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MICA 8003

Immunity and Immunopathology

Fall Semester, 2016
10:10-11:00 M-Th
2-118 Moos Tower

Instructors:
Marc Jenkins (Course Director), 6-2715, jenki002@umn.edu, 3-188 WMBB                    
Yoji Shimizu, 6-6849, shimi002@umn.edu, 2-110 WMBB
Mike Farrar, 5-0401, farra005@umn.edu, 2-116 WMBB .
Dan Mueller, 5-1155, muell002@umn.edu, 3-186 WMBB
Alex Khoruts, 6-1188, khoru001@umn.edu, 3-184 WMBB
Chris Pennell, 5-7138, penne001@umn.edu, 3-135 CCRB
Erik Peterson, 5-5634, peter899@umn.edu, 2-112 WMBB
Bryce Binstadt, 6-4598, binstadt@umn.edu, 2-114 WMBB
Stephen Jameson, 5-1496, james024@umn.edu, 2-184 WMBB
Thomas Griffith, 4-8269, tgriffit@umn.edu, 3-125 CCRB
Kris Hogquist, 5-1616, hogqu001@umn.edu, 2-186 WMBB
Sara Hamilton, hamil062@umn.edu, 2-184 WMBB

Moodle Site: https://ay16.moodle.umn.edu/course/view.php?id=6007

Text
Janeway’s Immunobiology.  9th Edition. K. Murphy, et al., Garland Publishing, New York, 2008.

Format
The course will be divided into 14 blocks usually consisting of 4 meetings per block. Within each block, the first two meetings will be lectures with assigned textbook chapters. The second to the last meeting of each block will be a journal club-style discussion of a paper that is related to the topic of the block. Students are expected to read the assigned paper before class and be ready to discuss it in detail. The instructor will post a problem-solving quiz on the Moodle site shortly after the second to the last meeting of the block. Students will submit their answers back to the instructor through the Moodle site before the beginning of the last meeting, after which the instructor will present acceptable answers and lead a discussion of alternative answers and their weaknesses. The instructor will summarize the Key Concepts of the block at the last meeting.

Exams
The grade will be based on problem-solving quizzes, one per block, and a fact-based short answer format final exam.

Quiz answers will be limited to 200 words. Answers longer than 200 words will be given a score of 0. Any material available in the scientific literature may be used to answer the quiz questions. However, students are expected to answer their own quiz independently. None of the quiz questions may be discussed with other members of the class until after the quiz. According to criteria discussed during the fourth session, the instructor will grade each quiz, and the graded quiz will be returned to students via the Moodle site.

The final exam will be 2 hours in length, closed book, short answer format, and focused solely on the Key Concepts from each block.

5 points will be given for each quiz for a total of 70 points and 30 points will be given for the final exam. 2 extra credit points will be given for attending all of the course meetings except for one excused absence.



Block Topic Lecturer Book chapters Dates
1 Humoral Innate Immunity Binstadt 2, 10-15 – 10-25 Sept. 6,7,8,12
2 Cellular Innate Immunity Peterson 3 Sept. 13, 14,15,19
3 Antigen Recognition Pennell 4; 5-1 – 5-16 Sept. 20,21,22,26
4 B Cell Development, Selection Farrar 8-1 – 8-9 Sept. 27,28,29 Oct. 3
5 Immune Receptor Signaling Shimizu 7 Oct. 4,5,6, 10
6 T Cell Development, Selection Hogquist 8-10 – 8-28 Oct. 11,12, 13 17
7 Primary Immune Response and Homeostasis Jenkins 9 – 10-14, 11-3 – 11-16 Oct. 18,19,20, 24
8 IPeripheral Tolerance and Autoimmunity Mueller 15-1 – 15-28 Oct. 25,26,27, 31
9 Immunity to Viruses Jameson 9-29 – 9-33, 13-22 – 13-24 Nov. 1,2,3, 7
10 Immune Memory Hamilton 11-17 – 11-24 Nov. 8,9,10, 14
11 Mucosal Immunity Khoruts 12 Nov. 15,16,17, 21
12 Immunity to Worms Jenkins 10-24 – 10-25, 11-4,11-5 Nov. 22,23, 28
13 Immunity to Bacteria Jenkins 11-5 - 11-7 Nov. 29,30 Dec. 1, 5
14 Immunity to Tumors Griffith 16-13 - 16-19 Dec. 6,7,8, 12
15 Review Jenkins   Dec. 13
         
  Final Exam     8:00-10:00 am Wednesday, December 21

 


MICA 8003 Reading List
Fall Semester 2016

1. Humoral Innate Immunity (Binstadt)
Nimmerjahn F, Ravetch JV. Divergent immunoglobulin g subclass activity through selective Fc receptor binding. Science. 2005. 310:1510-2.

2. Cellular Innate immunity (Peterson)
Pillai, PS, et al. 2016. Mxl reveals innate pathways to antiviral resistance and lethal influenza disease. Science 352:463.

3. Antigen recognition (Pennell)
Keck S, et al. Antigen affinity and antigen dose exert distinct influences on CD4 T-cell differentiation. Proc Natl Acad Sci U S A. 2014. 111:14852-7.

