Streptococcus pneumonia-Pneumonia, Otitis media, Meningitis, Peritonitis, and Sinusitis (40% drug resistant)

Neisseria meningitis

Prevnar

1.  What is it?

1.  First pneumococcal conjugate vaccine (PCV7)

Antigen used was of capsular polysaccharide of 7 serotypes of S. pneumonia

Neisseria meningitidis

1.  Gram + or -

2.  # of serotypes

3.  Type of Antigen produced and important types (5 types)

1.  Gram negative

2.  12 serotypes

3.  Capsular polysaccharides (A, B, C, Y, and W-135

Meningitis

1.  Mallmarks of meningitis (3)

1.  Pressure points on skin

Petechia-microhemorrhages

Purpura-hemorrhages in the skin

HEMORRHAGING CAUSED BY TNF ALPHA WHICH CAUSES VASCULAR APOPTOSIS

Activates clotting cascade

Can lead to gangreen and need for hyperberic oxygen because of clots in small vessels

1.  Apoptosis of artery endothelial cells

2.  Cachexia

3.  Activation of coagulation pathway

4.  Decreased myocardial contraction

5.  Relaxation of smooth muscle

Interleukin 1 (IL-1)

1.  What does it do (1)?

2.  Where does it come from?

1.  Causes increase in body temperature

Mentioned in relation to lipopolysaccharide (LPS) release

2.  Monocytes activated by LPS

1.  Meningitis Vaccines (2)

2.  Which cannot be given in children

3.  What serotype not covered

1.  Menactra's and Menomune

2.  Menomune

3.  B serotype is not covered by either vaccine

Less than 3000 MW compound that must conjugate with a host carrier (usually protein) to illicite an immune response

Causes a conformation change in the protein it conjugates to leading the immune system of the host to recognize it as foreign

1.  Penicillin-Beta lactam ring breaks which creates a charged molecule that can attach to albumin

2.  Cephalosporins

Major vs Minor Antigenic Determinants

1. Determined by

1.  Immediate allergic reaction

2.  Autoimmune reactions - can cause hemolytic anemia

3.  Vasculitis - Hapten binds to vascular endothelial cells causing antibodies to be produced against them and thereby destroying endothelial cells

Characterizing Antigens (Ags)

1.  What 3 amino acids are common in Ags

2.  3 other characteristics of Ags

1.  Tyrosine, tryptophan, and phenylalanine

2.  High molecular wt (>3000), defined tertiary structure, and foreignness

Microbial Antigens

1.  Microbial structures (4)

2.  Viral components (2)

1.  Capsules, flagella, pili, microbial toxins

2.  Capsids and envelope-associated glycoproteins

1.  Allergens

2.  Foreign tissue and cells

1.  Proteins from intracellular bacteria (Rickettsia and Chlamydias)

2.  Proteins escaping from lysosomes

3.  Tumor antigens from cancer cells

4.  Self peptides from human proteins

Electrophoresis of serum proteins leads to 4 bands (albumin, alpha, beta, and gamma) and the Abs are localized in the gamma band of protein

Globulins are larger than albumin and migrate through gel more slowly

MOST OF ANTIBODIES IN GAMMA FRACTION!!!

1.  Coat bacteria-Causes aggregation and phagocytic ingestion and complement activation

2.  Viruses-coat and aggregate neutralizing infective potential

3.  Foreign materials-aggregate and flag for macrophages

1.  Saliva

2.  Tears

3.  Cerebrospinal fluid

4.  Colostrum

5.  Intestinal surfaces

Y shapped with 2 heavy and 2 light chains with a carabohydrate linker to allow flexibility

Variable region is made by 2 heavy and light chains at top of Y and recognizes Ag

Fc region is the base of the antibody and can bind to immune cells to induce phagocytosis, complement activation, and mast cell degranulation

Digested with the enzymes Pepain and Pepsin

Pepain yielded 2 Fab regions and an intact Fc region

Pepsin yielded intact Fab of larger molecular weight (Fab'2) with no Fc piece (pFc')

