Immunological Prophile of FA. A Multicentric retrospective Analysis of 61 Patients
Authors: Terranova Paola , Cappelli Enrico , Peffault De Latour Regis , Svahn Johanna , Soulier Jean , Bredius Robbert , Kok Marleen , van der Zijde Els Jol , van Tol Marteen , Socié Gérard , Moins Helene , Dufour Carlo , Korthof Elisabeth T 
Published: October 2019

Abstract
Abstract 1347

INTRODUCTION:
Fanconi Anemia (FA) is an autosomal and X-linked recessive disease characterized by marrow failure, somatic malformations and cancer proneness primarily leading to AML and head and neck carcinomas. The disease is due to mutations in at least 15 genes responsible for a failure of DNA repair mechanisms that renders the cells sensitive to interstrand cross linkers leading to block of cell cycle in G2 phase. However there is evidence that FA proteins have multiple functions as they are also implicated in cytokine hypersensitivity, response to oxidative stress and immune response. Scanty information is available on immunological status in FA patients. We conducted a retrospective multi-centric analysis of the pre HSCT immunological status of 61 FA patients in aplastic phase by assessing peripheral blood immunophenotype and immunoglobulin serum level (46/61).

RESULTS:
Absolute lymphocyte number was within the normal range for age in 70% of patients (43/61). Only 10% of subjects (6/61) were severely lymphocytopenic ( <1.0×109/l). Absolute B cells were below the lower limit of the normal range for the age (10th percentile) in 75% of patients. Absolute CD3+ and CD8+ cells were within the normal distribution for age in virtually all cases (98% and 94% respectively) whereas CD4+ cells and NK cells were below the lower normal range in 45% and 49% of cases respectively. Within the T cell population, CD3+CD45RA+ (naive) cells were above the normal range in 68% of patients while CD3+CD45+RO+ (memory) cells were reduced in 60 % patients. In 70% (22/32) of the patients in whom we tested regulatory T cells (CD3+/CD4+/CD25bright+/FoxP3+) they were found below the lower normal range. Serum immunoglobulin A and G were within the age matched range of normal controls whereas IgMs were lower than normal range for age in 50% (23/46) of patients.

CONCLUSIONS:
This is the largest study ever conducted on the immunological status of FA patients suggesting that these subjects have an impaired immunity which is not directly reflected by the number of circulating lymphocytes. Reduction of B and also of CD4+cells is consistent with low IgM serum levels. Deficiency of regulatory T cells and the relative excess of CD3+and CD8+ lymphocytes are in keeping with the hypothesis that a dysregulated immunity might contribute to the development of marrow failure. In fact it is possible that the lack of inhibitory effect of T regulatory cells might facilitate CD3+ and CD8+ subsets to produce myelosuppressive cytokines TNF-alfa and IFN-gamma to which FA hematopoietic cells are hypersensitive (1–4). The reduction of T memory cells, that constitutionally have a more hampered DNA repair capability vs T naive cells (5), looks consistent with the classical DNA repair deficiency of FA. Overall these data suggest that specific immune function in FA: (a) is impaired in a rather independent fashion from lymphopenia, (b) might contribute to development of marrow failure and (c) might reflect, to some extent, multifunctionality of FA proteins. Next step is to assess cytokine serum levels, ongoing at writing, that may help to further comprehend the above data. -1- Fagerlie SR, Bagby GC. Immune defects in Fanconi anemia. Crit Rev Immunol. 2006;26(1):81–96 -2- Dufour C, Corcione A, Svahn J, Haupt R, Poggi V, Béka'ssy AN, Scimè R, Pistorio, Pistoia V. TNF-alpha and IFN-gamma are overexpressed in the bone marrow of Fanconi anemia patients and TNF-alpha suppresses erythropoiesis in vitro. Blood. 2003 Sep 15;102(6):2053–9. −3 - Briot D, Macé-Aimé G, Subra F, Rosselli F. Aberrant activation of stress-response pathways leads to TNF-alpha oversecretion in Fanconi anemia. Blood. 2008 Feb 15;111(4):1913–23. -4- Vanderwerf SM, Svahn J, Olson S, Rathbun RK, Harrington C, Yates J, Keeble W, Anderson DC, Anur P, Pereira NF, Pilonetto DV, Pasquini R, Bagby GC. TLR8-dependent TNF-(alpha) overexpression in Fanconi anemia group C cells. -5- Scarpaci S, Frasca D, Barattini P, Guidi L, Doria G. DNA damage recognition and repair capacities in human naïve and memory T cells from peripheral blood of young and elderly subjects. Mech Ageing Dev. 2003 Apr;124(4):517–24.

Disclosures:
No relevant conflicts of interest to declare.