Blood and immune disorders - uniba.sk · immature lymphocytes and their progenitors from BM but...

Blood and immune disorders

• Seminárka – deadline: 1.5.2016

• Názov témy: petercelec@gmail.com

Kind reminder

Contents

• Intro

• Anemia

• Inflammation

• Immunodeficiency/Hypersensitivity/Autoimmunity

• Lymphoma

• Leukemia

Blood

• Independent tissue?

• 4-6 li

• Plasma vs. Serum

• Formed blood elements, not cells!

Erytrocytes

Leukocytes

Thrombocytes

• Ph 7.35-7.45

K3EDTALi Heparin

Functions of Blood

• Transport

Gases O2 and CO2

Nutrients and waste

Hormones

• Termoregulation

• Immune response

• Prevention of water and nutrients lost – hemostasis

• Buffer pH

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

Hematopoiesis

• Bone marrow

• Erythropoietin!

Hemostasis

• Vascular spasmus

• Agregation of thrombocytes

• Coagulation

Erythropoiesis

Hemoglobin

Anemia

• ↓ number of circulating red blood cells (RBC) or level of hemoglobin, or both.• loss or destruction or deficient production of RBC

Anemic syndrome

• Pallor• Fatigue• Dyspnoe

• Tachykardia and palpitations• Headache, faintness, dim vision

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

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)

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)

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

Hemolytic anemias

• Inherited – enzyme defects

G6PD deficiency• X linked• RBC more vulnerable to oxidants →direct oxidation of Hb to methemoglobin &denaturing

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

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

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)

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

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)

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

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

Treatment

Causative…

Animal models

• Phenylhydrazine (WBC destruction)

• Hyperbaric chambers

• nephrectomy

• Epo CRE KO/flox

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

Acute Inflammation• Early response (few minutes – several days)• Nonspecific

• Signs: Rubor Calor Tumor Dolor Functio laesa

Acute Inflammation• Vascular stage • Cellular stage

No

rmal

Acu

te in

flam

mat

ion

Acute Inflammation

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

Nonspecific chronic Inflammation• Diffuse accumulation of macrophages and lymphocytes• Ongoing chemotaxis • Fibroblast proliferation• Scar formation

Granulomatous chronic Inflammation• Granuloma – small lesion in which there is a massing of macrophages surroudnedby lymphocytes

Local manifestation of inflammation

• Edema• Exudate (serous, hemorrhagic, fibrinous, purulent) • Abscess• Ulcer

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

• 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

Tissue repair• Tissue regeneration (replacement by the same cells)

• Raplacement by connective tissue (scar/fibrosis)

• Proliferation, regenration & ECM production

Animal models• Plethora..• LPS, bacteria, fungi, viruses, chemicalls

• Locally – e.g. periodontitis• Systemically – sepsis (LPS, bacteria)

Alterations in the immune response

• Immunodeficiency disease• Hypersensitivity disorders• Autoimmune diseases

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

Primary immunodeficiences• Genetic diseases

Antibody-mediated (X-linked agamaglobulinemia)

T-cell mediated (Di George syndrome)

Combined (SCID)

Complement (Hereditary angioedema)

Fagocytic (chronic granulomatosis)

Secondary immunodeficiences• Infections

• Malnutrition

• Immunosuppressive therapy

• Neoplasms

• Aging

Animal models

• Athymic nude mouse / Nu ( T-cell deficient)

• Nude Rat

• SCID mice

Nu/J

Nude rat

Hypersensitivity disorders = abnormal reaction to antigens

Type I (Anaphylactic)

Type II – Ab mediated reaction

Type III - Immunocomplexes

Type IV – T cell mediated reaction

Type V – stimulation

Autoimmune diseases ?Impaired ability of the immunesystem to differentiate between selfand nonself antigens.

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

• 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

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

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

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

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

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

Etiology

• Not fully...

• Radiation

• Antitumor drugs

• Genetic predisposition (patients with Down´s sy 10x ↑)

• retroviruses

Acute leukemias• Proliferation of precursor cells

• Sudden onset

• Acute Lymphocytic leukemia (immature precursors of T & B cels)

• Acute myelogenous leukemia (heterogenous)

ALL

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

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%)

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

Animal models

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