Flashcards in Immunology Test 2 Deck (344):
T Cells vs B Cells
T cells must be present at site of interaction with antigen presenting molecule; secretions are short range. B cells secrete antibody and don’t have to be present to see the result.
What activates T-Cells?
antiogen + Antigen presenting Molecule
is the precursor to all Helper T cells
Where do Th0 cells exist?
when presented by DC they move from afferent lymph to paracortex to show T-cells to cause them to divide and differentiate.
delayed hypersensitivity T-Cells; proliferate rapidly in lymph node; react with antigen precession cells and secretes cytokine to attract macrophages in Classically activate M1.
What does Th1 secrete when it encounters an APC?
IFN-gamma (a lymphokine and cytokine), as well as IL-2
is a pro-inflammatory cytokine that is chemotactic for macrophages
macrophages activated by IFNgama
classically activated to ingest bacteria and kill it.
Why does Th2 secrete IL-2?
help activate killer T-cells
What do the macrophages activated by Th1 secrete?
TNFalpha and IL-1
very similar to Th1, produces inflammatory IL-17 a more ferocious inflammatory agent than Th1.
what types of infection is Th1 involved in?
what types of infection is Th17 involved in?
fungal infections, and autoimmunity
what method of activation does Th17 utilize for its macrophages?
Classic M1 macrophages
lymphokines are a subset of..
leave node and circulate through blood and lymph to encounter antigen in tissue; secretes IL-4 t activate M2 macrophages
what does Th2 secrete?
chemotactic for eosinophils
What type of macrophages are activated by Th2?
Alternative activated or M2
M2 vs M1 activation
M1 = classical and it is involved in inflammtaion; M2 = healing (debris removal, scar, walling-off)
What does Th2 help to target?
Macrophages that target eosinophils
When does Th1 show up compared to Th2?
Th1 is first then Th2 takes over in repair and healing
Follicular Helper T-Cells; migrate into follicle in cortex when activated by DC; help B cells to recognize antigen and activate into antibody secreting plasma cell
Two functions of Tfh
1) help B cells recognize antigen and activate antibody secretion 2) Class switching from IgM
Regulatory T-Cell; very small population (only 5%) that suppress activation of other T-helper cells.
Treg in the gut
Secretes IL-10 and TGF-Beta to avoid immune response to food.
Phenotype of regulatory T-cells
Cytotoxic TCells (CTL)
signal target cell to activate apoptosis by engaging CD95 (death receptor) and secrete lytic granules (granzymes) and Perforins to allow penetration of granzymes.
lytic granules secreted by CTL
secreted by CTL to allow penetration of granzymes.
CTLs kill the body’s own liver cells, but not the virus itself
after response to antigen, the number of T-cell declines. These cells have same attributes of stem cells in that they can rapidly replicate in response to antigen (low concentrations)
CD3, CD4, CD8 - surface markers on T cell population; involved in Tcell activation
CD3 is on..
virtually all cells
CD4 is on…
only T-helper cells
CD8 is on…
only CTL cells
T cell will only recognize peptide antigen when it is bound to body’s own MHC molecule; A t cell is antigen specific and MHC restricted.
Major Histocompatibility Complex - fruit bowl on surface of APC that contains the epitope piece
Antigen Presentation - extrinsic
Antigen is broken down by lysosomal enzymes in DC, vesicles fuse with surface with MHC on inner surface —> fusion causes MHC on surface to express partially broken own antigen.
What are the antigen presenting cells?
Macrophages, dendritic cells, B-cells
Epitopes for T-cells must be
continuous epitopes (B cells can be continuous or discontinuous)
same structure as antibody, except two chains called Alpha and beta which a constant and variable region.
Do T-cells have variable regions?
Yes - they have special VDJ regions that recombine and have 3 CDRs.
Where does T-cell development take place?
CD3 is associated with..
the TCR and it transmits signal when the Th cell binds to correct antigen and MHC
when antigen interacts with TCRR, this becomes activated and activates a cascade of accessory molecular interaction that modify, enhance, diminish activation.
what CD types are on MHC Class II?
CD4 (shut off CD8); all Th cells
What CD types are on MHC class I?
