Review with Dr. Marion

First thing to consider when pathogen enters:
Within minutes- innate immunity responds- receptors include TLR. When pathogen or agent engages receptors, (do not use term bind- they may not bind to things they "sense"-how is not clear). There has been a paradigm shift in self-nonself recognition.
Question to think about: If you think about self/nonself from Janwway perspective, self/nonself discrimination by innate response is absolute, while for adaptive it is relative. Recpetors are designed to only recognize things on pathogens in innate response. In new paradigm that Janeway uses, he views self/nonself as job of APCs that sense whether something is a pathogen or not.
To have good immune response and make an antibody: Immunize mice. Add adjuvant with mycobacterium. Difficult to induce immune response without activating APC.
Why is self-nonself recognition by lymphocytes relative?
Within any individual, individual inherits set of molecules to respond to microbes, but TCR and BCR repertoire are broader due to somatic recombination.
When you think about function MHCI and II- what does it signal- intra or extracellular infection. Lymphocytes can’t see what it is (virus or bacterium or toxin). The cell knows by class I(intracellular) or II(outside brought in) APC presentation.
We inherit complete repertoire for TCR, derived somatically. Review thymic selection process – how thymus trains TCR to recognize MHC. Thymus is T cell school. 2exams-+selection. No binding to self-gone. Negative- do they recognize self too well-fail. Think about it like this:
Recognition generates +survival signal at beginning. Small number TCR expressed at the time. Want to be sure it recognizes MHC well. Peptide is not so relevant- low signal.
2nd half- lots of TCR expressed.
Since we have that generated potential, select only useful ones.
Pathogen in, innate recognition, produce cytokines. Cytokines induce inflammation.
Inflammation’s good side: immune response dependent on it for
1. activation of APC
2. transportation
One cytokine released quickly- TNF alpha- causes vascular dilation, increases expression of adhesion molecules (PCAM, integrins)on surface of endothelium (see Fitzpatrick lecture). Chemokine gradient is established so cells will follow it.
Another thing inflammation does- intiates clotting cascade. Look at endothelium- microclots form at either end of region of insult. Prevents pathogen from leaving. Forces accumulation of fluid in tissue to go to lymph system. Inflammation provides means to accumulate cells to pick up pathogens, block pathogen dispersal, and deliver APCs where immune response can occur.
Delivered to lymph node- best cells for delivering and initiating immune response?
dendritic cells. Why? What do they do in periphery? Roslaniec showed they endocytose stuff efficiently in periphery. Get schlepped into lymph and go to lymph node. Character of the cells changes- no longer endocytosing. Expression class I and II- go from eating to presenting. Change occurs when cell gets into lymph nodes.
Do not want response in periphery to minimize tissue damage and maximize presentation of antigen to T cells to find correct one. Lots of MHC and B7.1 and B7.2. Lots of activation of T cells.
If you monitor efferent lymph at lymph node, massive number of cells through daily, until you get an infection. Then almost no cells through. Why? Dendritic cells and T cells express integrins to help them stick together. Integrins expressed early to allow cells to extravasate, then dendritic cells go to lymph- Character and kinds of adhesins expressed changes. Integrins special so T cells can stick efficiently. Stop and sit. Interrogate surface. T cell specific, activated. 1st 24 hrs- T cells are expanding and expressing molecules causing them to stick to dendritic cells. They stay around long enough to get a lot of them.
Activated- express molecule to get out ,but bind to activated endothelium. Full circle.Bind to spot where it needs to be to deal w pathogen.
Big picture-innate cells induce inflammation, get pathogens to lymph nodes, activation of lymphocytes, clonal expansion, released to promote ability to go to tissue and do their jobs.
Other things important:
complement-
what does it do to bacteria? promotes phagocytosis.
Soluble proteins-part of innate immune function. Adaptive focuses response. Complement can amplify its effector function. It can recognize pathogens because it binds to structures on their surfaces. Once activates, nonspecific in function. What distinguishes pathogen and our cells- we have inhibitors. Inhibitors inactivate C3 convertase. Bacteria don’t have these inhibitors. Complement on- more gets deposited. Forms handles for phagocytes to grab bacteria. Also generate anaphylotoxins to generate inflammation. Provides mechanism for antibodies to direct phagocytes where they need to be.
Want big picture- clonal selection hypothesis. Everything about immune response follows those rules. Have to have clonal expansion, self/nonself, control immune response. Need system regulation to block activation of cells. Whole system is messy. No absolutes.Things generally go in one direction, but based on probability.
Impairment of either system- mess up response.
Few examples of kinds of questions- he asks based on our presentations in class- see those questions.
Going through a few examples:
Dendritic cells have scavenger receptors that pick up cellular debris. Have Fc recpetors for IgG. How they bind some things for endocytosis is not entirely known.
For viruses, some direct their own fate by getting in by infecting dendritic cell. they trigger innate response inside cell that cause cell to present peptides from the virus. Recognition from RNA from the virus. Dr. English’s lecture.
Compare and contrast the innate immune responses that control bacterial replication from those that control viral replication, with a focus on the following:
1. recognition of infected cells
2. effector cells and mechanisms responsible for limiting replication of the pathogen
Global question asking for overview. From Miller’s lecture. Innate have different means to recognize infection with bacterium or virus. How does it work? Which more imprtant for virus- class I, peptides gen intracellulary. class II binds to peptides in phagolysosome. effector cell for viral infection eliminate primary infection.day three thymectomy of neonatal mice produces profound autoimmunity including gastritis, thyroiditis, and type I diabetes as the mice develop. Would you expect adoptive transfer of bone marrow hematopoietic cells from an adult mouse to prevent the autoimmunity? Why, or why not?NO. Assume mice are same strain. Tregs wont develop- no thymus.Took adult peripheral T cells, could fix it.
Discuss role of cytokines (TNFalpha in inflammation)/chemokines in the process of leukocyte migration.Include in your answer:
1. Identify the principle cytokine mediating acute inflammatory response.
2. (went too fast to type)
What characteristics distinguish immune responses from adaptive immune response?
receptors germ line or somatic? clonal or non?
Affinity maturation is caused by somatic mutation and clonal selection. B cells alter their receptors- get better, chosen. CD40 is signal 2 for B cells. Hyper IgM syndrome is disease of this. Solution to this disease included people at St Jude- people had mutation in CD40. Got no IgG. What part of lymph node underdeveloped- follicles. Did not generate secondary activation of B cells and memory.
He likes those kinds of questions.
How would 2nd signal be generated for IgM without CD40- from innate immune ligands on pathogens. Enough antigen stimulates B cells, and T cells (to make a lot of cytokines)- enough antigen to crosslink receptors and enough cytokines- will get some B cell activation. Activation depends on getting enough stuff at a place to initiate phosphorylation cascade and get cell signalling.
He will post sample questions on blackboard.