Overproduction of CXC chemokines CXCL 1 CXCL 9

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Overproduction of CXC chemokines CXCL 1, CXCL 9, CXCL 10 and CXCL 12 in

Overproduction of CXC chemokines CXCL 1, CXCL 9, CXCL 10 and CXCL 12 in β-thalassemia major patients Directed by: Zahra mousavi Kerman university of medical science 1 Department of hematology

2 thalassemia

2 thalassemia

introduction 3 thalassemia: q Hereditary anemia q The most common genetic disorder in the

introduction 3 thalassemia: q Hereditary anemia q The most common genetic disorder in the world. q Disruption in the production of hemoglobin protein chains Lack of production decline production

4 Epidemiology q The disorder is mostly prevalent in the Eastern Mediterranean, South Asia,

4 Epidemiology q The disorder is mostly prevalent in the Eastern Mediterranean, South Asia, and Middle East countries q 1 in 100 000 and 1 in 10 000 worldwide and in the European Union countries respectively q 4% to 5% of Iranians are the carriers of b-thalassemia.

Types of thalassemia 5 Genetically α thalassemia Major β thalassemia Intermedia Phenotypic ẟβ thalassemia

Types of thalassemia 5 Genetically α thalassemia Major β thalassemia Intermedia Phenotypic ẟβ thalassemia Minor ϒẟβ thalassemia Minima

Thalassemia major 6 q Autosomal recessive inherited q Defect in the synthesis of beta

Thalassemia major 6 q Autosomal recessive inherited q Defect in the synthesis of beta chain q Beta thalassemia homozygous state q lack, or reduced production of beta chain q α to β ratio imbalance chain Decreased hemoglobin production Insoluble α 4 tetramer q Blood transfusions among two or a month Erythropoesis ineffective Severe anemia

Clinical signs 7 q paleness q Jaundice q Hepatosplenomegaly Clinical symptoms appear between 6

Clinical signs 7 q paleness q Jaundice q Hepatosplenomegaly Clinical symptoms appear between 6 to 24 months q Enlargement of bone spaces q Different body organ failure due to iron overload q Infection due to regular blood transfusions and increased pathogenicity of organisms in conditions of iron overload

Laboratory Diagnosis 8 q Microcytic and hypochrom cells q Reduce blood parameters such as

Laboratory Diagnosis 8 q Microcytic and hypochrom cells q Reduce blood parameters such as MCV, Hb, HCT q Increase Retic q Anisoctosis q Electrophoresis reduced Hb. A levels and increased Hb. F levels after 12 months

9 Treatment and management of diseases Blood transfusion Administration of iron chelators such as

9 Treatment and management of diseases Blood transfusion Administration of iron chelators such as ü Maintenance Treatment Deferoxamine Splenectomy Treatment of Complications ü certain cure bone marrow transplantation

10 Effects of repeated blood transfusions main cause of death Infection immune system abnormalities

10 Effects of repeated blood transfusions main cause of death Infection immune system abnormalities q A wide range of immune abnormalities are associated with bthalassemia in patients with a history ofroles multiple Chemokines play key in transfusions pathogenesis of inflammatory disorders of the immune system q causing iron overload q Risk of transmission of viruses with immuneosuppressive properties, such as HBV, HCV, HIV, EBV

chemokines 11 q Chemokines and their receptors are able to control the migration and

chemokines 11 q Chemokines and their receptors are able to control the migration and residence of all immune cells q Some chemokines are considered pro-inflammatory q others are considered homeostatic q They are functionally active in several important biological activities, which vary from recruitment of immune and hematological cells to the injured and infected tissues, stem cell homing, and mobilization to making balance between angiogenesis and angiostasis q chemokines were involved in cellular proliferation and acted as nuclear factors

chemokines 12 Classification ü α chemokines: CXCL ü ẟ chemokines: CX 3 CR ü

chemokines 12 Classification ü α chemokines: CXCL ü ẟ chemokines: CX 3 CR ü β chemokines: CCL ü ϒ chemokines: XCR

