lecture 10 Flashcards
diseases of white blood cells and lymph nodes - to be able to give examples of major diseases covered in the lecture involving WBCs and lymph nodes - to gain an understanding of the signs, molecular basis and treatments of major diseases involving white blood cells and lymph nodes
1
Q
What are the adult reference ranges for blood cells?
A
- 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
2
Q
How are reference ranges used?
A
- if someone lies outside the range it can indicate disease
3
Q
How do blood cells develop?
A
- from HSCs through well defined paths of differentiation, of which a number of the important transcription factors/chemokines are known
4
Q
Where is the ‘haematopoietic stem cell niche?
A
- in the bone marrow
- endosteal part of bone
5
Q
What cell types are found in the niche?
A
- endothelial cells
- nerve cells: can direct stem cell differentiation
- osteoblasts: may have a role in signalling
- stromal cells
6
Q
What organs are important for the development and maturation of WBCs?
A
- bone marrow: where they arise
- lymph nodes
- thymus: almost exclusively T cells
- spleen
7
Q
What are some of the major white blood cell types?
A
- 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
8
Q
What are all the names for neutrophils?
A
- neutrophil
- polymorphonuclear leukocyte, PMN, PML
- “Leukocyte”
- granulocyte, neutrophilic granulocyte
- polymorph
9
Q
What does a neutrophil generally look like?
A
- lobular nucleus
10
Q
What are the functions of a neutrophil?
A
- margination
- rolling
- adhesgion
- transmigration (diapedesis)
- chemotaxis
- phagocytosis: recognition, engulfment, killing (digestion)
- equilibrium with splenic pool
11
Q
What is leukopenia?
A
- 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
12
Q
What is neutropenia?
A
- a reduction in the number of neutrophils in the blood, occurs in a wide variety of circumstances
13
Q
What is agranulocytosis?
A
- a clinically significant reduction in neutrophils – susceptibility to bacterial and fungal infections
14
Q
What are reasons for inadequate production of neutrophils?
A
- stem cell suppression e.g. aplastic anaemias
- drugs especially chemo, many antibiotics
- inherited defects in specific genes impairing granulocytic differentiation - Kostmann Syndrome
15
Q
What are reasons for increased destruction of neutrophils?
A
- 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
16
Q
What is leukocytosis?
A
Increase in the number of white cells in the blood.
Reaction to a variety of inflammatory states.
17
Q
What is the pathogenesis of leukocytosis influenced by?
A
- 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
18
Q
What is leukocytosis often accompanied by in sepsis or severe inflammatory disorders?
A
- morphologic changes in the neutrophils
- e.g. toxic granulations, Döhle bodies, and cytoplasmic vacuoles
19
Q
What is lymphadenitis?
A
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
20
Q
What are lymphoid neoplasms?
A
- 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?
21
Q
What are myeloid neoplasms?
A
- 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
22
Q
What are the etiologic and pathogenetic factors in white cell neoplasia?
A
- 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
23
Q
Why are white cells so prone to translocation disorders?
A
- 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
24
Q
What is the molecular pathogenesis of acute leukaemia?
A
- 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
25
Q
What is the molecular pathogenesis of acute leukaemia?
A
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
Iatrogenic factors
- 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
Smoking
- the incidence of AML is increased 1.3- to 2-fold in smokers, due to exposure to carcinogens, such as benzene, in tobacco smoke
26
Q
What are the three major lymphotropic viruses?
A
- human t-cell leukaemia virus-1 (HTLV-1)
- epstein-barr virus (EBV)
- kaposi sarcoma herpesvirus/human herpesvirus-8 (KSHV/HHV-8)
27
Q
From which cells do lymphoid neoplasms normally arise?
A
- the vast majority (85% - 90%) of lymphoid neoplasms are of B-cell origin, with most of the remainder being T-cell tumours
28
Q
What is leukaemia?
A
- involve bone marrow and (usually, but not always) the peripheral blood
29
Q
What are lymphomas?
A
arise as discrete tissue ‘tumours’ - e.g. in lymph nodes
30
Q
What are the common clinical features of ALL?
A
- 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
31
Q
What is the prognosis for someone with ALL?
A
- 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
32
Q
What is ALL?
A
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”
33
Q
How do we diagnose ALL?
A
- blood smear (morphology) - accumulation of ‘blasts
- expression of particular markers/known receptors - e.g. intracellular TdT, CDs (22, 19, 10)
34
Q
What are the molecular features of ALL?
A
- 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
35
Q
How can you detect the difference between AML and ALL via blood smear?
A
AML
- more cytoplasm in blast cells
- CD34, CD64, CD33, CD15
ALL
- most taken up by nucleus
- intracellular TdT, CDs (22, 19, 10)
36
Q
What is multiple myeloma?
A
- 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
37
Q
What is the biochemical diagnosis of MM?
A
- 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
38
Q
What is the molecular and cellular pathogenesis of MM?
A
- 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
39
Q
What is the prognosis and treatment of MM?
A
- 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
40
Q
What is Anaplastic Large-Cell Lymphoma?
A
- defined by the presence of rearrangements in the anaplastic lymphoma kinase (ALK) gene
- rearrangements break the anaplastic lymphoma kinase (ALK) locus and lead to the formation of chimeric genes encoding ALK fusion proteins, constitutively active tyrosine kinases that trigger a number of proliferation and survival signalling pathways, including the JAK/STAT pathway
- the cure rate with chemotherapy is 75% to 80%
- inhibitors of ALK are under development and offer an excellent opportunity for the development of a selective, targeted therapy
- ALK-specific antigen vaccine
