basic immunology - web - slovenská zdravotnícka … syste… · · 2015-10-05subjects:...
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IMMUNE SYSTEM
RNDr. Mira Horváthová, PhD.
Department of Clinical Immunology and Allergology
Faculty of Medicine SMU in Bratislava
Subjects: Immunology
Study programme: General Medicine
Academic year: 2015/2016
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� Immune system (IS) a complex network of specialized cells, cell
products, tissues and molecules and their interactions incurred
during the phylogenetic development of organisms
� Arose in nearly all organisms as response to the external
environment in an effort to survive
� Evolution of the immune system is always co-evolution with � Evolution of the immune system is always co-evolution with
pathogens
� Diffuse organ that protects the body from pathogens and others
foreign substances, destroyed infected and malignant cells, and
removes cellular debris
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What are the parts of the IS?
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� IS - complex systemorgans, tissues, cells, molecules, regulatory substances - are interconnected – weight in an adult is about 1 kg of
� Organs of the IS
primary lymphoid organs: bone marrow and thymus
secondary lymphoids organs: spleen, lymph nodes, tonsils, appendix,appendix,
Peyer´s patches in the gut - GALT, gut-associated lymphoid tissue
MALT, mucosal-associated lymphoid tissue
BALT, bronchial-associated lymphoid tissue
� Cell of the IS – approximately 1012 cells
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Subjecting whole blood to density-gradient centrifugation fractionates the
sample into three constituents: erythrocytes, plasma and buffy coat. The
buffy coat, a thin layer sandwiched between the other components, is less
than 1% of the original whole blood sample, yet it contains the majority of
the white blood cells and platelets.
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Leukocytes
White blood cells
� multilobal nucleus - contain large amounts of cytoplasmic granules – granulocytes
� uniform nucleus – cytoplasm without granules or only a few granules - agranulocytes (35- 38%); lymphoid and myeloid lineage
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Agranulocytes – lymphoid lineage
Lymfocytes
� B cells – differentiate to plasma cells thatsynthesize immunoglobulinssynthesize immunoglobulins
• T cells – arise from bone marrow and mature in thymus
• NK cells – kill abnormal cells (infected, tumour)
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Mononuclear cells – myeloid lineage
� Monocytes - 1-2 days in the circulation, tissues - several months
� Macrophages - part of mononuclear phagocyte system, professional phagocyte system, professional phagocytes, act as antigen presentig cells(APC)
� Dendritic cells – Ag presentation; multiple cytoplasmic projections; lower ability of phagocytosis, myeloid and lymphoid origin
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Granular Leukocytes
multilobal nucleus and cytoplasmic granules -coloring dyes, basic or acidified
� Neutrophils� Neutrophils
� Basophils and Mast cells
� Eosinophils
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Neutrophils
� Polymorphonuclear Leukocytes
� 45-70% of the total Leu
� 2-5 nuclear segments
� life time in the blood 6–8 hr., tissues 1-2 days
� new cells are formed daily 5-1010 (10 billion)
� professional phagocytes
� accute infections
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Basophils and Mast cells
� role in allergic reaction
� granules contain histamine, heparin and other mediators of anaphylaxis
• participate in the early reactions of • participate in the early reactions of
hypersensitivity
� Basophils: 0-1% in circulation
� Mast cells – arise from hematopoietic stem cells and occur in tissues
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Eosinophils
� 0- 5% of peripheral blood Leu
� bilobed granulocytes
� professional phagocytes� professional phagocytes
� eosinophilic granules – major basic protein, eosinophil cationic protein, neurotoxin, eosinophil peroxidase
� important role in allergic reactions and in protection against parasitic diseases
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MOLECULES OF IS
Antibodies (Immunoglobulins)
Cytokines (Lymphokines, Interleukins)
Endogeneous Immunomodulators (Immunohormones)Endogeneous Immunomodulators (Immunohormones)
Complement System
HLA molecules (antigens)
Receptors
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THE MAIN FUNCTION OF IMMUNE SYSTEM
Recognize pathogen
Respond to it and remove it
Remember it
INNATE and ADAPTIVE
immune response
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� reacts to foreign dangerous agents
� imunological surveillance
� defence again pathogens
viruses, bacteria, fungi, protozoa, parasites
� detect and remove abnormal cells
e.g. tumour, damaged
IS
e.g. tumour, damaged
� anti-allergen action
� distinguish „self“ from „foreign“
� homeostasis preservation
� maintaining the integrity of macroorganism
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Antigen
any substance that induces specific immune response
IMMUNOGENICITY
SPECIFICITY or ANTIGENICITY
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Scheme of complete antigen – immunogen
Isolated antigenic
determinant
hapten, has the
Complete
(functional) antigen
consists of the
macromolecular
carrier and
determinant groups.
It has the ability to hapten, has the
ability to
specifically react
with the products
of immune
response, but can
not induce their
formation.
Is called
incomplete
antigens
It has the ability to
specifically react with
the products of the
immune response,
induces the
formation of
antibodies.