13 q elevated serum levels of TNF-a and IFN-a are well evidenced in thalassemia

13 q elevated serum levels of TNF-a and IFN-a are well evidenced in thalassemia q sufficient information regarding the role of chemokines is not available in pathogenesis of thalassemia q Therefore, we hypothesized that a relationship between serum chemokines and inflammatory responses in thalassemia patients may be established because of the presence of active inflammation in these patients.

chemokines 14

chemokines 14

methods 15 q 63 b-thalassemia major patients and 80 controls q. Peripheral blood specimens

methods 15 q 63 b-thalassemia major patients and 80 controls q. Peripheral blood specimens were collected q. The circulating levels of CXCL 1, CXCL 9, CXCL 10, and CXCL 12 were detected by enzyme-linked immunosorbent assay (R&D systems, UK) in thalassemia patients and healthy controls immediately after blood collection

Result 16 Circulating levels of CXCL 10 in b-thalassemia major patients and controls. Significant

Result 16 Circulating levels of CXCL 10 in b-thalassemia major patients and controls. Significant difference with control (P<. 05). Circulating levels of CXCL 1 b-thalassemia major patients and control. Significant difference with control (P<. 03).

Result 17 Circulating levels of CXCL 9 in β-thalassemia major patients and control. Significant

Result 17 Circulating levels of CXCL 9 in β-thalassemia major patients and control. Significant difference with (P<. 05). Circulating levels of CXCL 12 in β-thalassemia major patients and control. Significant difference with control (P=. 05).

Result 18 Demonstrates the chemokines serum levels in accordance to the transfusion intervals and

Result 18 Demonstrates the chemokines serum levels in accordance to the transfusion intervals and post-transfusion infections. HBV: Hepatitis B virus, HCV: Hepatitis C virus

Discussion 19 q The study showed elevated serum concentrations of CXCL 1, CXCL 9,

Discussion 19 q The study showed elevated serum concentrations of CXCL 1, CXCL 9, CXCL 10, and CXCL 12 in thalassemia patients than in age- and gendermatched controls. q This supports previous reports showing elevated serum levels of TNF-a, IL-1 a, and IFN-a in thalassemia patients. q A correlation was also reported between the severity of clinical symptoms and the cytokines level in b-thalassemia patients q Some of the previous studies showed that reactive T-cells are an enriched source of CXC chemokines and some studies revealed an increased number of these cells in b-thalassemia patients

Discussion 20 q thalassemia patients were previously transfused with packed red blood cells q

Discussion 20 q thalassemia patients were previously transfused with packed red blood cells q which sometimes is contaminated with other biological and cellular fractions including, leukocytes, plasma protein deposits, fragmented cells, and several other unknown materials q These are all antigenic and are able to stimulate the cellular immune system, which may lead to an elevated chemokine expression by tissue and cellular sources

Discussion 21 q This study established a relationship between the transfusion intervals and the

Discussion 21 q This study established a relationship between the transfusion intervals and the level of chemokines, revealing that chemokines increased if the patients had received more transfusions q This probably could be because of sensitization and further chemokine production by immune cells, bone marrow, and reticuloendothelial system because these cells are known as the most important sources of cytokines such as TNF-a, IFN-a, and chemokines. q The increased concentrations of these chemokines in thalassemia patients may also be attributed to the regulatory role played by TNF-a in up-regulation of chemokine.

Discussion 22 q Again, Salasa and co-workers showed that peripheral blood mononuclear cells from

Discussion 22 q Again, Salasa and co-workers showed that peripheral blood mononuclear cells from thalassemia patients secrete more IFN-a than the control group following stimulation q probably up-regulates the IFN-a–inducible chemokines in these patients.

23 Thanks for your attention

23 Thanks for your attention

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