Ch80: Disorders of Granulocytes and Monocytes Flashcards
for 63: Leukocytosis and Leukopenia
Major cells comprising the inflammatory and immune responses, including neutrophils, T and B lymphocytes, natural killer (NK) cells, monocytes, eosinophils, and basophils
Leukocytes
Normal blood leukocyte counts and their components
Normal blood leukocyte ct: 4.3-10.8 x 10^9/L
Neutrophils: 45-74% Bands: 0-4% Lymphocytes: 16-45% Monocytes: 4-10% Eosinophils: 0-7% Basophils: 0-2%
Regulates the leukocyte maturation
- Colony stimulating factors (CSFs)
2. Interleukins (ILs)
Presence of immature cells is termed as?
Shift to the left
Stage of neutrophil development where classic lysosomal granules, called primary, or azurophil, granules are produced
Promyelocyte
The first recognizable precursor cell in the stage of neutrophil development
Myeloblast
Primary granules in promyelocyte are active against which type of pathogens?
Gram negative bacteria, fungi, enveloped viruses
Family of cysteine-rich polypeptides with broad antimicrobial activity against bacteria, fungi, and enveloped viruses which are contained on Azurophil granules
Defensins
Stages of neutrophil development (increasing maturity)
- Myeloblast (prominent nucleoli)
- Promyelocyte (primary granules appear)
- Myelocyte (secondary granules appear)
- Metamyelocyte (kidney bean-shaped nucleus)
- Band form (condensed, band-shaped nucleus/sausage-shaped nucleus)
- Neutrophil (condensed, multilobed nucleus)
Fig 80-2, p. 414
Cell responsible for the synthesis of the specific, or secondary granules that do not function as lysosomes (unlike primary granules), but instead is important in modulating inflammation
Myelocyte
Nucleus of neutrophils normally contain up to 4 segments. MORE THAN 5 lobes suggests what?
- Folate or Vitamin B12 deficiency
2. Congenital neutrophenia syndrome of warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM)
Infrequent dominant benign inherited trait, resulting in neutrophils with distinctive BILOBED NUCLEI
Pelger-Huet anomaly
Nucleus has spectacle-like, or “pince-nez” configuration
Fig 80-5, p. 415
Immature or abnormally staining azurophil granules produced in severe acute bacterial infection; prominent neutrophil cytoplasmic granules
Toxic granulations
Cytoplasmic inclusions seen during infection and are fragments of ribosome-rich endoplasmic reticulum
Dohle bodies
Where is the large reserve of neutrophils located?
Bone marrow (90%)
Circulation: 2-3%, others: tissues
Glycoproteins expressed on neutrophils and endothelial cells that cause a low-affinity interaction resulting in “rolling” of the neutrophil along the endothelial surface
Selectins
Leukocyte glycoproteins that enables the neutrophils to “stick” to the endothelium
Integrins
Process of neutrophil migration or crawling of neutrophils between postcapillary endothelial cells into tissues
Diapedesis
Diapedesis involves what type of molecule?
platelet/endothelial cell adhesion molecule (PECAM) 1 (CD 31)
Examples of anaphylatoxins
- C3a
2. C5a
Examples of vasodilators
- Histamine
- Bradykinin
- Serotonin
- Nitric oxide
- Vascular endothelial growth factor (VEGF)
- Prostaglandin E and I
Half-life of neutrophil in circulation
6-7 hours
Where do senescent neutrophils cleared from circulation by macrophages?
Lung
Spleen
Duration at which neutrophils die in the tissues
1-4 days
Factors that prolong the lifespan of neutrophils
Granulocyte colony-stimulating factor (G-CSF)
IFN-y
In delayed type hypersensitivity, how long does monocyte accumulation occur
Within 6-12 hours of initiation of inflammation
Confers the characteristic green color to pus and may participate in turning off the inflammatory process by inactivating chemoattractants and immobilizing phagocytic cells
Myeloperoxidase
In the presence of fibrinogen, what induces IL-8 production by neutrophils providing autocrine amplification of inflammation
f-met-leu-phe OR Leukotriene B4
Four major groups of chemokines recognized based on cysteine structure near N terminus
- C (lymphotactin)
- CC (MIP-1)
- CXC (IL-8)
- CXXXC (Fractalkine)
What neutrophil count increases the susceptibility to infectious diseases?
