Impaired immune function in children and adults with Fanconi anemia

Myers, Kasiani C.; Sauter, Sharon; Zhang, Xue; Bleesing, Jacob; Davies, Stella M.; Wells, Susanne I.; Mehta, Parinda A.; Kumar, Ashish; Marmer, Daniel J.; Marsh, Rebecca; Brown, Darron R.; Kovacic, Melinda Butsch

doi:10.1002/pbc.26599

Cited by 23 publications

(38 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Just as important, HPV titers should be monitored for many years post vaccination to evaluate sustainability and to address the question of need for booster vaccine in this cancer prone population, particularly as some parents of children with FA request to have their younger children vaccinated. Additionally, B cell deficiency and dysfunction were observed in almost half of the participants with FA, a finding confirming previous reports [26, 27]. Immune dysfunction seen in participants with FA can change over time and response to vaccine may differ depending on their age at vaccination.…”

Section: Discussionsupporting

confidence: 88%

“…Nevertheless, molecular and cellular mechanisms responsible for protection from and clearance of HPV infection are not completely understood [23]. Since our group and others have previously shown heterogeneous immune defects in those living with FA, a better understanding of the role of HPV and host immunity would allow for a more thoughtful approach towards prevention of HPV infection and risk reduction for SCC in this vulnerable population particularly as the HPV vaccine is available and recommended [24–27]. …”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Antibody response to human papillomavirus vaccination and natural exposure in individuals with Fanconi Anemia

Mehta

Sauter

Zhang

et al. 2017

Vaccine

Self Cite

View full text Add to dashboard Cite

Fanconi anemia (FA) is a rare genetic disorder associated with predisposition to head and neck and gynecological squamous cell cancers. In the general population, these cancers are commonly linked to human papillomavirus (HPV) infection. Antibodies to natural HPV infection and HPV vaccination were evaluated in 63 individuals with FA while considering host immune factors. Approximately 30% of reportedly unvaccinated participants were seropositive (HPV6–38%, HPV11–25%, HPV16–26%, and HPV18–26%). Seropositivity was significantly associated with having had sex regardless of age (p=0.007). Most participants showed seropositivity after HPV vaccination (HPV6–100%, HPV11–100%, HPV16–100% and HPV18–92%). Interestingly, titers for all 4 subtypes were significantly lower in the post-hematopoietic stem cell transplant (HSCT) participants compared to those who received the vaccine, but had not undergone HSCT (HPV6- p=0.030, HPV11-p=0.003, HPV16-p=0.018, HPV18-p=<0.001). It is unclear if these titers sufficiently protect from new infection since protective serologic cut offs have not yet been defined for the HPV vaccine. Individual immune functions were not associated with HPV seropositivity, however, underlying heterogeneous immune deficiency may explain higher rates of seropositivity in our younger unvaccinated participants (age 4–13 years). To better measure the efficacy of HPV vaccination in those with FA and other immune-compromised or cancer-prone disorders, future well-controlled vaccine studies are required.

show abstract

Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Antibody response to human papillomavirus vaccination and natural exposure in individuals with Fanconi Anemia

Mehta

Sauter

Zhang

et al. 2017

Vaccine

Self Cite

View full text Add to dashboard Cite

show abstract

“…It is generally accepted that FANC pathway-deficient mice present mild hematopoietic phenotypes (49). The Fanca -/model we used (50) is known to present reduced platelet counts, which mimics patient thrombocytopenia, and altered immunoglobulin formation in association with alterations in the DNA damage response and B cell differentiation (51)(52)(53), abnormalities already reported in FA patients (54). Nevertheless, Fanca -/and WT mice, independently of their ages (3-6 months old, i.e., young, or more than 1 year old, i.e., old) present similar levels of Lin -Sca + Kit + (LSK) cells and their 3 subpopulations, longterm HSCs (LT-HSCs, Flt3 -CD34 -), short-term HSCs (ST-HSCs, Flt3 -CD34 + ), and multipotent progenitors (MPPs, Flt3 + CD34 + ), on which the maintenance of hematopoiesis depends (Figure 4, A-C).…”

