Transcript bacterial agents and in vitro susceptibility patterns

THE DEVELOPMENT OF
T LYMPHOCYTES
DEVELOPMENT OF T LYMPHOCYTES
* Development of T and B cells have similarities and
differences
* Similarities
* Derivation from stem cells in BM
* Antigen receptors produce by gene rearrangements
* Differences
* B cells rearrange receptor genes in BM while T cells rearrange
receptor genes in thymus
* T cell receptors have MHC restriction
DEVELOPMENT OF T LYMPHOCYTES
* T cells originate from stem cells in bone marrow and
migrate to thymus to mature
* Thymus
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*
*
Lymphoid organ in upper anterior thorax
Primary lymphoid organ
Fully developed before birth
Increases in size until puberty then degenerates
Degeneration has no discernible impact on T cell immunity
CELLULAR ORGANIZATION OF THE
THYMUS
* Consists of two symmetrical lobes each enclosed by
capsule from which trabeculae extend and divides each
lobe into lobules
* Lobule consists of
* Cortex
* Immature thymocytes, cortical epithelial cells and macrophages
* Medulla
* Mature thymocytes, medullary epithelial cells, dendritic cells and
macrophages
DEVELOPMENT OF T CELLS IN
THYMUS
* Immature cells enter thymus at subcapsular region of outer
cortex
* Express neither CD4 nor CD8
* Called “double-negative” thymocytes
* Double negative thymocytes initially express
* CD44 and CD25
* CD44 expression declines
* Rearrangement of genes for beta, gamma and delta chains
DEVELOPMENT OF T CELLS IN
THYMUS
* Lineages of T cell receptors
* Alpha:beta
* Gamma:delta
* “Thymocytes, start your rearrangements”
* Productive rearrangement of gamma and delta genes
* Gamma:delta receptor
* Productive rearrangement of beta gene
* Rearranged beta chain assembled with surrogate alpha chain (pTalpha) to form “pre T cell receptor”
* Alpha:beta receptor
GENE REARRANGEMENT IN
ALPHA:BETA T CELLS
* Beta chain rearranges first with potential 80% success rate
* Locus on homologous chromosome
* Two sets (beta 1 and 2) of D, J and C gene segments
* Beta chain combines with
* Surrogate alpha chain (pT-alpha), CD3 and zeta
* Pre T cell receptor
* Beta chain rearrangement stops and CD4 and CD8
expressed
* “Double-positive” thymocytes
* Alpha chain rearranged and pairs with beta chain
POSITIVE AND NEGATIVE SELECTION
OF DOUBLE POSITIVE
T-LYMPHOCYTES
* Alpha:beta T cells are screened
* Positive selection
* Selection of immature T cells which recognize self MHC
molecules
* Negative selection
* Elimination of immature T cells which are activated by self
peptides
* Gamma:delta T cells are not screened
POSITIVE SELECTION OF ALPHA:BETA
T CELLS
* Takes place in cortex of thymus
* Mediated by self peptide:self MHC molecules presented
on surface of cortical epithelial cells
* Cortical epithelial cells express
* MHC class I and MHC class II molecules
* T cells which recognize self peptide:self MHC continue
maturation
* T cells which do not recognize self peptide:self MHC
commit apoptosis
POSITIVE SELECTION CONTROLS
EXPRESSION OF CD4 AND CD8
CO-RECEPTORS
* “Double-positive” thymocyte interacts through its
alpha:beta receptor with either
* MHC I or MHC II
* Interaction results in “single-postive” thymocyte
* Interaction with MHC I results in CD8 T cells
* Interaction with MHC II results in CD4 T cells
* Mechanism by which interaction selects for “singlepositive” thymocytes is unknown
BARE LYMPHOCYTE SYNDROMES
* Immunodeficiency showing importance of MHC
molecules in selection of co-receptors and T cell
development
* Disease characterized by
* Severe immunodeficiency
* Lack of expression of either MHC I or MHC II by lymphocytes
and thymic epithelial cells
* Persons who lack expression of MHC I
* CD8 (-) and CD4 (+)
* Persons who lack expression of MHC II
* CD8 (+) and CD4 (-)
REMOVAL OF T CELLS SPECIFIC FOR
SELF ANTIGENS IN THYMUS BY
NEGATIVE SELECTION
* T cells which strongly bind self peptide:self MHC
molecules are potentially autoreactive
* Negative selection mediated by
* Dendritic cells and macrophages at cortico-medullary junction of
thymus
* Autoreactive T cells undergo apoptosis
* Mechanisms of positive and negative selection unknown
* Positive and negative selection results in highly
personalized T cell immunity
DEVELOPMENT OF T CELLS AFTER
LEAVING THYMUS
* Small percentage of alpha:beta T cells survive positive and
