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52 Cards in this Set

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Epitopes of T and B cells
T-cells respond to an epitope presented by antigen-presenting cells (APCs)

B-cells respond to soluble antigens. Then Later become plasma cells and secrete antibodies for those soluble antigens.
Antibody Structure
2 heavy chains
2 light chains
2 variable regions at the end of the Y
1 constant region
Mechanism of VDJ recombination
Codes for Human heavy chain

48 variable segments
23 diversity segments
6 joining segments
1 constant segment
How many different combinations can be made from the VDJ recombination?

In what chromosome is the VDJ gene on?
8700

Chromosome 14
________and ________stimulate V(D)J joining activity in vivo

Where are these genes expressed in ?
RAG1&RAG2

Pre-B and Pre-T cells
The recombination signal sequences (RSSs) in V(D)J recombination consist of:
Heptamer
Nonamer
Separated by 12-bp or 23-bp spacers
RAG1 and RAG2 introduce single-strand nicks into DNA adjacent to either a 12 signal or 23 signal

Results in transesterification where newly created 3’-OH group:
Attacks the opposite strand
Breaks it
Forms hairpin at the end of the coding segment
Which Igs are monomers? Dimers? Pentamer
IgG, IgE, IgD = monomers

IgA= Dimer

IgM= Pentamer
What are the heavy chains for all the Igs?

What are the light chains?
IgG = gamma1,2,3,4

IgE = Epsilon

IgD = Delta

IgA = Alpha 1,2

IgM = Mu 1,2

Light chains are all Kappa, lambda
Rate the Igs from highest conc. to lowest
IgG>IgA>IgM>IgD>IgE
What are the features of cytotoxicT-cells and helper T cells (CD Makers)
Cytotoxic T-cells = CD8+=MHC I

Helper T Cells =CD4+ = MHC II
The ability of a B cell to switch CH gene segments depends on its receiving help from
helper T cells.
Mechanism of gene amplification
• Assembling genes for antibody light chains and heavy chains from 2 or 3 component parts

• Joining the gene parts by an imprecise mechanism that can delete bases or add extra bases

• Causing a high rate of somatic mutations, probably during proliferation of a clone if immune cells
is Hodgkin's lymphoma a B-cell or T-cell disease?
B cell
Hodgkin's lymphoma is characterized by ______
Reed Sternberg cells

bi-nucleated giant cells with eosinophillic inclusions
Rye classifications (4)
based on amount of changes in lymph node morphology

Nodular Sclerosis - most common (60%)

Mixed Cellularity - older adults (30%)

Lymphocyte Depletion - least common (5%)

Lymphocyte Predominance - B cell (5%)
What is the Frequency, demographic, prognosis and description of

Nodular Sclerosis
Frequency = most frequent (60-80%)

demographics = more in women

prognosis = Relatively Good

description = by nodular division of affected lymph nodes by fibrous bands and by the presence of lacunar cells, Reed-Sternberg cell variants
What is the Frequency, demographic, prognosis and description of

Mixed Cellularity
Frequency = 2nd most common

demographics = men

prognosis = ---

description = polymorphic infiltrate of eosinophils, plasma cells, histiocytes, and Reed-Sternberg cells, and by areas of necrosis and fibrosis.
What is the Frequency, demographic, prognosis and description of

Lymphocyte depletion
Frequency = less common

demographics = men

prognosis = POOREST

description = few lymphocytes, numerous Reed-Sternberg cells, and extensive necrosis and fibrosis
What is the Frequency, demographic, prognosis and description of


Lymphocyte predominance
Frequency = RARE

demographics = men

prognosis = Good

description = large numbers of lymphocytes and histiocytes , and a paucity (scarcity)

Contains Popcorn Cells
Clinical features of Hodgkin’s Lymphoma
Is a malignant neoplasm with features (e.g., fever, inflammatory cell infiltrates) resembling an inflammatory disorder. So patient may go years without getting chemotherapy if undiagnosed

Is based on the degree of dissemination, involvement of extra lymphatic sites, and presence or absence of systemic signs such as fever
Bodily Involvement in Hodgkin’s Lymphoma
Neck and Mediastinum = 60-70%

Spleen = 35%

Para-aortic nodes = 30%

Inguinal and femoral nodes = 10%

Lung, liver, bone marrow, other in older patients = 5-10%
What percentage is B cells in Non-Hodgkin’s Lymphoma (NHL)?

