1
Q
Severe Combined Immunodeficiency Disease (SCID)
A
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
2
Q
SCID-X1
A
defect in gene for gamma chain for IL-2 receptor and other cytokines necessary for lymphoid development and signaling (XR)
3
Q
Adenosine deaminase enzyme deficiency
A
type of SCID
-adenosine accumulates in all cells, and impairs lymphocyte development selectively
4
Q
Treatment of ADA enzyme deficiency in some SCID cases (3)
A
-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)
5
Q
Pure B cell Deficiencies include…(4)
A
X-Linked (Bruton) Agammaglobulinemia
X-linked hyperIgM Syndrome
Common Variable Immunodeficiency (CVID)
Transient Hypogammaglobulinemia of Infancy
6
Q
Infections commonly associated with pure B cell deficiencies
A
high-grade (extracellular, pyogenic) bacterial pathogens
Including:
Staphylococcus aureus
Haemophilus influenzae
Streptococcus pneumoniae
7
Q
X-Linked (Bruton) Agammaglobulinemia
where is the block?
Where is the defect?
What kinds of infections are associated?
A
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
8
Q
X-linked hyperIgM Syndrome
A
high IgM, low IgG and IgA = defect in IgM-to-IgG switch mechanism
CD40 not on B cell or no CD40 ligand on Tfh
9
Q
Common Variable Immunodeficiency (CVID)
where is the block?
what kinds of infections?
treatments?
A
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
10
Q
Transient Hypogammaglobulinemia of Infancy
A
- 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
11
Q
Embryology of the thymus (2)
A
Stroma + Lymphoid
Stroma of thymus comes from endoderm and ectoderm of the 3rd and 4th pharyngeal pouches
Lymphoid part comes from bone marrow precursors
12
Q
DiGeorge Syndrome
A
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
13
Q
CATCH-22
A
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)
14
Q
Selective IgA Deficiency
A
- can’t make IgA, but make all other Igs
- Most common immunodeficiency disease
- Usually asymptomatic - diarrhea, sinopulmonary infections, more allergies
- Associated with Celiac Disease
15
Q
Nude Mouse
A
Fail to make thymic stroma (and hair) → no T cells
Immunologically similar to DiGeorge kids (different gene defect though)
16
Q
Treatment of immunodeficiency
A
1) Isolation (bubbles)
2) Prophylactic abx
3) Transplantation
4) IVIG, SCIG
17
Q
IVIG and SCIG
A
IVIG:
Given monthly, effective, expensive, short supply
99% IgG, half life of 3 weeks
SCIG:
slow subcutaneous infusions recently approved, done at home
18
Q
B cell immunodeficiency work up
A
- 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
19
Q
T cell immunodeficiency work up
A
- Skin tests with recall Ag panel
- Total lymphocyte count
- CD3, CD4, CD8 counts
- Mitogen responses (MLR, cytokine measurements)
- Sequence suspect genes
20
Q
Phagocytic immunodeficiency work up
A
- WBC count, differential, morphology
- NBT test, oxidative burst
- Assay for phagocytosis, chemotaxis
- Sequence suspect genes
21
Q
Complement immunodeficiency work up
A
- CH50
- Assay for C1 inhibitor
- Individual complement levels
22
Q
Viruses associated with secondary immunodeficiencies include… (4)
A
Measles
Epstein Barr virus
Mononucleosis
Cytomegalovirus (CMV)
23
Q
Secondary Immunodeficiencies
A
- Many viral illnesses are immunosuppressive, secondary infection common
- Drugs used in therapy of autoimmune/inflammatory conditions immunosuppressive (corticosteroids, antibodies)
24
Q
Hematologic Malignancies
A
CLONAL malignant population of cells derived from transformed cell of marrow derivation
- all are inherently malignant
- can contain both leukemic and lymphoma component
25
Leukemia
- malignancy of hematopoietic cells - chief involvement is blood and marrow
- Can include lymphoid and myeloid cells, both mature and immature
26
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
```
27
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
28
High Grade Lymphoma
more aggressive, more rapidly growing
Lymphoma = rapidly enlarging mass
29
Low grade Lymphoma
Lymphoma = mildly enlarged neck lymph node (present for years)
30
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
31
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
32
_________ 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
33
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
34
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
35
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
36
Human T cell Leukemia Virus-1 (HTLV-1) implicated in the development of __________
adult T cell leukemia/lymphoma (ATLL)
37
Kaposi Sarcoma Herpesvirus / Human Herpesvirus-8 (KSV / HHV-8) implicated in ____________
primary effusion lymphoma
38
Frequency In Children of...
