2±4.1 years, and the mean diagnosis age was 11.6±3.7 years. The diagnosis delay was 4.3±2.6 years, and the parental consanguinity rate was 75%. Most patients presented with recurrent infections, including upper respiratory tract infections (n=8), lower respiratory tract infections (n=9), and gastroenteritis (n=5). In addition, growth retardation (n=9) and bronchiectasis (n=5) were common comorbidities. Two patients presented with autoimmune thrombocytopenia and anemia, and one patient exhibited lung empyema. All the patients had immunoglobulin G deficiencies. Conclusion. CVID is a heterogeneous disease, so the diagnosis is frequently delayed. In the CVID patients with pulmonary complications, relationships were seen with the diagnosis delay, symptom onset age, and lung infection prevalence. Overall, the early diagnosis and treatment of PIDs can preclude life-threatening complications.

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Predictive Factors for and Complications of Bronchiectasis in Common Variable Immunodeficiency Disorders

Journal of Clinical Immunology ◽

10.1007/s10875-022-01206-8 ◽

2022 ◽

Author(s):

Johannes M. Sperlich ◽

Bodo Grimbacher ◽

Veronika Soetedjo ◽

Sarita Workman ◽

Siobhan O. Burns ◽

...

Keyword(s):

Quality Of Life ◽

Lung Function ◽

Respiratory Tract ◽

Common Variable Immunodeficiency ◽

Respiratory Tract Infections ◽

Forced Expiratory Volume ◽

Serum Immunoglobulin ◽

Tract Infections ◽

Common Variable

AbstractBronchiectasis is a frequent complication of common variable immunodeficiency disorders (CVID). In a cohort of patients with CVID, we sought to identify predictors of bronchiectasis. Secondly, we sought to describe the impact of bronchiectasis on lung function, infection risk, and quality of life. We conducted an observational cohort study of 110 patients with CVID and an available pulmonary computed tomography scan. The prevalence of bronchiectasis was 53%, with most of these patients (54%) having mild disease. Patients with bronchiectasis had lower median serum immunoglobulin (Ig) concentrations, especially long-term IgM (0 vs 0.25 g/l; p < 0.01) and pre-treatment IgG (1.3 vs 3.7 g/l; p < 0.01). CVID patients with bronchiectasis had worse forced expiratory volume in one second (2.10 vs 2.99 l; p < 0.01) and an annual decline in forced expiratory volume in one second of 25 ml/year (vs 8 ml/year in patients without bronchiectasis; p = 0.01). Patients with bronchiectasis also reported more annual respiratory tract infections (1.77 vs 1.25 infections/year, p = 0.04) and a poorer quality of life (26 vs 14 points in the St George’s Respiratory Questionnaire; p = 0.02). Low serum immunoglobulin M concentration identifies patients at risk for bronchiectasis in CVID and may play a role in pathogenesis. Bronchiectasis is relevant because it is associated with frequent respiratory tract infections, poorer lung function, a greater rate of lung function decline, and a lower quality of life.

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Deficiency of somatic hypermutation of the antibody light chain is associated with increased frequency of severe respiratory tract infection in common variable immunodeficiency

Blood ◽

10.1182/blood-2003-12-4359 ◽

2005 ◽

Vol 105 (2) ◽

pp. 511-517 ◽

Cited By ~ 58

Author(s):

Pernille Andersen ◽

Henrik Permin ◽

Vagn Andersen ◽

Lone Schejbel ◽

Peter Garred ◽

...

