Immunology - Leukocytes
*Leukocytes
*Lymphatic System
Notes:
- 2 ways lymphocytes can enter the lymph nodes
--> afferent lymphatic system route
--> blood vessel HEVs = high endothethial venules
*Lymph Nodes and Lymphocyte Maturation
- see lymphocyte page
T cell Development
T cell Development
B cell Development
Lymph Node Follicles
- either Primary lymph follicles
--> dormant B cells - Secondary follicles
--> formation of germ centres
--> active proliferation of activated plasma B cells
Primary Lymph Follicles = Dormant
- Plasma B Cells waiting to be activated
Clinical Cases
Clinical Case
Notes:
- note that
Clinical Case
Secondary Lymph Follicles with Germ centres
- Activated Plasma B Cells in Lymph Nodes
- form germ cells within follicles
Notes:
- note that there are two parts of releasing activated plasma B cells into the plasma for giving off antibodies in primary response
- these two parts have switched % of plasma cells,
- first part has little bit, most migrate to lymph nodes to form germ centres
--> most initial response are IgM - second part in the germ centres, only few become dormant long term memroy cells for that antigen, majority will class switch in the germinal centre and release as different isotypes for that antigen as plasma cells
--> most second response are IgG
Part 1 = initial activation of naive B cells in the lymph organs or peripheral tissues
- few become activated initial response IgM plasma cells that go out right away
- majority migrate to the lymph nodes to form germinal centres
Part 2 = Germinal centre dormant memory cells and isotype class switch + release second wave of troops
- few become memory cells and lay dormant in the germ centres
- most go through CD40 class switching from T cells to GAMED isotypes
- most become IgG = second wave of antibodies
Primary Development
In Bone Marrow
*Hematopoesis
*Common Myeloid Progenitor Cells
3 groups to MYeloid progeninator cell lines...
"ME, MY uncle BEN, and the OMEGA"
ME = Mast cells and Erythrocytes are one group
MY uncle BEN = myeloblasts make the biggest group
--> Basophils, Eosinophils, Neutrophils and Monocytes
OMEGA = megakaryocytes are their own group
--> they form platets
Myeloblasts
- ME and MY uncle BEN and the OMEGA
*Mast Cells
- ME and MY uncle BEN and the OMEGA
IgE - Independent Mast Cell Degranulation
Notes:
- IgE independent Mast cell degranulation happens from very specific drugs
--> most common are oppioids - works NOT through activating IgE antibodies, but through cAMP path of PKA and through Gq PI3 kinase path (=Tyrosin kinase reccptors)
- extreme itching of the arms, legs and back
--> does this get worse on more exposure like in allergic reactions?
Clinical Cases
Clinical Case
Clinical Case
Notes:
- note that
*Megakaryocytes
- ME and MY uncle BEN and the OMEGA
*RBCs = Erythrocytes
- ME and MY uncle BEN and the OMEGA
*Common Lymphoid Progenitor Cells
Small lymphocytes
*Lymphocytes
*Activation of B cells and T cells
- T cell Co stimulation / regulation
--> Th cell rule of 7 x 4 = 28
--> B7 on APC binds
--> CD28 on Th cell = co STIMULATE
--> CTLA-4 on Th cell = co REGULATE
--> separate PD-1 on Th cell = co REGULATE - B cell class switching = CD40 Ligand and CD40
--> "CD40 is 4 Different classes"
*NK = Natural Killer Cells
- lymphoid cells, BUT for the innate immunity
--> cytoctoxic = kill virally infected cells and tumor cells - NO COUNTRY FOR OLD MEN - NATURAL KILLER