Leukemia
Lymphoma
Leukemia = most common childhood cancer (37%)
Lymphoma = 3rd most common childhood cancer (24%)
39
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
40
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
41
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
42
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.)
43
Immunophenotyping
abs used to detect certain substances being expressed by cells (flow cytometry and immunohistochemistry) → morphologically identical cells put into definite lineage
44
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
45
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)
46
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
47
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
48
Plasma Cell Neoplasms: includes _______, ________ and _________
Includes MGUS, plasmacytoma, and multiple myeloma
49
AML diagnosis age
avg age at diagnosis is 65 years old
1.Rare in children and young adults (only 10% of childhood leukemias)
50
ALL diagnosis age
75% of cases occur in children under 6 years old
51
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
52
Leukemic Stem Cell:
Potential for self renewal → Inexhaustible source of leukemic cells that replace the bone marrow
53
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.
54
Signs/symptoms of acute leukemia die to
decreased # of normal peripheral blood cells due to marrow infiltration by leukemic cells
55
Symptoms of acute leukemia
Fatigue, malaise, dyspnea, easy bruising, weight loss, bone pain, abdominal pain, neurologic symptoms (rare)
56
Signs of acute leukemia
anemia, pallor, thrombocytopenia, hemorrhage, ecchymoses, petechiae, fundal hemorrhage
1. Fever, infection
2. Adenopathy, hepatosplenomegaly, mediastinal mass
3. Gum or skin infiltration, renal enlargement and insufficiency, cranial neuropathy (all rare)
57
ALL diagnostic markers:
1. CD34 → myeloblasts (generic marker of immaturity)
2. TdT → NOT myeloblast, NOT mature lymphocyte
a. Nuclear enzyme specific to lymphoblasts
3. B-lymphoblasts express B-lineage antigens (CD19, CD22)
a. do NOT express markers of mature B cells (CD20) or surface Ig
4. 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)
58
CD34
myeloblasts and lymphoblasts (generic marker of immaturity)
59
TdT
marker of immature T-lymphoblasts
60
CD19 and CD22
B lymphoblasts
61
CD3 and CD7
T lymphoblasts
62
AML Diagnostic markers
1. CD34 - generic marker of immaturity → myeloblasts and lymphoblasts
2. CD117 (C-Kit), myeloperoxidase - myeloid antigens → myeloblasts
3. CD64, CD14 - monocytic antigens → Monocyte differentiation
4. CD41, CD61 - megakaryocytic antigens → megakaryoblast differentiation
63
CD117 (C-Kit), myeloperoxidase
myeloblasts
64
CD64, CD14
Monocyte differentiation
65
CD41, CD61
Megakaryoblast differentiation
66
Most prevalent ALL
B-ALL (80-85% of all cases)
67
B-ALL present at what age?
childhood
68
B-ALL lack markers for ____ and ____
mature B calls (CD20)
| Surface Ig
69
T-ALL present at what age?