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Type of antigens
T-cell dependent Ag
T-cell independent AgT-cell independent Ag
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Superantigen
Allergen
Tolerogen
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Imunoglobulins (Ig) produced by plasma cells – B cell line;
part of immunoglobulin superfamily
Antibodies
COGNITIVE FUNCTION
EFFECTOR FUNCTION
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Affinity of antibody
the strenght of the reaction between a single antigenic
determinant (epitope) and a single combining site of
the antibody
Avidity of antibody
is a measure of the overall strenght of binding of an
antigen with many antigenic determinants and
multivalent antibodies
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Antibody response to an antigen
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Antibody Protection of the Host
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Immunological memory
Adaptive (or acquired immunity) creates immunological
memory after initial response to a specific pathogen,
leading to enhanced response after second exposure to
the same pathogen. the same pathogen.
No immunological memory in innate immune system
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membrane receptors, transmembrane receptors
communication between cells and outside world
extracellular signaling molecules
Cell surface receptors
extracellular signaling molecules
signal transduction
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Preformed receptors
components of innate immunity
PRR - Pattern recognition receptors
TLR - Toll-like receptors
KAR – Killer activation receptor
KIR – Killer-inhibition receptors
CR – Complement receptor
FcR – bind the antibodies at their Fc region
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CR – complement receptors
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KIR, KAR – on NK cells
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Generated receptors
� BCR – B cell receptor
� TCR – T cell receptor
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TCR – T cell receptor
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BCR – B cell receptor
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CD molecule
Lipid bilayers
Cluster of Differentiation
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The identification of immune cell subsets
CD14
monocytes/macrophages
CD3+
CD45+
Leukocytes
CD3+
CD3+CD4+ (Th)
CD3+CD8+ (Tc)
T-lymphocytes
CD3+HLADR+
activated T-Ly
CD19+
B-lymphocytesCD3-CD(56+16)+
NK cells
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Surface adhesion molecules
Immunoglobulin superfamilly
ICAM-1/CD54
ICAM-2/CD102
ICAM-3/CD50
Integrins
LFA-1...CD11a/CD18
VLA-4...CD49d/CD29
ICAM-3/CD50
VCAM-1/CD106
Selectins
E-selectin/CD62E
P-selectin/CD62P
L-selectin/CD62L
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Antigen presentation – a multistage process
uptake of antigen by antigen presenting cell (APC)
proteolytic cleavage
Ag degradation - immunogenic fragments (IFs)
complex IFs + HLA-molecules
exposition of IFs to extracellular space
recognition of IFs + HLA-molecules by T cells
phenomenon of MHC restriction
interaction between CD4 Th-Ly (or CD8 Tc-Ly)
and HLA II. class (or I. class) on APC
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Endogenous pathway of Ag presentation – intracellular
pathogens – viruses, tumor cells
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Exogenous pathway of Ag presentation – extracellular
pathogens
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COCO--STIMULATORY SIGNALSSTIMULATORY SIGNALS
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Immunological tolerance (IT)
a state of unresponsiveness of the immune system to
substances or tissue that have the capacity to elicit
immune response
NATURAL IT
SECONDARY IT
IT TO FETUS
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Disorders in mechanisms of immune
tolerance lead to diseases
AUTOIMMUNITY
ALLERGY
TUMOR
ALLERGY
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� basic regulators of Immune system
� tissue hormones - proteins secreted by leukocytes and other cells
� act through specific receptors
Cytokines
� pleiotropic effects - exert multiple action
� cytokine system is redundant – each cytokine can be replaced by others
� produced in a cascade
� cytokine network
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Classification of cytokines
Interleukins
Chemokines
Interferons
Transforming Growth Factors
Colony Stimulating Factors
Tumor Necrosis Factors
Other growth factors
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The distribution of cytokines according to function
� proinflammatory cytokines - TNF, IL-1, IL-6, IL-8, IL-12, ...
� anti-inflammatory – IL-4, IL-6, IL-10, TGF-β, ...
� cytokines with hematopoietic growth factor activity : IL-2, IL-
3, IL-4, IL-5, ... 3, IL-4, IL-5, ...
� cytokines of the humoral immunity (Th2): IL-4, IL-5, IL-9, IL-
10, IL-13, TGF-β, ...
� cytokines of the cell mediated immunity (Th1): IL-1, IL-2, IL-
12, IL-15, IFN-γ, TNF, ...
� cytokines with antiviral activity: IL-28, IFN-α, IFN-β, IFN-γ
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� mechanical barriers and mechanical reactions - skin, mucous
membranes, coughing, sneezing, ...
