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1

Identify the basic morphologic features of neutrophils and explain their production, distribution, and turnover.

Morphology: red cytoplasm and segmented nucleus.Production: Occurs in the marrow. Activated by granulocyte-macrophage colony-stimulating factor (M-CSF), F-CSFDistribution: remains in the marrow for a few days in a storage pool held in reserve to fight infections, is subsequently released into peripheral blood where it may migrate between the post-capillary venules and the laminar blood flow. After 6 hrs, the neutrophil moves into the tissues.Turnover: Once the neutrophil has reached the tissue turnover is 1-2 days.The neutrophil is a major component of the innate immune system migrating quickly to the site of infection where it ingests and kills microbes. It is the prototypic first responder but is also important in stimulating wound healing and tissue repair.

2

Identify the basic morphologic features of monocytes, and macrophages and explain their production, distribution, and turnover.

Morphology: blue/purple stain with u-shaped nucleus.Production: Derived from myeloid/monocyte precursor under stimulation of GM-CSF and M-CSFDistribution: Cells have a short development time in the bone marrow (7 days) then move to the peripheral blood for 3-5 days. Some emigrate to tissues where they develop into tissue based macrophagesTurnover: last for days-months.Major functions of these cells is to a) migrate from blood to sites of infection and provide effector cells to remove microbes, dead and dying inflammatory cells, and debris; b) filter out microbes from blood stream (spleen); c) process and present antigens to the adaptive immune system; and, d) remove apoptotic cells.

3

Identify the basic morphologic features of  eosinophils and explain their production, distribution, and turnover.

Morphology: red cytoplasm and bi-lobed nucleus.Production: produced in the bone marrow under influence of IL-5Distribution: After transversing the peripheral blood, eosinophils move to mucosal surfaces (GI tract, tracheobronchial tree, etc.Turnover: weeksThese cells play a role in allergic reactions, parasitic infections and response to tumors. They can play the role of a phagocyte and be immunostimulatory or immunoinhibitory.

4

Identify the basic morphologic features of basophils and explain their production, distribution, and turnover.

Morphology: prominent basophilic (blue-purple) primary granulesProduction: in the bone marrowDistribution: ?Turnover: ?These cells have receptors for IgE and appear to play a major role in hypersensitivity (allergic) reactions.

5

Define neutropenia and describe the clinical consequences of neutropenia.

Neutropenia is defined as a decrease in the absolute neutrophil count (bands and segs) below accepted norms. Neutropenia = risk for infection.

6

Diagram the major causes and differentiate the major acquired or congenital/genetic disorders of  decreased production neutropenia.

DECREASED PRODUCTION OF NEUTROPHILSAcquired: Chemotherapy drugs, Viral Infections (EBV, measles, CMV, hepatitis, HIV), Nutritional Deficiencies: Folate, B12, copper or protein/calorieCongenital/Genetic: Kostman Syndrome: autosomal dominant or recessive, severe peripheral neutropenia + marked decrease in myeloid production - leads to high risk for infection and eath before age 2 unless agressive treatment, Schwachman-Diamond Syndrome: neutropenia, pancreatic insufficiency (fat malabsorption, bony abnormalities, and growth delay) ½ develop aplastic anemaiaCyclic neutropenia: severe neutropenia (5-7 days) with periodicity (15-25 day cycles)

7

Diagram the major causes and differentiate the major disorders of increased turnover neutropenia.

Chronic benign neutropenia of childhoodAutoimmune neutropeniaAlloimmune neutropeniaSplenomegaly and hypersplenism

8

Discuss major treatment strategies including growth factors for treating neutropenia.

Broad spectrum antibiotics then specific antibiotics if infected site and involved organisms can be identified. Give Granulocyte Colony Stimulating Factor (G-CSF) to normalize production of neutrophils. Some antibody mediated syndromes may respond to intravenous gamma-globulin (IVIG)

9

Define leukocytosis and provide reasons for a high white blood cell count. Describe the term “left shift” and what it indicates.