T cell?
85% B-cell

15% T cell
What are the most common NHLs abnormalities in B cells ?

T cells?
CD19, CD20, sIg, CD10 (B-cells)

CD2, CD3,CD4,CD7, CD8 (T-cells)
What are the lymphomas that pertain to Non-Hodgkin’s Lymphoma (NHL)?
Mantle Cell

Follicular cell

Burkitt's

MALT
What are the genetic abnormalities (chromosomes and genes) of

Mantle cell lymphoma
t(11;14) bcl-1 proto-oncogene on 11

Causes overexpression of Cyclin D1 or Prad-1 or bcl-1
What are the genetic abnormalities (chromosomes and genes) of

Follicular Cell Lymphoma
t(14;18)(q32;q21) expression of bcl-2 (oncogene)

The most common form of Non-Hodgkin’s Lymphoma (NHL)
What are the genetic abnormalities (chromosomes and genes) of

Burkitt's lymphoma
AKA Small cleaved cell
Most common
t(8;14)(q24;q32) c-myc ; IgH gene

Other variants are
t(2;8)(p13;q24) IgK; c-myc
t(8;22)(q24;q11) IgLambda; c-myc
What are the genetic abnormalities (chromosomes and genes) of

MALT lymphoma
t(11;18)(q21;q21) api2; malt-1 genes
What are the characteristics of

Mantle cell lymphoma
Over expression of cyclin D1 (turns on cell cycle)

Cyclin D1 or PRAD-1 or bcl-1 is one of the key cell cycle regulators, and functions in association with cdk4 and / or cdk6 by phosphorylating the Rb protein.

It is a putative proto-oncogene overexpressed in a wide variety of human neoplasms including mantle cell lymphomas (MCL).
What are the characteristics of

Follicular Cell Lymphoma
Is a low-grade B-cell lymphoma, frequently following an indolent course in older persons.

Is the most common form of non-Hodgkin’s lymphoma.

; bcl-2 codes for an inter mitochondrial protein that interferes with apoptotic cell death.

Overexpression of Bcl-2 prevents the efflux of cytochrome c from the mitochondria and the initiation of apoptosis.
What grade ? What involvement of the body?

Burkitt's lymphoma
Is a high-grade (aggressive) B-cell lymphoma.

The African form involves the maxilla or mandible; the American form usually involves abdominal organs.

Is closely linked to EBV infection (especially in the African variety).
What are the characteristics of

MALT lymphoma
Mucosa-Associated Lymphoid Tissue

Chronic infection of the stomach by Helicobacter pylori.

Now, there is further evidence of linking Campylobacter jejuni, Borrelia burgdorferi and Chlamydia psittaci infection with immunoproliferative small intestine disease, MALT lymphoma of the skin and ocular adnexa respectively.

Localized to the stomach, indolent course.

Can be cured in many cases by antibiotics against H. pylori.
What are the characteristics of

MALT lymphoma
Mucosa-Associated Lymphoid Tissue

Chronic infection of the stomach by Helicobacter pylori.

Now, there is further evidence of linking Campylobacter jejuni, Borrelia burgdorferi and Chlamydia psittaci infection with immunoproliferative small intestine disease, MALT lymphoma of the skin and ocular adnexa respectively.

Localized to the stomach, indolent course.

