Infections in DNA Repair Defects: History
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Contributor:
Yesim Yilmaz Demirdag
,
Sudhir Gupta

DNA repair defects are rare heterogeneous conditions typically present with an increased risk of cancer, accelerated aging, and defects in the development of various organs and systems. The immune system can be affected in a subset of these disorders leading to susceptibility to infections and autoimmunity. Infections in DNA repair defects may occur due to primary defects in T, B, or NK cells and other factors such as anatomic defects, neurologic disorders, or during chemotherapy. 

  • inborn errors of immunity
  • immunodeficiency
  • DNA repair disorders
  • ataxia telangiectasia

1. Introduction

DNA damage can occur spontaneously or because of environmental exposure to various agents such as ultraviolet radiation, ionizing radiation, and chemicals, including alkylating agents, aromatic amines, and cross-linking agents [1]. Cells utilize several DNA repair mechanisms to avoid deleterious consequences of DNA damage, which may result in mutations and genomic instability. These mechanisms include DNA mismatch repair (MMR), base excision repair (BER), nucleotide excision repair (NER), single-strand break repair (SSBR), and double-strand break repair (DSBR) [2]. In general, DNA repair starts with damage recognition, activation of checkpoint proteins, and finally, activation of repair enzymes such as nucleases, helicases, polymerases, and ligases. Double-strand breaks are the most toxic DNA breaks resulting in cell death or large-scale gene rearrangement, causing cancer if not properly repaired. The two main DSBR pathways are homologous recombination (HR) and nonhomologous end-joining (NHEJ) pathways. HR is the most accurate because it uses the homologous sister chromatid as a template. Disorders of DNA repair mechanisms may result from alterations in these repair pathways, causing genomic instability and various disease phenotypes ranging from neurodevelopmental syndromes, immunodeficienciencies, increased risk of a variety of malignancies, to premature aging [3].
In addition to a spontaneous occurrence or triggered by environmental factors, in some cells, DNA breaks are programmable and necessary. A classic example of programmed DNA breaks occurs during somatic rearrangement of T cell receptors (TCR) and immunoglobulin receptor (or B cell receptors-BCR) genes, a process called V(D)J recombination, which is essential in the generation of diverse antigenic repertoire. DNA repair mechanisms play a crucial role in the development of these antigen receptors, which are critical for normal immune response. Defects in DNA repair pathways may lead to various alterations in the development and maturation of T and B cells, causing susceptibility to recurrent or severe infections [4]. The majority of DNA repair defects that are most associated with immunodeficiencies are due to defects in 3 repair pathways: DSBR, MMR (such as LIG4 deficiency, ataxia telangiectasia, and Nijmegen Breakage syndrome) and BER (UNG deficiency).

2. Ataxia-Telangiectasia

Ataxia Telangiectasia (AT) is a rare autosomal recessive (AR) disorder affecting multiple systems, primarily the nervous system, and immune system, with a median life expectancy of 25 years [5]. It is caused by mutations in the ATM (ataxia–telangiectasia, mutated) gene that encodes the protein ATM, a protein kinase that plays a critical role in DSBR.
In addition to the result of exposure to ionizing radiation and other external factors, double-strand breaks (DSB) occur during TCR as well as BCR gene rearrangements. When ATM does not function properly, the cell cycle does not stop to repair DSB. This results in defects in T cell receptor (TCR) and B cell receptor (BCR) rearrangement, which ultimately causes defects in the development of T and B cells [6][7]. 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 [7][8][9]. 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) [10][11]. Importantly, the hyper-IgM phenotype is associated with more severe infectious manifestations and lower survival rates [10][12].
The symptoms of AT usually develop early in the first 1–2 years of life and include progressive cerebellar ataxia, which is the most reported presentation [13]. Other neurologic symptoms include the progressive development of dysarthria, dysphagia, oculomotor apraxia, dystonia, tremor, and peripheral neuropathy. Some patients may also have progressive cognitive impairment. By 10 years of age, the majority of children are unable to walk. Telangiectasia often involves the bulbar conjunctivae, pinna of the ears, and other places in the body starting around 3–4 years of age. Frequent infections may start as early as the first months of life and mostly involves infections of the upper and lower respiratory tracts requiring prophylactic antibiotic therapy as well as immunoglobulin replacement therapy [7][8]. In contrast to progressive neurologic disease, progressive immunodeficiency is very rare in AT [7][14]. In addition to neurologic deterioration and infections, increased risk of malignancies, particularly leukemia, and lymphoma, and increased risk of toxicity associated with chemo- and radiation therapies further impact life expectancy in AT [13][15].