CD8 (shut off CD4); all CTL cells
MCH Class II
used by DC, macro, B-cells; selective for Th cells; antigen presenting cleft is made up of two peptides
MCH Class I
present on all nucleated cells; antigen presenting peptide is composed of one single peptide with stabilization constant peptide. Dependent on intrinsic pathway.
when contents uptake via the extrinsic pathway leak out of the vesicle and are put on the surface of MCH class cells.
what types of cells react to MCH Class i?
cells can bring samples in from periphery and arranged not only for Th response, but also for CTL
is on helper T cells and helps strengthen the binding between MHC class II and APC
B-cell as antigen presenting molecule
B cell binds to antigen and takes into cell and loads into Clas II MCH. Tfh recognizes MHC II and hopes B cell to release antibody. Epitope that the B cell sees is not the same as the Tfh epitope.
To activate B cell, is the epitope the same as the Tfh?
no! there is digestion in between.
what if you block B-cell endocytosis?
cannot be activated by T cells to make antibody
Which is a better APC DC or B cell?
DC because B cells don’t produce cytokines
don’t get help from T-cell for activation; it is a carbohydrate antigen with a large backbone. This clustered binding is enough signal for activation, but DOES NOT signal for class switching.
proteins that recognize simple sugar sequences (mannose Binding protein) and bind to T-cell and B Cells to simulate binding to an antigen when they are not.
a type of lectin that causes mitosis.
when a bunch of T-cells are activated at same time and leads to lethal pro-inflammatory response
Where does the thymus originate?
Epithelial from pharyngeal cleft, macrophages from marrow; thymocytes from bone marrow
lymphoid cells from marrow get into cortex and interact with these receptors who guide them into the T-cell differentiation pathway
large in size, double negatives (CD4-/CD8-) that have activated Rag1 and Rag2 for VDJ rearrangement.
General process of T-cell maturation
Double negative to double positive to mature phenotype with single positive.
How selective is the T-cell development?
Very selective and the majority of T-cells are double positive; fewer than 2% are exported from thymus.
A T-cell must meet there requirements…
1) not recognize self to cause autoimmunity (MCH alone or MHC with self peptide) 2) not recognize free antigen 3) recognize antigenic peptide plus self MHC
Thymic Epithelial Cells
the cells responsible or secretion of T-cells in the thymus. The cells express on their surface MHC class I and II.
T-Cell selection has three options
Non-selection, positive selection, negative selection
no binding to MHC because it does not recognize self MHC and leads to apoptosis.
CDR1 and CDR2 bind to alpha helices of MHC groove, but CDR3 does not interact with the endogenous peptide. This cell survives.
TCR binds to MHC with self peptide with TOO high of affinity that results in T-cell activation.
if developing T-cell binds with all 6 CDRs…
it becomes an autoimmune
Fate of negative selection..
apoptosis or regulatory T-cells -(thymic or natural regulatory-Tcell)
outcome of grafts of living tissues between two individuals
Mouse; found on Ch17 that encodes tissue rejection factors (histocompatibility antigens).
What is the histocompatibility complex on human cells?
Human Leukocyte Antigen that has four importan loci A, B, D, and DR with incredible genetic polymophism.
What chromosome is HLA located on?
What is the order of HLA?
closest to centromere Class II, Class III and then Class I (furthest from centromere)
Class II loci on HLA?
DP, DQ, DR (DR most important)
Class I loci on HLA?
B, C, A (most important A and B)
what loci do we need to know for transplants?
HLA A, B, DR
who are you more likely to match for antibodies with, your sister or your parent?
not much recombination in HLA genes!
Sites of coordination in amino acid sequence between epitope and MHC
how many CDRs does T cell receptor use to bind to MHC?
how many CDRs does Tcell receptor use to bind to epitope?
isografts - grafts between genetically identical individuals
allografts - grafts between non-identical membrane of same species
Xencografts: grafts between members of different species
Hyperacute rejection of graft
graft is given to patient with pre-existing antibody. Antibody binds to endothelial cells on grafts blood vessel and activate complement and vasospasm. Graft never perfuses with blood.
Th1 recognizes MHC with foreign antigen (class II - DR); and secrete IFNgamma and bring in macrophages from the graft recipeient. Th1 secrets nearby CTL that is bound to MHC antigen of Class I (HLA-A and HLA-B) to kill target graft.
what if donor has identical Class I, but different class ii?