Teenagers
70
T-ALL present with component of ___ that manifests as large ____
```
Lymphoblastic lymphoma (T-LBL)
mediastinal mass
```
71
Which has higher WBC count, T-ALL or B-ALL
T-ALL
72
T-ALL favors males or females
Males
73
3 commonly observed cytogenetic abnormalities in B-ALL
1. t(9;22); BCR-ABL1
2. 11q23; MLL
3. t(12;21); ETV-RUNX1
74
B-ALL with t(9;22); BCR-ABL1:
1. 25% of adult B-ALL (only 2% of childhood B-ALL)
2. Philadelphia Chromosome (chr22)
3. BCR-ABL fusion 190kd (different than CML) due to different breakpoint in BCR gene
4. Unfavorable prognostic factor
75
B-ALL with translocations of 11q23; MLL:
1. Can have MLL rearranged with multiple possible partner genes
2. Seen in B-ALL in neonates and young infants
3. POOR prognosis
76
B-ALL with t(12;21); ETV6-RUNX1:
1. 25% of childhood B-ALL cases
| 2. Very GOOD prognosis
77
7 factors leading to worse prognosis in ALL
```
Infants (less than 1yo)
Teens, adults (>10yo)
Very high WBC count
T-lymphoblastic
Hypodiploidy (less than 46)
Slow Response to Rx
Min. Residual Disease
```
78
3 factors leading to favorable prognosis in ALL
1. 1-10 years old
2. B-lymphoblastic
3. Hyperdiploidy (51-65)
79
Two diagnostic feactures of AML
1. Myeloblasts > 20% of nucleated cells in marrow and/or peripheral blood
- CD34 (generic marker of immaturity) and CD117 (C-KIT), and Myeloperoxidase seen (markers on myeloids)
- NEGATIVE for markers of lymphoid differentiation
2. Presence of certain recurrent cytogenetic abnormalities → diagnosis of AML regardless of blast count
80
Auer Rods
i. Fused azurophilic granules forming small stick-like structure in the cytoplasm
ii. Presence of auer rods allows identification of a blast as a myeloblast
iii. ONLY seen in abnormal myeloblasts
SUGGESTS AML
81
2 methods to detect AML cytogenetics
1. Cytogenetic analysis (FISH, karyotyping)
| 2. Molecular analysis (PCR)
82
AML with t(8;21); RUNX1-RUNX1T1:
__% of AML cases
Patients are typically ____
5%
| younger
83
AML with t(8;21); RUNX1-RUNX1T1 is associate with "_______"
AML with maturation
| - Some neut production still at diagnosis
84
RUNX1 encodes ____ which does what?
encodes alpha unit of core binding factor (CBF), a TF needed for hematopoiesis-> fusion-> blocks transcription of CBF-> block differentiation
85
Prognosis of AML with t(8;21); RUNX1-RUNX1T1
GOOD
86
AML with inv(16) or t(16;16); CBFB-MYH11:
___% of AML cases
patients are typically ____
5-10%
| younger
87
In the marrow of AML with inv (16) or t(16;16)->
frequent presence of immature eosinophils with abnormal basophilic granules = “baso eos”
88
in AML with inv(16) or t(16;16), there is an increase of ___ and _____
myeloblasts and monocytes= "myelomonnocytic leukemia"
89
CBFB
beta subunit of core binding factor (CBF)
90
Prognosis of ML with inv(16) or t(16;16)
good
91
APL with t(15;17); PML-RARa:
APL = Acute Promyelocytic Leukemia
Distinct subtype - abnormal promyelocytes predominate instead of blasts (5-10% of cases of AML)
92
Histology of
| APL
Hypergranular (obscure nucleus), multiple Auer rods (“faggot cells”)
93
Translocation associated with APL
t(15;17)
94
AML with t(1;22); RBM15-MKL1
1. Megakaryoblastic differentiation
2. Most often see in infants with Down Syndrome
3. Good prognosis with intensive chemo
95
AML with abnormalities of 11q23; MLL
1. MLL gene can be fused with multiple different partner genes
2. AML with translocation involving MLL → some monocytic differentiation
96
Two reasons it is important to recognize APL as subtype of AML
1. Gene fusion in APL fuses retinoic acid receptor-alpha (RARa) to another gene
- RARa needed for differentiation of promyelocytes, fused product does not work well and thus blocks differentiation
- Can overcome block with supraphysiologic dose of all-trans retinoic acid (ATRA) in combination with arsenic salts → patients DO NOT require chemo
2. Some cases of APL cause DIC → important to know its APL to watch out for DIC
97
Two categories of therapy related AML
1. t-AML secondary to alkylating agents or radiation
| 2. t-AML secondary to topoisomerase-II inhibitors
98
t-AML secondary to alkylating agents or radiation: (3)
1. Latency of 2-8 years from prior treatment
2. Progresses through initial MDS stage before reaching AML (20% blasts)
3. Complex karyotype that includes whole/partial loss of chr 5 and/or 7
99
t-AML secondary to topoisomerase-II inhibitors: (3)
1. Latency of 1-2 years from prior treatment
2. Presents as de no novo AML with no prior MDS phase
3. Rearrangement of MLL gene (11q23)
100
Prognosis of t-AML
VERY BAD PROGNOSIS
101
3 molecular markers for AML prognosis
1. FLT3 ITD
2. NPM1
3. CEBPA
102
FLT3 ITD
| - or + prognostic factor?