2.1. Respiratory Tract Infections in AT

In a large cohort of patients with AT, recurrent upper respiratory tract infections were reported by more than one-third of patients. Due to progressive neurologic disease, which results in respiratory failure, the prevalence of lower respiratory tract infections increases with age and may be seen in up to 38% of patients older than 20 years [7][8][16]. The major causes of death in AT include bacterial pneumonia and chronic lung disease [5][17]. A retrospective study analyzed 101 patients who did not have cancer and had chronic respiratory symptoms [18]. This included 36 patients with AT who were alive and 65 patients who died secondary to lung disease. Clinical symptoms included cough, fever, adventitial breath sounds, weight loss, post-tussive emesis, hemoptysis, and pleuritic chest pain. Radiological findings included but were not limited to bronchiectasis, hilar adenopathy, pneumothorax, pleural thickening, and sinusitis. Of the 101 patients, 79 had at least one microbial evaluation of their respiratory secretions, and 61 were positive. Bacterial pathogens isolated included Pseudomonas aeruginosa, Hemophilus influenzae, Staphylococcus aureus, Streptococcus pneumoniae, Escherichia coli, Streptococcus viridians, Candida albicans. Of seven patients in whom viral pneumonia was suspected, three had respiratory syncytial virus (RSV) infections, two had clinical and radiological pictures consistent with Varicella pneumonia, and the remaining two had serological evidence of acute EBV infection in association with new pulmonary infiltrates. No opportunistic or fungal pathogens were isolated, with the exception of Candida albicans, which was always found in conjunction with other microbes.
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 [9]. Interestingly, other studies found no correlation between the frequency of respiratory tract infections and immunoglobulin deficiencies [7][14]. On the other hand, patients with hyper IgM phenotype, where serum IgM levels are normal or elevated and IgG and/or IgA levels are low, presented with a more severe course and shorter survival due to recurrent and severe respiratory infections [10].

2.2. Bacterial Sepsis and Meningitis in AT

Bacterial sepsis and meningitis are seen as relatively rare in AT. Other factors, such as malignancy, chemotherapy, and indwelling catheters, contribute to the development of invasive infections caused by Streptococcus pneumoniae, Staphylococcus aureus, and Pseudomonas aeruginosa [7].

2.3. Viral Infections in AT

In one cohort, 44% of patients reported varicella infection, and severe varicella infection requiring hospitalization was reported in 5% of these patients. Warts were reported in 17%, and refractory warts were seen in 7% of total patients [7]. 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 [9][19][20][21]. Complications associated with live-viral vaccines for polio, measles, mumps, or varicella zoster have not been reported except for one vaccine-associated poliomyelitis case [22]. However, although causality is unclear, vaccine-strain rubella virus has been isolated in some cutaneous granulomas in patients with primary immunodeficiencies, specifically in DNA repair disorders, including AT [23][24][25].

2.4. Fungal Infections in AT

Interestingly, despite the high rate of low T cells, infections associated with cellular immunodeficiency are only rarely seen in AT. Moreover, despite the use of frequent antibiotics for respiratory infections, candida infections were reported only occasionally and mostly in the setting of chemotherapy. For example, candida esophagitis was reported in 3 of 100 patients with AT, and in one patient, it was associated with chemotherapy, in another patient, it was concurrent with EBV infection. Additionally, one patient developed candida esophagitis during severe varicella infection [7]. P. jiroveci pneumonia was extremely rare in AT [26].

