Flashcards in lecture 10 Deck (40):
What are the adult reference ranges for blood cells?
- white cells (x10^3/µL) = 4.8-10.8
- granulocytes (%) = 40-70
- neutrophils (x10^3/µL) = 1.4-6.5
- lymphocytes (x10^3/µL) = 1.2-3.4
- monocytes (x10^3/µL) = 0.1-0.6
- eosinophils (x10^3/µL) = 0-0.5
- basophils (x10^3/µL) = 0-0.02
- red cells (x10^3/µL) = 4.3-5, men; 3.5-5.0, women
- platelets (x10^3/µL) = 150-450
How are reference ranges used?
- if someone lies outside the range it can indicate disease
How do blood cells develop?
- from HSCs through well defined paths of differentiation, of which a number of the important transcription factors/chemokines are known
Where is the 'haematopoietic stem cell niche?
- in the bone marrow
- endosteal part of bone
What cell types are found in the niche?
- endothelial cells
- nerve cells: can direct stem cell differentiation
- osteoblasts: may have a role in signalling
- stromal cells
What organs are important for the development and maturation of WBCs?
- bone marrow: where they arise
- lymph nodes
- thymus: almost exclusively T cells
What are some of the major white blood cell types?
- B lymphocyte: antibody secretion after detection of antigen and differentiation into plasma cells
- CD4+ helper T lymphocyte: after presentation of antigen they release cytokines which stimulate activation of macrophages, inflammation and B lymphocytes
- CD8+ cytotoxic T lymphocyte: kill infected body cells
What are all the names for neutrophils?
- polymorphonuclear leukocyte, PMN, PML
- granulocyte, neutrophilic granulocyte
What does a neutrophil generally look like?
- lobular nucleus
What are the functions of a neutrophil?
- transmigration (diapedesis)
- phagocytosis: recognition, engulfment, killing (digestion)
- equilibrium with splenic pool
What is leukopenia?
- the number of circulating white cells may be markedly decreased in a variety of disorders
- an abnormally low white cell count (leukopenia) usually results from reduced numbers of neutrophils
What is neutropenia?
- a reduction in the number of neutrophils in the blood, occurs in a wide variety of circumstances
What is agranulocytosis?
- a clinically significant reduction in neutrophils – susceptibility to bacterial and fungal infections
What are reasons for inadequate production of neutrophils?
- stem cell suppression e.g. aplastic anaemias
- drugs especially chemo, many antibiotics
- inherited defects in specific genes impairing granulocytic differentiation - Kostmann Syndrome
What are reasons for increased destruction of neutrophils?
- immune mediated
– idiopathic, or consequence of immune disorder, e.g. SLE (system lupus erythematosus )
– after "sensitisation" by drugs - antibiotics
- splenic sequestration, spleen-blockage-enlargement - can be fatal in children
- increased peripheral demand, as in overwhelming infections, especially fungal
What is leukocytosis?
Increase in the number of white cells in the blood.
Reaction to a variety of inflammatory states.
What is the pathogenesis of leukocytosis influenced by?
- size of the myeloid and lymphoid precursor and storage cell pools in the bone marrow, thymus, circulation and peripheral tissues
- rate of release of cells from the storage pools into the circulation
- the proportion of cells that are adherent to blood vessel walls at any time (the marginal pool)
- the rate of extravasation of cells from the blood into tissues
What is leukocytosis often accompanied by in sepsis or severe inflammatory disorders?
- morphologic changes in the neutrophils
- e.g. toxic granulations, Döhle bodies, and cytoplasmic vacuoles
What is lymphadenitis?
Acute nonspecific lymphadenitis - usually self limiting
- very sore lymph nodes
- caused by microbial drainage from infections of the teeth or tonsils
- acute lymphadenitis in mesenteric lymph nodes draining acute appendicitis
- systemic viral infections (particularly in children) and bacteremia often produce acute generalised lymphadenopathy
What are lymphoid neoplasms?
