blood and immune disorders - uniba.sk · immature lymphocytes and their progenitors from bm but...
TRANSCRIPT
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Blood and immune disorders
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Contents
• Intro
• Anemia
• Inflammation
• Immunodeficiency/Hypersensitivity/Autoimmunity
• Lymphoma
• Leukemia
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Blood
• Independent tissue?
• 4-6 li
• Plasma vs. Serum
• Formed blood elements, not cells!
Erytrocytes
Leukocytes
Thrombocytes
• Ph 7.35-7.45
K3EDTALi Heparin
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Functions of Blood
• Transport
Gases O2 and CO2
Nutrients and waste
Hormones
• Termoregulation
• Immune response
• Prevention of water and nutrients lost – hemostasis
• Buffer pH
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Formed elements of the blood
• Most abundant
• 120 days
• hemoglobin
Erythrocytes Leukocytes Thrombocytes
Granulocytes Agranulocytes
55-56%
enzymes
phagocytosis
0.3-0.5%
histamin
• 1% blood volume
• Hours to days
1-3%
Enzymes
allergies,
parasites
20-30%
B-cells
T-cells
• Hours to years
3-8%
Phagocytes
APC
• 1-3 days/years
• 8-9 days
hemostasis
mediators
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Hematopoiesis
• Bone marrow
• Erythropoietin!
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Hemostasis
• Vascular spasmus
• Agregation of thrombocytes
• Coagulation
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Erythropoiesis
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Hemoglobin
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Anemia
• ↓ number of circulating red blood cells (RBC) or level of hemoglobin, or both.• loss or destruction or deficient production of RBC
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Anemic syndrome
• Pallor• Fatigue• Dyspnoe
• Tachykardia and palpitations• Headache, faintness, dim vision
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Cell volume:microcyticnormocyticmacrocytic
Anemia
• ↓ number of circulating red blood cells (RBC) or level of hemoglobin, or both.• loss or destruction or deficient production of RBC
Cause:Blood loss anemiaHemolytic anemias (↑ RBC destruction,Sickle cell, thalassemias)Anemias of deficient RBC production(iron deficiency, megaloblastic & aplastic)
Hb concentration/ERY count:hypochromicnormochromichyperchromic
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Blood loss anemia
• Blood loss o acute (hypovolemia, shock; if controlled, hypoxia → erythropoietin, 3-4wks)
(normocytic, normochromic)o chronic (= blood volume, compensatory mechanisms
iron deficiency anemia when Fe stores depleted) (microcytic, hypochromic)
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Hemolytic anemias• Premature destruction of RBC• Retention of iron & products of haemoglobin destruction• ↑ erythropoiesis• ↑ reticulocytes in the circulation• Mild jaundice
• Hemolysis:o Intravascular (transfusion, mechanic injury, toxins)o Extravascular (spleen phagocytosis of abnormal RBS)
• Types:o inherited (sickle cell anemia, thalassemias)o acquired (drugs, bacterial or other toxins, antibodies, trauma)
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Hemolytic anemias
• InheritedHereditary spherocytosis
• AD trait• Def. membrane proteins
(ankyrin, spectrin)• X splenectomy
Sickle cell anemia
• AR: Point mutation in β-chain of Hb
• hemoltic anemia & vessel occlusion
• BM transplantation
Thalassemias
• AR: Def. synthesis of α or β• Minor (Tt) vs major (tt)• α (↑ β-chains); β (↑ α-chains)• excess iron stored
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Hemolytic anemias
• Inherited – enzyme defects
G6PD deficiency• X linked• RBC more vulnerable to oxidants →direct oxidation of Hb to methemoglobin &denaturing
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Hemolytic anemias
• Acquired
• External factorso direct membrane destruction – drugs, chemicals, toxins, venoms, infections, prosthetic
heart valves, vasculitis, severe burns
o antibody-mediated lysis – autoantibodies vs alloantibodies
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Anemias from deficient RBC production
• Decreased production of erythrocytes by the bone marrow• Deficiency of nutrients for synthesis of Hb (iron) or DNA (folic acid, cobalamin)
o Iron deficiency anemiao Megaloblastic anemiaso Aplastic anemiao Chronic disease anemia
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Anemias from deficient RBC production
Iron-deficiency anemia
o Dietary deficiencyo Loss of blood (chronic)o Increased demand
o ↓ hemoglobin synthesis
Iron is recycled, but small portion is lost by feces.
