IMMUNE SYSTEM

Subjects: Immunology
Study programme: General Medicine

RNDr. Mira Horváthová, PhD.

Academic year: 2015/2016 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. Isolated antigenic
determinant
It has the ability to hapten, has the
specifically react with ability to
the products of the specifically react
immune response, with the products
induces the of immune
formation of response, but can
antibodies. 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 CD14
monocytes/macrophages

CD3+
CD3+CD4+ (Th)
CD3+CD8+ (Tc) CD3+HLADR+
T-lymphocytes activated T-Ly

CD19+ CD3-CD(56+16)+
B-lymphocytes NK cells
 Surface adhesion molecules

Immunoglobulin superfamilly
ICAM-1/CD54
ICAM-2/CD102
ICAM-3/CD50
VCAM-1/CD106

Selectins
E-selectin/CD62E Integrins
P-selectin/CD62P LFA-1...CD11a/CD18
L-selectin/CD62L 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, IL-

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

 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 C3a, C5a, C5b67
Thrombocyte aggregation C3a, C5a
Inhibition of macrophage migration and induction of macrophage
Bb
spreading
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

 Receptors for complement fragments
Receptor Ligand Activity Distribution
CR1 (CD35) C3b, C4b, Stimulates degradation and Er, Ne, Ma/Mo, Eo, DC,
iC3b phagocytosis B-ly, some T-ly
CR2 (CD21) C3d, C3dg, Part of B-ly coreceptor, B-ly, DC
iC3b, EBV binds EBV
CR3 iC3b Stimulates phagocytosis Ne, Ma/Mo, NK, some T-
(CD11b/18) ly
CR4 iC3b Stimulates phagocytosis Ne, Ma/Mo, NK, some T-
(CD11c/18) ly
C3a/C4a C3a, C4a Induces degranulation of Mast cells, Ba, Ne,
receptor mast cells and basophils Endothelial cells
C5a receptor C5a Induces degranulation of Mast cells, Ba, Ne,
(CD88) mast cells and basophils 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 Th17

TGF-β IL-17
IL-4
CD3+CD8+ CD3+CD4+ IL-10
 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, Roitt's Essential Immunology,
Ivan Roitt at al., 2006 P. J. Delves et al., 2011