Disorders of granulocyte/monocytes Flashcards
Monocyte/tissue macrophage:
What is their development time in the bone marrow?
How long do they last in the peripheral blood once they move out from the bone marrow?
What are their functions?
Derived from myeloid/monocyte precursor under stimulation of GM - CSF and M - CSF, these cells have a shorter development time in the bone marrow (7 days) since they are relased after last mitotic division and this NO STORAGE is provided in the boen marrow. They move to the peripheral blood for 3-5 days.
Some then emigrate to tissues where they develop into tissue based macrophages lasting for days - months.
Major functions of these cells:
a) Migrate from blood to sites of infection and inflammation 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.
d) Remove apoptotic cells.
Neutrophils
How long it is located in the storage pool of the bone marrow as a reserve to fight infections?
Once it has been in the blood (margination and laminar blood flow-peripheral) it moves to after how many hours?
It is the first responder in an innate immune respone and it is important for _______ and _______ repair.
The polymorphonuclear leukocyte (PMN), neutrophil or granulocyte is produced in the marrow (GM - CSF, G - CSF), remains there for a few days in a storage pool (10-14 days) held in reserve to fight infections.
It is subsequently released into peripheral blood where it may marginate between the post-capillary venules and the laminar blood flow. After 6 hrs, the neutrophil moves into the tissues where it turns over in 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.
Eosinophil
Produced in the bone marrow under the influence of what interleukin?
Nucleus has what shape?
What are its main roles?
Can it function as a phagocyte?
Basophils
They have receptors for what Ig?
What is their function?
Production and kinetics of neutrophils
Neutropenia
Neutropenia refers to decrease in what neutrophil precursors?
What are some differences in the numbers due to ethnic and racial differences?
What other factor may have an effect on neutropenia?
- Definition: Decrease in the absolute neutrophil count (include bands and segmented polymorphonuclear leukocytes) below accepted norms for age and other considerations.
- Age related:
Term newborn (up to 1 week) < 3,000 (highest)
Infant (1 week – 2 years) < 1,100
Child, adolescent, adult < 1,500 (Normal)
Ethnic and racial groups ~ 900
**Altitude (lower ANC above 5,000 ft. in infants).
What is the risk posed to the body by neutropenia?
- Assumption: Neutropenia implies decrease delivery of neutrophils to tissues → tips balance in favor of bugs and inability to localize and resolve bacterial and fungal infections. Possible life-threatening consequences.
- Risk*
ANC/μl
1,000 – 1,500 None
1,000 – 500 Minimal – mild
500 – 250 Moderate to severe (skin, mucous membranes)
<250 Severe (sepsis, pneumonia, etc.)
*assumption of risk true when there is ↓ production
How do you evaluate neutropenia?
How do you classify neutropenia?
What are the two classification of neutropenias?
What does primary refer to?
What does secondary refer to?
I. Marked decrease bone marrow reserve (primary or secondary)
A. Primary disorders (congenital or pathological): Severe Congenital Neutropenia (Kostmann syndrome, Shwachman-Diamond syndrome, Cyclic neutropenia)
B. Part of a complex phenotype, (Glycogenosis Ib, Cartilage-hair hypoplasia)
C. Secondary: **Chemotherapy, **drug induced (non-immune), **nutritional, **viral infection
D. Other: e.g., idiopathic
II. Normal marrow reserve (usually secondary)
A. Immune: Chronic benign neutropenia of childhood, autoimmune, alloimmune, drug induced, infection
B. Non-immune: Infection, hypersplenism, excessive margination
Consider also acute neutropenia (< 3 mos) or chronic (> 3 mos)
Secondary neutropenia:
Infection associated
- Most common cause of neutropenia
- Usually acute, resolves days to months
- Multiple mechanisms (one or more)
- Increased utilization
- Complement mediated margination
- Marrow suppression/failure, direct effect
- Cytokine/chemokine induced margination
- Antibody production
Secondary neutropenia:
Drugs/toxins
Secondary neutropenia:
How do you manage secondary neutropenias?