--> air compressor = perforins poke holes
--> granzymes go through the perforins holes and cause apoptosis - Granulocyte that kills cells that have no MHC1 antigen on their surface
--> NK only kills them if they get the coin flip wrong - express special CD 16 and CD56
--> think of NK travelling in texas on Route 16 + Route 56
*T cells
- 3 types of T cells
--> CD4/MHC2 = Th helper cells
--> CD8/MHC1 = Tc cytotoxic Tcells
--> CD3(general) = regulatory T cells
--> CD25 + FOX = specific regulatory markers
CD 8+ T cells = Killer Cytotoxic T cells
T cell Development
- see lymph nodes
CD 4+ T cells = Helper T cells
- sub classes TH1 and TH2
TH1 and TH2 Case example
Notes:
- note that T helper cells = CD4+ are first naive t helper cells
--> they are then activated by APCs to either go into TH1 or TH2 cells
--> this depends on the type of cell that activates them and hence the cytokines that are released from the APC - think IL-4 are again "for helping" --> they activate the secondary measure = TH2
--> TH2 then secretes many interleukins for stimulaing the B cell antibody response - for macrophage activation from TH cells, this requires the t cell to be activated itself by a macrophage
- if the APC is a macrophage, it release IL-12 or IFN-gamma
--> IL-12 and IFN - gamma differentiate the naive Th cell into TH1 - TH1 then activates direct cell madiate immunity
--> macrophages and CD8 killer t cells
Clinical Case
Infectious Mononucleosis (Mono) and Reactive Lymphocytes
- secondary to EBV usually
- reactive macrophages release perforin and granzymes
- granzymes = granular enzymes = grandiose apoptosis
Clinical Case
Notes:
- note that Infectious mononucleosis from EBV are reactive cytotoxic lymphocyte = mostly natural killer cells and t cells
- they have cytotoxic granuoles = perforin and granzymes
*Macrophages
Specialized
Macrophages
Langerhan's Cells
- specialized macrophages of the dermal layers of skin
Example:
Notes:
- Langerhans cells are specialized macrophages in the dermal layers of the skin
--> Langerhans cells are "longer hands" - Kupffer cells are specialized macrophages in the venous system of the liver
--> Kupffer cells cuff "alcoholics" = found in the liver
*Granulocytes
- My Uncle BEN...
- basophils, Eosinophils, neutrophils
*Eosinophils
- it's EAZY eatin parasites when you're PAACN alot of MBP
- helminths = parasites
it's EAZY eatin parasites when you're PAACN alot of MBP = major basic protein
- P = parasites
- A = asthma
- A = allergic
--> Ellergic IgE and IL-4 - C = chronic adrenal insufficiency
- N = neoplasms
Mastocytosis
- Mast cells mainly release Histamine
- thus mastocytosis presents with anything with H1 and H2 receptors
- H2 in the stomach --> high gastric acid and ulcers
*Left shift vs Right Shift Leukocytosis
- Left shift = regressive = high number of immature leukocytes in the blood
- right shift = HSN = hypersegmented neutrophils in the blood
*Right Shift Leukocytosis
- Left shift = regressive = high number of immature leukocytes in the blood
- right shift = HSN = hypersegmented neutrophils in the blood
*Left shift Leukocytosis
- Left shift = regressive = high number of immature leukocytes in the blood
*DRESS Syndrome
- DRESS = Drug Reaction Eosinophilia / SYSTEMIC symptoms
- from a drug 2-8 weeks after starting it
- very common with certain AEDs
--> similar to Steve Johson syndorme?
*Neutrophils
- granulocyte
- part of
--> My Uncle BEN...