microcytic & hypochromic(poikilocytosis, anisocytosis)
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Anemias from deficient RBC production
Cobalamin (B12) deficiency anemia
Megaloblastic anemias
Impaired DNA synthesis
Enlarged red cells
• DNA synthesis
o dietary deficiency (rare)o gasterectomyo Ileal resectiono Inflamm. or neopasms in the ileumo malabsorption
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Folic acid deficiency induced anemia
Anemias from deficient RBC production
Megaloblastic anemias
Impaired DNA synthesis
Enlarged red cells
• DNA synthesis
o similar manifestation as in previouso malnutrition/dietary lack (elderly)o alcoholism o sprueo Drugso neoplasmso pregnancy (deficiency)
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Anemias from deficient RBC production
Aplastic anemia
• primary condition of RBC stem cells that results in a reduction of all three hematopoietic cell lines (RBC, WBC, platelets)
• Etiology – external factors, e.g. radiation, AIDS, 2/3 are idiopatic
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Anemias from deficient RBC production
Anemia of chronic diseases
• often complication of chronic infection, inflammation and cancer• IL-1, IL-6 & TNF ↓ synthesis of EPO• Chronic liver disease• Chronic kidney disease
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Treatment
Causative…
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Animal models
• Phenylhydrazine (WBC destruction)
• Hyperbaric chambers
• nephrectomy
• Epo CRE KO/flox
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Inflammation• acute• chronic
• local• systemic
• Response of body intended to eliminate the initial course ofcell injury (immune reaction to MO, injury, ischemic damage)
• Destroying, diluting or neutralizing the primary course
• Inflammation is intimately intervowen with the repair processes inwhich damaged tissue is replaced by regeneration of parenchymal cells orby filling in the residual defects with fibrous scar tissue
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Acute Inflammation• Early response (few minutes – several days)• Nonspecific
• Signs: Rubor Calor Tumor Dolor Functio laesa
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Acute Inflammation• Vascular stage • Cellular stage
No
rmal
Acu
te in
flam
mat
ion
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Acute Inflammation
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Chronic Inflammation• Self – perpetuating (weeks, months ... years)
• Result of a recurrent or progressive acute inflammatory response or from low-gradesmoldering responses that fail to awake acute response
• Mononuclear cells (macrophages) and lymphocytes
• Proliferation of fibroblasts
• Non-specific• Granulomatous
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Nonspecific chronic Inflammation• Diffuse accumulation of macrophages and lymphocytes• Ongoing chemotaxis • Fibroblast proliferation• Scar formation
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Granulomatous chronic Inflammation• Granuloma – small lesion in which there is a massing of macrophages surroudnedby lymphocytes
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Local manifestation of inflammation
• Edema• Exudate (serous, hemorrhagic, fibrinous, purulent) • Abscess• Ulcer
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Systemic manifestation of inflammation• inflammatory mediators are released to circulation
• Acute phase response hours or days after inflammation
IL-1, IL-6, TNF-α
[c] plasma proteins, ↑ ERY sedimentation rate, fever, ↑ leukocytes, skeletal muscle catabolism, negative nitrogen balance
Acute phase proteinsCRP, fibrinogen
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• SIRS (systemic inflammatory response syndrome)• Sepsis (bacteria)• Multiple organ dysfunction
SIRS:
•Temperature > 38 C or < 36 C
• WBC count > 12 000 or < 4 000
• Respiratory rate > 20 bpm or Pa CO2 < 32 mmHg
• Heart rate > 90 bpm
Systemic manifestation of inflammation
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Tissue repair• Tissue regeneration (replacement by the same cells)
• Raplacement by connective tissue (scar/fibrosis)
• Proliferation, regenration & ECM production
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Animal models• Plethora..• LPS, bacteria, fungi, viruses, chemicalls
• Locally – e.g. periodontitis• Systemically – sepsis (LPS, bacteria)
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Alterations in the immune response
• Immunodeficiency disease• Hypersensitivity disorders• Autoimmune diseases
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Immunodeficiency diseases• Abnormality in one or more branches of the immune system that renders a
person susceptible to diseases normally prevented an intact immune system
• Types Cellular Humoral
Primary Acquired
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Primary immunodeficiences• Genetic diseases
Antibody-mediated (X-linked agamaglobulinemia)
T-cell mediated (Di George syndrome)
Combined (SCID)
Complement (Hereditary angioedema)
Fagocytic (chronic granulomatosis)
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Secondary immunodeficiences• Infections
• Malnutrition
• Immunosuppressive therapy
• Neoplasms
• Aging
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Animal models
• Athymic nude mouse / Nu ( T-cell deficient)
• Nude Rat
• SCID mice
Nu/J
Nude rat
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Hypersensitivity disorders = abnormal reaction to antigens
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Type I (Anaphylactic)
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Type II – Ab mediated reaction
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Type III - Immunocomplexes
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Type IV – T cell mediated reaction
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Type V – stimulation
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Autoimmune diseases ?Impaired ability of the immunesystem to differentiate between selfand nonself antigens.