3. Nijmegen Breakage Syndrome

Nijmegen breakage syndrome (NBS) is another rare AR defect in DSBR. It is most commonly seen in Slavic populations due to a founder mutation in the gene NBS-1, encoding protein named “nibrin” [27]. Nibrin is part of a trimeric complex which also includes MRE11 and RAD50 (the MRN complex). The MRN complex is involved in DSBR by both homologous recombination and nonhomologous end joining. Nibrin recognizes DSB and initiates the relocation of the MRN complex to the sites of DSBs. In addition to a direct role in DNA repair, the MRN complex is also involved in the activation of ATM [28][29].
The hallmark of NBS is microcephaly, usually since birth, with normal or mildly impaired psychomotor development. Other cardinal features include a typical facial appearance with a prominent midface, recurrent respiratory infections, chromosomal instability, radiation hypersensitivity, and predisposition to malignancy [27][30]. Some patients may also have café au lait spots, clinodactyly and syndactyly.
Combined humoral and cellular immunodeficiencies are extremely common and highly variable in NBS. In a large cohort, abnormal levels of total serum immunoglobulins were found only in 32 out of 40 patients (80%). The most common immunoglobulin deficiency was combined IgG and IgA deficiency (25%). Interestingly, 36·8% of patients with normal total IgG levels had low IgG subclasses (mainly IgG2 and/or IgG4). Five of 40 patients had markedly elevated concentrations of IgM. Reduced absolute counts of CD4+ T cells were found in 95% and CD8+ T cells in 80% of patients. An elevated number of NK cells was seen in 62.5% of patients. In contrast to AT, in more than 50% of patients with NBS, immunodeficiency may progress over time [31]. Patients with recurrent infections are treated with immunoglobulin replacement therapy and prophylactic antibiotics.
Despite confirmed immunodeficiency, some patients do not develop frequent infections and do not require prophylactic antibiotics or immunoglobulin treatment for many years or until the development of a malignancy.

3.1. Bacterial Infections in NBS

The most common infections in NBS include bacterial respiratory tract infections which have been reported in more than 50% of patients [27][30][31][32].
Mycobacterial infections have been reported in only a few patients [32][33][34].

3.2. Viral Infections in NBS

Herpes simplex infections with recurrent relapses may be seen in up to 30% of patients with NBS, some of which may be associated with chemotherapy [35].
In a large retrospective study, chronic hepatitis infections were reported in 23% of patients, including 14 children with HBV, three with HCV, two with co-infection with HCV and HBV, and five children with severe and recurrent HZV infection [32].
Other studies also showed that severe or chronic viral infections, especially those caused by lymphotropic and/or hepatotropic viruses such as EBV, CMV, HBV, and HCV, may occur, and they may mimic lymphoma or leukemia [36][37]. In some patients, two and even three viral infections co-existed [32][36]. The median maximum load of EBV DNA was higher in patients with CD3+ T cells of <300 cells/μL compared with those with normal CD3+ T cell levels [36].
In a large prospective study, 38.6% of 57 children with NBS developed lymphatic malignancies [36]. In 68.2% of these patients, viral genetic material was demonstrated before the development of malignancy, including EBV in 63.6%, HBV in 31.8%, HCV in 13.6%, and co-infection with two or three viruses in 8 children. There were statistically significant correlations between monoclonal gammopathy and the persistent presence of EBV DNA and HCV RNA. Although the exact mechanism was not investigated, these findings may suggest that chronic viral (such as EBV or HCV) stimulation may contribute to the development of monoclonal malignancies.
Like in AT, the vaccine-strain rubella virus has been isolated in some cutaneous granulomas in patients with NBS, and hematopoietic stem cell transplantation resulted in scarring resolution of granuloma in two patients [23].

3.3. Fungal Infections in NBS

Mucosal candidiasis was reported in as many as 50% of patients with NBS, and some of these patients were on chemotherapy [35][38]. For example, pulmonary fungal infections were suspected in 2.7% of patients and recurrent oral candidiasis in 4.5% [32].

