C2006/F2402 '08 -- Outline for Lecture 24

(c) 2008 Deborah Mowshowitz . Last updated 04/28/2008 10:01 AM.  

Handouts:  (Not on web.) 24A =  Regulation of Blood Pressure; 24B = Cells involved in immune system; clonal selection

For a good set of pictures and notes on kidney function see the filtration & absorption page from David Currie. (http://faculty.etsu.edu/currie/filtreab.htm)

Here's an article from the LA Times on the latest artificial kidney.

  I. Kidney Function, cont.

      A. Function of Nephron so far -- Let's follow some liquid through (review)

1. Filtration occurs in glomerulus

2. Reabsorption (of most substances) occurs in proximal tubule

3. Transport of Na+/water in Loop of Henley (See Sadava fig. 51.10)

a. Luminal cell membranes in descending loop and lower part of ascending loop are permeable to water.

b. Luminal cell membranes in rest of ascending are impermeable to water and pump NaCl from lumen to interstitial fluid. (See 23D.)

c. NaCl pumped out (reabsorbed) from ascending loop accumulates in medulla, forming a gradient of increasing osmolarity (outside the tubule) as reach bottom of loop = core of medulla.

d. Filtrate from proximal tubule loses water (water reabsorbed) as filtrate descends into medulla NaCl stays in tubule high concentration NaCl in tubule to be removed in ascending.

e. If NaCl diffuses into descending loop, it is carried around and pumped out in ascending = escalator effect.

f. Why called countercurrent? Because flow in two sides of loop is in opposite directions  physically and with respect to osmolarity. First leg (descending) of loop removes water higher osmolarity in filtrate; second leg (ascending) removes salt lower osmolarity in filtrate.

See problems 12-1 & 12-2.

B. Distal Tubule and Collecting Ducts -- Role of ADH and aldosterone

1. Overall

a. Filtrate entering here is at minimum osmolarity

b. More water and/or Na+ removed (reabsorbed) under influence of aldosterone and ADH

2. Role/Mech. of action of ADH

a. ADH (using cAMP) stimulates insertion of water channels/pores into membranes of collecting duct (and maybe late distal tubule)

b. Water flows out ADH-stimulated channels (if in membrane) because of salt gradient in medulla.

c. Diabetes insipidus -- result of no ADH or no response to ADH

3. Role of aldosterone (in water/Na+ balance)

a. Promotes reabsorption of Na+; water follows.

b. Amount of Na+ reabsorbed due to aldosterone is small % of total, but adds up; affects blood pressure. 

4. Question to think about: Where are the receptors for ADH? Aldosterone?

See problems 12-9, 12- 11 & 12-15.

II. Regulation of kidney function   See Sadava sect. 51.6.

    A. Regulation of release of ADH from post. pituitary (See Sadava fig. 51.14)

1. Sensors -- 2 types, since regulating two different variables

a. Stretch receptors in arteries (sensors for blood volume) -- this comes into play only if large volume change

b. Osmo-receptors in HT (sensors for solute levels in blood) -- this is the primary sensor

2. Response: ADH release up if osmolarity of blood up or stretch receptors (way) down

3. Thirst: ADH release & thirst both triggered by same receptors.

4. Feedback Loop: ADH release (& thirst up) water intake up, water loss down in kidney, & constriction of arterioles in extremities* restore blood volume, reduce osmolarity (and restore blood pressure)

*Remember ADH = vasopressin

5. Speed: Effects of ADH are relatively fast -- no prot. synthesis required. (Effect on water loss takes a while, since ADH affects formation of new urine, not state of pre-existing urine.)

    B. Regulation of GFR & release of aldosterone

1. What is GFR? GFR = glomerular filtration rate = measurement of flow through kidney. GFR must be adequate to keep kidneys functioning properly. Flow is adjusted through local effects and overall control of blood pressure.

2. Autoregulation -- Local GFR Adjustments -- dilate/constrict afferent arteriole

Low BP (low flow through kidney)  dilation of afferent arteriole (to glomerulus) increases flow through kidney increase in GFR. High BP has opposite effect.