� chemical barriers - eg. enzymes in saliva, NaCl (sodium chloride)
in tears, HCl (sodium chloride) in the stomach
Non-specific immune system
� chemicals - complement proteins, interferon, histamine, pyrogens
� cells - granulocytes: Neu, Eo, Ba; agranulocytes: Mo/Ma, NK, mast
cells
� phagocytosis
� inflammation
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� abbreviation "C„
� a set of about 40 executive and regulatory glycoproteins
� three biochemical pathway activate C system: classical, alternative
Complement key system for surveillance and immunological homeostasis
� three biochemical pathway activate C system: classical, alternative
and the lectin pathway
� components C1 to C9, factors B, D, and properdin, co-factors -
components are activated through cascade mechanism
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Complement activation
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CELL LYSIS C5b-C9, MAC
INFLAMMATORY RESPONSE
Basophils and mast cells degranulation C3a, C4a, C5a
Neutrophils dagranulation C5a
Eosinophils degranulation C3a, C5a
Leukocytes extravasation and chemotaxis at sites of inflammation C3a, C5a, C5b67
Thrombocyte aggregation C3a, C5a
Biological effects of complement
Inhibition of macrophage migration and induction of macrophage
spreadingBb
Release of neutrophils from the bone marrow C3c
Release of hydrolytic enzymes from neutrophils C5a
Increase of CR1 and CR3 expression on neutrophils C5a
OPSONISATION AND STIMULATION OF PHAGOCYTOSIS C3b, C4b, iC3b
NEUTRALISATION OF VIRUSES C3b, MAC
SOLUBILIZATION AND REMOVAL OF IMMUNE COMPLEXES C3b
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Receptors for complement fragments
Receptor Ligand Activity Distribution
CR1 (CD35) C3b, C4b,
iC3b
Stimulates degradation and
phagocytosis
Er, Ne, Ma/Mo, Eo, DC,
B-ly, some T-ly
CR2 (CD21) C3d, C3dg,
iC3b, EBV
Part of B-ly coreceptor,
binds EBV
B-ly, DC
CR3
(CD11b/18)
iC3b Stimulates phagocytosis Ne, Ma/Mo, NK, some T-
ly(CD11b/18) ly
CR4
(CD11c/18)
iC3b Stimulates phagocytosis Ne, Ma/Mo, NK, some T-
ly
C3a/C4a
receptor
C3a, C4a Induces degranulation of
mast cells and basophils
Mast cells, Ba, Ne,
Endothelial cells
C5a receptor
(CD88)
C5a Induces degranulation of
mast cells and basophils
Mast cells, Ba, Ne,
Ma/Mo, Thrombocytes,
Endothelial cells
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� phylogenetically and ontogenetically the oldest defense
mechanism
� protective response - immune cells, blood vessels, and
molecular mediators
Inflammatory process
molecular mediators
� eliminate the initial cause of cell injury, clear out necrotic cells
and damaged tissues, initiate tissue repair
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Four stages
Vascular response
Aute cellular responses
Chronic cellular responses
Characteristics of inflammatory process
Chronic cellular responses
Healing
Neutrophil – important in acute inflammation
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Various immune cells
Major plasma enzyme systems
Inflammatory response
Regulatory molecules
Neuroendocrine regulators
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� cytokines, chemokines and other chemotactic factors
� histamine, serotonin, prostaglandins, leukotrienes
� lysosomal enzymes mainly from professional phagocytes
Inflammatory mediators
� lysosomal enzymes mainly from professional phagocytes
� acute phase proteins - serum amyloid A, CRP, complement
proteins, fibrinogen, alpha-1-antitrypsin, haptoglobin,
ceruloplasmin, etc.
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Basic mechanisms of innate immunity
Professional phagocytes - Ne, Eo, Mo/Ma
Phagocytosis
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protection against pathogens – innate immune system
Ag processing – adaptive immune response
Phagocytosis –bridge between the innate and adaptive immunity
Ag processing – adaptive immune response
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Phagocytosis - multistage process
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Specific immune system
T-lymphocytes B-lymphocytesT-lymphocytes B-lymphocytes
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Helper Th-lymphocytes (Th1, Th2, Th3, Th17, Th9)
Cytotoxic Tc-lymphocytes (perforins, toxic lymphokines- TNF-β, ...)
T-lymphocytes
Regulatory Treg-lymphocytes (CD4+CD25+Foxp3+)
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Subpopulation of T-lymphocytes
CD3+CD8+ CD3+CD4+
Th3
TGF-βIL-4IL-10
Th17
IL-17
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humoral immunity
arise from hematopoietic stem cells in the bone marrow
B-lymphocytes
arise from hematopoietic stem cells in the bone marrow
differentiate into plasma cells - produce antibodies
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Differentiation of B-lymphocytes
proliferation formation of memory and effector cells
activation differentiation
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Disorders of immune system
� failures of host defense mechanisms - reduced resistance to
infection – immunodeficiency
� pathological reactivity to external factors – allergies
� inadequacy in self-tolerance - pathological reactivity to
internal factors - autoimmune diseases
� immune surveillance deficiencies - cancers
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Literature
Immunology, 8th Edition
With STUDENT CONSULT
Online Access
By David Male, MA, PhD, By David Male, MA, PhD,
Jonathan Brostoff, MA, DM,
DSc(Med), FRCP, FRCPath, David
Roth, MD, PhD and Ivan Roitt,
2013
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Immunology for Medical
Students, 2nd Edition,
With STUDENT CONSULT
Online Access
By Roderick Nairn, PhD and
Matthew Helbert,
2007
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Roitt's Essential Immunology,
P. J. Delves et al., 2011Immunology,
Ivan Roitt at al., 2006