Below 1000 cells/uL
Level of ANC where control of endogenous microbial flora is impaired
ANC <500/uL
ANC level at which the local inflammatory process is absent
ANC <200/uL
Causes of neutropenia
- Depressed production
- Increased peripheral destruction
- Excessive peripheral pooling
Cancer chemotherapy can produce what type of neutrophil disorder?
Acute neutropenia
With increased risk of infection vs chronic neutropenia
Most common cause of neutropenia
Iatrogenic
Due to cytotoxic or immunosuppresive therapies for malignancy or control of autoimmune disorders
Decrease production of rapidly growing progenitor (stem) cells of the marrow
Drugs that can cause NEUTROPENIA by inhibiting myeloid precursors
- Chloramphenicol
- Co-trimoxazole
- Flucytosine
- Vidarabine
- Zidovudine
Drugs can induce immune-mediated peripheral destruction of neutrophil precursors which can be seen within 7 days of exposure to drug. Most frequent causes are:
- Sulfa-containing compounds
- Penicillins
- Cephalosporins
Treatment for drug-induced neutropenia
Discontinuation of offending drug
Recovery within 5-7 days and complete by 10 days
Autoimmune neutropenia caused by circulating antineutrophil antibodies are caused by this condition::
Viral infections including HIV
Management for autoimmune neutropenia
- Glucocorticoids
- Cyclosporine
- Methotrexate
Congenital form of neutropenia
- Kostmann’s syndrome (neutrophil ct <100/uL)
GENE: antiapoptosis gene HAX-1 - Severe chronic neutropenia (300-1500/uL)
MUTATION: neutrophil elastase (ELANE) - Cyclic hematopoiesis
- Shwachman-Diamond syndrome
Pancreatic insuffiency due to mutations in the gene Shwachman-Bodian-Diamond syndrome gene
Shwachman-Diamond syndrome
Syndrome characterized by neutrophil hypersegmentation and bone marrow myeloid arrest due to mutations in the chemokine receptor CXCR4
WHIM
Warts, hypogammaglobulinemia, infections, myelokathexis (retention of wbc in marrow)
Drug when ingested during pregnancy can cause neutropenia in newborn by either depressed production or peripheral destruction
Thiazides
Triad of rheumatoid arthritis, splenomegaly, and neutropenia
Felty’s syndrome
Mechanisms of neutrophilia
- Increased production
- Increased marrow release
- Defective margination
Most important acute cause of neutrophilia
Infection
Increased production + Increased marrow release
Term for persistent neutrophilia (>30,000-50,000/uL) seen in leukemia where circulating neutrophils are usually mature and not clonally derived
Leukemoid reaction
Causes of neutrophilia
- Infection
- Chronic inflammation
- Myeloproliferative diseases
- Glucocorticoids
- Exercise, excitement, stress
- Cigarette smoking
Table 80-2, p. 418
Types of Leukocyte Adhesion Deficiency (LAD) and their clinical manifestations
Type 1 : Delayed separation of umbilical cord, sustained neutrophilia, recurrent infections of skin and mucosa, gingivitis, periodontal disease (MC bacteria: Staph aureus, enteric gram(-) bacteria)
Type 2 : Mental retardation, short stature, Bombay (hh) blood phenotype, recurrent infections, neutrophilia
Type 3: Petechial hemorrhage, recurrent infections
Table 80-4, p. 420
Also known as congenital disorder of glycosylation IIc (CDGIIc) due to mutation in a GDP-fucose transporter (SLC35C1)
Leukocyte Adhesion Deficiency 2 (LAD 2)
Most common neutrophil defect; primary granule defect inherited as autosomal recessive trate
Myeloperoxidase deficiency
A rare disease with autosomal recessive inheritance due to defects in the lysosomal transport protein LYST (gene CHS1 at lq42)
Chediak-Higashi syndrome (CHS)
Genetics: Autosomal Recessive
Clinical: Recurrent pyogenic infections esp with S. aureus
Defect: Reduced chemotaxis and phagolysosome fusion, CHS1 gene
Diagnosis: Giant primary granules in neutrophils (Wright’s stain); genetic detection
Group of disorders of granulocyte and monocyte oxidative metabolism and an important model of defective neutrophil oxidative metabolism
