Week 4 Flashcards
Severe Combined Immunodeficiency Disease (SCID)
Low T AND B cells
- block in development of lymphoid stem cell or its maturation
- Children rarely survive past 1 year
- Different variations but is a group of diseases with a similar phenotype
- Most are XR, some are AR
SCID-X1
defect in gene for gamma chain for IL-2 receptor and other cytokines necessary for lymphoid development and signaling (XR)
Adenosine deaminase enzyme deficiency
type of SCID
-adenosine accumulates in all cells, and impairs lymphocyte development selectively
Treatment of ADA enzyme deficiency in some SCID cases (3)
-Irradiated red cells (very high concentration of ADA in RBCs)
(Irradiation kills lymphocytes, but not RBCs)
- Purified ADA stabilized by polyethylene glycol
- Replacement gene therapy (still under research)
Pure B cell Deficiencies include…(4)
X-Linked (Bruton) Agammaglobulinemia
X-linked hyperIgM Syndrome
Common Variable Immunodeficiency (CVID)
Transient Hypogammaglobulinemia of Infancy
Infections commonly associated with pure B cell deficiencies
high-grade (extracellular, pyogenic) bacterial pathogens
Including:
Staphylococcus aureus
Haemophilus influenzae
Streptococcus pneumoniae
X-Linked (Bruton) Agammaglobulinemia
where is the block?
Where is the defect?
What kinds of infections are associated?
developmental block between pre-B cell and B cell → normal pre-B in marrow, NO B cells or antibody
Defect in tyrosine kinase gene
BACTERIAL infections (pneumonia, chronic diarrhea), ENTEROVIRUS infections (enter through mucous membranes - no IgA there) e.g. polio
X-linked hyperIgM Syndrome
high IgM, low IgG and IgA = defect in IgM-to-IgG switch mechanism
CD40 not on B cell or no CD40 ligand on Tfh
Common Variable Immunodeficiency (CVID)
where is the block?
what kinds of infections?
treatments?
Normal # of pre-B cells and B cells, but B cells difficult to trigger to make specific antibody (very low serum IgG)
Recurrent BACTERIAL infections
Treat with IVIG or SCIG
Transient Hypogammaglobulinemia of Infancy
- lasts from 6-18 months
- Slow to get IgG production going
- Recurrent, persistent, Gram-positive bacterial infections
- 15% of al chronic diarrhea in infants due to this condition
Embryology of the thymus (2)
Stroma + Lymphoid
Stroma of thymus comes from endoderm and ectoderm of the 3rd and 4th pharyngeal pouches
Lymphoid part comes from bone marrow precursors
DiGeorge Syndrome
Abnormal development of 3rd/4th pharyngeal pouches → stroma does not support thymic lymphoid development → No T cells, normal B cells (but no Tfh cells)
45 gene deletion on chr 22
Associated with parathyroid problem (same embryological origin)
Common VIRAL and FUNGAL infections
CATCH-22
CATCH-22
Massive defect on chromosome 22 (de novo mutation)
Calcium (calcium convulsions)
Appearance (wide set eyes, low set ears)
Thymus
Clefts (palate)
Heart (big vessel abnormalities)
Selective IgA Deficiency
- can’t make IgA, but make all other Igs
- Most common immunodeficiency disease
- Usually asymptomatic - diarrhea, sinopulmonary infections, more allergies
- Associated with Celiac Disease
Nude Mouse
Fail to make thymic stroma (and hair) → no T cells
Immunologically similar to DiGeorge kids (different gene defect though)
Treatment of immunodeficiency
1) Isolation (bubbles)
2) Prophylactic abx
3) Transplantation
4) IVIG, SCIG
IVIG and SCIG
IVIG:
Given monthly, effective, expensive, short supply
99% IgG, half life of 3 weeks
SCIG:
slow subcutaneous infusions recently approved, done at home
B cell immunodeficiency work up
- Serum protein electrophoresis
- Quantitative Ig (G,A,M) levels
- Specific Abs prior to immunizations
- ABO isohemagglutinins
- Ab responses to novel Ags
- Sequence suspect genes
- lymph node biopsy
T cell immunodeficiency work up
- Skin tests with recall Ag panel
- Total lymphocyte count
- CD3, CD4, CD8 counts
- Mitogen responses (MLR, cytokine measurements)
- Sequence suspect genes
Phagocytic immunodeficiency work up
- WBC count, differential, morphology
- NBT test, oxidative burst
- Assay for phagocytosis, chemotaxis
- Sequence suspect genes
Complement immunodeficiency work up
- CH50
- Assay for C1 inhibitor
- Individual complement levels
Viruses associated with secondary immunodeficiencies include… (4)
Measles
Epstein Barr virus
Mononucleosis
Cytomegalovirus (CMV)
Secondary Immunodeficiencies
- Many viral illnesses are immunosuppressive, secondary infection common
- Drugs used in therapy of autoimmune/inflammatory conditions immunosuppressive (corticosteroids, antibodies)
Hematologic Malignancies
CLONAL malignant population of cells derived from transformed cell of marrow derivation
- all are inherently malignant
- can contain both leukemic and lymphoma component
Leukemia
- malignancy of hematopoietic cells - chief involvement is blood and marrow
- Can include lymphoid and myeloid cells, both mature and immature
Lymphoma
malignancy of hematopoietic cells derived from lymphocytes or their precursors
Presents as a solid mass
Nodal = presenting as enlarged lymph nodes Extranodal = present at sites such as skin, brain, GI tract
Extramedullary myeloid tumor (aka granulocytic sarcoma
Malignancy of hematopoietic cells derived from myeloid cells or their precursors (granulocytes, monocytes, etc.)