- Withdraw unnecessary drugs and eliminate toxins
- Treatment of underlying disorder
- Replacement of specific deficiency
- Aggressive management of infections
- Supportive care, may include prophylactic antibiotics
- G-CSF in some conditions (e.g., chemotherapy)
Immune neutropenias
What does this refers to?
How is the neutrophil production and storage in the bone marrow?
Why is there a decrease in neutrophil number?
What are the four caterogies?
Autoimmune
With what disease it is usually associated with?
Bone marrow cellularity is?
How do you treat it?
Mechanism: antibody mediated; ↑ turnover. May be associated with other hematologic antibodies.
Clinical features:
- May also find platelet, red blood cell, other hematologic antibodies.
- Associated with Systemic Lupus Erythematosus (SLE) or other autoimmune disorders, immunodeficiency states (dysgammaglobulinemia, hypogammaglobulinemia, HIV, etc.), Chronic active hepatitis
- Variable ANC, marrow shows normal cellularity, late maturation arrest
Management:
- Treat primary autoimmune disorder and/or hematologic antibodies
- G-CSF may be helpful in case of severe infection or marrow storage pool depletion
Alloimmune Neutropenia
What is the mechanism?
Often confused with neutropenia caused by _____.
What is seen in the bone marrow?
Mechanism: maternal alloimmunization to neutrophil-specific antigens (NA), transplacental passage and binding to neonatal neutrophils.
With passive transfer of antibody from mother’s circulation attacking baby’s cells causing neutropenia, alloimmune neutropenia shares a common pathophysiology with Rh hemolytic disease and alloimmune thrombocytopenia of the newborn. Transplacental passage of neonatal cells which contain antigens not expressed by maternal cells into the maternal circulation sensitizes the mother to produce antibodies against the infant’s antigens. Accumulation of IgG class antibodies by the fetus provides a pool of antibodies which bind the infant’s neutrophils and cause neutropenia.
Clinical features:
- Neutropenia usually for 2-4 weeks, occasionally up to 3-4 mos. Can be profound.
- Affected patients mostly are asymptomatic or may develop skin infections, and rarely pneumonia, sepsis or meningitis
- Confused with neutropenia caused by sepsis
- Marrow shows *myeloid hyperplasia with maturation arrest at mature precursors.
Management:
- Antibiotics and supportive care for infections.
- Consider G-CSF in face of severe infection.
Cyclic neutropenia
What type of inheritance?
What gene mutations cause this?
ANC=absolute neutrophil count
Cyclic neutropenia is characterized by severe peripheral neutropenia for 5 - 7 days with specific periodicity (15 - 25 day cycles).
-Recurrent fevers and mouth ulcers may accompany infections during the time of neutropenia.
At other times in the cycle, the ANC is normal and there is no greater risk for infection.
This condition has also been linked to apoptosis in marrow precursors and mutations in the gene for elastase .
Shwachman-Diamond Syndrome
Apoptosis is associated with what receptor? Which decreases which cells?
Type of inheritance?
What are some clinical features?
How to treat it?
Mechanism/Inheritance/Genetics:
- FAS receptor associated apoptosis of marrow precursors, ↓ CD34+ cells, marrow stromal defect
- Autosomal Recessive inheritance
- Many have defect in SBDS gene, chromosome 7 (7q11)
Clinical features:
- Multisystem disease: neutropenia (90-95%), pancreatic insufficiency, metaphyseal chondrodysplasia, other dysmorphic features.
- 25% develop marrow aplasia, 25% develop MDS/AML
- May have associated neutrophil dysfunction
- Recurrent infections
Management:
- Aggressive antibiotic therapy and supportive care for infection
- Pancreatic enzyme replacement; G-CSF
- BMT for severe complications
Treatment for neutropenias
Eosinophilia
Absolute eosinophil count >350/μl
- Allergic reactions (asthma, hay fever, etc)
- Drugs
- Parasites
- Malignancy
•Gastrointestinal disorders
Monocytosis/ monocytemia
Basophilia
Increase in peripheral bas ophils 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).