Keyword(s):

Tract Infection ◽

Respiratory Tract ◽

Respiratory Tract Infection ◽

Light Chain ◽

Common Variable Immunodeficiency ◽

Somatic Hypermutation ◽

Hot Spot ◽

Reference Interval ◽

Immunoglobulin Genes ◽

Common Variable

AbstractReduced levels of somatic hypermutation (SHM) have recently been described in IgG-switched immunoglobulin genes in a minority of patients with common variable immunodeficiency (CVID), demonstrating a disruption of the normal linkage between isotype switch and SHM. To see if, irrespective of isotype, there is a tendency to use unmutated immunoglobulin genes in CVID, we studied SHM in κ light-chain transcripts using a VκA27-specific restriction enzyme-based hot-spot mutation assay (IgκREHMA). Hot-spot mutations were found in 48% (median; reference interval, 28%-62%) of transcripts from 53 healthy controls. Values were significantly lower in 31 patients (median, 7.5%; range, 0%-73%; P < .0000001) of whom 24 (77%) had levels below the reference interval. Low levels of SHM correlated with increased frequency of severe respiratory tract infection (SRTI; P < .005), but not with diarrhea (P = .8). Mannose-binding lectin (MBL) deficiency also correlated with SRTI score (P = .009). However, the correlation of SHM and SRTI was also seen when only patients with normal MBL genotypes were analyzed (n = 18, P = .006). A slight decline of mutated fractions over years was noted (P = .01). This suggests that most patients with CVID fail to recruit affinity-maturated B cells, adding a qualitative deficiency to the quantitative deficiency characterizing these patients.

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Intravenous immunoglobulin replacement prevents severe and lower respiratory tract infections, but not upper respiratory tract and non-respiratory infections in common variable immune deficiency

Allergy ◽

10.1111/j.1398-9995.2005.00756.x ◽

2005 ◽

Vol 60 (3) ◽

pp. 385-390 ◽

Cited By ~ 21

Author(s):

O. Favre ◽

A. Leimgruber ◽

A. Nicole ◽

F. Spertini

Keyword(s):

Immune Deficiency ◽

Respiratory Tract ◽

Respiratory Tract Infections ◽

Respiratory Infections ◽

Upper Respiratory Tract ◽

Lower Respiratory Tract Infections ◽

Upper Respiratory ◽

Immunoglobulin Replacement ◽

Tract Infections ◽

Common Variable

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Patients with Common Variable Immunodeficiency Complicated by Autoimmune Phenomena Have Lymphopenia and Reduced Treg, Th17, and NK Cells

Journal of Clinical Medicine ◽

10.3390/jcm10153356 ◽

2021 ◽

Vol 10 (15) ◽

pp. 3356

Author(s):

Ewa Więsik-Szewczyk ◽

Elżbieta Rutkowska ◽

Iwona Kwiecień ◽

Marcelina Korzeniowska ◽

Dariusz Sołdacki ◽

...

Keyword(s):

B Cells ◽

Nk Cells ◽

Common Variable Immunodeficiency ◽

Lupus Erythematosus ◽

Memory B Cells ◽

T Cell Subsets ◽

Primary Immune Deficiency ◽

Immunological Markers ◽

Autoimmune Phenomena ◽

Common Variable

Most patients with primary immune deficiency suffer from recurrent infections; however, paradoxical autoimmune phenomena can also manifest. The aim of this study was to identify immunological markers of autoimmune phenomena associated with common variable immunodeficiency (CVID). The study included 33 adults with CVID divided into two groups: (1) those with noninfectious autoimmune complications (CVID-C (n = 24)) and (2) those with only infectious symptoms (CVID-OI (n = 9)). Flow cytometry of peripheral blood was performed and compared with systemic lupus erythematosus (SLE) patients (n = 17) and healthy controls (n = 20). We found that all lymphocytes were lower in CVID-C and SLE. NK cells were lowest in CVID-C. Th17 cells were significantly reduced in CVID-C and SLE. Tregs were significantly lower in CVID-C and SLE. Bregs did not significantly differ between any groups. Class-switched memory B cells were significantly lower in CVID-C and CVID-OI. Lastly, plasmablasts were significantly higher in SLE. Among the T cell subsets, CVID-C patients had lower naive and recent thymic emigrant CD4+ T cells. In conclusion, reduced Treg, Th17, and NK cells are features of CVID with autoimmune complications, and class-switched memory B cells can help distinguish patients with different causes of autoimmunity. Future studies are needed to confirm whether reductions of Treg, Th17, and NK cells might be a biomarker of more complicated CVID cases.

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