4. Cell Development, selection (Farrar)
Nutt SL, Heavey B, Rolink AG, Busslinger M. Commitment to the B-lymphoid lineage depends on the transcription factor Pax5. Nature. 1999. 401:556-562.

5. Immune receptor signaling (Shimizu)
Li F-Y, et al. Second messenger role for Mg2+ revealed by human T-cell immunodeficiency. Nature. 2011. 475:471-476.

6. T cell development, selection (Hogquist)
Anderson MS, et al. Projection of an immunological self shadow within the thymus by the aire protein. Science. 2002. 298:1395-401.

7. Primary immune response and homeostasis (Jenkins)
Schwickert, TA, et al.  2011. A dynamic T cell-limited checkpoint regulates affinity-dependent B cell entry into the germinal center. JEM 208(6):1243-1252.

8. Peripheral tolerance and autoimmunity (Mueller)
Probst HC, Lagnel J, Kollias G, van den Broek M. Inducible transgenic mice reveal resting dendritic cells as potent inducers of CD8+ T cell tolerance. Immunity. 2003. 18:713-720.

Hunt, T., et al. 2015. The Ro60 autoantigen binds endogenous retroelements and regulates inflammatory gene expression. Science 350(6259):455.

9. Immunity to viruses (Jameson)
Hansen SG, et al. Evasion of CD8+ T cells is critical for superinfection by cytomegalovirus. Science. 2010. 328:102-6.

10. Immune memory (Hamilton)
Miller JD, et al. Human effector and memory CD8+ T cell responses to smallpox and yellow fever vaccines. Immunity. 2008. 28:710-22.

11. Mucosal immunity (Khoruts)
Bloom SM, et al. Commensal Bacteroides species induce colitis in host-genotype- specific fashion in a mouse model of inflammatory bowel disease. Cell Host Microbe. 2011. 9:390-403.

12. Immunity to worms (Jenkins)
Voehringer, D., et al. 2006. Type 2 immunity is controlled by IL-4/IL-13 expression in hematopoietic non-eosinophil cells of the innate immune system.  JEM 203(6):1435-1446.

13. Immunity to bacteria (Jenkins)
Mogues T, Goodrich ME, Ryan L, LaCourse R, North RJ. The relative importance of T cell subsets in immunity and immunopathology of airborne Mycobacterium tuberculosis infection in mice. J Exp Med. 2001. 193:271-80.

14. Immunity to tumors (Griffith)
Koebel CM, et al. Adaptive immunity maintains occult cancer in an equilibrium state. Nature. 2007. 450:903-7.

Block 1
Humoral Innate Immunity

1) The humoral innate immune system consists of complement and bioactive small molecules (e.g. eicosenoids, vasoactive amines, anti-microbial peptides).

2) Acute inflammation is a consequence of innate immune activation or antigen-antibody complexes characterized by pain and changes in blood vessels.

3) The complement system is a tightly regulated enzyme cascade activated by 3 pathways (classical, alternative, and lectin), which produces products that promote inflammation and phagocytosis.

4) The Fc region of an antibody molecule determines its effector functions: IgG targets microbes for Fc receptor-mediated phagocytosis, IgM activates complement, and IgA is secreted into mucus.

Block 2
Cellular Innate Immunity

1) Phagocytes are an important component of the cellular innate immune system.

2) The cellular innate immune response is triggered by Pathogen Associated Molecular Pattern (PAMP) receptors (NOD, TLR, RIG-I) on myeloid cells.

3) Inflammasomes couple PAMP receptors to the release of pro-inflammatory cytokines of the IL-1b family.

4) Activated myeloid cells produce chemokines and cytokines, including CXCL8, TNFa, IL-6, and type 1 Interferons. Such soluble mediators undergird innate responses to infection, including inflammation and anti-viral host defense.

5) Natural Killer (NK) cells integrate signals emanating from counterbalanced activating and inhibitory receptors, as well as cytokine receptors, to determine cytotoxicity levels.  Host cells that have lost MHC class I expression due to viral infection or transformation become NK cell targets.

Block 3
Antigen Recognition

1) B cell antigen receptors (BCRs, antibodies) bind conformational epitopes; T cell antigen receptors (TCRs) bind peptide-major histocompatibility complex (MHC) epitopes formed by antigen processing. TCRs on CD4+ T cells bind peptide-MHC class II epitopes, TCRs on CD8+ T cells bind peptide-MHC class I epitopes. Antigens are substances that contain one or more epitopes.

2) Somatic gene rearrangements yield the diversity and specificity of BCRs and TCRs.

3) BCR variable region genes undergo somatic hypermutation during an immune response. This process, combined with clonal selection, yields B cells producing high affinity antibodies and is called affinity maturation.

4) Affinity is the strength of binding of one ligand to one receptor at a single site. Avidity is the sum total of the strength of binding of multiple sites on polymeric receptor to ligands.

5) The MHC is polymorphic and polygenic.

Block 4
B Cell Development, Selection

1) B cells develop from hematopoietic stem cells in fetal liver and adult bone marrow.

