Download IMMUNE SYSTEM

IMMUNE SYSTEM
Subjects: Immunology
Study programme: General Medicine
Academic year: 2015/2016
RNDr. Mira Horváthová, PhD.
Department of Clinical Immunology and Allergology
Faculty of Medicine SMU in Bratislava
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
pathogens
Diffuse organ that protects the body from pathogens and others
foreign substances, destroyed infected and malignant cells, and
removes cellular debris
What are the parts of the IS?
IS - complex system
organs, 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,
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
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.
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
Agranulocytes – lymphoid lineage
Lymfocytes
B cells – differentiate to plasma cells that
synthesize immunoglobulins
• T cells – arise from bone marrow and
mature in thymus
• NK cells – kill abnormal cells (infected,
tumour)
Mononuclear cells – myeloid lineage
Monocytes - 1-2 days in the circulation,
tissues - several months
Macrophages - part of mononuclear
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
Granular Leukocytes
multilobal nucleus and cytoplasmic granules coloring dyes, basic or acidified
Neutrophils
Basophils and Mast cells
Eosinophils
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
Basophils and Mast cells
role in allergic reaction
granules contain histamine, heparin and other
mediators of anaphylaxis
• participate in the early reactions of
hypersensitivity
Basophils: 0-1% in circulation
Mast cells – arise from hematopoietic stem
cells and occur in tissues
Eosinophils
0- 5% of peripheral blood Leu
bilobed granulocytes
professional phagocytes
eosinophilic granules – major basic protein,
eosinophil cationic protein, neurotoxin,
eosinophil peroxidase
important role in allergic reactions and in
protection against parasitic diseases
MOLECULES OF IS
Antibodies (Immunoglobulins)
Cytokines (Lymphokines, Interleukins)
Endogeneous Immunomodulators (Immunohormones)
Complement System
HLA molecules (antigens)
Receptors
THE MAIN FUNCTION OF IMMUNE SYSTEM
Recognize pathogen
Respond to it and remove it
Remember it
INNATE and ADAPTIVE
immune response
IS
reacts to foreign dangerous agents
imunological surveillance
defence again pathogens
viruses, bacteria, fungi, protozoa, parasites
detect and remove abnormal cells
e.g. tumour, damaged
anti-allergen action
distinguish „self“ from „foreign“
homeostasis preservation
maintaining the integrity of macroorganism
Antigen
any substance that induces specific immune response
IMMUNOGENICITY
SPECIFICITY or ANTIGENICITY
Scheme of complete antigen – immunogen
Complete
(functional) antigen
consists of the
macromolecular
carrier and
determinant groups.
It has the ability to
specifically react with
the products of the
immune response,
induces the
formation of
antibodies.
Isolated antigenic
determinant
hapten, has the
ability to
specifically react
with the products
of immune
response, but can
not induce their
formation.
Is called
incomplete
antigens
Type of antigens
T-cell dependent Ag
T-cell independent Ag
Superantigen
Allergen
Tolerogen
Antibodies
Imunoglobulins (Ig) produced by plasma cells – B cell line;
part of immunoglobulin superfamily
COGNITIVE FUNCTION
EFFECTOR FUNCTION
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
Antibody response to an antigen
Antibody Protection of the Host
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.
No immunological memory in innate immune system
Cell surface receptors
membrane receptors, transmembrane receptors
communication between cells and outside world
extracellular signaling molecules
signal transduction
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
CR – complement receptors
KIR, KAR – on NK cells
Generated receptors
BCR – B cell receptor
TCR – T cell receptor
TCR – T cell receptor
BCR – B cell receptor
Lipid bilayers
CD molecule
Cluster of Differentiation
The identification of immune cell subsets
CD45+
Leukocytes
CD3+
CD3+CD4+ (Th)
CD3+CD8+ (Tc)
T-lymphocytes
CD19+
B-lymphocytes
CD14
monocytes/macrophages
CD3+HLADR+
activated T-Ly
CD3-CD(56+16)+
NK cells
Surface adhesion molecules
Immunoglobulin superfamilly
ICAM-1/CD54
ICAM-2/CD102
ICAM-3/CD50
VCAM-1/CD106
Selectins
E-selectin/CD62E
P-selectin/CD62P
L-selectin/CD62L
Integrins
LFA-1...CD11a/CD18
VLA-4...CD49d/CD29
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
Endogenous pathway of Ag presentation – intracellular
pathogens – viruses, tumor cells
Exogenous pathway of Ag presentation – extracellular
pathogens
CO
CO--STIMULATORY SIGNALS
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
Disorders in mechanisms of immune
tolerance lead to diseases
AUTOIMMUNITY
ALLERGY
TUMOR
Cytokines
basic regulators of Immune system
tissue hormones - proteins secreted by leukocytes and other cells
act through specific receptors
pleiotropic effects - exert multiple action
cytokine system is redundant – each cytokine can be replaced by
others
produced in a cascade
cytokine network
Classification of cytokines
Interleukins
Chemokines
Interferons
Transforming Growth Factors
Colony Stimulating Factors
Tumor Necrosis Factors
Other growth factors
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, IL3, IL-4, IL-5, ...