Th1 is activated, but not CTL. graft is still rejected but slower
What if donor is different Class I, but identical Class II?
no TH1 is activated, IL-2 will not be generated and few CTL is activated.
which match is more important Class I or II?
why do we respond more strongly to something that is not a pathogen (graft?)
receptor interacts with MHC in a slightly skewed position, and it thinks that the MHC is foreign and leads to destruction. The response is much slower if it is completely foreign (ie horse skin vs human)
HLA linked Diseases
modifications of self proteins create novel epitopes that associate strongly with MHC alleys.
natural, active immunity
immunity from exposure to a pathogen; longest lasting
Natural, passive immunity
enjoying the products of someone else immune response, pregnancy with IgG
Artifical Active immunity
immunization with vaccines, toxioid or antigen preparations
what does a dirty vaccine indicate?
more complex the mixture of molecules, the more likely to have unpleasant side effects
which provide better immunity - live or killed?
Live - infectious but attenuated.
Artificial, Passive Immunity
immune serum or purified antibodies to protect pt at risk of disease. We have antiwar for tetanus, rabies, hepatitis, chicken pox.
inactivate toxin that is almost always as effective at eliciting an immune response
active immunization with vaccine growth on human diploid cells; onset is slow so immunization can occur after exposure.
whooping cough; old vaccine was ineffective and has been replaced with acellular pertussis. But vaccine is present for strains in 1950, so not completely effective
Rates increase significantly when immunizations go down; has extremely high heard immunization
capsular carbohydrates are T-independent,b ut fail to generate an immune response. So if you couple a complex carb with a protein “carrier” to which Tfh cells could respond and aid B cell in making anti-carbohydrate IgG antibody.
what type of antibodies to B-cells make that are simulated by complex carbohydrates?
what kind of antibody do the B-cells make when stimulated by conjugate vaccine?
what deos the protein antigen from a conjugate vaccine get loaded onto?
MHC Class II
a vaccine against rotavirus that was taken off the market because it caused intussusception leading to necrosis and peritonitis due to hypertrophy of Peyer Patch.
telescoping of the bowel, risking blood supply loss causing necrosis and peritonitis
substances added to vaccines to make them more immunogenic
how to adjuvants work?
cause an innate immune response that leads to more effect adaptive response.
most common adjuvant?
potassium aluminum sulfate adjuvant that mimics PAMPs to stimulated DC that drive Tfh.
decrease in infection rate in the non-immune part of the herd.
extracellular bacteria are mostly combated by antibody; some are destroyed by C9 of the MAC; intracellular bacteria can survive in the macrophage but are killed if activated by Th1 cells.
Most important principle of immunity
humoral immunity may prevent illness, but once ill, T cell immunity is necessary for recovery.
local immunity (IgA) prevent the invasion of a virus; if it gets into blood it is stopped by IgG; if virus infects cells, T-Cell response is required and virus stimulates cytokine and chemokines to activate DC cells to pick up debris and process the peptides. Presented on Class II and cross-presented on Class I (for CTL)
what viruses are the hardest to deal with?
viruses that never appear in blood or lymph, but go latent (herpes)
reciprocal of the maximal diluation of patient’s serum that is still positive in some defined test.
immunizing for the DNA that the antigen is encoded from so it would be translated in cell; advantages is quicker vaccine production, more stable faccine, and antigen would be made in body cells producing a natural, active immunity.
Monocytes/Macrophage - Time in marrow
Short time - 7 days
Monocytes/Macrophage - days in intravascular compartments
Monocytes/Macrophage - presence in tissues
Monocytes/Macrophage - histology
gray cyto, kidney shaped nulcues, changing morphology with tissues
Monocytes/Macrophage - function
1)move to sites of infec/inflam 2) filter (splenic macrophage) 3) processing and presenting antigens 4) clearance of apoptotic cells
why is clearance of apoptotic cells important
could cause severe inflammation and devastating tissue injury if not removed.
Neutrophil - Storage pool
Neutrophil - peripheral blood
Neutrophil - function
innate immune system, non-specific defense against microbes, response to injury
what happens with neutrophils in tissue?
look for sights of potential infection and either kill the infection source or die themselves and get turned over my monocytes
what do neutrophils recognize?
they have no memory, but look for pattern recognition on microbes
Eosinophil - Bone marrow
influenced by IL-5
Eosinophil - histological features
large eosinophilic granules, bi-lobed nuclei
where doe eosinophils reside?
external surfaces (tracheobronchial tree, GI tract
how long do eosinophils survive in periphery?