Section: Fanc Core Complex Loss Of Function Leads To Mitf Overexpressmentioning

confidence: 93%

Microphthalmia transcription factor expression contributes to bone marrow failure in Fanconi anemia

Oppezzo¹,

Bourseguin²,

Renaud³

et al. 2020

Journal of Clinical Investigation

View full text Add to dashboard Cite

Fancd2-/and WT MEFs, but clearly lower in these cells than in Fanca-/or Fancc-/-MEFs (Figure 1F and data not shown). Together, our previous data robustly demonstrate that loss of function of key components of the FANC core complex is associated with high expression of MiTF at both the RNA and protein levels. SMAD and p38 signaling pathways are necessary but not sufficient to activate MiTF expression in FA MEFs. The increase in Mitf expression in FANC pathway-deficient MEFs with increasing time in the same culture medium (Figure 1, D and E) could be induced by cellto-cell contacts or in an autocrine manner by cell-secreted factor or factors. Consistent with the latter hypothesis, we observed that Mitf expression is robustly induced at both the protein and RNA levels by 24 hours after replating FANC pathway-deficient MEFs in a "conditioned" medium in which the same cells previously grew for 72 hours (Figure 2, A and B, and data not shown). Notably, WT-derived 72-hour-old conditioned medium was unable to significantly induce Mitf in Fanca-/or Fancc-/-MEFs. Similarly, Fanca-/-or Fancc-/-derived conditioned medium was unable to induce Mitf in WT MEFs (Figure 2, A and B, and data not shown). Thus, it is conceivable that Mitf is induced in response to the accumulation in the culture medium of factor or factors secreted by the Fanc-deficient cells themselves. FA cells appear able to secrete and respond to such factor(s), whereas WT cells are poor secretors and nonresponders. Next, we performed ELISA to determine the presence, if any, of known extracellular factors in the culture medium of MEFs. To better perform our analysis, 2 days after dilution, the complete culture medium was washed out, and the cells were fed 2 more days with medium without serum (a longer incubation affects cell morphology, indicating the presence of stress and survival). The serumfree medium was collected and filtered to eliminate detached cells and cellular debris to perform ELISA. We failed to detect TNF-α or IL-1β in FA-derived conditioned medium, but revealed 4 to 6 times higher concentrations of 2 TGF family members (43, 44), TGF-β and activin A (Figure 2, C and D). Finally, the conditioned medium was analyzed by mass spectrometry. Again, we identified high levels of both TGF-β and activin A in the culture medium isolated from FANC pathway-deficient MEFs, but did not distinguish other growth factors differentially expressed between WT and FA MEFs (data not shown). Thus, 2 alternative approaches validated that cultured FANC pathway-deficient MEFs secrete TGF-β and activin A. TGF-β and activin A determine cell fate and hematopoiesis by signaling mainly through the Smad and p38 pathways (8, 43-46), which were previously described as chronically activated in FA cells (24, 32). In Fanca-/or Fancc-/-MEFs maintained for 24 hours in 72-hour-old conditioned medium, we observed a modest but reproducible increase in Smad2/3 phosphorylation and extremely strong phosphorylation of p38 (Figure 2E). The culture of WT MEFs in conditioned medium (both from FA...

show abstract

“…Fanconi anemia (FA), the most common form of the aplastic anemias, is a recessive genetic disorder with an estimated carriership of 1:300 and disease prevalence of 4—7:1 000 000 . FA is characterized by genome instability, bone marrow failure, and cancer predisposition . Several studies showed a significant humoral and cellular immune dysfunction in patients with FA .…”

Section: Introductionmentioning

confidence: 99%

“…3 Several studies showed a significant humoral and cellular immune dysfunction in patients with FA. 3 As a result of the high variety in presentation, the diagnosis of FA will often be confirmed after the pancytopenia appears. The most frequently associated congenital malformations are those of the skeletal system, mainly radius and thumb.…”

Section: Introductionmentioning

confidence: 99%