negative selection
* Mature naïve T cells recirculate between blood and
secondary lymphoid tissues
* Mature T cells are longer liver than mature B cells
* Encounter with antigen
* T cell rich areas of secondary lymphoid tissues
DEVELOLPMENT OF T CELLS AFTER
LEAVING THYMUS
* Following activation by antigen T cells differentiate into
different effector cells
* CD8 to cytotoxic T cells
* CD4 to
* TH1
* TH2
* Healthy individuals
* Twice number of CD4 as CD8 cells
* Flow cytometry
* Identification and enumeration of T cells
REFERENCE RANGES FOR T
LYMPHOCYTES IN ADULTS
Absolute #
Percent
CD3
782-2204
60-87
CD4
443-1345
31-58
CD8
171-914
13-40
CD4/CD8 ratio
> 1.0
T LYMPHOCYTES AND MALIGNANT
DISEASES
* T cell cancers primarily associated with
* Early and late stages of development
* Classification of malignant T-cells diseases
* Leukemia
* Malignant disease with origin in bone marrow
* Chronic lymphocytic leukemia (CLL)
* Lymphoma
* Malignant disease with origin in lymph nodes or lymphatic tissue
* Mycosis fungoides and Sezary syndrome
Figure 5-16
ACUTE LYMPHOBLASTIC
(LYMPHOCYTIC) LEUKEMIA (ALL)
* Approximately 4,000 new cases each year in US
* Most common cancer of children
* Majority resemble immature B cells
* B-ALL or C (common)-ALL
* Minority resemble immature T cells
* T-ALL
ACUTE LYMPHOBLASTIC
(LYMPHOCYTIC) LEUKEMIA (ALL)
* Causes
* Translocation of genes
* Philadelphia translocation involving 9 and 22 (20%)
* Acquired mutational event
* Effects
* Turns on oncogene
* Turns off tumor suppressor gene
* Results
* Large numbers of immature, abnormal lymphocytes produced in bone
marrow
* Decrease production of RBC, WBC and platelets with resulting clinical
manifestations
ADULT T-CELL LEUKEMIA /
LYMPHOMA (ATLL)
* Cutaneous T-cell lymphoma (CTCL)
* CD4 origin
* Incubation period
* 20 to 40 years
* Clinical courses
* Acute (aggressive)
* Chronic (indolent)
* Etiology
* Human T-Cell Lymphotrophic Virus I (HTLV-I)
ADULT T-CELL LEUKEMIA /
LYMPHOMA (ATLL)
* Human T-cell Lymphotrophic virus type 1 (HTLV-1)
* First human retrovirus identified
* Endemic in southern Japan, Caribbean and central Africa
* Uses CD25 to enter lymphocytes
* Virus is immunosuppressive and oncogenic
* Mechanism of immunosuppression
* Stimulation of CD4 TH1 cells
* Mechanism of oncogenicity
* Not well illucidated
* Tax protein central molecule
MYCOSIS FUNGOIDES (MF)
* Cutaneous T-cell lymphoma (CTCL)
* Most common (50%)
* CD4 T cells
* Etiology is unknown
* Clinical course
* Indolent
* Cutaneous patches to plaques to tumors (mushroomlike) w/wo pruritis
MYCOSIS FUNGOIDES (MF)
* Laboratory diagnosis
* Histopathology of skin biopsy
* Hematoxylin and eosin stain
* Immunohistochemical stains
* Treatment depends on stage
* Topical steroids and nitrogen mustards
* PUVA photochemotherapy
* Psoralens
* UVA radiation
SEZARY SYNDROME (SS)
* Cutaneous T-cell lymphoma (CTCL)
* CD4 origin
* Considered terminal stage of MF
* Clinical manifestations and course
* Skin is bright red, scaly and very itchy
* Entire skin involved, lymph nodes, viscera and blood
* Aggressive course
* Death by OI secondary to immunosuppression
SEZARY SYNDROME (SS)
* Clinical pathology
* Sezary cells (> 1,000/uL) in peripheral blood
* CD4/CD8 ratio of > 10
* Loss of normal T cell antigens
* CD2, CD5, CD7
* Anatomic pathology
* Skin biopsy shows
* Cerebriform lymphocytes in epidermis and upper
dermis with Pautrier’s microabscess formation
CASE STUDY
* 49 year WM presents with 3 month history of
* Lesions located on buttocks and hips
* Flat, pinkish-red patchy lesions
* Sometimes itchy
* Differential diagnosis of
* Eczema, psoriasis, contact dermatitis
* Treatment
* Topical and oral steroids
CASE STUDY
* Cutaneous rash and itch intermittent for 5 years
* Presents at age 54 with more extensive rash and itch
* Flat, pinkish-red patchy lesions (25%)
* Dry, slightly raised scaling plaques which are very
itchy (75%)
* Specimens
* Punch biopsy of skin for histopathology
* Blood for CBC with diff and flow cytometry
CASE STUDY
* Histopathology
* Hematoxylin / Eosin stain
* Dense infiltrate of medium sized cerebriform
lymphocytes in epidermis, upper dermis and
perivascular. Pautrier’s microabscesses present.
* Immunohistochemical stains
* Strong reactivity with CD3 and CD4 T cell antigens
* CBC showed < 1,000 Sezary cells/uL
* Flow cytometry showed CD4/CD8 ratio of 1.0