Digibind

1.  Used to treat

2.  What is it composed of?

1.  Digoxin overdose

2.  Fab regions purified against Digoxin (same concept used in antivenoms)

1.  Polymorphonuclear leukocytes (PMNs)

2.  Macrophages

3.  Monocytes

4.  Basophils

5.  Mast cells

6.  NK cells

Classes of Abs

1.  What differs among the different classes?

2.  Names of the different classes (5)

1.  Different heavy chain constant regions

2.  IgGAMED

Kappa or Lamba

Each B cell produces an antibody with either kappa or lambda light chians but not both

1.  Distribution

2.  Half-life in serum

3.  Concentration

4.  Ability to fix complement

5.  Ability to bind to Fc receptors on cells

IgM Ab

1.  When produced

2.  Location

3.  MW

4.  % total serum Abs

5.  Does it cross the placenta?

6.  # of Ag it can bind

7.  What holds it together

1.  Initial response

2.  Serum (some very unique form is found in external fluid)

3.  900,000 MW

4.  5-10%

5.  No

6.  Can bind 10 Ag

7.  J chain and disulfide bond link

IgG

1.  When is it produced?

2.  Found in high levels where

3.  MW

4.  Can it cross the placenta?

5.  Four subclasses (which two needed for vaccines to work but are not present until 6-8 months post-birth)

1.  Secondary or anamnestic response

2.  High in serum

3.  150,000 MW

4.  Crosses placenta

5.  IgG1-4

IgG 2 and 4 are needed for vaccine

Primary Antibody Immune Response

1.  Lag to Ab in blood

2.  Antibody isotype predominating

3.  Ab affinity

4.  Magnitude of response compared with secondary

1.  5-10 days

2.  Smaller

3.  IgM > IgG

4.  Lower affinity of Ab for Ag than secondary response

Secondary Antibody Response

1.  Lag until AB in blood

2.  Peak response compared to primary antibody

3.  Predominant antibody

4.  Antibody affinity compared to primary response

1.  Usually 1-3 days
2.  Larger

3.  IgG...Can also see increased IgA and IgE depending on the situation

4.  Antibody affinity for Ag is much higher

1.  Inject toxin/virus into mouse

2.  Transfer lymphocytes from that mouse to irradiated mouse

3.  Expose to antigen again

4.  Note the immune response in the formerly irradiated mouse

The neonatal gut has the FcRn receptor which transports it actively through cells into serum thereby confering immunity to te neonate

The receptor also helps the fetus through the placenta

Transporter also exists in adult gut to protect from food borne pathogens

You can get the Rh badness only if mom is Rh (-) and dad is Rh (+)

1.  First pregnancy you produce IgM against the Rh in the fetuses blood which cannot cross placenta

2.   Second pregnancy mom makes IgG against fetus's blood producing hemolytic anemia and "blue baby"

Secretory IgA

1.  Found in (5)

2.  Subclasses (2)

3.  Important protein making it secretory

4.  # of antibodies linked and what links them

5.  Major function of secretory IgA

1.  Tears, saliva, colostrum, spinal fluid, GI secretions

2.  IgA1 and 2

3.  Poly Ig receptor

4.  2 Abs linked by J chain

5.  Mucosal immunity beneath epithelial and GI cells (Peyer's patches)

Smoking decreases IgA in upper respiratory

IgA Transport

1.  What is the transport protein?

2.  What does the protein bind to on the IgA dimer?

3.  In addition to transporting, what else does the transport protein do?

1.  Membrane bound poly-Ig receptor

2.  Binds the J-chain containing the polymeric IgA

3.  The poly-Ig receptor protects the IgA from being degraded inside the cell

IgE

1.  What dose this Ab do?

2.  Concentration relative to other Abs

3.  What unit is present that other Abs don't have and why does IgE have it?

1.  Mediates allergic hypersensitivity reactions in asthma, urticaria, and rhinitis to name a few

2.  Lowest concentration (ng/100mL0

3.  Has additional CH4 unit where the Fc region of the antibody is which allows it to bind to mast cells and basophils causing them to degranulate

Mast Cell/Basophil Response-Dr. Flaherty

1.  Immediate response proteins (3)

2.  How long before the secondary response kicks in?

1.  Heparin, Tripase, and Histamine

2.  4-8 hrs later you get the secondary response

Multiple Myeloma

1.  Derived from

2.  Characterized radiologically by

3.  What happens in multiple myeloma (3)

4.  Why do patients frequently suffer from kidney failure?

1.  Single B cell clone meaning a homogeneous Ab population

2.  Multiple destructive lesions on the skeletal system and severe bone demineralization (fractures)

3.  Neoplastic cells form sheets replacing normal bone marrow; Plasma cell activating factor found withing bone marrow causing plasma cell proliferation; Myeloma cells produce osteoclas-stimulating factor (cytokine) which demineralizes bone

4.  Excess calcium from bone demineralization (usual cause of death)

What are Bence Jones Proteins?

