Development of Cells in the Adaptive Immune Response Flashcards
B-2 Cells
Develop after birth
Do not express CD5 glycoprotein
Replaced from bone marrow
Primary location is lymphoid organs
Produces only highly specific antibodies
Naive Cell Populations and their genotype
gamma delta T cells: CD3+gammadelta TCR+CD4-CD8- T cells
Helper T Cells: CD3+alphabeta TCR+CD4+CD8- T cells
Cytotoxic T Cells: CD3+alphabeta TCR+CD4-CD8+ T cells
What happens in Positive Selection?
- The Double positive cells bind to MHC I or MHC II on epithelial cells. Successful binding renders the cell MHC-restricted to self
- Binding to either MHC I or MHC II causes the other MHC molecule (CD4 OR CD8) to be eleminated and cells become single positive
- Self MHC-restricted cells move on to the medulla
T- Cell Maturation (Phase 1)
- T Cell precursors from the bone marrow enter the thymus
- T Cell lacks TCRs, CD3, CD4, CD8 surface and express early developmental antigens
- Beta chain rearranged by DN3 and pre-TCR expressed
- DN4 caused alpha chain rearrangement, with allows expression of a Double Positive aB TCR
MHC II pathway
- The antigen enters the macrophage
- It is ingested by lysosomes and then spit out
- Antigen then binds to the MHCII molecule
- The MHCII molecules goes to the surface of the cell, wheere it binds to the T- cell receptor of the Helper T cell
What components make up the surrogate light chain?
VpreB and gamma5
DN2 (Genotype, Location, Description)
Genotype: c-kit (CD117)++, CD44+, CD25+
Location: Subcapsular Cortex
Description: TCR gamma, delta, and Beta chain rearrangment; T- cell lineage commitment
Failure of light chain to rearrange leads to _________ or ____________
Apoptosis; light chain editing
Signals sent once Pre-TCR is formed by Beta chain rearrangement
Cell becomes permissive for TCR alpha-chain locus arrangement
Stimulates expression of CD4 and CD8 coreceptors
Stimulates proliferation
Stops additional TCR Beta-chain locus rearrangement
Other cells arising from Double Positive thymocytes
Natural Killer T cells- Innate Immunity, expresses TCR with invariant alpha chain. Binds to CD1, not classical MHC
Tregs- CD4 CD25
IELs (intraepithelial)- innate immunity, CD8, mucousal surfaces
TH17- Inflammation; protects againts fungal and bacterial infections
DiGeorge Syndrome results from delection in chromosome __________
22
Bruton’s Hypogammaglobulinemia
X-linked agammaglobulinemia (XLA)
Extremely low IgG levels and absence of other Ig classes
Babies are born with very few peripheral B cells and suffer recurrent bacterial infections
Defect in Bruton’s Tyrosine Kinase which is required for signal transduction through the pre-B/ B cells receptor; without functional Btk in developing B cells, cell development is arrested at pre-B stage
Heavy chain rearranged but light chains reamin in germline configuration
Disease manageable with antibiotics and passively administerd antibodies
What are the 10 Warning Signes of Primary Immunodeficiency
- Four or more new ear infections within 1 year
- Two or more serious sinus infections within 1 year
- Two or more months on antibiotics with little effect
- Two or more pneumonias within 1 year
- Failure of an infant to gain weight or grow normally
- Recurrent, deep skin or organ absesses
- Persistent thrush in mouth or fungal infection or skin
- Need for intravenous anitbiotics to clear infection
- Two or more deep-seated infections including septicemia
- A family history of Primary Immunodeficiency
The CD3 complex is composed of 4 distinct chains: __________,_________,____________, and ________
2 Episilon, delta, gamma,
Hyper IgE Syndrome (Job’s Syndrome)
Autosomal dominant mutation in the STAT3 gene
STAT3 gene is involved in intracellular signaling induced by IL-6 and TGF-Beta
Important in TH17 cell differentation
TH17 protects against fungal and bacterial infections; role in inflammation
Characterized by: Skin abscesses, recurrent pneumonia, eczema, elevated IgE, facial abnormalities, and bone fragility
What are the subsets of B cells?
B-1 cells (minor subset)
B-2 Cells (major subset)
Marginal Zone B cells
Which cells rearrange the Beta chain gene?
DN3
Functions of gamma- delta T cell
Lysis of infected or stressed cells
Cytokine and chemokine production
B cell help and IgE production
Priming of alphaBeta T cells via antigen presentation
Dendritc cell maturation
Regulation of stromal cell function via growth factor production
In the ________ stage, Double positive cells express a mature _______________
DN4; alphaBeta TCR
What happens in negative selection?