Presents as a solid mass
High Grade Lymphoma
more aggressive, more rapidly growing
Lymphoma = rapidly enlarging mass
Low grade Lymphoma
Lymphoma = mildly enlarged neck lymph node (present for years)
Acute leukemia
Rapidly progressive course, rapidly fatal without treatment
-Failed production of normal marrow cells due to predominance of leukemic cells (leukemic cells usually blasts)
→ low platelets, low neutrophils, low RBC
Chronic Leukemia
CLL or CML
Subtle symptoms, noticed incidentally on CBC performed for another reason
Increased WBC count - accumulation of normal-appearing (but clonal) mature blood cells
_________ are common in immunoglobulin and T cell receptor genes in lymphomas because…
balanced translocations
During initial Ig/T cell receptor rearrangement during maturation of B and T cells there is normal (but high) levels of genomic instability
EX) Class recombination, somatic hypermutation for B cells
Importance of specific recurrent translocations (one EX)
EX) t(9;22) = Chronic Myelogenous Leukemia (CML)
- Important as diagnostic markers in hematologic malignancies
- Their persistence suggests critical role in development of hematologic malignancy they are associated with
3 oncogenic viruses in lymphoma
1) Epstein-Barr Virus
2) Human T cell Leukemia Virus-1 (HTLK-1)
3) Kaposi Sarcoma Herpesvirus / Human Herpesvirus-8 (KSV / HHV-8
Epstein-Barr Virus (EBV) implicated in the development of _______, _________ and _______
implicated in development of classical Hodgkin Lymphoma, Burkit Lymphoma and some other B cell non-Hodgkin lymphomas
Human T cell Leukemia Virus-1 (HTLV-1) implicated in the development of __________
adult T cell leukemia/lymphoma (ATLL)
Kaposi Sarcoma Herpesvirus / Human Herpesvirus-8 (KSV / HHV-8) implicated in ____________
primary effusion lymphoma
Frequency In Children of…
Leukemia
Lymphoma
Leukemia = most common childhood cancer (37%)
Lymphoma = 3rd most common childhood cancer (24%)
Frequency and death in adults of…
Leukemia
Non-Hodgkin Lymphoma
Non-Hodgkin Lymphoma = 7th most frequent, 7th most deadly
Leukemia = 10th most frequent, not very deadly anymore because of good treatment
Classification of hematologic malignancies (6)
1) Myeloid vs. Lymphoid vs. other
2) Microscopic appearance of malignant cells
3) Histologic growth pattern of malignant cells in marrow, lymph node, or other tissue
4) Presence / absence of specific cytogenetic findings or molecular findings
5) Relative amount of malignant cells present in the blood or marrow
6) Presence or absence of certain cell surface markers / cytoplasmic markers / nuclear markers
Myeloid vs. Lymphoid vs. Other
Myeloid: resemble cells of granulocytic, monocytic, erythroid, megakaryocytic, and/or mast cell lineages
Lymphoid: resemble cells of the B cell, T cell and NK cell lineages
Other: resemble histiocytes, dendritic cells, Langerhans cells
Acute Leukemia:
Most common cell type
Morphology
Rapid accumulation of immature cells in marrow, replace normal marrow cells, accumulate in blood → other cytopenias
Cell Type: almost always BLASTS (myeloid or lymphoid)
Morphology: certain line of differentiation (monocytic, megakaryocytic, etc.)