1.  What disease are they associated with?

2.  What are the proteins and where are they found

1.  Multiple myeloma

2.  Free antibody light chains in the urine which are the first sign of the disease

1.  Thalidomide - not if pregnant

2.  Neovestat-anti-angiogenic compound from cartilage

3.  Inorganic and Organic Arsenic Trioxide (melarsoprol) - inhibits growth and induces apoptosis in leukemic cells

ULTIMATELY NOT CURABLE

1.  Define epitope

2.  How many amino acids and sugars usually create epitope?

1.  Fragment of Ag resulting in activation of B and T cells

2.  5-15 amino acids and 3-4 sugars

1.  Continuous - Primary structure of a protein; Abs usually bind these with less afinity than folded proteins

2.  Discontinuous - Result from folding of protein so that primary sequences far separated lead to epitope

Linear epitopes

Primary sequence of amino acids

T cells recognize intracelluar Ag...means it is processed within the cell and chopped into small linear segments and presented to the T cell

B cells recognize extracellular Ag which if it is a protein is most likely folded into its tertiary structure without being chopped up into nice linear segments

Proteins molecules secreated by bacteria

Normal for bacteria...toxic to us

Tetanus

1.  Aerobic or Anaerobic?

2.  Most common cause in infants

3.  Mechanism of action

4.  What is vaccine?

1.  Anaerobic

2.  Unsterile delivery conditions

3.  Increases ACh production leading to lock up of muscle

4. Tetanus toxoid

1.  Blood group Ags

2.  Lipopolysaccharide (LPS)-endotoxin

3.  Capsular polysaccharides-both pneummococcus and meningitis

Bacterial Endotoxin

1.  What is it?

2.  What does it cause (2)

3. Comes from Gram (+) or Gram (-)

1.  Lipopolysaccharide

2.  Septic shock and acute respiratory distress syndrome (ARDS)

3.  Gram (-)

1.  O-specific polysaccharide-site of serological specificity (different portion depending on bacteria)

2.  Core polysaccharides-conserved linker

3.  Lipid A-anchor in the membrane that when the bacteria dies causes bad immune response

Endotoxin Shock

1.  What does LPS bind to

2.  What dose this binding increase (3)

1.  LPS binds CD14 receptor on monocytes (also macrophages)

2.  Increases TNF-alpha, Free radicals, and Interleukin-1 (IL-1)

1.  Apoptosis of artery endothelial cells

2.  Cachexia (wasting)

3.  Activation of coagulatio pathway

4.  Decreased myocardial contraction

5.  Relaxation of smooth muscle

6.  Hypovolemic shock in cases of a bunch of LPS release

1.  Pneumonia

2.  Otitis media

3.  Meningitis

4.  Peritonitis

5.  Sinusitis

1.  Monocytes/Macrophages

2.  Dendritic cells - most effecient

Langerhan's in skin

Follicular in lymph nodes (from Dr. F's words)

3.  B cells

1.  Which cells are most efficient at presenting  Ag?

2.  What are they specialized forms of?

3.  Where are they located?

4.  How do they work?

1.  Interdigitating dendritic cells (IDCs)

2.  Specialized forms of macrophages

3.  Located in the skin/nonlymphoid tissue

4.  First they take up and digest antigen (immature IDC).  Then they become veiled IDCs and migrate through lymphatic vessels to lymphoid tissue.  Finally, become mature IDCs and activate immune response.

What happends to IDCs when the reach the lymph node?

