Serio, Bianca (2008) IMPACT OF IMMUNOGENETIC POLYMORPHISMS ON IMMUNE RESPONSE AND CLINICAL FEATURES IN BONE MARROW FAILURE SYNDROMES. [Tesi di dottorato] (Unpublished)

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Hematopietic stem cells (HSC) are responsible for the production of mature blood cells in bone marrow; peripheral pancytopenia may result from several different conditions, including hematological or extra-hematological diseases (mostly cancers) affecting the marrow function as well as primary failure of hematopoiesis. Although the clinical presentation may appear homogeneous, primary bone marrow failure syndromes are a heterogeneous group of diseases with specific pathogenic mechanisms, which share a profound impairment of the hematopoietic stem cell pool resulting in selective or global marrow aplasia. Immune elimination of stem cells due to the presence of a cross-reactive antigen or autoantigen restricted to the stem cell compartment may be responsible for AA. Similar pathophysiologic mechanisms may also operate in related disease such as paroxysmal nocturnal hemoglobinuria (PNH) or some forms of myelodisplastic syndromes (MDS). Most often these disease are characterized by an extrinsic damage of hematopoietic stem cells that affect their function. Effector mechanisms in hematopoietic inhibition may involve various pathways, including release of cytokine leading to apoptosis of hematopoietic progenitor and stem cells. In MDS, various possible mechanisms have been postulated to explain the occurrence of cytopenia due to inhibition of normal residual hematopoiesis. For exemple, the immune attack can be part of physiologic anti-tumor surveillance response to abnormal and/or dysplastic cells in the bone marrow. In such situation, the immune attack may be sufficiently specific and results in collateral damage with inhibition of normal hematopoiesis. Conversely, the initial immune attack may be directed against normal stem cells as in AA, resulting in selection pressure and outgrowth and escape mutant hematopietic clones. Similar consideration apply to the evolution of glycophosphatidyl- deficient clones in PNH. Our hypothesis is that the human leukocyte antigen (HLA) and killer inhibitory receptor (KIR) background as well as the quality of the cytokine response due to genetic variants of the cytokine, cytokine receptors genes and their promoters may modulate the quality of immune response and predispose to aberrant overshooting immune reactions. Such reaction may determine the risk for immune-mediated bone marrow failure. The association of BMF with a number of immunogenetic factors was analysed in 167 patients, including human leucocyte antigen (HLA) and killer-cell immunoglobulin-like receptor (KIR) genotype, KIR/KIR-L mismatch, CTLA-4 (+49 A/G),CD16−158V/F, and cytokine single nucleotide polymorphisms including: IL-1α (-889 T/C), IL-1R (-1970 C/T), IL-1RA (11100 T/C), IL-4RA (+ 190 G/A), IL-1β (-511 C/T, +3962 T/C), IL-6 (-174 C/G, nt565 G/A), IL-10 (-1082 G/A, –819 C/T, -592 C/A), IL-12 (-1188 C/A), TGF-β (codon 10 C/T, codon 25 G/C), TGF-βR2 (+358 A), INF-γ (+874 A/T), TNF-α (-308 G/A, –238 G/A), IL2 (-330 T/G, +166 (G/T), IL4 (-1098 T/G, -590 T/C, -33 T/C). Our data suggest that genetic regulation of inflammatory and T-cell-mediated immunological pathways could be involved in the pathgenesis of bone marrow failure, reinforcing the view that both AA and PNH are organ-specific autoimmune disorders.

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