See problem 12-4.

3. Renin/Angiotensin/Aldosterone System

a. Low BP or GFR in Kidney kidney secretes renin

b. Renin catalyzes rate limiting step in conversion of angiotensin precursor (in blood) angiotensin II (active)

c. Effects of Angiotensin II

(1). Acts on adrenal cortex aldosterone Na+ reabsorbed in kidney and elsewhere

(2). Acts directly to raise BP -- is vasoconstrictor. (Also stimulates thirst & release of ADH)

(3). Note that effects of aldosterone are slower than others as they involve steroid binding to receptor  synthesis of new protein

See problem 12-8.  By now you should be able to do all of problem set 12 except 12-5. (For 12-5 & 12-14, consider the max. osmolarity of urine. It's 1200 mOsm -- less than sea water.)

III. Summary of regula
tion of blood pressure (see  handout 24A. & Sadava Sect. 49.5 --figs. 49.17 & 49.18 (49.18 & 49.19) )

    A. Co-ordination of control

1. Major circuit that controls BP

a. IC = cardiovascular control center in medulla -- part of brain stem (Sadava fig. 49.18 [49.19]).

b. sensors = stretch receptors (= baroreceptors) in major arteries

c. effectors = heart, peripheral blood vessels (constrict/relax)

d. circuits -- uses PS and S.

See problems 11-10 & 11-16.

2. IC has other inputs and outputs

a. Additional input from

(1). chemoreceptors in arteries (for oxygen)

(2). chemo- and baro- receptors in higher brain

b. Additional output -- to adrenal medulla through sympathetic system   ( epinephrine)

3. Other effectors/sensors operate independently of IC (Sadava 49.17 [49.18])

a. HT controls production of ADH/vasopressin & thirst -- system effects vasoconstriction, water intake & conservation.

b. Renin/angiotensin/aldosterone system controlled by kidney GFR (& other inputs) -- systemic effects on vasoconstriction and salt (therefore water) retention

c. These factors affect both blood volume and capacitance of blood vessels

IV. Specific
(= Acquired) Immune Response -- Major cells and Features

We have already discussed antibodies as chemical reagents. How do antibodies, and the entire immune system, really work  physiologically? (Sadava, Chap. 18)

    A. Specific Immune system has 2 branches

1. In both branches:  Cells make a specific protein that binds to a foreign substance = antigen. Protein and antigen match up like ligand and receptor (or enzyme and substrate). Binding of specific protein to its target antigen is specific, and usually leads to destruction of target.

2. Humoral response -- Specific cell protein is an antibody. Why 'humoral?' Binding and destruction of antigen done by proteins in "humors" = antibodies in blood and secretions (for ex. milk, tears).

Example: B cells release antibody Ab (antibody) binds Ag (antigen -- usually on surface of microbe) trigger destruction of microbes (microbes are engulfed by phagocytes or lysed) often with the help of a set of proteins called complement. (See Sadava 18.10 (18.11) & table below.)  Allergies are a side effect of this system.

3. Cellular or cell-mediated response -- Specific cell protein is on surface of T cells, not released. Protein is called a TCR (T cell receptor). Binding and destruction of antigen done by whole cells bearing a TCR.

Example: T cells TCR on surface; TCR's (of cytotoxic T cells) bind to Ag on surface of virus infected eukaryotic cell destroy target cell by triggering apoptosis. (Apoptosis is triggered by juxtacrine signaling and/or perforin. See table below.) This is probably why grafts fail; foreign cells of graft look like infected (defective?) cells and are destroyed. 

4. Big difference between the two branches -- Location of Target (as well as specific protein)

a. Humoral Response. Antibody (B cell protein) binds to antigens in solution or on surfaces of bacteria & viruses. Neither the protein mediating the immune response (antibody) nor its normal target (antigen) are on eukaryotic cell surfaces.

b. Cell-Mediated Response. TCR binds only to antigens on surfaces of other eukaryotic cells. Both the protein mediating the immune response (TCR) and its target must be on eukaryotic cell surfaces.