--> basophils, Eosinophils, neutrophils
*B cells
VDJ Rearrangement
- how B cells make many different kinds of antibodies
B Cell *Activation
- require dimerization of B cell receptors
- tyrosine protein of the receptors come together and release cascade that makes NF-kappa-B
- NF-kappaB = is pro-inflammatory gene regulator
--> makes the initial pro-inflammatory chemokines
= IL 1, 6 + TNF-Alpha - also makes IL - 2 = B cell autocrine/paracrine proliferator
- makes BCL-2 = antiapoptosis factor
--> is a fail safe to prevent the IL2 proliferation from being stopped
Default Plasma cells = B cells begin as IgM Plasma Cells
CD 40 Class Switching of B cells
- B cells have CD 40 used for class switching
- CD40L on T h cells activates the B cell to class switch to a different antibody
- CD40 = "4D = 4 Different classes"
- think of B cells as NAIVE and STUPID
- they Th cell once binds CD40L to CD40 for class switch
- also send cytokines to the B cell to tell it what kind of antibodies to make
Cytokines and Class Switch
Exon Splicing for Class Switch
- VDJ region
- AIDs
Example- IgG differention
click to edit
click to edit
IgM Plasma cells
- can be class switched to other IGs
- done by activated Th cells
once a plasma b cell is class switched from IgM
--> it can NEVER reverse back to IgM class
Secondary CD21 B cell activation
- Bcells can also be activated through the secondary CD21 pathway
--> complement system pathway
Notes:
6 and 6 rule for B cells
- 6 month rule
--> most mature B cells will never be activated and will live for 6 months before they are degraded and new B cells are made - 6 week rule
--> if a B cell is activated into a plasma cell
--> thus producing antibodies
--> regardless of the class type, this plasma cell will survive for ONLY 6 weeks before degraded
--> it will also not proliferate during this time
B cell Receptors
- are essentially antibodies attached to B cells with a transmembrane part to them
- their variable region is called the Fab region
- Fab = fragment antigen binding site
--> Valence refers to the amount of Fab or binding availability different antibodies have - As B cells mature they release their B cell receptors as antibodies
Notes:
- T cells are made in the bone marrow initially
- they migrate to the thymus in 1st trimester gestation of fetus
- T cells are double negative for both CD 4 and 8 at the thymus
- also TCR = toll cell receptor negative
- they develop from the outside in
--> cortex to medulla - cortex --> positive selection for TCR that works and CD4 8 +
- medulla = negative selection
--> they lose one of their CD4 or CD8
Cases
T cell maturation
Notes:
- note that both T cells and B cell are made in the bone marrow
--> T cells then migrate and mature in the thymus and B cells remain in the bone marrow to mature
--> reason why T cells are called thymocytes - T cells go from
--> Pro - T cells (double negative, arrive at the thymus)
--> immature T cells (double positive = CD4 and CD8)
--> they then go from cortex (positive selection) to the medulla (negative selection)
--> mature T cells with either CD4 or CD8
Clinical Case
T cell maturation case 2
Notes:
- note
Clinical Case
*Activation of T cells
- T cell Co stimulation / regulation
--> Th cell rule of 7 x 4 = 28
--> B7 on APC binds
--> CD28 on Th cell = co STIMULATE
--> CTLA-4 on Th cell = co REGULATE
--> separate PD-1 on Th cell = co REGULATE
Th cell *rule of 7 x 4 = 28 for T cell CO stimulators/regulators
- B7 on APC binds
--> CD28 on Th cell = co STIMULATE
--> CTLA-4 on Th cell = co REGULATE - separate PD-1 on Th cell = co REGULATE
*Mabs blockers for PD and CTLA-4 = Cancer Immunotherapy
- used in melanoma and RCC
*Anatomy of Lymph Nodes
- paracortex = T cells in the paracortex around the centre of the lymph nodes
--> here the APCs = dendrocytes present antigens to the T cells there - germinal centres = B cells lay dormant in the germinal centres
--> they wait for the activated T cells to activate them and tell them which antibodies to produce
NADPH oxidase killing by Neutrophils
- NADPH is the main enzyme that starts off the reaction
--> NADPH makes superoxide, then superoxide, then bleach finally = OHCl
Different types of Neutrophils
- left shift = band cells
*Left Shift Neutrophils
- just like BLAST cells, IMMATURE neutrophils have fatter and bigger nuclei that go from
--> metamyelocyte
--> to BAND NEUTROPHIL
--> to a hypersegmented 3 nuclei - get a left shift in response to infection
Causes of Left Shift and Raised Neutrophil count
- bacterial infection
- chronic infection leads to BENIGN LEUKOMOID REACTION
*BENIGN LEUKOMOID REACTION
- Causes Left Shift and Raised Neutrophil count
- get DOHLE bodies as well
--> these are ribosomes = blue
*DOHLE bodies
- these are ribosomes = light blue
Clinical Cases
Clinical Case
Clinical Case
Notes:
- note that
Different types of RBC inclusion bodies
- splenectomy = Howell- Jolly bodies
*Basophillic Stipplin
- stippling = means ribosomes collecting up
- this means there are abnormal proteins or something wrong with protein synthesis
- in RBCs this means usually problem with HEME synthesis
--> Thal, sideroblastic, lead poisioning, etc.