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Immunology
Cancer and Medical Treatments
Autoimmune Disease
www.kind.med.tu-muenchen.de
Hypersensitivity
Infectious Diseases
www.lytnyc.com
Immunology
Bach J. N Engl J Med 2002;347:911-920.
Immunity
Immunity:
from immunis = exempt
-> individuals who had recovered from certain
infectious diseases will not contract the disease again
Vaccine:
from vacca (= cow), term coined by Pasteur in honor
of Jenner’s cowpox/chicken pox studies
Herd immunity:
When a critical mass is immune to an infection, this
infection is less likely to spread to individuals who are
not immune
Bendall et al., Science 2011
Cells and Organs
innate
PRRs: pattern recognition receptors;
detect PAMPs:
Pathogen-associated molecular patterns
adaptive
Rearranged and edited receptors:
Incredibly high diversity
Adapts to better recognize, eliminate, and remember
Physical and chemical barriers
Dranoff, Nat. Reviews Cancer 2004
Communication through cytokines
Hematopoiesis
www.dentalarticles.com
The Adaptive Immune System
Cellular immune responses:
T cells
Antigen presentation
CD4 T cell help
Humoral immune responses
B cells
T cells
Adaptive Immune Cells
http://cancerlabtechperspective.blogspot.dk/
Lymphocyte receptors
Adaptive Immune Cells
http://www.sbs.utexas.edu/sanders/Bio347/Lectures/2006
T cells
Adaptive Immune Cells
Recognize peptides of a specific length presented by antigen-presenting cells on MHC molecules
T helper cells and cytotoxic T cells (CD4 and CD8), ratio ~ 2:1
CTL: eliminates cells that display foreign antigens complexed with MHC class I
TH1: help the immune response against intracellular pathogens
TH2: help the immune response against extracellular pathogens
TH17: help cell-mediated immunity and the immune response towards fungi
TFH: help humoral immunity
Treg: inhibit immune responses
All these subsets fulfill their functions to a large extent by secreting specific sets of cytokines that drive special
arms of the immune system
T cells
Adaptive Immune Cells
O'Shea and Paul. 2010. Science
B cells
Adaptive Immune Cells
http://cancerlabtechperspective.blogspot.dk/
B cells
Adaptive Immune Cells
• B cells can recognize soluble or particulate antigen
• Plasma cells secrete 100s – more than 1000 immunoglobulin molecules per second!
• Can undergo somatic hypermutation and class switching (affinity maturation)
Georgio et al., Nat Biotechnology 2014
B cells
Adaptive Immune Cells
Georgio et al., Nat Biotechnology 2014
Tan et al., JCI 2014
B cells
Adaptive Immune Cells
Hematopoiesis
www.dentalarticles.com
NK and NKT cells
NK cells
• 5-10% of all lymphocytes
• Efficient cell killers by releasing cytotoxic granules
• Recognize the absence of MHC class I on target cells
• Express antibody receptors -> leads to decoration of antibodies:
when those bind to target, the NK cells is triggered to release its
cytotoxic contents
NKT cells
• Carry TCRs and sometimes CD4
• Recognize specific lipids and glycolipids presented by CD1
• Carry antibody receptors
• Can release granules and many cytokines (stimulatory as well as
inhibitory)
• Apparently involved in asthma, but inhibitory in cases of
autoimmunity and cancer
Vivier et al., Science 2011
Hematopoiesis
www.dentalarticles.com
Innate Immune Cells - Granulocytes
Neutrophils:
• Frontline attackers during an immune response
• Multi-lobed nuclei
• Carrying tons of granules containing proteins such
as cytokines and antimicrobial peptides
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50-70% of circulating leukocytes
Leukocytosis due to transient increase of neutrophils -> indication of infection
Phagocytose pathogens
Secrete cytokine, antimicrobial and tissue-remodeling inducing peptides, and others
Dominant first responders and main cellular component of pus
Eosinophils:
Neutrophil
Basophil
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1-3% of circulating leukocytes
Phagocytic, but not to the same extent as neutrophils
Mostly important in worm defense, role in asthma and allergy
Secrete cytokines, incl. Chemokines, and proteases
Basophils:
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<1 % of circulating leukocytes
Nonphagocytic
Release basophilic protein in response to antibody-binding
Histamine: increases blood vessel permeability and smooth muscle activity
Critical in the defense towards parasites (helminthes) and drivers of allergic reactions
Mast cells:
Mast cell
Eosinophil
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<1% of circulating leukocytes
Mature in the tissues
Histamines and other pharmacologically active compounds
Involved in allergies
Relationship to basophils not fully clear
Hematopoiesis
Dendritic cell
www.dentalarticles.com
Innate Immune Cells – professional antigen-presenting cells
Monocytes and Macrophages, Dendritic Cells
• Can recognize and respond to pathogens
• Secrete proteins that attract and stimulate other immune cells
• Phagocytose and digest pathogens to present peptide on their surface to lymphocytes
• Express co-stimulatory molecules
From: animatedhealthcare.com
Innate Immune Cells – Activation
Kaufmann, Nat. Reviews Microbiology 2007
Innate Immune Cells – Monocytes and Macrophages
Monocytes
• 5-10% of white blood cells
• Heterogenous: migrate to tissues and give rise to multiple phagocytic cells, such as macrophages and dendritic cells