- include a diverse group of tumours of B-cell, T-cell, and NK-cell origin
- in many instances the phenotype of the neoplastic cell closely resembles that of a particular stage of normal lymphocyte differentiation, a feature that is used in the diagnosis and classification of these disorders?
What are myeloid neoplasms?
- arise from early haematopoietic progenitors
3 categories of myeloid neoplasia:
- acute myeloid leukaemias (AML), in which immature progenitor cells accumulate in the bone marrow
- myelodysplastic syndromes, which are associated with ineffective haematopoiesis and resultant peripheral blood cytopenias
- chronic myeloproliferative leukemia (CML) - increased production of one or more terminally differentiated myeloid elements (e.g. granulocytes) usually leads to elevated peripheral blood counts
What are the etiologic and pathogenetic factors in white cell neoplasia?
- nonrandom chromosomal abnormalities, most commonly translocations, are present in the majority of white cell neoplasms
- these translocations result in gene fusions generating abnormal oncogenic mRNAs and proteins
- e.g. The philadelphia chromosome t(9;22) is present in approximately 3% of children with ALL and leads to production of a BCR-ABL1 fusion protein with tyrosine kinase activity
Why are white cells so prone to translocation disorders?
- because they're dividing rapidly, increasing the statistical chance that something may happen
- also perhaps genetically predisposed to not being able to check for errors properly
What is the molecular pathogenesis of acute leukaemia?
- acute leukaemia arise from complementary mutations that block differentiation at early stages of white cell development, enhance self-renewal, and increase growth and survival
- e.g. BCR-ABL, breakpoint chromosomal region - Abelson kinase fusion gene; PML-RAR-alpha, promyelocyctic leukaemia-retinoic acid receptor alpha fusion; MLL, mixed-lineage leukaemia gene
- BCR-ABL leads to increased growth of progenitor cells, tyrosine kinase mutation
- PML-RAR-alpha blocks transcription factor mutations that lead to differentiation
MLL: fusion with FPG (abnormal function), or repeat of part of MLL gene producing a duplicate domain
What is the molecular pathogenesis of acute leukaemia?
chronic immune stimulation
- several environmental agents that cause localised chronic immune stimulation predispose to lymphoid neoplasia, which almost always arises within the inflamed tissue
- H. pylori infection and gastric B-cell lymphomas
- Gluten-sensitive enteropathy and intestinal T-cell lymphomas
- radiation therapy and certain forms of chemotherapy used treat cancer increase the risk of subsequent myeloid and lymphoid neoplasms
- stems from the mutagenic effects of ionising radiation and chemotherapeutic drugs on hematolymphoid progenitor cells
- the incidence of AML is increased 1.3- to 2-fold in smokers, due to exposure to carcinogens, such as benzene, in tobacco smoke
What are the three major lymphotropic viruses?
- human t-cell leukaemia virus-1 (HTLV-1)
- epstein-barr virus (EBV)
- kaposi sarcoma herpesvirus/human herpesvirus-8 (KSHV/HHV-8)
From which cells do lymphoid neoplasms normally arise?
- the vast majority (85% - 90%) of lymphoid neoplasms are of B-cell origin, with most of the remainder being T-cell tumours
What is leukaemia?
- involve bone marrow and (usually, but not always) the peripheral blood
What are lymphomas?
arise as discrete tissue 'tumours' - e.g. in lymph nodes
What are the common clinical features of ALL?
- abrupt stormy onset within days to a few weeks of the first symptoms
- symptoms related to depression of marrow function, including fatigue due to anaemia; fever, reflecting infections secondary to neutropenia; and bleeding due to thrombocytopenia
- mass effects caused by neoplastic infiltration (which are more common ALL), including bone pain resulting from marrow expansion; generalised lymphadenopathy, splenomegaly, a hepatomegaly; testicular enlargement; and in T-ALL, complications related to compression of large vessels and airways in the mediastinum
- (not common)central nervous system manifestations such as headache, vomiting, and nerve palsies resulting from meningeal spread, all of which are also more common in ALL
What is the prognosis for someone with ALL?