Chronic granulomatous disease (CGD)
Genetics: X-linked recessive trait (70%)
Clinical: Severe infection of skin, ears, lungs, liver and bone with catalase-positive microorganisms (S. aureus, B. cepacia, Aspergillus)
Defect: No respiratory burst due to lack of one of 5 NADPH oxidase subunits in neutrophils, monocytes, eosinophils
Diagnosis: Dihydrorhodamine (oxidation test) OR nitroblue tetrazolium (dye test); genetic detection
T or F: Macrophages are not only phagocytic, but secretory cells that produce cytokines (TNF-a, IL1, IL8, IL12, IL18)
True
Cytokine that initiates fever in hypothalamus, mobilize leukocytes from bone marrow and activates lymphocytes and neutrophils
IL-1
Pyrogen important in pathogenesis of gram-negative shock and induces catabolic changes contributing to profound wasting (cachexia) in chronic diseases
TNF-alpha
Some conditions associated with MONOCYTOSIS
- Tuberculosis
- Brucellosis
- Subacute bacterial endocarditis
- Rocky Mountain spotted fever
- Malaria
- Visceral leishmaniasis (kala azar)
Mutation in TNF-a receptor characterized by recurrent fever in the absence of infection, due to persistent stimulation of TNF-a receptor
TNF-a receptor-associated periodic syndrome (TRAPS)
Syndrome of Pyoderma gangrenosum, Acne, and sterile Pyogenic Arthritis caused by mutation in PSTPIP1
PAPA syndrome
Conditions associated with MONOCYTOPENIA
- Acute infections
- Stress
- After treatment with glucocorticoids
- Due to myelotoxic drugs
Diseases
- Aplastic anemia
- Hairy cell leukemia
- AML
Definition of EOSINOPHILIA
Presence of >500 eosinophils per uL of blood common in many settings besides parasite infection
Common cause of EOSINOPHILIA
Allergic reaction to drugs
Iodides, ASA, sulfas, nitrofurantoin, penicillins, cephalosporins
Other causes of eosinophilia
- Allergies
- Collagen vascular diseases (RA, periarteritis nodosa)
- Malignancy (Hodgkin’s disease, mycosis fungoides, CML, CA of lung, stomach, pancreas, overy, uterus)
- Helminthic infections
Dominant eosinophil growth factor inhibited by monoclonal antibody Mepolizumab
IL-5
Most dramatic hypereosinophilic syndromes
Loeffler's syndrome Tropical pulmonary eosinophilia Loeffler's endocarditis Eosinophilic leukemia Idiopathic hypereosinophilic syndrome (50,000-100,000/uL)
T or F: Effect of eosinophilia on the heart can produce restrictive endomyocardiopathy
True
Others: thrombosis, endocardial fibrosis
Multisystem disease with prominent cutaneous, hematologic, and visceral manifestations characterized by eosinophilia (>1000/uL) and generalized disabling myalgia without other recognized cause
Eosinophilia-myalgia syndrome
Cause: ingestion of contaminants in L-tryptophan-containing products
Treatment: Withdrawal of products and administration of glucocorticoids
Causes of EOSINOPENIA
- Stress (acute bacterial infection)
2. After treatment with glucocorticoids
Rare multisystem disease in which the immune and somatic systems are affected, including neutrophils, monocytes, Tcells, Bcells, and osteoclasts
Hyperimmunoglobulin E-recurrent infection syndrome (JOB’S SYNDROME)
Clinical: Characteristic facies of broad nose, kyphoscoliosis, eczema; cold abscessess; primary teeth that do not deciduate
Defect: reduced chemotaxis, memory T and B cells, STAT3 mutation, DOCK8 deficiency
Diagnostic: somatic and immune features, serum IgE>2000 IU/ml; genetic testing
Management of patients with chronic or cyclic neutrophil counts <500/uL
May benefit from
- Prophylactic antibiotics (e.g. Co-tri 160/800mg BID, levofloxacin, ciprofloxacin)
- G-CSF
Management of severe, persistent lymphocyte dysfunction due to cytotoxic chemotherapy
(e.g. mga Chemo patients sa ward)
- Co-trimoxazole : prevents Pneumocystis jiroveci pneumonia
- Avoid heavy exposure to airborne soil, dust, decaying matter (rich in Nocardia and spores of Aspergillus and other fungi)