What is the function of the neutrophils?
What are the sequence of events that allow neutrophils to go into tissues?
What are some examples of reactive oxygen species?
Apart from ROS what other oxygen independent mechanism aid in destruction of pathogens?
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 more extensive process of firm adhesion mediated by a separate set of adhesion proteins. Passing through the junctions between endothelial cells (diapedesis), the cells move towards the offending organisms (chemotaxis), following the trail of chemoattractants (bacterial products, complement products such as C5a, cytokines and chemokines) up the concentration gradients to engage the microbial invader.
At the site of infection, the microbe, properly 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 (superoxide anion, O 2 - ; hydrogen peroxide, H2O2 ; hypochlorous acid, HClO; and hydroxyl radical, . OH).
Together, the reactive oxygen species (ROS) and oxygen independent mechanisms (defensins, lysozyme, _cathepsins, protease_s) are focused on the phagolysosome and lead to the death and dissolution of the microbe.
Constituents of phagocyte function (not for memorization)
What is the repiratory burst?
Respiratory burst
Enzyme oxidase system assembls where in the neutrophil?
In the plasma membrane
Laboratory testing for innate immunity disorders
What are the 4 activities that can be tested for neutrophil function?
What is an important adhesion molecules tested for?
Chediak-Higashi Syndrome
What is the defect?
What is a characteristic seen in neutrophils in persons with this disease?
Giant granules are seen
Leukocyte Adhesion Deficiency I
What is the clinical presentation?
What is the functional defect?
What is the molecular defect?
What is the inheritance pattern?
Clinical presentation:
-Recurrent soft tissue infections (skin, mucous membranes), gingivitis, mucositis, periodontitis, cellulitis, abscesses.
**Delayed separation of umbilical cord/omphalitis.
-Poor wound healing.
What is the functional:
Neutrophilia.
–>Decreased adherence to endothelial surface leading to a defect in movement of neutrophils to infected tissue sites.
Molecular defect:
Complete or partial deficiency of CD18 resulting in lack of expression of CD11b/CD18.
Autosomal recessive
Chediak Higashi Syndrome (CHS)
What are the functional defects?
Functionl defect:
-Neutropenia
*Giant granules in all leukocytes
- Abnormal degranulation
- Major defect in movement, also decreased degranulation and microbicidal activity (mild).
Myeloperoxidase Deficiency
What is the clinical presentation?
Increase fungal infection are associated with what disease?
What is the functional defect?
Significant defect in killing what?
What type of inheritance?
Clinical Presentation:
*******Generally healthy.
Increase fungal infections when associated with diabetes
Functional defect:
Partial or complete deficiency of myeloperoxidase. Mild defect in killing bacteria, significant defect in killing candida.
Molecular defect:
Post-translational modification defect in processing protein.
Autosomal recessive.
Chronic Granulomatous Disease*
(CGD)
What is the clinical presentation? What type of bacteria are seen?
What is the functional defect?
What is normal?
What is the molecular defect?
Clinical presentation:
Recurrent purulent infections with catalase positive bacteria and fungi involving skin and mucous membranes. Deep infections of lung, liver, spleen, lymph nodes and bones.
Functional Defect:
-Neutrophilia (high number od neutrophils).
-Normal adherence, chemotaxis, ingestion and degranulation.
Defect in oxidase enzyme system. No toxic oxygen metabolites produced. Absent or reduced ability to kill coagulase positive bacteria and fungi (e.g., staph, E-coli).
Molecular Defect:
Defects in one of 4 oxidase components. Absent cytochrome b558 associated with gp91phox (sex-linked recessive), p22phox (autosomal recessive), or absent p47phox (autosomal recessive), p67phox (autosomal recessive). Mild x-linked variant: G-6-PD deficiency in PMNs.
***oxygen Free radicals can also come from bacteria.
Complement system
Complement system:
Management of innate immune diseases:
Transplantation or gene therapy