cytokines of the humoral immunity (Th2): IL-4, IL-5, IL-9, IL10, IL-13, TGF-β, ...
cytokines of the cell mediated immunity (Th1): IL-1, IL-2, IL12, IL-15, IFN-γ, TNF, ...
cytokines with antiviral activity: IL-28, IFN-α, IFN-β, IFN-γ
Non-specific immune system
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
chemicals - complement proteins, interferon, histamine, pyrogens
cells - granulocytes: Neu, Eo, Ba; agranulocytes: Mo/Ma, NK, mast
cells
phagocytosis
inflammation
Complement
key system for surveillance and immunological homeostasis
abbreviation "C„
a set of about 40 executive and regulatory glycoproteins
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
Complement activation
Biological effects of complement
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
Thrombocyte aggregation
C3a, C5a, C5b67
C3a, C5a
Inhibition of macrophage migration and induction of macrophage
spreading
Bb
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
NEUTRALISATION OF VIRUSES
SOLUBILIZATION AND REMOVAL OF IMMUNE COMPLEXES
C3b, C4b, iC3b
C3b, MAC
C3b
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 Tly
CR4
(CD11c/18)
iC3b
Stimulates phagocytosis
Ne, Ma/Mo, NK, some Tly
C3a/C4a
receptor
C3a, C4a
Induces degranulation of
Mast cells, Ba, Ne,
Endothelial cells
C5a receptor
(CD88)
C5a
mast cells and basophils
Induces degranulation of
mast cells and basophils
Mast cells, Ba, Ne,
Ma/Mo, Thrombocytes,
Endothelial cells
Inflammatory process
phylogenetically and ontogenetically the oldest defense
mechanism
protective response - immune cells, blood vessels, and
molecular mediators
eliminate the initial cause of cell injury, clear out necrotic cells
and damaged tissues, initiate tissue repair
Characteristics of inflammatory process
Four stages
Vascular response
Aute cellular responses
Chronic cellular responses
Healing
Neutrophil – important in acute inflammation
Inflammatory response
Various immune cells
Major plasma enzyme systems
Regulatory molecules
Neuroendocrine regulators
Inflammatory mediators
cytokines, chemokines and other chemotactic factors
histamine, serotonin, prostaglandins, leukotrienes
lysosomal enzymes mainly from professional phagocytes
acute phase proteins - serum amyloid A, CRP, complement
proteins, fibrinogen, alpha-1-antitrypsin, haptoglobin,
ceruloplasmin, etc.
Phagocytosis
Basic mechanisms of innate immunity
Professional phagocytes - Ne, Eo, Mo/Ma
Phagocytosis –
bridge between the innate and adaptive immunity
protection against pathogens – innate immune system
Ag processing – adaptive immune response
Phagocytosis - multistage process
Specific immune system
T-lymphocytes
B-lymphocytes
T-lymphocytes
Helper Th-lymphocytes (Th1, Th2, Th3, Th17, Th9)
Cytotoxic Tc-lymphocytes (perforins, toxic lymphokines- TNF-β, ...)
Regulatory Treg-lymphocytes (CD4+CD25+Foxp3+)
Subpopulation of T-lymphocytes
Th3
CD3+CD8+
CD3+CD4+
TGF-β
IL-4
IL-10
Th17
IL-17
B-lymphocytes
humoral immunity
arise from hematopoietic stem cells in the bone marrow
differentiate into plasma cells - produce antibodies
Differentiation of B-lymphocytes
activation
proliferation
differentiation
formation of memory
and effector cells
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
Literature
Immunology, 8th Edition
With STUDENT CONSULT
Online Access
By David Male, MA, PhD,
Jonathan Brostoff, MA, DM,
DSc(Med), FRCP, FRCPath, David
Roth, MD, PhD and Ivan Roitt,
2013
Immunology for Medical
Students, 2nd Edition,
With STUDENT CONSULT
Online Access
By Roderick Nairn, PhD and
Matthew Helbert,
2007
Immunology,
Ivan Roitt at al., 2006
Roitt's Essential Immunology,
P. J. Delves et al., 2011