4. Bloom Syndrome

Bloom syndrome, a rare AR syndrome, is associated with strong genetic instability characterized by cytogenetic abnormalities such as numerous chromosomal breaks and predisposition to all types of cancers starting at an early age. It is caused by mutations in the BLM gene, which encodes a 3′-5′DNA helicase [39]. This is an extremely rare condition of <300 cases registered in the Bloom Syndrome registry. It is more prevalent in populations with high consanguinity rates, such as among Ashkenazi Jews whose ancestors were from Poland or Ukraine.
Clinical features of Bloom syndrome include prenatal and postnatal growth retardation, microcephaly, and butterfly-shaped facial erythema due to photosensitivity. The most significant manifestation of Bloom syndrome is the development of cancer of any type starting at an early age, including more than one type of independent cancer [40].
Patients with Bloom syndrome have variable immunodeficiencies, mostly mild antibody deficiencies. Although they develop recurrent infections of the respiratory and gastrointestinal tracts, they are not susceptible to severe or opportunistic infections [41][42]. Treatment includes immunoglobulin replacement and/or prophylactic antibiotics in patients with recurrent infections.

5. Immunodeficiency, Centromeric Instability and Facial Anomalies (ICF) Syndrome

ICF syndrome is a heterogenous autosomal recessive disorder. The number of genes associated with ICF increased from 1 to 4 in the past couple of years, and they include DNA methyltransferase 3B (DNMT3B), zinc-finger and BTB domain-containing 24 (ZBTB24), cell division cycle associated 7 (CDCA7), and helicase, lymphoid specific (HELLS). About 50% of patients with ICF carry biallelic mutations in the DNMT3B gene.
In addition to 3 characteristic findings (variable immunodeficiency, cytogenetic abnormalities, and facial dysmorphism), patients with ICF may present with prenatal and postnasal growth retardation, neurodevelopmental abnormalities, and hematological malignancies [43][44]. Facial features include hypertelorism, flat nasal bridge, epicanthal folds, macroglossia, and micrognathia.
In one study, hypogammaglobulinemia/agammaglobulinemia was seen in almost all patients regardless of the genotype [44][45]. As a result, recurrent and severe respiratory, gastrointestinal, and skin infections with common organisms are very common in ICF. On the other hand, T cell numbers are normal in the majority of patients during the early years of life, and some patients may develop progressive T cell lymphopenia [44][46]. Opportunistic infections (Candida albicans, Pneumocystis jiroveci) have been reported in a small number of patients [44][45][47]. ICF rarely presented with severe combined immunodeficiency, and one of those patients died from rubella pneumonia [48][49].

6. POLE1 Deficiency (FILS Syndrome and IMAGe Syndrome)

Facial dysmorphism, immunodeficiency, livedo, and short stature (FILS) syndrome is a recently described autosomal recessive DNA breakage syndrome caused by a single homozygous intronic variant in POLE1, which encodes the catalytic subunit of polymerase E [50][51]. Patients may have intrauterine growth restriction, short limbs, dysmorphic features including malar and mandibular hypoplasia, lacy reticular pigmentation of the face and extremities, recurrent pruritic papular eruptions, small and dysplastic teeth, and feeding aversion [50]. Normal total B, T cells, low class-switched and non-switched memory B cells, and high memory T cells, low NK cells, high IgA, normal total IgG, and low IgM, IgG2, and IgG4 have been reported [50][52]. Recurrent or severe infections were observed in some but not all patients and include chronic rhinosinusitis, purulent otitis media, pulmonary infections, as well as acute CMV infection associated with pancytopenia, splenomegaly, and hepatitis. One patient had recurrent meningitis caused by Streptococcus pneumonia [51].
Recently a different intronic variant (c.1686+32C > G) in POLE1 as part of a common haplotype in combination with different loss-of-function variants in trans was described in 15 patients from 12 families [53]. They had clinical features similar to IMAGe syndrome (intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita, and genitourinary anomalies in males), a disorder previously associated with gain-of-function mutations in CDKN1C. Five of those patients had increased susceptibility to respiratory infections with lymphopenia and/or low IgM levels. Three patients had low NK cell levels, and one of these patients developed CMV pneumonia and then EBV-associated hemophagocytic lymphohistiocytosis (HLH), requiring allogeneic bone marrow transplantation. Another patient died from an HSV infection at 22 months.

This entry is adapted from the peer-reviewed paper 10.3390/pathogens12030440

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