Impaired immune function in children with Fanconi anaemia

Abstract

Summary Fanconi anaemia is an autosomal recessive or X-linked disease characterized by progressive bone marrow failure, variable congenital abnormalities and a predisposition to malignancy. Reports of immune function in this population are limited, and include only specific areas of immune performance, showing variable defects. We report a cross-sectional immunological assessment in 10 children with FA. Absolute numbers of B cells and natural killer (NK) cells were reduced compared to controls (P = 0·048 and P = 0·0002, respectively), while absolute number of T cells were within normal range. Perforin and granzyme content of NK cells was reduced (P < 0·00001 and P = 0·0057, respectively) along with the NK cell cytotoxicity (P < 0·001). Antigen proliferation in response to tetanus was decreased (P = 0·008) while responses to candida and phytohaemagglutinin were not. Cytotoxic T cell function was also reduced (P < 0·0001). Immunoglobulin G levels were normal in those evaluated. Our series represents the first attempt at a comprehensive quantitative and functional evaluation of immune function in this rare group of patients and demonstrates a significant deficit in the NK cell compartment, a novel quantitative B cell defect, along with abnormal cytotoxic function. These findings may be especially relevant in this patient population with known predisposition to DNA damage and malignancy.

Oxidative stress in Fanconi anaemia: from cells and molecules towards prospects in clinical management

“…This particular B-cell phenotype, not expected in children but in advanced age, may be due to a premature senescence affecting B cells in FA children (Myers et al , 2011 ).…”

Cerebral toxoplasmosis after haematopoietic stem cell transplantation

“…Fanconi Anaemia is autosomal recessive or X-linked congenital disease, characterized by progressive bone marrow failure, developmental defects, predisposition to malignancy and different alterations in immunologic function (impairment of T-cell function, NK and macrophage function [7,8]. Haematopoietic stem cell transplantation may be associated with several complications, including neurologic, which may be secondary to the treatment toxicity, prolonged immunosuppression or an underlying disease.…”

Deletion of Fanca or Fancd2 dysregulates Treg in mice

“…For example, in the first systematic and broad evaluation of immune function in FA patients, Myers and colleagues reported that absolute numbers of B cells and natural killer (NK) cells were reduced in FA patients compared with controls, whereas the absolute number of T cells was within normal range, although cytotoxic T-cell function was reduced. 17 Perforin and granzyme content of NK-cells was reduced along with NK-cell cytotoxicity (P , .001). Antigen proliferation in response to tetanus was also decreased whereas responses to candida and phytohemagglutinin were preserved.…”

“…Loss of FA functions causes excessive apoptosis of hematopoietic stem and progenitor cells (HSC/P) leading to BMF in the early stage of FA. [13][14][15][16][17] As the disease progresses, apoptosis as well as genomic instability impose a selective pressure on FA HSC/P cells. The loss of stem cell fitness in FA HSC/P cells permits the emergence of resistant clones, which could be transformed to leukemia.…”

“…Antigen proliferation in response to tetanus was also decreased whereas responses to candida and phytohemagglutinin were preserved. 17 Furthermore, impaired cytoskeletal rearrangements in Fancc ) have been linked to the cell-autonomous defects detected in vitro, as well as altered monocyte/macrophage trafficking in vivo. 18 More recent studies, using primary samples, linked immunological alterations to cell apoptosis and tissue inflammation in FA patients.…”