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

� 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

What are the parts of the IS?

� 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

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 thatsynthesize immunoglobulinssynthesize 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 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� 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 • 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� 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)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

� 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

Antigen

any substance that induces specific immune response

IMMUNOGENICITY

SPECIFICITY or ANTIGENICITY

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.

Type of antigens

T-cell dependent Ag

T-cell independent AgT-cell independent Ag

Superantigen

Allergen

Tolerogen

Imunoglobulins (Ig) produced by plasma cells – B cell line;

part of immunoglobulin superfamily

Antibodies

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. the same pathogen.

No immunological memory in innate immune system

membrane receptors, transmembrane receptors

communication between cells and outside world

extracellular signaling molecules

Cell surface receptors

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

CD molecule

Lipid bilayers

Cluster of Differentiation

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

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

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

COCO--STIMULATORY SIGNALSSTIMULATORY 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

ALLERGY

� 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

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, ... 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

� 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

� 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

Complement activation

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

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

� 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

Four stages

Vascular response

Aute cellular responses

Chronic cellular responses

Characteristics of inflammatory process

Chronic cellular responses

Healing

Neutrophil – important in acute inflammation

Various immune cells

Major plasma enzyme systems

Inflammatory response

Regulatory molecules

Neuroendocrine regulators

� 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.

Basic mechanisms of innate immunity

Professional phagocytes - Ne, Eo, Mo/Ma

Phagocytosis

protection against pathogens – innate immune system

Ag processing – adaptive immune response

Phagocytosis –bridge between the innate and adaptive immunity

Ag processing – adaptive immune response

Phagocytosis - multistage process

Specific immune system

T-lymphocytes B-lymphocytesT-lymphocytes B-lymphocytes

Helper Th-lymphocytes (Th1, Th2, Th3, Th17, Th9)

Cytotoxic Tc-lymphocytes (perforins, toxic lymphokines- TNF-β, ...)

T-lymphocytes

Regulatory Treg-lymphocytes (CD4+CD25+Foxp3+)

Subpopulation of T-lymphocytes

CD3+CD8+ CD3+CD4+

Th3

TGF-βIL-4IL-10

Th17

IL-17

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

Differentiation of B-lymphocytes

proliferation formation of memory and effector cells

activation differentiation

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, 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

Roitt's Essential Immunology,

P. J. Delves et al., 2011Immunology,

Ivan Roitt at al., 2006