1.  Enter through afferent lymphatic vessel to the T cell zone

2.  Activate both cytotoxic and helper T cells

3.  Helper T cells migrate to cortex where B cells are located

4.  Activate B cells which quickly form germinal centers (plasma B cells) and pump out antibody

5.  Antibody and T/B cells that leave lymph node leave through the efferent lymphatic vessel

One long alpha chain stabilized by beta2 microglobulin

CONSTITUTIVLY EXPRESSED ON ALL NUCLEATED CELLS

2 chains (Alpha and Beta)

INDUCED ON APCS AND B CELLS

MHC Class II Antigen Processing

1.  Where does Ag come from?

2.  How is Ag processed?

3.  What blocks Ag binding site in Class II receptor initially?

4.  How is #3 broken down and what remains?

5.  What allows release of #4?

6.  Final step

7.  What cell does this typically present to during infections?

1.  Exogenous Ag

2.  Broken up in phagolysosomes (40 Acid-dependent hydrolases)

3.  The invarient chain

4.  Digested slowly in lysosome until CLIP remains in groove

5.  HLA-DM allows release of 4 which allows Ag to bind to the peptide grove in MHC class II

6.  MHC II with Ag goes on vesicle to surface of APC

7.  T helper cells to activate them

MHC Class I Antigen Processing

1.  What process prepares Ag?

2.  What proteins allows Ag to pass from cytosol to ER?

3.  What initially stabilizes Class I in ER?

4.  What proteins then help form stable Class I (3)?

5.  What happens when Ag added?

6.  What cell does this typically present to during infection?

1.  Ubiquitination of lysine which allows degradation of intracellular proteins in proteasomes

2.  TAP (ATP dependent)

3.  Calnexin

4.  Calreticulin, Tapasin, and TAP

5.  Proteins from #4 dissociate and MCH Class I goes to cell surface in vesicle

6.  Cytolytic T cells

1.  What does li-Key do physiologicall?

2.  Medical result

1.  Binds to MHC class II and losens its grip on Ag in peptide grove

2.   Cannot activate the immune system because you cannot present Ag to T and B cells to activate them

1.  Size of Ag in Class I MHC

2.  Location of binding sites on peptide for class I MHC

3.  Size of Ag in Classs II MHC

4.  Location of binding sites on peptide for class II MHC

1.  8-12 Amino acids Class I

2.  On the N and C-terminus which is why it has to be smaller

3.  8-30 Amino acids Class II

4.  In the middle of the peptide so you can have a longer peptide

T Cell Receptor (TCR)

1.  How many Ag can a single T cell recognize?

2.  Types of T cells receptors (4) and what T cell they appear on

3.  Two subtypes of TCRs, where they are located, and what they are dependent on for activation

1.  Each T cell is specific for 1 epitope on 1 antigen

2.  CD4 Th1, CD4 Th2, CD8 Tc1, and CD8 Tc2

NOTE, APPROXIMATELY 10^13 OF EACH T CELL TYPE

3.  Alpha/Beta - found in peripharal blood and depend on macrophage presentation for activation

Delta/Gamma - Found in mucosal intraepitheial cells (Peyer's patches) and DO NOT require macrophages for interaction (These are the neighborhood watch of T cells)

TCR Signaling Complex

1.  Why can TCRs not signal?

2.  What complex allows TCR to signal?

3.  Molecules that stabilize MHC-TCR complex for Class I and Class II interaction

1.  TCR can't signal b/c they don't have cytoplasmic tail capable of signaling

2.  CD3 complex is the TCR and all associated signaling molecules

3.  CD8 stabilizes Class I and CD 4 stabilizes Class II

CD8 Tc Cells

1.  What does the Tc1 varient CD8 cell do?

2.  What does the Tc2 varient CD8 cell do and when do you need it?

1.  Tc1 kills tumor or viral infected cells by cell to cell contact

2.  Produces antiviral protein preventing viral replication but not killing the cell (Useful when you have something like a nerve virus where you don't exactly want to kill neurons)

CD4 Th cells

1.  What do Th1 CD4 cells do (4)?

2.  What do Th 2 CD4 cells do?

1.  Th1 function in delayed hypersensitivity reactions, stimulate phagocytosis, inflammation, and destruction of intracellular parasites

PHAGOCYTOSIS AND INFLAMMATION RESULT FROMMACROPHAGE ACTIVATION!!!

2.  Th2 cells stimulate B cells to produce Ab

Monocytes, macrophages, neutrophils, and dendritic cells

Eosinophils can...but not their primary function

Both involve innate and adaptive responses, but secondary response relies more heavily on adaptive response to prevent secondary infection.