Can be cured in many cases by antibiotics against H. pylori.
Real Classification of Non-Hodgkin’s Lymphoma (NHL)
1)Indolent (low risk)
a)CLL/SLL; Waldenström’s macroglobulinemia; follicular lymphoma

2)Aggressive (intermediate risk)
a) Mantle Cell Lymphoma; follicular large cell; diffuse large B cell; primary mediastinal large B cell

3) Very Aggressive (High Risk)
a) Precursor B-lymphoblastic; Burkitt’s
Lymph node biopsy workup
H/E stain

Immunohistochemistry
monoclonal AB for specific markers ( +/- expression)

Flow cytometry

Molecular studies (Southern blot, PCR)

Cytogenetics- karotyping of chromosomes
In Multiple Myeloma, What is normally the largest peak on a gel electrophoresis
Albumin
In Multiple Myeloma, What is abnormally the largest peak on a gel electrophoresis
IgG
In Multiple Myeloma, What is the M spike?
A protein normally found on the surface of cells; serum levels reflect the extent of disease

The M-components (monoclonal overproduction are responsible for myeloma protein-related clinical manifestations such as :

Hyperviscosity syndrome
Cryoglobulinemia
Amyloidosis
In Multiple Myeloma, what are the prognostic factors for albumin?
Serum levels often an indication of general health status; higher levels may indicate better prognosis ≥3.5 g/dL
Clinical Stages of MM
Monoclonal Gammapathy of undetermined significance (MGUS)

Indolent

Smoldering

Multiple Myeloma

Plasma Cell Leukemia
MGUS
Monoclonal Gammopathy of undetermined significance

MGUS-->Aneuploidy or 1% of MGUS==> Plasma Cell Myeloma (PCM)
Plasma cell dyscrasias
Malignant plasma cells do not function properly and their increased numbers produce excess immunoglobulins of a single type (M proteins) that the body does not need along with reduced amounts of normal immunoglobulins.
Role of Bence-Jones proteins and renal failure
Renal failure is complex, but the excretion of monoclonal light chains appears to play a predominant role:

• Bence Jones protein are readily filtered by the renal glomeruli in MM 84% free light chains 16% BJ protiens

• Increase in re-absorption load, leading to renal failure
T-cell receptor rearrangements
7p15, 7q35, 14q11
Mycosis fungoides
Cutaneous T-cell Lymphomas Mycosis fungoides

Present as an erythematous, eczematoid, or psoriasiform process, progressing to raised plaques and then to a tumor stage.

Is marked histologically by dermal infiltrates of atypical CD4+ T-cells with cerebriform nuclei.

Small pockets of tumor cells within the epidermis are referred to as Pautrier’ s microabscesses.

Eventually disseminates to lymph nodes and internal organs.
Double minutes/episomal gene amplification
Double minutes are small fragments of extrachromosomal DNA, which have been observed in a large number of human tumors

They are a manifestation of gene amplification during the development of tumors, which give the cells selective advantages for growth and survival.

They frequently harbor amplified oncogenes and genes
episomal gene amplification
NUP214-ABL1
• T-ALL Genetic abnormality
INK4/ARF locus at 9p21
Hypotheses for less common T-cell neoplasms
Hypothesis 1: Somatic mutation of the receptor does not take place in the periphery like B cells. This may protect T cells from promiscuous mutations.

Hypothesis 2: DNA repair mechanisms may be more efficient in T cells

Hypothesis 3: Turnover mechanisms may be more efficient at recognizing and eliminating damaged T cells than B cells.
T-cell development
During T-cell development genes important in thymocyte development are in open chromatin configuration which makes them vulnerable to the action of recombinase enzymes.

Aberrant expression can give rise to T-ALL with differentiation lack at various stages of maturation

T-cell commitment mediated by expression of GATA-3 transcription factor or Notch-1 transmembrane receptor signaling.

ProT cell (CD34, CD 38, CD44 positive) migrates to the thymus where it enters the cortex expresses CD2 and proceeds through steps of maturation while migrating toward the medulla.

Tripotential
Gamma/delta receptors (fetal development)
Alpha/beta receptors (predominates after birth)
NK cells
Genetic abnormality of Anaplastic Large cell lymphoma ?

Which lymphoma does this belong to?
t(2;5)(p23;q35) alk; npm

T-cell lymphoma