Immunology 2016 Bios E 60 Immunology Course Director

Immunology 2016

Bios. E 60: Immunology Course Director Mihaela Gadjeva(mgadjeva@rics. bwh. harvard. edu) TAs Peter Sage (peter_sage@hms. harvard. edu) Vikram Juneja (vikram_juneja@hst. harvard. edu)

On-line and on-site education Lectures-attendance is optional Sections- attendance is required Exams-

How do we grade? ? 55% Final Exam 35% Midterm exam 10% Section

How did it all started? Edward Jenner invented vaccination in 1796. He introduced a new technique: inoculation with cowpox to protect against smallpox

Immune recognition Effector function Immune regulation Immunological memory

Innate and adaptive immunity. The mechanisms of innate immunity provide the initial defense against infections. Adaptive immune responses develop later and consist of activation of lymphocytes. The kinetics of the innate and adaptive immune responses are approximations and may vary in different infections.

Innate Immunity Adaptive Immunity Fast Slow Limited in specificity Highly diverse Response to repeated challenge is the same as the initial Pattern recognition molecules and phagocytes Response is magnified Antigen-specific receptors and lymphocytes

Key cellular components of the immune system

Neutrophil chasing bacteria Fenteany et al, 2004, Cytoskeletal remodeling in leukocyte function

“Bonding the Foe” Resting PMNs NET-ing PMNs

Innate and adaptive immunity. The mechanisms of innate immunity provide the initial defense against infections. Adaptive immune responses develop later and consist of activation of lymphocytes. The kinetics of the innate and adaptive immune responses are approximations and may vary in different infections.

Where do these cells reside in the body? Do they migrate, how, and why?

Lymphocyte School System Pre. School-Kindergarden-Low. Middle-High School Primary lymphoid organs - sites where lymphocytes are generated. These are the bone marrow and the thymus. College Secondary or peripheral lymphoid organs-sites where mature lymphocytes are maintained and adaptive immune responses are initiated. These are the lymph nodes, the spleen, and the mucosal lymphoid tissues.

HIGHLY-ORGANIZED HIGHWAY SYSTEM Lymph drainage ensures that antigenic material from peripheral sites is efficiently transported to draining LNs and presented to lymphocytes that home to the LN from the blood.

The innate system provides an initial discrimination between self and nonself.

Activation of specialized antigen-presenting cells is a necessary first step for induction of adaptive immunity

Multi-photon imaging allows three-dimensional time-lapse imaging of fluorescent signals deep below the surface of living tissues, allowing cell migration and cell–cell interactions to be tracked. The fluorescent images are of slightly lower resolution compared with those obtained by traditional confocal microscopy. However, multiphoton imaging has several notable advantages compared with other fluorescence-based techniques, including: greatly diminished phototoxicity to living cells; reduced bleaching of fluorescent dyes; the ability to excite several different fluorophores with the same excitation beam; the phenomenon of second harmonic generation of ultraviolet photons by collagen fibres, which allows non-invasive imaging of extracellular matrix components; and deeper tissue penetration (in our hands, the maximal imaging depth in mouse lymph nodes is ~100 μm for confocal microscopy versus ~400 μm for multi-photon excitation).

DC Entering Lymph node

a | The microcirculation of the lymph node has been visualized by intravenous injection of a mixture of green and red fluorescent dextrans. The plasma markers fill all microvessels, which are yellow. The preparation is partly covered by fatty tissue, which diffracts fluorescent light emitted from the superficial epigastric vein resulting in a ‘bubbly’ appearance. To identify the different lymphoid compartments, purified fluorescent B cells (green) and T cells (red) were injected intravenously 20 hours before. After their entry into the lymph node through high endothelial venules (HEVs), the homed cells segregate. B cells populate the more distal B-cell follicles, whereas T cells remain in the paracortex. b | A higher magnification of the boxed region in panel a illustrates the relationship of B and T cells and the microcirculation

B cell follicle

T cells and B cells

T cell area in the LN

CD 4 T cell - DC interactions

How do cells travel?

Clonal expansion-a characteristic feature of immune responses

What are the epitopes?

Antibodies deal with extracellular forms of antigens

Summary Phases of adaptive immune responses. Adaptive immune responses consist of distinct phases, the first three being the recognition of antigen, the activation of lymphocytes, and the elimination of antigen (the effector phase). The response contracts (declines) as antigen-stimulated lymphocytes die by apoptosis, restoring homeostasis, and the antigen-specific cells that survive are responsible for memory. The duration of each phase may vary in different immune responses. The y-axis represents an arbitrary measure of the magnitude of the response. These principles apply to humoral immunity (mediated by B lymphocytes) and cell-mediated immunity (mediated by T lymphocytes).

Specificity, memory, and contraction of adaptive immune responses. Antigens X and Y induce the production of different antibodies (specificity). The secondary response to antigen X is more rapid and larger than the primary response (memory). Antibody levels decline with time after each immunization (contraction, the process that maintains homeo-stasis). The same features are seen in cell-mediated immune responses.

Summary Reading material: Chapter 1 Janeway’s Immunobiolog Key vocabulary: Antigen, Antibody, lymphocytes, innate and adaptive immunity, pattern recognition receptors, clonal expansion, clonal deletion, sites for primary and secondary lymphocyte development, structure of lymph nodes, spleen, APC, immunologic tolerance Key concepts: Lymphocytes develop within specific anatomical sites where they acquire signals that drive their maturation. Lymphocytes migrate from the central to the peripheral lymphoid sites and this is associated with their maturation state. The lymphocytes that have antigen presenting functions migrate to the tissues, where they are quiescent till infection occurs. After activation these cells migrate to the draining lymph nodes to induce adaptive immunity Basic principles of clonal selection hypothesis Effector mechanisms of the adaptive immunity: Antibodies mediate antigen neutralization, opsonosation, and ultimately, clearance. Effector T cells facilitate activation of B cells, macrophages,

ELISPOT

Western Blotting