internal tandem duplications (ITDs) in FLT3 gene
Negative prognostic factor for AML, NOS (not otherwise specified)
103
NPM1
| - or + prognostic factor?
Positivity for a mutation of the nucleophosmin-1 gene
Positive prognostic factor in AML, NOS (only if negative for FLT3 ITD)
104
CEBPA
| - or + prognostic factor?
Positivity for a mutation of the CEBPA gene
Positive prognostic factor in AML, NOS (only if negative for FLT3 ITD)Ca
105
Myelodysplastic syndrome
condition where marrow is replaced by a malignant clone derived from a transformed stem cell/progenitor cell
106
Two main features of myelodysplastic syndrome
1. Clone of cells ineffective at hematopoiesis
| 2. Increased risk of transformation to AML
107
Two clinical scenarios of MDS
1. Primary (idiopathic) MDS
| 2. Secondary (Therapy-related) MDS (t-MDS)
108
Primary idiopathic MDS age of onset/diagnosis
over 50 years old, insidious onset, median age of diagnosis is 70 years old
109
Secondary (Therapy-Related) MDS: (3)
1. Part of t-AML spectrum
2. Occurs 2-8 years after use of alkylating agents or radiation
3. Whole or partial deletions of chr 5 and/or 7
110
Diagnosis of MDS
Persistent peripheral cytopenia in one or more lineages that cannot be otherwise explained
111
Three tests to make a diagnosis of MDS
1. Morphologic evidence of dysplastic change- in at least 10% of cells in one or more lineages
2. Increased myeloblasts but less than 20% of blood and marrow cells
3. Clonal cytogenetic findings typical of MDS
112
Dyserythropoiesis
RBC precursors with nuclear budding, irregularly-shaped nuclei, lack of coordination between nuclear and cytoplasmic maturation, increased ring sideroblasts (iron backing up in cytoplasm)
113
Dysgranulopoiesis
Nuclear hypolobation of mature neutrophils, including neutrophils with bilobed nuclei called pseudo-Pelger-Huet cells, also cytoplasmic hypogranularity of neutrophils
114
Dysmegakaryopoiesis
Megakaryocytes with hypolobated or non-lobated nuclei, often hyperchromatic nuclei, megakaryocytes often of small size
115
Clonal cytogenetic findings typical of MDS
Complex karyotypes (monosomy 7 or 5, deletion 7q or 5q, trisomy 8)
116
Negative for elevated myeloblasts and negative for clonal cytogenetic evidence of MDS →
potential non-neoplastic causes of secondary myelodysplasia
117
Four possible causes of secondary myelodysplasia (may mimic MDS
1. Certain drugs (e.g. chemo drugs)
2. VB12, Folic acid, essential element deficiencies
3. Viral infections
4. Toxin exposure (e.g. arsenic, heavy metals)
118
Diagnostic criteria of low grade MDS
myeloblasts NOT increased in frequency (less than 5% of marrow cells, and less than 2% peripheral blood cells)
119
3 types of low grade MDS
1. Refractory cytopenia with Unilineage Dysplasia (RC-UD) = good prognosis, median survival over 5 years, AML transformation rate only 2% at 5 years
- Mostly cases of refractory anemia, rarely refractory neutropenia or refractory thrombocytopenia
2. Refractory Cytopenia with Multilineage Dysplasia (RC-MD) = worse than RC-UD, median survival of 2.5 years, AML transformation rate 10% at 2 years
- Low grade MDS dysplasia in 2 or more lineages
3. MDS with isolated 5q Deletion = low grade MDS associated with anemia
120
High grade MDS diagnostic criteria
myeloblasts are increased in frequency, but less than 20% (> 5% of marrow cells, and/or > 2% peripheral blood cells)
121
2 types of high grade MDS
1. Refractory Anemia with Excess Blasts-1 (RAEB-1) = 5-9% blasts in marrow, or 2-4% blasts in peripheral blood → 16 month survival, 25% transform to AML