Eosinophil - Function
Phaocyte, role in allergy, paraste infection, response to tumor, immunoenhancing or immune suppressive
Basophil - histology
similar size to eosinophils, bi lobed nulcue, prominent purple/blue granules
what receptors are on basophils?
Basophil - function
pathophysiology hypersensitivity reactions
what cells make up cells in the progenitor compartment?
what compartment are the myeloid precursors in?
what cells make up the myeloid precursors in the mitotic compartment
myeloblast, premyelocye, myelocyte
Process of myeloid precursors
proliferation and maturation
Percentage of myeloid precursors in mitotic compartment?
Myelocyte 16%>promyelocyte 4%> myeoblast 1%
How long to myeloid precursors stay in the mitotic compartment
what myeloid precursors are in the storage compartment?
Metamyelocytes, Band and sets
what process occurs in the storage compartment?
what is the % of the myeloid precursors in the storage compartment?
Band 30%> metamyelocyte 22% > Seg 21%
which is larger the mitotic compartment or storage compartment?
storage with 73%, while mitotic has 21%
what is the role of the myeloid precursors?
terminal cells of the neutrophil line. They are active and their job is not to proliferate, but finish maturing and form the storage compartment.
what is the function of the storage pool?
a collection of cells that can be localized to fight infection quickly.
pools of neutrophils that hang on the edge of post capillary venules
What is the ration of neutrophils in peripheral blood and marginating pool?
1 to 1
how long do neutrophils live in peripheral blood
how long to neutrophils live in the tissue?
around 24 hours. Before they undergo apoptosis and are turned over by monocytes
where are neutrophils depleted in neutropenia?
neutropenia - definition
decrease in absolute neutrophil count (including band and set polymorphonuclear leukocytes) below accepted age norm
General pattern for neutrophil count
greatest at newborn, but decrease after 1 week and up until 2 years, then increase during childhood to adulthood. 3000- 1,1000 — 1500
What things affect neutrophil norms
ethnic and racial groups have lower norms, and altitude above 5,000 Ft lowers the norm in infants
implications of neutropenia
decreased delivery of neutrophils to tissue causes inability to resolve bacterial and fungal infections and localized infection
ANC of 1,500-1,000
AND of 1,000- 500
moderate to mild neutropenia
Moderate to severe neutropenia
what are the symptoms of moderate to severe neutropenia
skin, mucous membrane infections
Symptoms of severe neutropenia
what sites should you focus your physical exam on in neutropenia
teeth and gums, lymph nodes, hepatoslenomegaly, infected sites.
why should we look carefully at gums in neutropenia?
they are the only place on the body with direct penetration of mucosal barrier
how often would you perform a CBC and why in neutropenia
2x a week for 6 weeks; to see if neutropenia is persistent or intermittent. If it cycles, want to see how low the cycles and evaluate their absolute risk
What laboratory tests should you perform for neutropenia?
CBC (with retic), Bone marrow aspirate/biopsy, blood chemistries with LDH, uric Acid, alkaline phosphate, anti-neutrophil antibodies
primary decreased bone marrow reserve
all cells have gone away as in Kostmann, Scwachman-Diamond, cyclic neutropenia
Potions for a decreased marrow reserve?
primary disorders, part of complex phenotype combined with other diseases, Secondary disorders, or idiopathic
Secondary decreased bone marrow disorders
decrease in marrow due to chemo, drug induced, nutritional, viral infection
Normal Marrow Reserve
usually indicates an increased or normal production of neutrophils;. Due to immune or non-immune causes
Immune - normal marrow reserve
chronic benign neutropenia in childhood, autoimmune, alloimmune, drug induced, infection
Non-Immune normal marrow reserve
infection, hypersplenism, excessive margination
Infection associated neutropenia
a secondary cause; most common cause
Mechanisms of Infection associated neutropenia
Increased utilization, excessive complement mediated margination, marrow suppression/failure, unusual cytokine/chemokine induced margination, antibody production
infections associated with neutropenia
viral, bacterial, fungal, protozoal, rickettsial
clinical characteristics of antibiotics induced neutropenia
onset: days to weeks; acute symptoms, recurrence with small dose of antibodies; positive antibody test
Clinical characteristics of toxin neutropenia
onset is weeks to months, directly toxic to cells, rechallange with high dose may relapse after latent period
toxic drug that causes neutropenia
Hypersensitivity in secondary neutropenia
onset is weeks to months, associcated with rash, fever, lymphadenopathy, hepatitis, nephritis, rarely aplastic anemia
drugs that cause hypersensitivity neutropenia
hypersensitivity vs. Toxic neutrophilia
toxic is directly toxic to cells; hypersensitivity elicits are more inflammatory response in nature and less toxic.