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Autoimmune diseases
• Myastenia gravis (Typ II)
Antibodies against acetylcholine receptor
(nervous-muscular plate)
Muscular fatigue – attenuated breathing
• Systemic lupus erythematosus (Typ III)
Antibodies against DNA, RBC etc.
Deposition of immune complexes (joints, kidneys)
Redness of face, arthritis, nephritis
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• Rheumatoid arthritis (Typ III) Rheumatoid factor – IgM against IgG Depositions of immune complexes in joints
• Diabetes mellitus I (Typ IV) Cytotoxic T lymphocytes destroy pancreatic β-cells Molecular mimicry
• Morbus Basedow (Typ V) Autoantibodies against TSH receptors Stimulation of receptors
Autoimmune diseases
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Malignant lymphomas
• Solid tumors derived from neoplastic lymphoid tissue cells (i.e. lymphocytes or histiocytes) and their precursors or derivatives.
• Hodkin’s disease
• Non-Hodkin’s lymphoma
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Hodkin’s lymphoma
• Specialized form which features the presence of abnormal cell – Reed-Sternberg cell
• Painless and progressive enlargement of 1 lymph node → spread
• Etiology: unknown
• Radiation or radiation & chemotherapy
Reed-Sternberg cell
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Non-Hodkin’s disease
• Heterogenous group of solid tumors composed of neoplastic lymphid cells
• Malignant transformation at any time of B or T cell differentiation
• Etiology: unknown
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Leukemias• Malignant neoplasms of cells
originally derived from hematopoietic
cells
• Diffuse replacement of bone marrow
with unregulated, proliferating,
immature neoplastic cells
• Leukemic cells spill out to blood
where they are seen in large numbers
• “leukemia“ “white blood“
• Solid organ infliltration
• Lymphocytic vs myelogenic vs
biphenotypic
• Acute vs chronic
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Leukemias
• Acute lymphoblastic leukemia (ALL)
• Chronic lymphocytic leukemia (CLL)
immature lymphocytes and their progenitors from BM
but infiltrate the spleen, lymph nodes and CNS and others
• Acute myelogenic leukemia (AML)
• Chronic myelogenic leukemia (CML)
pluripotent myeloid stem cells in BM, interfere with the maturarion of all blood cells, incl. granulocytes, ERY, thrombocytes
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Etiology
• Not fully...
• Radiation
• Antitumor drugs
• Genetic predisposition (patients with Down´s sy 10x ↑)
• retroviruses
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Acute leukemias• Proliferation of precursor cells
• Sudden onset
• Acute Lymphocytic leukemia (immature precursors of T & B cels)
• Acute myelogenous leukemia (heterogenous)
ALL
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Acute leukemias - manifestations
• Both ALL & AML have similar clinical features:
fatigue
Pallor
low grade fever, night sweats, weight loss
Repeated infections
Easy bruising
Nosebleeds and other types of hemorrhage
lymphadenoma, splenomegaly, hepatomegaly
Cranial nerve palsies, nausea, vomiting, papilledema, occasional seizures and coma
Leukostasis
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Chronic leukemias• Proliferation of well differentiated myeloid or lymphoid cells
• Chronic lymphocytic leukemia
lymphoproliferative – lymphocytosis, lymphadenopathy & splenomegaly
95% - malignant proliferation of B-cells which are immunologically incompetent -hypogammaglobulinemia
• Chronic myelogenous leukemia
Malignant transformation of pluripotent hematopoietic stem cell
Philadelphia chromosome (95%)
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Chronic leukemias - manifestations
• Chronic lymphocytic leukemia
slow and indolent course
manifestatoins result from progressive infiltration of neoplastic lymphocytes in BM and extramedullary tissues and secondary immunologic defects
Blood count
Fatigue, lymphatic swelling, splenomegaly later
• Chronic myelogenous leukemia
Triphasic course: a) chronic b) short accelerated phase c) terminal blast crisis
A) leukocytosis, fatigue, anemia, weakness
B) splenomegaly and progressive symptoms, incr. Basophil count, low-grade fever, night sweats, bone pain, weight loss, bleeding and bruising may occur
C) evolution to acute leukemia, ↑ myeloid precursors esp. blast cells, splenomegaly, infiltration of lymph nodes
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Animal models
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