9/24 Flashcards
Allogenic vs. Autogenic
Allogenic: two members of the same species who are genetically different
Transplant will be rejected unless therapeutic intervention
Autogenic: cells or tissues that are derived from the same individual, twins count as autogenic
Major Histocompatibility Complex
Cluster of genes on Chromosome 6, also called human leukocyte antigens
Present on WBCs but not RBCs, allows adaptive immune cells to distinguish self from non-self
MHC Class I
HLA-A to HLA-G but no HLA-D
HLA-A,B,C are highly polymorphic and present antigens to T cells, heavy chains with monomorphic beta2-microglobulin
Expressed on almost all cells but not RBCs
MHC Class II
HLA-DM,DO,DP,DQ,DR
HLA-DP,DQ,DR are polymorphic and present antigens to T cells
Expressed on professional antigen presenting cells like APCs, dendritic cells, macrophages, and B cells
Antigen Processing and Presentation
MHC Class I: intracellular proteins degraded by proteasomes into peptide antigens, transported to ER by transporter associated with antigen processing (TAP), loaded onto peptide-binding glove of MHC Class I molecules
Present to CD8 T cell (Cytotoxic T cell) to kill/lyse
MHC Class II: same but professional APCs engulf proteins in extracellular environment and degrade via phagolysosome
Present to CD4 T cell (helper T cell) to release cytokines
Antigen Presentation by B cell
B cell is triggered when it encounters its antigen binds, engulfs antigen and degrades in phagosome, displays antigen fragments on its MHC Class II receptor, helper T cell looks at MHC Class II receptor and releases cytokines to help the B cell multiply and mature into plasma cells that release antibodies
B Cell Activation: Helper T cells (TH1 or TH2) provide signals to B cells via CD40L/CD40 and cytokines that activate B cells and induce isotope switching, CD4 T cells become reactivated by antigen presentation and produce more cytokines
Killing of Pathogens by B Cells
Classical Complement Pathway
Opsonization: Fc receptors on phagocytes and NK cells bind to the Fc end of antibodies to mediate endocytosis and lysis
Thymic Education
Primary purpose of T cell development is to generate diverse repertoire of T cells that distinguish between self and nonself
T Cell Development Pathway
T cell precursors originating from the bone marrow to the thymus in the blood
Mature naive T cells leave the thymus and travel to the secondary lymphoid tissues like lymph node, spleen, gut associated lymphoid tissue (GALT)
DiGeorge’s Syndrome
Fail to develop a thymus, severely immunocompromised
Deletion in Chromosome 22
Cell Surface Markers Associated with T Cell Development
- CD34+ proginetor cells enter thymus via blood vessels
- Interact with stromatolites epithelial cells and the immature T cells divide and differentiate
- Stem cell markers (CD34 and CD44) are downregulated and T cell-specific markers are upregulated
- IL-7 produced by stromatolites cells is a critical initial step in thymocyte differentiation
Mutations in IL-7 receptors result in no T Cell Development and Severe Combined Immunodeficiency Syndrome
Double Negative T Cell Proginetor
Happens in sub-capsular region of thymic cortex
Beta, gamma, and delta rearrangement occur first
1-5% have gamma and delta chains rearrange first, no MHC presentation on surface, like innate immune cells since traffic to Inflammation site due to specific chemokine receptor expression
Un-committed double-positive thymocyte has beta chain with CD8 and CD4
Alpha, gamma, and delta rearrangement, gamma/delta rarely happen and lose CD4/8
Positive Selection
Retina Cells that recognize self MHC
Occurs only for alpha/beta T cells, happens in cortex of at cells
Only 2% of double positive thymocytes hav T cell receptors that can recognize self, positive selection retains those that can recognize self, destroy others
Cortical epithelial cells express self peptides, if a T cell receptor (alpha/beta chain receptor) binds effectively to MHC/peptide complex a survival signal is sent to the T cell, weak binding leads to T cell apoptosis
If TCR binds to MHC Class I then the CD8 receptor will also bind to MHC Class I Receptor, the CD8 receptor is upregulated and CD4 is downregulated, opposite for MHC Class II
Bare Lymphocyte Syndrome
No surface expression of MHC Class I or II molecules, due to transport defect
Severely immunocompromised
Negative Selection
Deletes self-reactive T cells
Occurs in the cortico-medullary junction of thymus
Involves dendritic cells and macrophages
Tight binding to MHC/peptide complex results in cell death
Autoimmune regulator (aire): TF expressed in thymus that promotes expression of different tissue genes in thymus at low levels
Autoimmune Polyendicrinolathy-Candidiasis-Ectodermal Dystrophy: die from increased susceptibility yeast infections, autoimmune problems
TCR Gene Rearrangement