Mechanism of Cancer Chemo on secondary neutropenia
suppression of myelopoiesis
Findings of chemo induced neutropenia
other cytopenias present such as anemia, thrombocytopenia
Aplastic anemia induced secondary neutropenia mechanism
stem cell failure with other cytopenias present
Vitamin B12 and folate deficienty induced secondary neutropenia mechanism
ineffective hematopoeisis; intramedually death secondary to effets of deficient on replication
Vit B12 and Folate deficiency neutropenia findings
other cytopenias (thrombocytopenia) with megaloblast changes in marrow
Hypersplenism induced neutropenia mechanism
reticuloendothelial sequestration with other cytopennia
Causes of secondary neutropenia
Drug/toxin induced, chemo, aplastic anemia, Vitb12 and folate deficiency, hypersplenism
management of Secondary neutropenia
withdrawal of drugs or toxins, treatment of underlying disorder, replacement of deficienty, management of infections, support care with prophylactic, G-CSF in some conditions
G-CSF in treatment of secondary neutropenia
used in chemotherapy, primary cytokines to cause production in marrow
Marrow production in immune neutropenia
Normal to increased
Storage pool in immune neutropenia
normal to mildly decreased
Mechanism of immune neutropenia
increased turnover of neutrophils, vascular compartment decreased levels
Categories of Immune neutropenias
alloimmune, chronic benign childhood neutropenia, autoimmune, drug-induced
Fe saturation under 10%
Anemia of Chronic inflammation iron saturation
autoimmune neutropenia clinical features
may find ITP, AIHA, and other hematologic antibodies, immunodeficiency states, variable ANC, normal cellularity, late maturation arrest
Management of autoimmune neutropenia
treat primary autoimmune disorder, G-CSF may be helpful
Alloimmune neutropenia - mechanism
maternal: to neutrophil specific antigens, transplacental passage and bidning to neonatal neutrophils
Clinical features of alloillumine neutropenia
usually lasts 2-4 weeks; occasionally 3-4 months; may be asymptomatic, but could develop skin infections and rarely sepsis or meningitis. Confused with neutropenia by sepsis; myeloid hyperplasia with arrest at mature; small storage pool
In response to EPO injections, you would expect..
increased reticulocyte count, fall if MCV if Fe deficient, treatment is controversial whether it makes them feel better.
Management of alloimmune neutropenia
antibiotics and supportive care for infection, IVIG infusion, consider G-CSF for severe infection
abnormal patelets, wbc, Rbc
MCV in sickle cell anemai
normal to high; except in sickle Beta than
what cells are involved primary neutropenia
stem cells and neutrophil precursors
RBC unequal in size
bluish cells in reticulocytes
congenital disorders of Stem cells and myeloid precurosors
Congenital Neutropenia (Kostmann’s Syndrome), cyclic neutropenia, Shwachman-Diamond, Glycogenosis Ib, neutropenia with metabolic disease or immune disorders
Kostmann’s Syndrome - Mechanism
apoptosis of myeloid precursors associated with Elastase (ELA-2) mutations; sometimes defects in G-CSF receptor
Kostmann's Syndrome - inheritance
AD, AR, sporadic
Kostmann's Syndrome - Clinical Features
severe neutropenia in infancy, monocytosis, eosinophilia (putting out other cells, but no neutrophils), Myeloid hypoplasia in marrow; tno storage pool; recurrent purulent infections, risk of AML or myelodysplaisa
Why does Kostmann’s not have a storage pool?