Leukocytosis is an increase in total number of WBCs beyond normal values. Think of infection, inflammation, non-specific physiologic stress, or malignancy (leukemia). Left shift is a term referring to changes in the white cell differential with an increase in segs and bands and possibly some immature myeloid precursors usually only found in marrow (metamyelocytes or myelocytes).

10

Define eosinophilia and point out major causes.

Eosinophilia is a condition in which the eosinophil count in the peripheral blood exceeds (450/μl).Etiologies fall into a few categories: allergies/allergic disorders (asthma, atopic dermatitis, hay fever, hives, etc.), parasitic infections, and drug reactions (allergic). Rarer causes include pemphigus, tumors or malignancies, and other infections like chronic active hepatitis. Hypereosinophilic syndromes and eosinophilic leukemia are rare.

11

Define basophilia and point out major causes.

Increase in peripheral basophils is seen primarily in drug or food hypersensitivity or urticaria. It may also be seen in infection or inflammation (rheumatoid arthritis, ulcerative colitis, influenza, chickenpox, smallpox, tuberculosis) as well as myeloproliferative diseases (CML, myeloid metaplasia).

12

Define monocytosis and point out major causes.

Increased monocytes.Monocytosis may be found in hematologic (pre) malignancies (AML, pre-leukemia states, lymphoma, Hodgkin’s disease), collagen vascular disease (SLE, RA), granulomatous disease (sarcoid, ulcerative colitis, Crohn’s disease), infection (subacute bacterial endocarditis, syphilis, tuberculosis, protozoal rickettsial, and Pertussis infections), and carcinoma.

13

Describe the normal functions of neutrophils.

In brief, the primary functions of neutrophils include adherence, chemotaxis, ingestion, and degranulation/microbicidal activity.Neutrophils move in the laminar flow of the blood but are initially pulled to areas of infection by interacting with endothelial cells in a rolling motion.This is followed by a process of adhesion mediated by a separate set of adhesion proteins. They then pass through endothelial cell junctions (diapedesis), and move towards the offending organisms (chemotaxis), following the trail of chemoattractants (such as C5a, cytokines and chemokines)up the concentration gradients to engage the microbial invader.At the site of infection, the microbe, opsonized with C3b or antibody, is enveloped by pseudopods which, like arms, embrace the organism. With fusion of the pseudopods, a phagosome is formed encasing the ingested particle in a small volume. Granules of each class fuse with the growing phagolysosome and the oxidase enzyme system is assembled in the membrane initiating the respiratory burst and generating reactive oxygen species. Together, the reactive oxygen species (ROS) and oxygen independent mechanisms are focused on the phagolysosome and lead to the death and dissolution of the microbe.

14

How is neutrophil function affected by leukocyte adhesion deficiency I (LAD I)?

Causes complete or partial deficiency of CD18. Which leads to Neutrophilia. Decreased adherence to endothelial surface leading to a defect in movement of neutrophils to infected tissue sites.The results: Recurrent soft tissue infections (skin, mucous membranes), gingivitis, mucositis, peridontitis, cellulitis, abscesses.Also delayed separation of umbilical cord/omphalitis. Poor wound healing.

15

How is neutrophil function affected by leukocyte adhesion deficiency II (LAD II)?

The problem: Abnormal transferase resulting in abnormal fucosylation of adhesion molecules (Sialyl LeX) and poor interaction with selectins.The result: Neutrophilia. Decreased rolling on endothelial surfaces as a prelude to tight adherence.Which causes: Recurrent infections, mental retardation. Short stature, craniofacial abnormalities.

16

How is neutrophil function affected by actin dysfunction?

The problem: ↓ actin assembly.The result: ↓ chemotaxis, ↓ ingestion.Which causes: Recurrent severe infections (skin, sepsis). Poor wound healing.

17

How is neutrophil function affected by Specific Granule Deficiency?

The problem: Defect in a transcription factor (CEEPE) results in ↓ production of specific granule proteins.The result: decreased chemotaxis and microbicidal activityWhich causes: Recurrent skin and deep tissue infections

18

How is neutrophil function affected by Myeloperoxidase deficiency? 