2. Refractory Anemia with Excess Blasts-2 (RAEB-2) = 10-19% blasts in marrow, or 5-19% blasts in peripheral blood → 9 month survival, 33% transform to AML
BAD prognosis - may or may not progress to AML, but frequently die secondary to bone marrow failure
122
Myeloproliferative Neoplasms (MPNs)
characterized by increased numbers of NORMAL (not dysplastic) blood cells in one or more myeloid lineages (effective hematopoiesis), partially or entirely replaces normal marrow cells in multiple lineages
123
MPN age
Disease of adults in 50s-70, rare in children
124
3 Characteristics of MPNs
1. Increase # of one or more blood cell type with correspondingly hypercellular marrow
2. Splenomegaly/Hepatomegaly common
3. Insidious onset, incidentally noticed on CBC - without treatment will progress to bad outcomes
125
Why does splenomegaly and hepatomegaly occur in patients with MPN
1. Sequestration of excess blood cells
| 2. Extramedullary hematopoiesis (body trying to make enough blood cells)
126
Three Negative End Points for MPNs
1) Transformation to AML (sometimes ALL) - less common in MPNs than in MDS
2) Development of myelodysplasia with ineffective hematopoiesis (transform to MDS)
3) Excessive marrow fibrosis → BM failure
127
4 types of MPNs
1. Chronic myelogenous leukemia (CML)
2. Polycythemia vera (PV) (“a lot of blood cells, truly”)
3. Primary Myelofibrosis (PMF)
4. Essential Thrombocythemia (ET)
128
CML cytogenetics
Clonal hematopoietic stem cell disorder, BCR-ABL1 gene fusion
129
CML progression
Chronic phase → Accelerated phase → Blast Phase
130
Chronic phase of CML marrow findings
```
Hypercellular marrow
Granulocytic hyperplasia
NORMAL blasts
NO dysplasia in marrow or blood
Neutrophil leukocytosis (also basophilia / thrombocytopenia)
```
131
Blast phase of CML marrow findings
20% or more blasts in marrow/blood (myeloblasts or lymphoblasts)
132
Genetics of CML
a. BCR-ABL1 gene fusion t(9;22)→ fusion on chr 22 (Philadelphia Chromosome) → constitutive activation of growth pathways
b. 210 kD (p210) fusion protein (190kD fusion for adult B-ALL)
133
Prognosis of CML
Much better, used to be only 2-3 years
→ targeted therapies (PTKIs)
134
Polycythemia vera
Erythrocytosis and can also have increased neutrophils/platelets → BM shows trilineage hyperplasia and large bizarre megakaryocytes
135
Marrow of polycythemia vera
Polycythemic stage: increased peripheral blood counts
Spent phase: marrow shows myelofibrosis, low peripheral blood cell counts
136
Genetic of polycythemia vera
JAK2 gene point mutation (V617F) encoding JAK2 cell signaling protein
137
Key concern with polycythemia vera
Clotting (venous or arterial thrombosis)
138
Primary myelofibrosis (PMF)
Granulocytic and megakaryocytic hyperplasia (but NO erythrocytosis), with eventual progression to myelofibrosis
Mutations in JAK2 in 50% of PMF cases
139
PMF stages
Prefibrotic stage: marrow is hypercellular (mega/gran), large bizarre, megakaryocytes clustered + marked thrombocytosis/neutrophilia
a.Better survival with diagnosis at this stage
Fibrotic Stage:
a. BM significant reticulin (collagen IV) stage, loss of marrow space → intramedullary extramedullary hematopoiesis
b. Peripheral blood = leukoerythroblastosis
i. Increased immature granulocytes (myelocytes, metamyelocytes), immature nucleated RBCs
ii. Dacrocytes (tear-drop shaped RBCs)
c. Enlargement of other organs due to extramedullary hematopoiesis (spleen, liver, lymph nodes)