Primary is inital exposure, secondary is another exposure after primary infection has run its course

Innate immunity is:  always present, cannot become more powerful, not depending on lymphocytic (adaptive) immunity but works with adaptive immune system, composed of barriers, phagocytes, NK cells and complement

Adaptive immunity is:  Lymphocyte driven; requires 7-10 days for activation following initial exposure; requires only 3 days after second exposure and is much more powerful

Specificity - Clonal selection produces antibodies more specific for the Ag and is responsible for attacking self-antigen

Memory - A second exposure to a pathogen induces much larger response than the first

1.  Immunity to microbes

2.  Successful transplantation

3.  Vaccines

4.  Monoclonal Abs

1.  Autoimmune disorders

2.  Immunodeficiency

3.  Allergy

Neutrophils

1.  Location

2.  Function

3.  Major structural features (2)

1.  Located in systemic circulation until infection

2.  Phagocytosis and distruction of pathogens with granules

3.  3 lobed nucleus and granules to break down bacteria

LOBED NUCLEUS ALLOWS EASIER DIAPEDESIS!!!

Neutrophil Granules

1.  What is in primary (azurophilic) granules (7)

2.  What is in secondary granules that is SPECIFIC TO NEUTROPHILS (2)

1.  Acid hydrolases, myeloperoxidase, muramidase (lysozyme), defensins, seprocidins, cathelicidins, and bacterial permeability-inducing (BPI) protein (Last 4 and specifically antibacterial)

2.  Lactoferrin and lysozyme

NOTE:  GRANULES CAN BE RELEASED OUTSIDE NEUTROPHIL

Monocytes/Macrophages

1.  Location

2.  Function

3.  Major structural features

1.  Monocytes-circulation; macrophages-tissue

2.  Phagocytosis and antigen presentation (activated by IFN-gamma)

3.  Monocytes are smaller than macrophages with few granules; macrophages have a huge nucleus with granules and pseudopodia and old vesicles full of digested stuff

B cells

1.  Location

2.  Function

3.  Major Structural Features

1.  Circulate in blood and lymph

2.  Recognize pathogens and differentiate into plasma and memory B cells

3.  Small, mostly nucleus; Abs on surface act as receptors; IgAlpha and IgBeta (CD79a and b) are accessory molecules

Plasma B Cells

1.  Location

2.  Function

3.  Major structural features

1.  Secondary lymphoid organs and bone marrow (source of Abs in blood once infection clears)

2.  Ab factory

3.  Huge cell with tons of ER, Golgi, and ribosomes to pump out Abs

T cells

1.  Origin

2.  Location

3.  Function

4.  Major structural features (3)

1.  Thymus

2.  Circulate in blood and lymph until infection

3.  Recognize and destroy infected or cancerous cells (CD8) or activate immune response (CD4)

4.  TCR-CD3 complex on surface; Alpha/Beta found on CD4 and CD8 (cytotoxic); Gamma/Delta found on CD8 in mucosa

Eosinophils

1.  Location

2.  Function

3.  Major structural features

1.  Circulation until pathogen detected

2.  Damage large extracellular parasites, hypersensitivity, and secondarily phagocytosis

3.  Reddish/dark purple granules which contain chemicals to kill parasites

NK Cells

1.  Location

2.  Function

3.  Part of which immunity?

1.  Circulate in blood and lymph until infection

2.  Recognize and kill infected and tumor cells

3.  INNATE IMMUNITY!!!

NOTE:  I could not find any major structural features for these cells

Basophils/Mast Cells

1.  Location

2.  Function

3.  Major structural features

1.  Basophils are located in circulation and mast cells in tissue (ONLY IN MENINGES OF BRAIN!!!)

2.  Mediate inflammation and hypersensitivity reactions

3.  Purple granules and Fc receptors for IgE antibody

The granules contain anaphylatic substances and substances involved in immunity against parasites

Dendritic Cells

1.  Name and location of 4 types

2.  Function

3.  Major structural features

1.  Langerhans-skin; Interstitial-all organs except brain; Monocyte-derived-tissues then lymph node to lymph node (I think these are the Interdigitating Cells (IDCs) Dr. F Mentioned); Plasmacytoid-derived-same as monocyte derived