The problem: Post-translational modification defect in processing protein.The Result: Partial or complete deficiency of myeloperoxidase. Mild defect in killing bacteria, significant defect in killing candida.Which causes: Generally healthy. Increase fungal infections when associated with diabetes.

19

How is neutrophil function affected by Chediak-Higashi syndrome?

The problem: Alterations in membrane fusion with formation of giant, leaky granules. Other metabolic abnormalities in microtubule assembly.The result: Neutropenia. Giant granules in all leukocytes. Abnormal degranulation. Major defect in movement, also decreased degranulation and microbicidal activity.Which causes: Oculocutaneous albanism, nystagmus photophobia. Recurrent infections of skin, mucous membranes and respiratory tract by bacteria. Lymphoproliferative phase associated with fever, hepatosplenomegaly and hemophagocytic disorder. Neurodegenerative syndrome.

20

How is neutrophil function affected by Chronic Ganulomatous disease (CGD)?

The problem: Defects in one of 4 oxidase components.The result: Neutrophilia. Normal adherence, chemotaxis, ingestion and degranulation. Defect in oxidase enzyme system. No toxic oxygen metabolites produced.Recurrent purulent infections with catalase positive bacteria and fungi involving skin and mucous membranes. Deep infections of lung, liver, spleen, lymph nodes and bones.

21

Describe the NADPH oxidase enzyme system, techniques used to determine its activity, and the consequences of a defect in one of its components.

The oxidase enzyme system is composed of 6 or more proteins which are distributed in the plasma membrane or specific granule membrane or in the cytosol. With a phagocytic stimulus, assembly of the cytosolic components with the membrane components assembles the system and results in activity with addition of an electron to oxygen to form superoxide anion from which H2O2 and the other reactive oxygen species (ROS) can rapidly be formed.Defect evidenced by failure to reduce nitro blue tetrazolium (NBT) dye, oxidize dihydrorhodamine, or produce O2-.Defect impairs bactericidal activity.

22

Characterize the types of infections you might expect to see with defects of phagocyte function.

High rate of bacterial and fungal infections.Infections with atypical or unusual microorganisms (e.g., Aspergillus, disseminated candida, lymphadenitis due to Serratia and other gram negative organisms, infections with Cepacia Burkholderi.Catalase positive organisms in patients with CGD.Infections of exceptional severity.Peridontal disease in childhood.Recurrent infections in areas of the body which interface with the microbial world.

23

Characterize the types of infections you might expect to see with defects of complement.

Bacterial infections which might be seen with antibody deficiency (e.g., pyogenic organisms, H. influenzae, S. pneumoniae).Terminal complement deficiencies (C5-C9) have problems with Neisseria organisms.

24

Discuss tests which would characterize a phagocyte problem. Differentiate between screening or confirmatory tests.

Screening:CBC and white cell differential/morphologyBacteriocidal assayChemotaxis assayNBT for CGD (NADPH deficiency)Confirmatory:Adherence tests, production of superoxide, essentially watching the neutrophil's entire process to see if something is out of whack. More expensive/complicated if screening test is positive. 

25

Discuss tests which would characterize a complement problem. Differentiate between screening or confirmatory tests.

Screening:Measurement of C3 levelsCH50 (test of lysing activity of complement)Confirmatory:Measurement of all complement componentsEvaluation of alternative vs. classical (vs. lectin) pathway activity.  

26

Discuss management strategies for patients with innate immune disorders.

 Anticipation of infection and aggressive attempts to define the causative agent.Surgical procedures for infected sites may be both diagnostic and therapeutic.Prompt initiation of broad spectrum antibiotics covering a wide range of organisms, switching to specific coverage when microbial diagnosis is known.For severe quantitative disorders of neutrophils, G-CSF may be used at a dose of 3 μg/kg/day to resolve the neutropenia.Specific syndromes of neutrophil dysfunction may benefit from prophylactic antibiotics or cytokine therapy (e.g., INFγ for CGD).Transplantation with hematopoietic stem cells has the capability to reconstitute neutrophil numbers and/or function.Gene therapy: proof of concept studies has demonstrated reconstitution. Specific problems need to be resolved before a practical solution is achieved.