d. Falling WBC counts
140
Essential thrombocythemia (ET)
1. Sustained, marked thrombocytosis
2. No granulocytic hyperplasia in marrow - marrow is normocellular but with atypical megakaryocytes larger and even more bizarre
3. Mutation in JAK2 found in 50% of ET cases
4. Symptom free for long periods with occasional severe thrombotic or hemorrhagic events
141
Why do we need a second and third generation PTKIs
Imatinib (Gleevec) - PTKI used to treat CML
PTKIs effectively select to form new subclones against which the PTKI is not effective → second generation PTKI for CML = Dasatinib
142
Death in PV patients
venous or arterial thrombosis (20% of patients)
Three sites of thrombosis associated with PV:
1. Mesenteric vein
2. Portal vein
3. Splenic vein
143
Treatment for PV
Serial phlebotomy (and aspirin to prevent clots)
144
Type II immunopathology
antibody (IgG, IgM, IgA) directed against self
TISSUE specific autoimmunity - Ab directed against specific target tissue or cell
145
Mechanisms of tissue damage (3)
1) Neutralization
2) Complement mediated damage
3) Stimulatory hypersensitivity
146
Neutralization
EX)
protein inactivated by autoantibody
EX) IFN-y auto-antibodies → Th1 cells functionless → multiple infections - underlying pathology is autoimmunity, manifests as immunodeficiency
147
Complement-Mediated Damage
tissues with ab against them damaged by lysis, phagocytosis, or by release of phagocyte lysosomal enzymes and ROS → inflammatory response
148
Stimulatory Hypersensitivity
EX)
autoantibody directed against cell-receptor → mimic receptor agonist
EX) Hyperthyroidism (Graves Disease)
149
Graves Disease (4)
Hyperthyroidism
"Stimulatory autoimmunity" to TSH receptor on thyroid cells
Thyroid cells have TSH receptor on them that recognizes TSH from pituitary and is told to make MORE thyroid hormones
Autoantibodies against TSH receptor on thyroid cells → agonist interaction → oversecretion of thyroid hormones, no normal feedback controls
150
Myasthenia gravis is characterized by ________, and can be treated with ________
progressive muscle weakness (more common in women)
IVIG
151
Myasthenia gravis mechanism
Antibody made to alpha subunit of acetylcholine receptor (AChR) → blocks receptor and activates complement and neutrophils → damage receptor → signal gets weaker to muscle → muscle gets weaker
*Complement and neutrophil mediated damage*
152
AIRE gene in myasthenia gravis
AIRE gene → thymic expression of CHRNA1 (gene for alpha subunit of AChR)
In this disease protein NOT expressed in thymus, Th clones reactive with AChR not deleted by negative selection → B cells get help making ab to receptor
153
Dressler's Syndrome
immune response to pericardial or myocardial antigens
Persistent cardiac pain, fever, malaise, and pericardial effusion seen after heart attack (and heart surgery)
“Post cardiac injury syndrome”
Treat with anti-inflammatory agents
Resolves as heart heals
154
Goodpasture's Disease (5)
1) autoantibodies to lung and kidney basement membranes (CT framework)
2) Epitope on antigen (type IV collagen) only in lung/kidney
3) Primary symptoms is persistent glomerulonephritis
(in smokers → ab to lung → hemoptysis)
4) Ab directed against BM → staining by IF sharp and linear
5) Complement mediated destruction**
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Autoimmune thrombocytopenia purpura (ATP) (3)
bleeding abnormality due to destruction of platelets by autoantibody
Platelets are opsonized and their destruction (in the spleen) is rapid.