- Cells again bind to self MHC
- Medullary epithelial cells express AIRE transcription factor which facilitates the expression of tissue specific proteins to which thymocytes bind
- If those cells binds to avidly to MHC, self-peptide will undergo apoptosis and die
Checkpoints for B -Cell Receptor Development
- The early pro-B Cell commitss to the B-cell lineage
- Heavy chain rearrangement: Generates heavy chain gene diversity in pro- B cell population
- First checkpoint: Selects for functional heavy chain
- Light chain gene rearrangement: Generates light chain gene diversity in pre- B cell population
- Second check point: Selects for functional light chains
- Immature B cell: Makes functional IgM
Stages of B cell Development
- Lymphoid stem cell
- Pro B cell
- Pre B cell
- immature B cell
- Naive B cell
- Mature B cell
Positive selection occurs in the ___________
Cortex
Which immunoglobulins are present of Mature B cells?
IgM and IgD
Marginal Zone B cells
Located in the outer cones of white pulp of the spleen
First B cells encountered by blood-borne antigens which enter the spleen
Broadly cross reactive antibodies (IgM)
Do not require T cell help
DN1 (Genotype, Location, Description)
Genotype: c-kit (CD117)++, CD44+, CD25-
Location: Bone Marrow to Thymus
Description: Migration to thymus
Failure of heavy chain to rearrange leads to __________
apoptosis
Which DN stage expresses a double positive, mature alphaBeta TCR?
DN4
B cell Maturation
- VCAM 1 binds VLA-4 on pro-B cells
- SCF binds c-kit on pro-B cells
- IL-7 binds IL-7 receptor
- Pre- B Cells Formed
- Immature B cells formed
Negative selection occurs in the ____________
Medulla
DN3 (Genotype, Location, Description)
Genotype: c-kit (CD117)+, CD44-, CD25+
Location: Subcapsular cortex
Description: Expression of pre-TCR; Beta selection
MHCI pathway
- Antigen is intracelluar and cell is infected
- The viral DNA leaves nucleus and is transcibed to viral mRNA
- The viral mRNA is translated to viral peptides.
- The viral peptides bind to the MHC I
- The MHCI goes to the serve of the cell
- The T cell receptor binds the the peptide, which is still attached to the MHCI
7.
DiGeorge Syndrome
Results from delections in chromosome 22
T box transciption factor delection most significant
Occurs during embryonic development when facial structures, heart, parathyroid, and thymus are forming
Patients present with symptoms not only of immunodeficiency, but hypothyroidism and congenital heart anomalies, cleft palate, delayed development; behavioral and emotional problems
Degrees of DiGeorge syndrome vary widely
Severe DiGeorge syndrome leaves patient no T cell function and therefore poor antibody response
Patients susceptible to all kinds of opportunistic pathogens, bacterial, viral, fungal
What is the role of CD4+?
It lines up the receptor and the MHCII molecule
Bone marrow _________cells support B cell development by stabilizing them in the bone marrow long enough to receive signals for differentation.
Stromal
What effect does notch have on T cell?
Notch signaling regulates cell fate decisions during development.Notch signaling is essential for initial commitment to the T cell lineage and may function together with signals from the pre-TCR and the TCR to regulate subsequent steps of T cell development.
Thymocytes that successfuly rearrange gamma and delta genes will express __________. Once this component is expressed what happens?
CD3. Gamma, delta T cell is ready to leave the thymus
DN3 cells will bind a pre alpha chain, forming a _________and express __________. Cells are then committed to a ____________ lineage.
Pre-TCR; CD3; alphaBeta TCR
Reticular Dysgenesis
Disruption in hematopoietic cell development
All downstream development impaired
Condition called De Vaal’s Syndrome
Symptoms include: Severe opportunistic infections (bacterial, viral, and fungal), severly impaired development, underdeveloped thymus, reduced lymphocytes, and severe leukemia)
B-1 Cells
Develop early in embryonic life
Express CD5
Self renewing
Primary location is body cavities
Produce polyspecific antibodies
Source of natural antibodies (IgM)
Part of the first line defense against invasion by a variety of bacterial organism
Do not require T cell help
What differentiates the Pre-B cell receptor from the B-Cell receptor?
The presence of the surrogate light chain (VpreB and gamma5)
Treatment for DiGeorge Syndrome
Limited Thymus Function- Infections recurrent but may not be severe; treatment same as with normal childhood infection
Severe Thymic Dysfunction- Susceptible to all types of infections; thymic transplant
DN4 (Genotype, Location, Description)
Genotype: c-kit (CD117) lowf-, CD44-, CD25-
Location: Subcapsular cortex to the cortex
Description: Proliferation, allelic exclusion of B chain locus; alpha- chain locus rearrangement begins; becomes double positive thymocyte
Final step of lineage determination
DN2
