Immunology - Part III

Question 1

B-cell receptors (destined to become antibody molecules after activation)

Answer 1

• assembled in way that produces receptors covering a vast repertoir
• V, D, J genes all contribute to antibody binding ability
• Huge immune repertoire – millions of specificities including b and t cells – where are those receptors from since not millions of genes for these receptors
• If 23,000 genes then how come proteins with millions of specificities
  
  • In your genome you have sections of DNA that code for parts of variable regions of the antibody
  • Section of the gene that codes for an antibody molecule
  • Constant region genes – regions of DNA
  • Sections of DNA that code for joining region genes and then sections known as diversity regions (D region genes) and then variable region genes
  • When a B cell is maturing and developing its specificity it randomly selects one C, one J, one D, and one V type and then it gets transcribed into an RNA and then spliced and processed and translated get the antibody molecule placed in the membrane
  • Switch to IgM for while then IgE for while
  • All little DNA regions that can be mixed and matched for millions of types of specificities and starting regions are immune repertoire that you inherit form your parents àDNA splicing instead of RNA splicing

Question 2

Somatic Recombination

Answer 2

• Variable region genes (500 variable region genes), then there is a region with a number of diversity region genes (15 or so) and then there’s a region not necessarily right next to each other with J region genes where only 5 of them and then constant region genes
• On a random basis as B cell matures it says I’m going to use V3, D12, J3 and hook up to IgM and so then it takes DNA in btween D3 and D12 and cuts out and throws it away and region btwn D15 and J2 and cuts out and throws it away and then you get a gene that looks like that
• V1 and V2 are still there w/V3 hooked up to D12 and J3 and IgM and other heavy chains and so then transcribe
• Somatic recombination – recombination within your genome
  
  • Make IgM type antibody molecule and at some later point you switch to IgE so take out the IgM heavy chain and G heavy chain and throw it away and then hook up to IgE type so variable regions are the same and no different for IgM to IgE but constant region is diff so it will cause diff things to happen – mast cells will release histamine

Question 3

Ex of Somatic Recombination

Answer 3

• Heavy Chains: 500 V genes
• 6 J genes
• 20 D genes
• 500 x 6 x 20 = 60,000 diff combinations of possible heavy chains
• For light chains:
• 1500 types of light chains – kappa or lambda
• 1500 x 60,000 = 9 x 107
• Rapidly diff types of specificities
• There are new mistakes that appear due to mutations so could add even more variable to what you may see –
• Mature B cell makes more of the antibody that is randomly selected here except for additional
• As assemble cell surface receptor they randomly regenerate antibody via recombination

Question 4

Heavy Chain genes

Answer 4

• In heavy, light and T cell receptors – this idea is going on to generate millions of specificities in the T cells

Question 5

Light Chain Genes

Answer 5

• no D region genes here
• makes either gamma or kappa gene here

Question 6

Family of receptors that share immune domain

Answer 6

• Family of immune receptors – T and B cell receptors and MHCI and MHCII
• particular kind of folding domain in these types of molecules that do recognition Called the immunoglobulin domain
• Draw this way to remind us that within the variable regions there is some similarity in the folding which is used by recognition source molecules
• Evolution from common recognition protein
• There are similar sorts of molecules that can find in primitive vertebrates like sharks etc

Question 7

Possible Self-tolerance mechanism in T cells

Answer 7

• tolerance - when immune system recognies antigen but doesn’t respond to it
• self-tolerance - immune system won’t activate without recognition of both signals (energy); self antigens only provoke one signal
• tolerance develops as you grow older
  
  • gain antibodies from mother’s milk
  • can do skin grafts in baby animals becasue they don’t have antibodies to reject it yet
  • tolerant b/c don’t distinguish self vs. other yet

Question 8

Possible Autoimmune Mimicry

Answer 8

• important to have balance of diff populations of cells in the gut; large doses of antibiotics kill off microorganisms which causes issues - clostridium c. difficile which may take star to take over gut environment after antibiotics
• autoimmunity - immune system becomes confused and starts to attack normal healthy tissues as if they were invader
  
  • pathogen displays antigen that is similar to self - which stimulates T cell to attack both foreign cells and safe cells
  • due to some confusion by mimicry
• HLA, human leukocyte antigens = MHC in humans
  
  • MHC markers are highly diverse so a microorganism can’t mimic the HLA markers and escapte detectiong by posing as a self
  • but mimicry is going on, see MH1 on normal body cell displaying as self antigen
• autoimmune disease - treating self tissues as invader; result of possible mimicry

Question 9

Where autoimmunity may strike

Answer 9

• Diseases - know starred ones:
  