Beta Chain Rearrangement: has V, D, J, and C regions (Alpha chain doesn’t have D region)
D region combines with J and excise DNA between, V region combines with DJ region and excise DNA in between
Alpha Chain a Rearrangement: V region combines with J region
How get vast heterogeneity:
1. Multiple V, D, and J segments
- Addition or deletion of bases during gene Rearrangement
- Different isotypes of alpha and beta for pairing
Naive T Cell Adhesion to Lymph Nodes
Lymph nodes express chemokines CCL19,21 from stromal and dendritic cells
Naive T cells express CCR7, a receptor for those chemokines
Get tighter binding and then do diapedesis
Activation of Naive T Cells
Dendritic Cells and Macrophages are APCs, express small amount of MHC receptors normally but have others like scavenger and TLR, activation increases expression of MHC and B7
Signal 1: TCR of T Cell binds to MHC/peptide Complex on APC
Signal 2: costimulation, CD28 of T Cell binds to B7 (CD80/CD86) on APC
Immunological synapse: region of contact/comm. between T cell and APC
T Cell Receptor Signaling
TCR is associated with the CD3 complex, cytosolic tails of the CD3 complex have immunoreceptor tyrosine-based activation motifs (ITAMS) which associate with protein tyrosine kinases (PTK)
PTKs (like Zap70) activated by TCR binding to MHC receptors, phosphorylated tyrosines in ITAMs
Signaling molecules bind to ITAMs and become activated, lead to changes in gene transcription
NkB induces expression of IL-2 and the alpha chain of IL-2 to make high affinity receptors, proliferation to get clinal expansion
CTLA-4
Unregulated on activated T cells, dampens T cell proliferation and cytokine production
Deficiency causes lymphoproliferative disease
CD4 T Cell Types
TH1: make IFN-gamma and IL-2
Activate macrophages/B cells, make opsonizing antibodies like IgG1
TH2: make IL-4 and IL-5
General activation of B cells to make antibodies
IFN-gamma and IL-4 suppress the differentiation of the other cell type, infections become biased towards one type of TH cell like Mycobacterium leprae
Macrophage Activation
Need two signals from CD4 TH1 Cells-
- IFNgamma
- CD40
Activation produces microcidal substances
B Cell Activation
Signal 1: antigen binds to B cell receptor
Signal 2: CD40 ligand on T Cells binds to CD40R, most potent activating signal for B cells, needed for isotype class switching
Triggers NF-kB mediated transcription of Adhesion molecules, strengthens cognate interaction between B and T cell
TH2 cell releases IL-4 to cause B cell proliferation/differentiation
CD8+ T Cells (Cytotoxic T Cells)
Cytotoxic T cells collide with infected cells, Adhesion molecules allow close contact for TCR to bind to MHC Class I
If infected: lytic granules in cytotoxic T cells will localize in area of cell contact, have perforin to make hole and granzyme to degrade proteins that can start apoptosis
Infected cell dies from apoptosis, cytotoxic T Cell can go to next cell
Immunological Memory
Most effector T cells die after responding to an infection, memory T cells live though
Memory T cells do immune surveillance in spleen, blood, and tissues
Do not depend on costimulation the second time so can use lower levels of antigen
Secondary T cell response is rapid, reason for vaccines
Integumentary System Components and Functions
Components-
- Skin
- Accessory structures and epidermal derivatives: oil/sweat glands, hair, nails
Functions-
1. Protection: physical, chemical, pathogenic, water loss/uptake, UV radiation
- Sensation
- Temperature regulation: sweat glands and dense vasculature do this
- Metabolic: make Vitamin D
- Waste elimination: ammonia, urea, water, salt
Layers of the Dermis
- Papillary Layer: superficial, loose connective tissue, ridges increase surface area of contact
- Reticular Layer: deep, dense irregular connective tissue, type III collagen and some elastic fibers
Skin Thickness
Gross Anatomy: epidermis and dermis
Upper back thickest at 5 mm, thinnest is scalp at 1 mm
Histology: epidermis only
Thickest is on soles of hands/feet at 400-1400 um, thinnest is 75-150 um
Fascia
Sheet of connective tissue that separates, supports, and/or interconnects different structures
Provide route for blood vessels, nerves, and lymphatics to travel
Superficial facia
Subcutaneous Layer
Hypodermis
Below dermis and above deep fascia, made of white adipose tissue and loose connective tissue, varies in thickness
Has an extensive vascular network
Binds skin to underlying tissue but allows skin movement, energy reserve and insulator
Deep Fascia
Below hypodermis and above muscle, made of dense connective tissue
Intermuscular septa form muscular compartments and permit travel of neurovascular structures to the muscles, retinacula to hold tendons in place, elastic stocking around muscles to help compress veins better
Different names based on body location