    B. What Cells are involved?  What are B cells and T cells? See handout 24B. White blood cells (leukocytes) -- contain no hemoglobin. WBC divided into two main types

1. Phagocytes -- macrophages, dendritic cells, etc. ( See Sadava  fig. 18.2). Involved in processing antigens so lymphocytes can respond to them, and/or engulfing (& destroying) antigens identified by the immune system.

2. Lymphocytes. Found in lymph nodes and elsewhere. Do actual production of antibodies and/or execution of cellular immune response.

a. Divided into B and T cells.

(1). Both B & T cells come from same line of stem cells in bone marrow.

(2). B cells mature in bone marrow; T cells in thymus

(3). B cells produce & secrete antibodies. Major players in humoral response.

b. There are 2 types of T cells

(1). Helper T's (TH)

(a). These are required for function of both TC's and B's . (For details see texts.)

(b). Usually have protein called CD4 on their surface. Therefore said to be CD4+

(c). HIV binds to CD4. Therefore CD4 (accidentally) acts as an HIV receptor (there are other co-receptors, such as CD5) -- allows HIV to enter helper T cells. HIV infection loss of helper T's complete loss of immune function. (See Sadava figs. 18-20 to 18-22 (18.21 & 22).

(d). There are actually two main subtypes of helper T cells; much current research involves disentangling their functions. See advanced texts if you are interested.

(2). Cytotoxic T's (CTL or TC )

(a). Responsible for destructive part of cellular immune response.

(b). Usually have protein called CD8 on their surface. Therefore said to be CD8+

(3). All T cells have TCR's on their surface -- TCR's are not secreted or released from cell surface.

(a). TCR's of helper T's bind to Ag on surface of cells of immune system.  Interaction helps activate one or both partners -- promotes the immune response.

(b). TCR's of cytotoxic T's bind to Ag on surface of rogue cells (infected, cancerous, etc.) and destroy target cells.

    C. Table: Summary of Major features of 2 branches of specific immune system. Any features not covered yet will be covered later; this is here for reference. See notes after the table.

Immune Response Type Humoral Cell-Mediated

Cell involved in Response

B cells

T cells

Protein Made by Cell

Antibody (Ab)

T cell receptor (TCR)*

Location of Protein

In serum, tears, etc. (released by B cell) or on B cell surface.

Always on  T cell surface (attached to T cell)

Protein Recognizes

Free Antigens (Ag) or Ag attached to microbial surfaces

Antigens attached to surfaces of eukaryotic cells #

Aide in killing targets



Usual targets (for killing)

Microbes, soluble proteins

Infected or cancerous cells (for Tc or CTL)

Side Affect


Graft rejection

*T cell receptor is NOT the receptor for T cells -- it is the protein on the T cells that is the receptor for an antigen. It is the receptor of T cells, not the receptor for T cells. 

** Complement = a series of proteins found in blood. Activation of complement involves a cascade of activations similar to that involved in blood clotting. Complement binds to antibody-antigen complexes attached to microbes and triggers phagocytosis or lysis of the microbe bearing the complex.

# Antigen must be attached to a euk. cell surface protein called MHC. (Details later.)

##Cytotoxic T cells use proteins called perforins to make holes in their targets. Then other proteins enter the holes and trigger apoptosis.  Note complement is similar to perforins but works on prokaryotic invaders; perforins work on rogue eukaryotic cells. Many texts say perforin lyses cells -- it makes holes in membrane, and then water enters, causing cells to swell and burst. (This is the way complement kills bacteria.) Newer data indicates perforin works to trigger apoptosis.

    D. What are the Important Features of the Adaptive Immune Response that need to be explained?

1. Specificity & Diversity -- each Ab or TCR is directed against one epitope or antigenic determinant (= piece of antigen -- see Sadava sect. 18.3 (fig. 18.6), and there are many, many different antigens. How can you make so many different Ab's or TCR's, each specific for a particular antigen or piece of it?

