Infections and immune dysregulation in ataxia-telangiectasia children with hyper-IgM and non-hyper-IgM phenotypes: A single-center experience

Abstract

Ataxia-telangiectasia (A-T) is a severe syndromic neurodegenerative inborn error of immunity characterized by DNA reparation defect, chromosomal instability, and hypersensitivity to ionizing radiation, thereby predisposing affected individuals to malignant transformation. While the leading disease symptomatology is associated with progressively debilitating cerebellar ataxia accompanied by central and peripheral nervous system dysfunctions, A-T is a multisystemic disorder manifesting with the heterogeneity of phenotypic features. These include airway and interstitial lung disease, chronic liver disease, endocrine abnormalities, and cutaneous and deep-organ granulomatosis. The impaired thymic T cell production, defective B cell development and antibody production, as well as bone marrow failure, contribute to a combined immunodeficiency predisposing to infectious complications, immune dysregulation, and organ-specific immunopathology, with the A-T hyper-IgM (HIGM) phenotype determining the more severe disease course. This study aimed to clarify the immunodeficiency and associated immune dysregulation as well as organ-specific immunopathology in children with A-T. We also sought to determine whether the hyper-IgM and non-hyper-IgM phenotypes play a discriminatory role and have prognostic significance in anticipating the clinical course and outcome of the disease. We retrospectively reviewed the medical records of twelve A-T patients, aged from two to eighteen years. The patients' infectious history, organ-specific symptomatology, and immunological workup including serum alpha-fetoprotein, immunoglobulin isotypes, IgG subclasses, and lymphocyte compartments were examined. For further comparative analysis, all the subjects were divided into two groups, HIGM A-T and non-HIGM A-T. The clinical evaluation of the study group showed that recurrent respiratory tract infections due to viral and bacterial pathogens and a chronic obstructive airway disease along with impaired humoral immunity, in particular complete IgA deficiency, were noted in all the A-T patients, with both HIGM and non-HIGM phenotypes. The most important features with the discriminatory role between groups, were autoimmune disorders, observable four times more frequently in HIGM than in non-HIGM A-T. Two patients with the HIGM A-T phenotype were deceased due to liver failure and chronic Epstein-Barr virus (EBV) infection. It may therefore be assumed that the HIGM form of A-T is associated with more profound T cell dysfunction, defective immunoglobulin class switching, chronic EBV expansion, and poorer prognosis.

Successful Treatment of Large B-Cell Lymphoma in a Child with Compound Heterozygous Mutation in the ATM Gene

“…A thorough clinical evaluation by a multidisciplinary team, as well as in-depth immunological diagnostics, including assessment of humoral and cellular immune responses [ 33 ], in conjunction with molecular genetic testing, leads to the diagnosis of AT. Immunoglobulin replacement therapy and antibiotics are the mainstays of prophylaxis against infections in AT.…”

Infections in DNA Repair Defects

“…Prevalence, severity, and type of immunologic abnormalities in AT are highly variable and usually associated with lymphopenia, low immunoglobulin levels (IgG/IgA or IgM), low IgG2 or IgG3 and suboptimal polysaccharide antibody responses. Despite low CD4+ T cell counts, T cell function is usually preserved [ 10 , 11 , 12 ]. About 10–20% of patients with AT present with hyper-IgM phenotype, which is likely due to a blockade in early B cell development resulting in immunoglobulin class-switching defect (CSD) [ 13 , 14 ].…”

“…A single-center study on 12 patients with AT demonstrated that while patients with low IgG2 had recurrent infections due to S. pneumoniae , bacterial pathogens were not demonstrated in the airways of 4 patients with IgG3 deficiency [ 12 ]. Interestingly, other studies found no correlation between the frequency of respiratory tract infections and immunoglobulin deficiencies [ 10 , 17 ].…”

“…No patient had a cytomegalovirus infection in this cohort. In addition to chronic EBV infection, EBV-associated tumors such as smooth muscle tumors in the liver and nodular sclerosing Hodgkin lymphoma and mucosa-associated lymphoid tissue (MALT Lymphoma) in the parotid gland have been reported in AT [ 12 , 22 , 23 , 24 ]. Complications associated with live-viral vaccines for polio, measles, mumps, or varicella zoster have not been reported except for one vaccine-associated poliomyelitis case [ 25 ].…”