arrest in maturation in promyelocyte and myelocyte stage (mitotic pool)
Treatment of Kostmann’s
aggressive treatment of infection, G-CSF 3-100 to keep ANC high, consider BMT for poor response to G-CSF
Cyclic Neutropenia Mechanism
ELA-2 mutation and apoptosis in precursors and cyclic hematopoesis
Inheritance of cyclic neutropenia
Symptoms of cyclic neutropenia
fever, pharyngitis, aphthous ulcers, gingivitis, periodontitis
antibodies against platelets
how long do cycles last in cyclic neutropenia
21 +/- 3 days; the rest of the time neutrophils are normal
ANC in cyclic neutropenia
fragmented part of red blood cell, jagged with two pointed ends and no area of central pallor
Bone marrow in cyclic neutropenia
myeloid hypoplasia, arrest at myelocyte level during neutropenia
management of cyclic neutropenia
aggressive antibiotics, G-CSF daily to increase the low value of ANC so risk of infection decreases
Shwachman-Diamond Syndrome - mechanism
FAS associated premature apoptosis of marrow precursors; Decreased CD34+, marrow stromal defect
Shwachman-Diamond Syndrome - inheritance/genetics
AR, defect in SBDC gene on Ch17
Clinical features of sHwachman-Diamond
multisystem - neutropenia, pancreatic insufficiency, metaphyseal chondrodysplasia, dysmorphic features, 25% develop marrow aplasia, 25% develop MDS/AML; neutrophil dysfunction, recurrent infection
Management of SHwachman -Diamond
pancreatic enzyme replacement, aggressive antibiotic therapy, BMT for severe
Cartilage Hair hypoplasia
AR, short limbed dwarf, fine hair, neutropenia
X linked, nail dystrophy, hyperpigmentation, marrow hypoplasia, neutropenia
Chronic idiopathic neutropenia mechanism
myeloid hypoplasia and maturation arrest at myelocyte, metamyelocyte or blast stage, no specific inheritance
Clinical features of idiopathic neutropenia
mod to severe neutropenia, recurrent infections, no neutrophil antibodies
management of idiopathic neutropenia
increase in total WBC risk of infection, inflammation, malignancy, Increase in neutrophils (segs and band)
increased production, enhanced release of storage pool, decreased egress from ciruculation, reduced migration
Allergic disorder, dematits, parasitic infections, tumor, GI disorder, Hereditary, hyperesinophilic syndromes,
>1,000 newborn; >500 children, adults
Causes of Monocytosis
hematologic disorders, collagen vascular disease, granulomatous disease, infection, malignant disease
Causes of monocytopenia
glucocorticoid admin, infection with endotoxemia
hypersensitivity reactions, inflammation and infection, myeloproliferative disease
glucocorticoid admin, thyrotoxicosis
where do lymphocytes enter the lymph node?
through afferent lymphatic vessels and into the sub capsular space.
how does lymph lead the lymph node?
efferent lymphatic vessels
short connective tissue in the lymph nodes that extend and divide the cortex.
are located in the cortex and paracortex, used by dendritic cells to hang on as they flow through the lymph node.
In the cortex that houses B cells and germinal centers
located in the follicle; regions of active cell proliferation and apoptosis. Made up of B cells, dividing B cells, and macrophages.
Composition of cortex vs. paracortex lymph node
Cortex is B cells; Parapcortex is T-Cells (with some B)
Lymph node Medulla
region of loosely arranged cords of cells containing B cells, a few T cells and plasma cells.
High Endothelial Venule
Vessels that have endothelial bulges that act as sites of recognition and diapedesis of lymphocytes from blood into the lymphatic node space. Notable for their rounded protrusions into the lumen
Primary Follicle of Lymph Node
also called primary lymphatic nodule; not vernal in center of follicle, but tight knit cells.
What are the different layers of the germinal center
inner follicle cells, mantle zone of closely packed lymphocytes and marginal zode of looser packed lymphocytes.
What cells are in the follicle center? be specific
Centroblasts and centrocytes (plasma cells)
Tingible body macrophages
engulf apoptotic cells
where do most macrophages exist in the lymph node?
Trabeculae of the thymus
the bilobed thymus is ensheathed in connective tissue septa that divides the tissue into pseudo lobules
located closest to the capsular sheath, more densly packed set of developing thymocytes or T-cells (appears darker with nucleus).
where do mature thymocyte precursors reside in the thymus?