- with aggressive chemotherapy about 95% of children with ALL obtain a complete remission, and 75% to 85% are cured
- however ALL remains the leading cause of cancer deaths in children, and only 35% to 40% of adults are cured
What is ALL?
Acute lymphoblastic leukaemia/lymphomas
- composed of immature B (pre-B) or T (pre-T) cells, which are referred to as lymphoblasts
- about 85% are B-ALLs, which typically manifest as childhood acute "leukaemias"
- the less common T-ALLs tend to present in adolescent males and thymic "lymphomas"
How do we diagnose ALL?
- blood smear (morphology) - accumulation of 'blasts
- expression of particular markers/known receptors - e.g. intracellular TdT, CDs (22, 19, 10)
What are the molecular features of ALL?
- approximately 90% of ALLs have numerical or structural chromosomal changes/mutations
- with respect to gene mutations: single mutations are not sufficient to produce 'ALL'
- studies of identical twins with concordant B-ALL: same mutation but different 'evolution' over time ie. further mutations required
- many of the chromosomal aberrations seen in ALL d ysregulate the expression and function of transcription factors that are required for normal B- and T-cell development
- T-ALLs - NOTCH1 TF
- B-ALLs - PAX5, E2A, TFs
How can you detect the difference between AML and ALL via blood smear?
- more cytoplasm in blast cells
- CD34, CD64, CD33, CD15
- most taken up by nucleus
- intracellular TdT, CDs (22, 19, 10)
What is multiple myeloma?
- causes 1% of all cancer deaths in Western countries
- Its incidence is higher in men and people of African descent
- It is chiefly a disease of the elderly, with a peak age of incidence 65 to 70 years
- plasma cell neoplasm characterised by multifocal involvement of the skeleton
- less common manifests in lymph nodes and/or skin
- normal marrow cells are largely replaced by plasma cells, including forms with multiple nuclei, prominent nucleoli, and cytoplasmic droplets containing Ig
What is the biochemical diagnosis of MM?
- in 99% of patients, laboratory analyses reveal increased levels of Igs in the blood and/or light chains (Bence Jones proteins) in the urine
- the most common monoclonal Ig ("M protein") is IgG (~55% of patients), followed by IgA (~25% of cases)
- myelomas expressing IgM, IgD, or IgE occur but are rare
- you get a really thick band as opposed to a smear on gel electrophoresis
What is the molecular and cellular pathogenesis of MM?
- the Ig genes in myeloma cells always show evidence of somatic hypermutation
- the cell of origin is considered to be a post-germinal centre B cell that homes to the bone marrow and has differentiated into a plasma cell
- may originate in and be maintained by stem-like cells resembling small B lymphocytes via oncogenic signals generated by the "hedgehog" pathway for self-renewal
- a key factor promoting the proliferation and survival of myeloma cells is IL-6 via autocrine and paracrine signalling from stromal cells
- factors produced by neoplastic plasma cells mediate bone destruction, the major pathologic feature of multiple myeloma
- myeloma-derived MIP1-alpha upregulates the expression of the receptor activator NF-kappaB ligand (RANKL) by bone marrow stromal cells, which in turn activates osteoclasts
- further enhancing this effect is the Wnt-pathway mediated inhibition of osteoblasts
What is the prognosis and treatment of MM?
- prognosis is variable but generally poor
- median survival is 4 - 6 years, and cures have yet to be achieved
- patients with multiple bony lesions, if untreated, rarely survive for more than 6-12 months, whereas patients with "smouldering myeloma" may be asymptomatic for many years
- translocations involving cyclin D1 are associated with a good outcome, whereas deletions of 13q, deletions of 17p, and the t(4;14) all require aggressive therapies
- chemotherapy induces remission in 50% to 70% of patients