Immunophenotyping
abs used to detect certain substances being expressed by cells (flow cytometry and immunohistochemistry) → morphologically identical cells put into definite lineage
Myelodysplastic Syndrome (MDS) (3)
Neoplastic clone stem cell takes over marrow → can’t make normal blood cells in one or more lineages (dysplasia)
May progress to AML
Persistently low blood counts in one or more lineages
Myeloproliferative Neoplasms (MPNs) (3)
Neoplastic clonal proliferations of marrow - clone makes normal functioning blood cells, but makes too many of them in one or more lineages
Subsequent increased blood counts
Can progress to acute leukemia (less than for MDS)
Classical Hodgkin Lymphoma (CHL)
Driven by Hodgkin-Reed-Sternberg (HRS) cells derived from B cells
-old school classification still used even though its from B cells
Non-Hodgkin Lymphoma (2)
Any malignancy derived from mature B cells (excluding CHL or plasma cells neoplasms), T cells, or NK cells
Large majority derived from B cells
Plasma Cell Neoplasms: includes _______, ________ and _________
Includes MGUS, plasmacytoma, and multiple myeloma
AML diagnosis age
avg age at diagnosis is 65 years old
1.Rare in children and young adults (only 10% of childhood leukemias)
ALL diagnosis age
75% of cases occur in children under 6 years old
Prognosis of ALL
generally good prognosis in children (95% complete remission following chemotherapy, 80% cure rates)
1.Worse in adults - complete remission 60-80%, cure rate
Leukemic Stem Cell:
Potential for self renewal → Inexhaustible source of leukemic cells that replace the bone marrow
Risk factors for acute leukemia (6)
i. Majority of ALs occur in absence of risk factors
ii. Previous chemo, esp. DNA alkylating agents and topoisomerase-II inhibitors
iii. Tobacco smoke
iv. Ionizing radiation
v. Benzene exposure
vi. Genetic syndromes including Down syndrome, Bloom syndrome, Fanconi anemia, and ataxia-telangiectasia.
Signs/symptoms of acute leukemia die to
decreased # of normal peripheral blood cells due to marrow infiltration by leukemic cells
Symptoms of acute leukemia
Fatigue, malaise, dyspnea, easy bruising, weight loss, bone pain, abdominal pain, neurologic symptoms (rare)
Signs of acute leukemia
anemia, pallor, thrombocytopenia, hemorrhage, ecchymoses, petechiae, fundal hemorrhage
- Fever, infection
- Adenopathy, hepatosplenomegaly, mediastinal mass
- Gum or skin infiltration, renal enlargement and insufficiency, cranial neuropathy (all rare)
ALL diagnostic markers:
- CD34 → myeloblasts (generic marker of immaturity)
- TdT → NOT myeloblast, NOT mature lymphocyte
a. Nuclear enzyme specific to lymphoblasts - B-lymphoblasts express B-lineage antigens (CD19, CD22)
a. do NOT express markers of mature B cells (CD20) or surface Ig - T-Lymphoblasts express T-lineage antigens (CD3, CD7)
a. May express CD4 and CD8 concurrently (or just one, or neither)
b. Express T-lineage antigens ONLY seen in mature T cells (CD99, CD1a)
CD34
myeloblasts and lymphoblasts (generic marker of immaturity)
TdT
marker of immature T-lymphoblasts
CD19 and CD22
B lymphoblasts
CD3 and CD7
T lymphoblasts
AML Diagnostic markers
- CD34 - generic marker of immaturity → myeloblasts and lymphoblasts
- CD117 (C-Kit), myeloperoxidase - myeloid antigens → myeloblasts
- CD64, CD14 - monocytic antigens → Monocyte differentiation
- CD41, CD61 - megakaryocytic antigens → megakaryoblast differentiation
CD117 (C-Kit), myeloperoxidase
myeloblasts
CD64, CD14
Monocyte differentiation
CD41, CD61
Megakaryoblast differentiation
Most prevalent ALL
B-ALL (80-85% of all cases)
B-ALL present at what age?
childhood
B-ALL lack markers for ____ and ____
mature B calls (CD20)
Surface Ig