2) A hierarchy of antibody gene rearrangements and selection against autoreactive cells generates the pre-immune BCR repertoire.

3) A network of transcription factors and cytokine signaling pathways regulate the development of B cells.

4) Perturbations in the normal developmental program of B cells can give rise to immune deficiency diseases and acute lymphoblastic leukemia.

Block 5
Immune Receptor Signaling

1) TCRs and BCRs contain invariant accessory chains that transmit intracellular signals.
 
2) Receptors transmit intracellular signals via protein modifications that regulate conformation, stability, enzymatic activity, temporal assembly, and subcellular localization of multi-protein signaling complexes.
 
3) Antigen receptor signaling is highly sensitive and specific.
 
4) The immunological synapse is a cytoskeleton-dependent macromolecular structure that enhances T cell responses to weak antigen signals and attenuates responses to strong antigen signals.
 
5) Antigen-dependent T cell stimulation is initiated and sustained by receptor microclusters that vary in protein composition and localization over time.

Block 6
T Cell Development, Selection

1) The thymus is required for T cell development from bone marrow precursors.

2) Positive selection generates a MHC-restricted repertoire.

3) Clonal deletion and regulatory T cells (Tregs) generate a self-tolerant repertoire

4) T cell effector function is linked to MHC specificity (lineage commitment).

5) TCR and cytokine signals are required for naïve T cell homeostasis.

Block 7
Primary Immune Response and Homeostasis

1) Primary immune responses occur in secondary lymphoid organs.

2) Dendritic cells initiate the primary T cell response by presenting peptide-MHC complexes to naïve T cells.

3) Naïve T cells require TCR, CD28, and cytokine signals to proliferate and differentiate productively.

4) A naïve B cell must bind an antigen via its BCR, present a peptide-MHC class II epitope derived from that antigen to a CD4+ helper T cell and receive signals from the helper cell to be optimally activated.

5) Following optimal activation, naïve B cells can become plasma cells, germinal center cells, or memory cells, and undergo immunogloblulin isotype-switching, and somatic mutation.

Block 8
Peripheral Tolerance and Autoimmunity

1) Peripheral self-tolerance relies on the deletion or inactivation of self antigen-reactive lymphocytes or their inhibition by regulatory T cells.

2) Autoimmunity is a disease resulting from the breakdown of one or more of these mechanisms.

3) Autoimmunity develops in genetically predisposed individuals as a result of some environmental trigger.

Block 9
Immunity to Viruses

1) IFNs (type-I and IFN-gamma) are critical cytokines in the immune response to many viruses because they produce an intrinsic anti-viral state in infected cells.

2) The immune response to viruses involves elimination of infected cells by cytotoxic lymphocytes (CD8+ T cells and NK cells) and free viruses by antibodies.

3) Cytotoxic T cells are generated from CD8+ naive T cells stimulated by a peptide-MHC class I epitope in the presence of co-stimulatory molecules and inflammatory cytokines.

4) Some viruses have developed elaborate mechanisms to persist in the host by evading the innate and adaptive immune responses.

Block 10
Immune Memory

1) Memory cells are long-lived, functionally improved, quiescent cells derived from naïve cells that proliferated in response to an epitope.

2) Memory cells proliferate and acquire effector functions very rapidly after a second exposure to the relevant epitope.

3) Serum antibodies are maintained by long-lived plasma cells.

Block 11
Mucosal Immunity

1) Commensal microbes, the physical barrier of mucosal surfaces, and the IgA-mediated immune barrier are all linked in a mutualist relationship.

2) The mucosal immune system protects against pathogens and controls the composition of the commensal flora.

3) Non-inflammatory immune mechanisms are used to maintain mucosal integrity.

 Block 12
Immunity to Worms

1) Th2 cells produce IL-4 and develop from naive precursors stimulated by a peptide-MHC class II epitope in the presence of IL-4.

2) Th2 cells provide protection from worms via an expulsion mechanism.

3) Worm expulsion is facilitated by mast cell activation via IgE, goblet cell production of mucus, and eosinophil toxins.
 
Block 13
Immunity to Bacteria

1) Th1 andTh17 cells are CD4+ T cells involved in protective immunity to intracellular phagosomal or extracellular bacteria, respectively.

2) Th1 cells produce interferon (IFN)-gamma and develop from naive precursors stimulated by a peptide-MHC class II epitope in the presence of IL-12.

3) Th17 cells produce IL-17A and develop from naive precursors stimulated by a peptide-MHC class II epitope in the presence of IL-6 and TGF-beta.

4) Antibodies can prevent colonization, promote phagocytosis, or participate in bacterial lysis.

5) Cytotoxic CD8+ T cells provide protective immunity to intracellular cytosolic bacteria by killing infected host cells.

Block 14
Immunity to Tumors

1) The adaptive immune system can recognize tumors and distinguish them from self-tissue.
 
2) Several major immune effector functions can act against tumors.
 
3) Tumors can evade the immune response by multiple mechanisms.
 
4) Immune responses can be manipulated to achieve effective immunotherapy.