• Inflammatory monocytes and patrolling monocytes
Macrophages
• Inflammatory macrophages with dual role: phagocytosis and antigen presentation
• Other macrophages are long-term residents in tissues and help repair and regeneration
• Osteoclasts: bones, Microglial Cells: brain, Alveolar macrophages: lung, Kupffer cells: liver
• Opsonization
From: www.vet.uga.edu
Dendritic Cells
DCs are key sentinel cells that possess distinct
“stellate” morphology and unparalleled ability
to stimulate naïve T cells (Steinman 2007)
• Arise from myeloid and lymphoid progenitors
• Can take up antigen in one location and present it in
another
• Phagocytosis, receptor-mediated endocytosis,
pinocytosis
• Activation leads to loss of phagocytic activity and gain of
antigen presentation capability, as well as migration
From: amaltherapeutics.com
Antigen presentation
Signal 1: TCR stimulation
Signal 2: Costimulation
Signal 3: Cytokines
Antigen presentation
Harding and Boom, Nat. Reviews Microbiology, 2010
Subramanian and Tabas, Nat. Imm. News and Views, 2014
Hansen and Bouvier, Nat. Reviews Imm., 2009
Networks in Immunology
Primary lymphoid organs – Bone Marrow
Supports stem cell self-renewal and differentiation into all myeloid and erythroid cells and B cells
Is a pool for fully mature memory cells, such as plasma cells
Osteoblasts: generate bone and control the differentiation of HSCs
Endothelial Cells: line the blood vessels, regulate HSC differentiation
Reticular Cells: send processes connecting cells to bone and blood vessels
Sympathetic neurons: control the release of hematopoietic cells from the BM
Lymphoid and myeloid cells mature in environmental micro-niches
Endosteal niche:
Occupied by quiescent HSC in close association with osteoblasts
Vascular niche:
Occupied by HSCs that have been mobilized to differentiate or circulate
Primary lymphoid organs - Thymus
Supports T cell development, place of T cell selection
Immature T cells: thymocytes
Corticomedullary junction:
T cell precursors enter the thymus and mature single-positive T cells exit the thymus
Subcapsular Cortex:
double-negative T cell precursors proliferate and begin to assemble TCR
Cortex:
contains double-positive T cell precursors with functional TCR and CD4 and CD8
contains cortical thymic epithelial cells to test MHC-peptide complex binding
Positive selection: Survival, maturation and migration to the medulla of T cells
that recognize self MHC-peptides with intermediate affinity
Medulla:
T cell maturation
Contains medullary thymic epithelial cells for negative selection of potentially dangerous
T cell clones
Negative selection: cell-death of T cells that bind self-MHC complexes too high
Secondary lymphoid organs (SLOs)
• Spleen, lymph nodes, mucosa-associated lymphoid tissues (tonsils, peyer’s
patches, appendix,…)
• Contain anatomically distinct regions of B- and T-cell activity
• Contain follicles for B-cell development and selection
• Most cells enter SLOs from the blood through high endothelial venules and
leave them through the lymphatics
• Antigen and antigen presenting cells enter SLOs through the lymphatics
(except spleen – only served by blood!)
• Cell movement in the lymph is directed by chemokines
Secondary lymphoid organs – spleen
• Specialized in filtering blood and trapping blood-borne
antigens
• Not supplied by lymphatic vessels
• Red pulp: Red blood cell graveyard
• White pulp: lymphocyte rich
• Marginal zone: populated by a unique set of macrophages
and B cells -> first line of defense
galleryhip.com
1. Antigens and lymphocytes come in through the splenic
artery and interact first with the marginal zone
2. Antigens get processed by dendritic cells
3. Dendritic cells travel to PALS
4. Antigen presentation to lymphocytes in PALS
5. Activated lymphocytes leave through splenic vein
Secondary lymphoid organs – Lymph Nodes (LNs)
Networks of stromal cells packed with lymphocytes, macrophages, and dendritic cells
Cortex:
Mostly B cells, macrophages, and follicular dendritic cells organized in follicles
Antigen comes in through afferent lymphatics
Paracortex:
Mostly T cells and dendritic cells that migrated from the tissues
Medulla:
Most inner layer, lymphocytes exit the LNs here through efferent lymphatics
Some plasma cells that actively secrete antibodies
Swartz and Lund, Nat Reviews Cancer, 2013
Secondary lymphoid organs – Lymph Nodes (LNs)
T cells in the LNs:
Low peptide: green
High peptide: blue
DCs: red
• T cells probe DCs for antigen in the LN
• Stable contacts are formed when a
stimulation threshold is reached
• Stable contacts lead to T cell activation
Henrickson et al., Nat. Immunology 2008
Secondary lymphoid organs – Lymph Nodes (LNs)
B cell migration pathways within follicles during early activation.
1: CXCR5
2: CXCR5, CCR7
3: CXCR5, Ebi2
4: CXCR5, Ebi2
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4
2
1
Pereira et al., Nature 2009
Islam and Luster,
Nat. Med. Reviews 2012
The Multistep model of lymphocyte migration
Fibroblastic reticular cells
Capillary endothelial cells
High endothelial cells
Selectin-mediated Rolling
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Activation
2
1
Firm adhesion
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3
Diapedesis
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3
Selectin
Chemokine receptor
Inactive/active integrin
Addressin
Chemokine
Adhesion molecule