  • graves disease - target is thyroid; fat pads behind eyes, creates condition called exopthalmia, bug eyes
  • type I diabetes - targets pancreatic beta cells which make insulin, viral infection may precede diabetes
  • MS - brain and spinal chord is target
  • rheumatoid arthritis - target is connective tissue
  • schleroderma - target is heart, lungs, gut, kidney, centromere - hard skin
  • sjogren’s syndrome - dry mucous membranes and glands, target is liver, kidney, brain, thyroid, salivary gland
  • systematic tupus erythematosus - target is DNA, platelets, other tissues
  • lupus - comes and goes - butterfly rash caused
  • pemphigus vulgaris - blisters
• potential viral infection preceded onset of diabetes - possible mimicry

Question 10

Celiac Disease

Answer 10

• potential connection to previous viral infection
• gluten - protein found in grains, can be difficult to digest
  
  • undigested gluten interacts w/epithelial cells of GI/small intestine lumen which held together via tight junctions (enterocytes) –> release protein called Zomulin –> promotes epithelial cells to release tight junctions, allows some fragments to get thru
    
    • secretion of cytokines/proteins which stimulates lymphocytes that attack cells lining intestine
    • once accumulation of gluten inside and cells damaged then protein released during this attack is tissue transglutaminase which prompt immune attack on epithelial cells
    • Antibodies to TTG measure gluten sensitivity/ determine celiacs
    • leaky membrane and start attacking some cells

Question 11

Crohn’s Disease

Answer 11

• autoimmune disease not associated w/gluten
• but leads to inflammatory bowel disease (IBD) - inflammation = immune response

Question 12

Irritable Bowel Syndrome (IBS)

Answer 12

functional; physical response that disrupts normal flow of material thru digestive tract - cramps, spasms

not IBD/autoimmune

Question 13

Autoimmune Disorder - Myasthenia Gravis

Answer 13

• targets neuromuscular junctions - acetyl choline neurotransmitter receptors
• 75% of folks affected have thymus abnormalities; removal of thymas halts progression of MG
• T cells are targeting Ach receptors; removing thymus can be helpful
• droopy eye

Question 14

Scleroderma

Answer 14

• ‘hard skin’
• overproduction of collagen and other possible organ damage
• systemic or local effects like alopecia
• chronic w/acute episodes
• produced auto-antibodies that target centromeres

Question 15

Hygiene Hypothesis

Answer 15

• modern Western societies are too clean so reduced exposure to parasites, which our system is developed to fight
• essentially branch of immune system not being used
  
  • unemployed actors become involved in allergies/autoimmune disorders
• incidence of celiacs/autoimmune in Karelia, Russia is 0.2% where more traditional culture w/out clean water
  
  • Finland = modern, developed, western has 2% celiacs but similar genetic background as russia
  • western societies allow immune system to get out of balance by not using part used for fighting off parasites
• increasing incidence of allergy and autoimmune disorders in western countries from 1950s - associated w/lessened exposure to parasites
  
  • “epidemic of absence”

Question 16

Exposure to parasites - distribution of autoimmune disorders and helminths

Answer 16

• exposure to parasites may strengthen immune system against autoimmune disorders
• more developed westernized countries have high incidence of autoimmune disease while places w/worms don’t have high incidence of autoimmune disease
• we are so clean our immune system is out of balance

Question 17

Speculations on ways infections w/parasitic worms may help autoimmune problems

Answer 17

• infection w/worm prevents effector T cells from triggering autoimmune rxn thru 3 mechanisms
  
  • increases activity of regulatory T cells and stimulates cytokine release that dampens effector T cells
  • turning on macrophages and regulatory dendritic cells prevent effector dendritic cells from activating T cells
  • changing intestinal flrora boost probiotic bacteria
• regulatory signals stimulated by presence of worms - gets autoimmune response to calm down

Question 18

Pathogens that evade immune defenses

Answer 18

• pathogens that evade immune response: hide out in various ways
• Tb - hides inside phagocyte and resists digestion by macrophage in lungs, hides out in endosome; gives up on trying to kill it and walls it off so creates areas called tubicules
• Leprosy - waxy exterior coat so evades immune defenses
• Malaria - hides inside rbc so coordinate when burst out and infect additional new cells - chills/fevers because that is when rbc break out and jump into new one; surface molecules act as pyrogens that cause fevers
• Salmonella - hides in epithelial cells in digestive tract
• Chagas and African sleeping sickness- Trypanosoma, which change surface molecules so that immune system gets confused

Question 19

Antigenic variation in African Trypanosomes

Answer 19

• trypanosomes can change surface molecules
• just as antibodies peak, new type of surface antigen starts up and so makes new antibodies and so then starts making another type of surface molecules
  
  • happens over and over and how parasite works
• this confuses immune system by the time response built up to recognize one surface marker - trypanosome changes marker

side note: vitamine C is not protective - small evidence that it may reduce timing of sickness