What defines the cortex vs medulla of the thymus?
density of the T-cell packing. Cortex is densly packed with immature thymocytes. Medulla is loosely packed more mature thymocytes
Where are the blast cells in the thymus
just beneath the capsular, give rise to the immature thymocytes in the cortex.
IF T cells return to the thymus, where do they congregate?
Epithelioreticular cells, cells that are epithelial-like, dendritic cells, or macrophages. provide matrix and envelop developing thymocytes in large folds as T-cell matures from cortex towards medulla.
Stromal cell Role
negative and positive T- cell selection, secrete cytokines and thymic hormones important for thymocyte maturation; DIFFERENTIATIO OF SELF FROM NON_SELF
Does the thymus contain reticular fibers?
No, because there is no bulk flow through it. Stromal cells provide support and have Hassal’s Corpuscles
concentric layers of reticular cells in Thymus medulla. Produce thymic stromal lymphoprotin that suppressing autoimmune events.
How does blood get into the thymus?
enter through small arteries through outer capsule and penetrate into thymus and spread within CT septa between lobules.
Blood thymus barrier
Combined layers of ensheathed endothelioreticular cells that are connected by tight junctions in vessels
Importances of Blood Thymus Barrier
so maturing thymocytes are not exposed to any molecules circulating in blood.
what is the arteriole blood supply to the thymus?
internal thoracic and inferior thyroid
Where is the blood thymus barrier in the thymus?
cortex, but not medulla.
what is unique to the thymus
there is no afferent lymphatics
what is unique to the spleen
open blood circulation through porous splenic sinuses.
what artery supplies the spleen?
what vein drains the sleep?
Blood flow in the spleen
in through the splenic artery and then branches to central arterioles that run deeper into the spleen, but as they get deeper then are lined with discontinuous endothelial cells, allowing platelets, RBC and leukocytes to enter sinuses that contain loosely packed arrangements of cells
periarteriolar lymphoid sheath
lymphocid tissue that is arranged around central arterioles that is composed of T-cells
loosely-arrnaged channels/sinuses that blood flow through after leaving central arterioles. (the space)
more organized lymphoid tissue in spleen, found directly outside the central arterioles.
Reticular fibers of spleen
found primarily in red pump
Macrophages in spleen location
in senescent red cells and platelets
Macrophages function in spleen
moging senescetn RBCs and platelets, recycing iron, and converting hemoglobin in bilirubin.; removal of debris and bacteria
Mucosal-Associated Lymphoid Tissue examples
tonsils (palatine, lingual), pharyngeal (adenoids), esophageal nodules, Bronchial nodes and large number of cells might increase in abundance and size as get distal.
nodules located in the muscosa and submucosa of the colon
involved in MALT, special surface epithelial cells found in small intestine and respiratory tract and deliver antigen to underlying lymphoid tissue.
what antibodies are involved in MALTs?
IgA; are secreted across mucosal epithelia and in bile. Activated B-cells that were exposed to antigen in MALT, enter lymph, undergo mitotic expansion in mesenteric lymph node, flow out thoracic duct and enter blood, and then pass through underlying CT at any region in intestine to become antibody secreting plasma cells.
component cells of MALT
T and B cells, plasma cells, macrophages
Structures of MALTs
lymphoid tissue is not packaged within capsule CT
distribution of lymphocytes in MALT
larger, dividing immatre lymphocytes in center and smaller,, more dense lymphocytes in periphery.
Challenged white pulp nodules
clearly visible germinal center in the spleen.
Periarteriolar lymphatic sheath
consist of T-cells
Unchallenged White Pulp Nodules
clearly visible nodule in spleen, made of B cells. Non dividing.
General outline of innate immune system
Infection/tissue damage triggers through TLR receptors inflammatory mediators that case vascular dilation, permeability, and emigration of leukocytes which trigger emigration of phagocytes and monocytes in innate response and EVENTUALLY emigration of monocytes and lymphocytes in adaptive response
Receptors in Rolling/Adherence
Sialyx LeX, L-Selectin, B2 integrins (CD11b/CD18)
Biochemical process of the Rolling/Adherence Receptors
PM associated, granule containing store recpetors, actin cytoskeleton and accessory proteins
C5a, N-formyl oligopeptides, lipid compounds, GM-CSF, IL8, TNFalpha
Chemotaxis Receptors organlles/biochemical process
PM, actin and accessory proteins, granules (specific), glycolysis as energy source
FcR1,2,3; C3b, CR-1
Ingestion receptors organelles and biochemical process
PM, actin cyto and accessory proteins, glycolysis
FcR1, 2, 3, C3b, CR-1
Degranulation Killing Organelles and biochemical process
PM, actin ctyoskeleton, Azurophilic and specific granules; phagolysosomal formation, glycolysis
the processing of taking oxygen and making oxygen radicals that are toxic and can interact with phagocytosed substane for degradation
Where do the electrons originate to make Superoxide radical?