ATP is seen in young healthy people weeks after a viral infection or in older people in association with many other autoantibodies.
156
Treatment of Autoimmune thrombocytopenia purpura
TX: suppress immune system and/or remove the spleen
157
Autoimmune hemolytic anemia (AIHA)
autoantibody to RBCs
- can be induced by drugs (usually temporarily)
- associated with other autoimmune syndromes and cancer
158
Paroxysmal cold hemoglobinuria (PCH)
hemolysis after exposure to cold, ab binds RBCs at 15 degrees celsius
159
Rheumatic heart disease
- heart disease post streptococcal infection
- Cross-reaction between strep M-protein antigen and structure on heart’s endothelial lining (lamin on heart valves)
- Neutrophil mediated tissue destruction of valves
160
Rheumatic Fever
same disease, more widespread manifestations (cross-reactions in skin and CNS as well)
161
Incidence of rheumatic heart disease declined in the west but not developing countries. Why?
Antibiotics given quickly for strep treatment in west, but in developing countries strep infections allowed to last longer and occur more frequently
162
Hashimoto’s thyroiditis
hypothyroidism
Ab to thyroid antigens (thyroglobulin, and thyroid peroxidase)
Inflammatory and destructive (NOT stimulatory)
Lots of overlap with Graves disease
163
Linear vs. Lumpy-bumpy immunofluorescent patterns
Linear:
- Type II immunopathology
- indicate ab is binding to a specific structure (e.g. basement membrane)
- Fluorescent antibody will show a clear structure that it is coating
Lumpy-bumpy:
- type III immunopathology.
- indicate immune complex pathologies, whereby antigen and antibody clump together and precipitate.
- Do not line any particular structures, they just bind together in large groups
164
Direct test for Goodpastures
use kidney tissue
1) Take patient kidney (will already have antibody on its glomerular BM)
2) Add fluorescently labeled goat antisera to human IgG.
3) Goodpasture’s (ab present on GBM)→ binding occurs along glomerulus
165
Indirect test for Goodpastures
use serum + normal human tissue
1) Normal kidney (no Ab in it)
2) Add patient’s serum with Anti-GBM antibodies
3) Labeled anti-IgG reveals that Abs in patient's serum bound GBM sample
Ab directed against BM, not trapped in clumps → staining is sharp and linear, not “lumpy-bumpy” (as in Type III immune complex conditions)
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Hybrid (foreign + self) antigen formation
5 steps
1) B cell binds self + foreign epitope - couples foreign with self protein
2) It then ingests and digests
3) Foreign epitope is presented to Th2 on Class II MHC AND self protein is presented to Th2 on Class II MHC
4) TfH → cytokines, engages coreceptors
5) B cell is activated, secretes antibody to self
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Forbidden Clone
clone of autoreactive T cells that escape normal thymic clonal deletion mechanisms → T cell matures so that encounters with antigen immunize it
168
Cross-Reaction between foreign antigen + self antigen
ab produced against some infection (foreign) kills off disease, but this ab is also kind of like a self antigen, so it starts reacting with self
EX) Rheumatic Heart Disease
169
Innocent Bystander
Damage to normal tissue infected by antigen
EX) TB - infectious bacteria localized in lungs → lung tissue damaged as body tries to rid itself of infection.
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Release of a sequestered antigen
- Special case in which antigen cannot get out into general system → NOT immunogenic
- Antigens somehow allowed to get out → immune response initiated in region where antigen is sequestered → damage to that tissue → more release of antigens → further immune response
EX) Men who get mumps becoming sterile
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Failure of regulatory mechanisms
Proper balance between Th1, Th17, Tfh, Th2, and Treg activity assures appropriate immune response
Disrupt this balance → immune response exaggerated, self/nonself discrimination breaks down? -- still under study
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AIRE gene
causes thymic stromal genes to express a wide variety of “out-of-place” peptides so that reactive T cells may be removed from the repertoire.
Made in thymus to help negatively select anti-self T-cells
Aire-deficient people develop several autoimmune diseases
Blood and Lymph
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