2.  Antigen capture and presentation (phagocytosis and pinocytosis)

3.  Long extensions used to present Ag to lymphoid cells

Follicular Dendritic Cells

1.  Origin

2.  Location

3.  Function

4.  Major structural features

5.  Related to other dendritic cells?

1.  Probably not bone marrow...basically unknown at this point

2.  Lymph node follicles only

3.  Aid in maturation of B cells

4.  Look like dendritic cells

5.  Not at all related to other dendritic cells

Location where lymphocytes are produced, mature, and are selected in primary lymphoid organs

Thymus and Bone marrow in humans

Lymphocytes exert their effector functions here

Spleen, lymph nodes, MALT and GALT

Thymus

1.  Function in?

2.  What cells helps develop the thymus function?

3.  Location

4.  What type of development pattern (ie, direction of development)

5. Function of Hassall's corpuscles

1.  T cell maturation

2.  Nurse cells aid T cell development

3.  Upper anterior portion of chest

4.  Cortex to medulla development pattern

5.  Found in medulla and contains degenerating T cells...function unknown

Lymph Nodes

1.  What brings lymph in/out?

2.  What is the Hilus?

3.  What is located in the cortex (4)?

4.  What is located in the paracortex?

5.  What is in the medulla?

1.  Afferent in and Efferent out

2.  Location of blood vessels

3.  B cell area; Germinal centers; Macrophages; Follicular dendrites

4.  T cell area

5.  Cords containing B, T, and plasma cells in addition to macrophages

Spleen

1.  Function

2.  Location

3.  What is white pulp?

4.  What is red pulp?

5.  What's in marginal zone?

1.  Filters blood borne pathogens; and recycles red blood cells

2.  Behind stomach

3.  Site of interaction with blood-borne Ag (T cells)

4.  Destruction of red blood cells and platelets; reservoir for red blood cells, platelets, and granulocytes

5.  Facilitates lymphocyte Ag interaction through vessel/sinus network and cell population

Describe the process of diapedesis

Occurs in all immune cells with slightly different mechanism...this is for neutrophils and monocytes

1.  Infection/inflammation causes upregulation of adhesion molecules (P and E-selectins) on endothelial cells of vasculature near infection

2.  Leukocyte interacts with these weakly to slow down and begin to roll

3.  Interaction strengthens and leukocyte stops (integrin; Receptor for ingegrin is ICAM-1)

4.  Leukocyte releases permeabilty molecules to weaken vessels

5.  Migration through the epithelial vessel wall toward infection/inflammation

Lymphoid Tissues

1.  4 Major locations

2.  Composed of (3)

3.  Function

4.  Major Ab produced

1.  Mucosa (MALT); Gut (GALT); Bronchus (BALT), and Genitourinary tract (Ex.  Peyer's patches and tonsils)

2.  Lymphocytes and plasma cells and dendritic cells for a larger immune response

3.  To protect these surfaces from microbes

4.  Secretory IgA to get across the cell surface and stop pathogen before it can infect

1.  Chemotaxis and adherence to microbe

2.  Ingestion of microbe

3.  Formation of phagosome

4.  Fustion of phagosome withy lysosome to form phagolysosome

5.  Digestion of ingested microbe by enzymes

6.  Formation of residual body containing indigestable material OR ANTIGEN PRESENTATION!!!

7.  Discharge of waste material (not as common as once thought)

1.  Direct cell-to-cell contact (integrins)

2.  Interaction with secreted molecules

1.  Endocrine-act on cells at distant sites (hormones)

2.  Paracrine-Act on neighboring cells (neurotransmitters)

3.  Autocrine-cells response to molecules it produced (macrophages make and respond to TNF)

Receptor Tyrosine Kinases

1.  3 domains and function

2.  What activates and how does it activate?

3.

Apoptosis

1.  Caspase 8 Function

2.  Caspase 9 Function

3.  Caspase 3 Function

4.  CD # for Fas and FasL

1.  External mediator of apoptosis

2.  Internal mediator of apoptosis (mitochondrial dysfunction)

3.  Both 9 and 8 meet at 3-->DNA fragmentation

3.  CD95 and CD95L...Fas is on Tc cell