what is protective of oxygen radicals
SOD catalase, GHS
Also known as GP91Phox; protein that uses NADPH to transfer electrons to make superoxide
works with P22phox on membrane, to interact with cytosolic PHox proteins in complex to take NADPH and electrons to make superoxide.
Screening of Innate Immune Disorders
CBC, Diff, morphology, Bactericidal activity, chemotaxis activity, Expression of antibodies, DHR oxidation
Mix cells with bacteria and see how they kill it
put cells above filter and in bottom chamber, put C5a and incubate and see # and distance through filter
A compound that oxidizes dye to fluorescent compound. If you treat with bacteria to enlist more oxygen radicals, fluorescence should increase
Leukocyte Adhesion Deficiency 1 - clinical
Soft tissue infections (skin, mucosa), gingivitis, mucositis, periodontist, delayed separation of umbilical cord, poor wound healing
Leukocyte Adhesion Deficiency 1 - Functional Defect
Decreased adherence of neutrophils to endothelial surface, defect in movement of neutrophils to tissue. Neutrophilia
Leukocyte Adhesion Deficiency 1 - molecular Defect
Complete or partical deficiency of CD18; AR
Chediak-Higashi Syndrome - Clinical
Oculocuatenous albinism (white forelock), nystagmus photophobia (light bothers eye), recurrent infections, fever, hepatosplenomegaly, hemophagocytic disorder, neurodegenerative syndrome
Chediak-Higashi Syndrome - Functional defect
Giant granules in leukocytes, defect in movement and decreased degranulation and microbicidal activity. Neutropenia
Chediak-Higashi Syndrome - Molecular Defect
alterations in membrane fusion by forming leaky granules. Altered MT assembly. CHS1 gene, AR
Myeloperoxidase Defieciency - Clinical Presentation
Generally healthy; increased fungal infections with diabetics
Myeloperoxidase Defieciency - Functional Defect
Partial/complete deficiency of myeloperoxidase (converts Superoxide to hydrogen peroxide); defect in killing bacteria, significant defect in killing candida
Myeloperoxidase Defieciency - Molecular Defect
Post translational modification defect in protein processing; AR
enzyme that converts superoxide to hydrogen peroxide
Chronic Granulomatous Disease - Clinical
Recurrent purulent infections with catalase positive bacteria, fungi on skin and mucosa. Deep infections in lung, spleen, lymph nodes, bones
CGD - Functional Defect
Neutrophilia, normal adherence and chemotaxis, ingestion and degranulation. Defect in oxidase enzyme. No toxic oxygen metabolites produced, so absent or reduced ability to kill coagulase positive bacteria and fungi.
CGD - molecular defects
Absent Cyto B558 (Gp91Phox complex); absent P22Phox; Absent p47 Phox; Absent p67Pox; Mild X-linked variant in G-6-PD deficiency in PMNs
Cyto B558 absence- inheritance
Sex linked recessive
p22Phox - inheritance
Characteristics of phagocyte disorder
1) High rate of bacterial or fungal infections 2) infections against atypical pathogens, 3) exception severity of infection; 5) periodontal disease in children 6) infections occur at interface area, more common than deep (though those do occur)
what activate complement system?
lectins, bacterial protein, surface bound IgG
Deficiency in C1q, C2, C4 complications
SLE (lupus), autoimmunity, inflammatory vascular disease
Deficiency in C3 complication
Recurrent bacterial infections
Deficiency in C5-C9 complications
severe infection with neisseria (meningaococcus)
Management of innate immune disorders
1) anticipate infection and aggressive attempts to define causative event; 2) surgical procedures to be both diagnostic and therapeutic 3) prompt broad spectrum antibiotics, switch when microbial diagnosis is made 4) some may need 3ug/kg/day 5)some need prophylactic antibiotics