2. Memory -- secondary response is faster, larger, better than primary response. In secondary response, make more Ab, Ab is more effective (binds better to Ag because of slight changes in amino acid sequence of Ab), and Ab response lasts longer. (Sadava 18.8; 7th ed only) How is this done?

3. Tolerance -- can distinguish self/nonself or normal/abnormal -- make Ab only to foreign/abnormal stuff (except in disease states). TCR only directed against infected cells, not normal ones. How does this work?

4. Response is adaptable -- response depends on amount and type of antigen (& history of previous exposure). How do you "know" which antibody (or TCR) to make in response to a particular antigen?

5. How do helper T cells fit in? How do helper T's and cytotoxic T's distinguish their targets?

V. Clonal Selection -- How do you account for the "important features" listed above?

    A. B cells (See Handout 24B bottom = Sadava fig. 18.6 (18.7))

1. Each cell differentiates produces a single type of Ab on surface ("virgin" or "naive" B). Each cell rearranges its DNA during differentiation, so each cell has a unique set of Ab coding genes and makes a unique antibody -- that is, with a unique set of "grabbers."

Note: As B cells mature and specialize, small changes in the antibody they make may occur because of alternative splicing and/or additional rearrangements of the DNA. This is why Ab made in secondary response is better at binding Ag. (More on this next time.)

2. Ab on surface of cell acts as a "trap". Surface antibody acts as trap/receptor for Ag. (Surface antibody also called BCR or B cell antigen receptor in parallel to terminology for TCR.)

3. Activation or destruction of B cell is triggered by binding of Ag to surface Ab (BCR)

a. Destruction. If Ag is perceived as "self" cell destroyed or suppressed ( tolerance).

b. Activation. If Ag is perceived as foreign cell divides clonal expansion, further differentiation into

(1). Effector cells -- short lived but secrete lots of Ab destroy or inactivate targets; class of Ab determines fine points. (In earlier lecture we explained how alternative splicing can allow cell to switch from making surface bound Ab to secreted Ab.)

(2). Memory cells -- long lived and more specialized to make Ab; wait for next time (responsible for memory). 

c. Whether antigen is perceived as "self" or "foreign" depends on time of exposure to the antigen (embryonic vs adult) and additional factors. (This turns out to be very complicated, so we are ignoring the "additional factors.")

4. What's the point?

a. Clonal Selection: Each cell makes a little Ab before any Ag present. Each cell makes a different Ab. This antibody stays on the cell surface and acts as BCR = trap for antigen. Ag acts as a trigger -- binding of Ag to "trap" stimulates only those cells that happen to make Ab that binds to that particular trigger.

b. Clonal expansion: The cells triggered by binding of Ag grow and divide   (more) effector cells  & memory cells . Both types of cells make only the antibody that binds to the trigger Ag.

c. Clonal suppression: The cells triggered by binding of Ag are destroyed or suppressed (prevented from multiplying &/or making Ab.)

d. What does this explain?

1. Clonal selection is the part that accounts for specificity, diversity, and adaptability.

2. Clonal expansion and suppression are the parts that account for memory & tolerance -- memory when Ag triggers expansion (as in b) , and tolerance when Ag triggers destruction or suppression (as in c) .

5. Why do you need helper T cells? For most antigens, helper T must bind to B cell-Ag complex in order to activate B cell. (Activated cell makes secreted Ab.)

Try Problem 13-4.

    B. T cells -- similar process as with B cells -- DNA rearrangement occurs so one type of protein with unique binding site made per cell -- but there are differences. More details next time.

    C. Clonal vs. Natural Selection. Note how clonal selection and natural selection compare. In both cases, need to have many variants (diff. antibodies or dif. organisms) to be able to respond to unpredictable environmental challenges. How is this done? In both cases, make many variants and conditions select (promote propagation of) cells making the few suitable Ab (or carrying out a rare, useful function); the rest are wasted. Random generation of variants seems wasteful, but is the biological solution to preparing for change without conscious planning ahead.

Next time (last lecture!!): Wrap up of whatever we don't cover above, plus how helper T cells work, role of MHC, Ab structure and Ab genes.