Assessing Immunoglobulin Deficiencies Among Pediatric Patients With T1D

Among pediatric patients, immunoglobulin deficiencies (IgDs) frequently coexist with type 1 diabetes (T1D) and may be associated with several autoimmune and non-immune related disorders, according to new research published in Pediatric Diabetes. Results also suggest the conditions’ potential common genetic background.

“Primary immunodeficiencies (PIDs), currently referred to as inborn errors of immunity (IEI), are inherited disorders of the immune system function,” researchers wrote. PIDs may predispose individuals to “an increased frequency and/or severity of infections, symptoms of immune dysregulation like autoimmunity or autoinflammation, and/or immunodeficiency in a patient with syndromic features or malignancy.”

Although it is known T1D results from the autoimmune destruction of pancreatic β-cells, the disease is heterogenic, while research indicates its pathogenesis may be more complex than previously thought. For example, a 2020 study screening children for islet antibodies in Germany found “a 0.31% prevalence of presymptomatic T1D in children aged 2 to 5 years, including 0.02% of children with multiple islet autoantibodies and dysglycemia (stage 2 T1D) and 0.03% with previously undiagnosed stage 3 T1D.”

Over 60 susceptibility genetic loci have also already been identified for T1D and most were found in immune-related genes.

To evaluate the prevalence of IgD among pediatric patients with T1D and to identify characteristics of patients with immunoglobulin serum deficits, children and adolescents were recruited from a single pediatric diabetes care center in Poland. All participants were between the ages of 4 and 18 and had T1D for more than 1 year.

Researchers collected serum samples during routine follow-up visits and caregivers were asked to complete a questionnaire on symptoms of PID, autoimmune and non-autoimmune comorbidities and their treatment, along with children’s detailed family history.

“IgG and IgM deficiency (IgGD, IgMD) were defined as IgG/IgM > 2 standard deviations (SD) below age-adjusted mean. IgE deficiency was defined as IgE<2kIU/l,” researchers wrote. “IgA deficiency (IgAD) was defined as IgA>2SD below age-adjusted mean irrespective of other immunoglobulin classes (absolute if <0.07 g/l, partial otherwise) and as selective IgAD when IgA>2SD below age-adjusted mean with normal IgG and IgM (absolute if <0.07 g/l, partial otherwise).”

The final analysis consisted of 395 patients from whom both serum samples and questionnaires were obtained. The majority (n = 211) were boys, and none of the patients were on immunoglobulin substitution or pharmacological treatment at the time of evaluation. Median (interquartile range [IQR]) participant age was 11.2 (8.4-13.7) years and patients had a median diabetes duration of 3.6 (1.1-6.0) years.

Analyses revealed:

• 90 patients (22.8%) were found to have hypogammaglobulinemia
• IgGD and IgAD were the most common with each found in 40 of 395 patients (10.1%)
• Complex IgD was found in 7 patients
• Increased odds of infection-related hospitalization (compared to children without any IgD) was associated with having any kind of IgD and IgAD: odds ratio (OR) 2.1 (95% CI, 1.2-3.7) and OR 3.7 (95% CI, 1.8-7.5), respectively
• IgAD was associated with having a first-degree relative with T1D (OR 3.3; 95% CI, 1.4-7.6) and suffering from non-autoimmune comorbidities (OR 3.3; 95% CI, 1.4 – 7.6), especially neurological disorders (OR 3.5; 95% CI, 1.2 – 10.5)
• Overall, results support the existing hypothesis “that patients with T1D may harbor heterogenous immunophenotypes.” Researchers continued, “We demonstrated that immunodeficiencies and their constellations are likely to have clinical impact on T1D management and its comorbidities.”

For the first time, the study shows selective lgAD is strongly associated with comorbidities—in particular neurological disorders—marking a potentially important clinical feature for searching for further phenotypes associated with autoimmune dysregulation of unknown genetics.

Some clinical characteristics included in the study were self-reported and thus subjective, marking a limitation. Researchers were also unable to obtain clear data regarding PID in patients’ family histories, in part because the condition is underdiagnosed in the adult population. A separate independent cohort study is needed to replicate results.

Based on the findings, authors suggest evaluation of serum immunoglobulin levels be routinely carried out in patients with T1D “because it may provide key information on humoral immune status and help to identify patients with characteristic immunophenotypes.”

Future studies may help uncover underlying defective immune pathways leading to the development of T1D and autoimmunity, they concluded.

Reference

Hogendorf A, Małgorzata S, Joanna K, et al. Clinical heterogeneity among pediatric patients with autoimmune type 1 diabetes stratified by immunoglobulin deficiency. Pediatr Diabetes. Published online April 10, 2021. doi:10.1111/pedi.13208