Physiological regulation

of the immune system

Regulation by antigen

Induce immune responses and extinction

Affinity maturation of B lymphocytes

Maintaining immunological memory

Antigenic competition

Threshold density of the complex MHC II-gp Ag on APC

Regulation by antibodies

Antibodies competes with the BCR for antigen (negative regulator of B lymphocyte stimulating)

IgG immune complexes bind to the BCR and FcgR on B cells, resulting in blocking activation of B lymphocytes

It is still unclear meaning of regulation via idiotypic network

Regulation by cytokines and cellular contact

Interaction APC - T lymphocyte

Interaction TH1 – macrophages

Interaction TH2 - B lymphocytes

Mutual regulation of activity TH1 versus TH2

Development of leukocyte subpopulations

Negative regulation of effector cells:

CTLA-4 - T cell inhibitory receptor, binds ligands CD80

and CD86

Inhibitory receptors of NK cells

Self-destruction interaction of the apoptotic receptor Fas

with ligand FasL on the surface of activated T

lymphocytes

Factors influencing the outcome of the immune response

The same antigen can induce an active immune response or an active state of tolerance, the result of response depends on many factors:

State of the immune system

Properties of antigen

Dose of antigen

Route of antigen administration

Cytokines

(Tissue hormones)

Cytokines

Regulatory proteins and glycoproteins produced by leukocytes and other cells

Essential regulators of the immune system

Apply outside the immune system (angiogenesis, tissue regeneration, carcinogenesis, treatment of many brain functions, embryonic development ...)

Cytokines - secreted      - membrane (CD 80, CD86, CD40L, FasL ..)

Pleiotropic effect

Operates in a cascade

Cytokine Network

Cytokine system is redundant

Effects of cytokines - autocrine - paracrine

- endocrine

Are known as interleukins (exception: TNF, lymphotoxin, TGF, interferons, CSF and growth factors)

B cells communicate via cytokines with other

inflammatory cells, such as T cells and macrophages

Distribution of cytokines by function

Proinflammatory cytokines (IL-1, IL-6,IL- 8,IL- 12,IL- 18, TNF)

Antiinflammatory cytokines (IL-1Ra, IL-4, IL-10, TGF)

Cytokines with the activity of hematopoietic cells growth factor (IL-2, 3, 4, 5, 6, 7, 9, 11, 14, 15, CSF, SCF, LIF, EPO)

Cytokines applying in TH2 humoral immunity (IL-4, 5, 9, 13)

Cytokines applying in the cell-mediated immunity TH1 (IL-2, 12, IFN, GM-CSF, lymphotoxin)

Cytokines with anti-virus effect (IFN-, IFN-, IFN- )

Overview of the most important cytokines

Cytokine Produced FunctionIL-1 MF, N T cell costimulation, induction of TNF and IL-8, pyrogen

IL-2 Th1 Growth factor for T cells

IL-4 Th2, basophils Th2 differentiation, B cell stimulation, isotype switching to IgE and IgG4, Th1 inhibition

IL-5 Th2, eosinophils

B cell stimulation, growth factor for eosinophils

IL-6 Th2, MF, N T and B cell stimulation, stimulation of Ig production, induction of acute phase proteins synthesis, pyrogen

IL-8 MF, other cells Granulocyte activation and chemotaxis (primarily neutrophils)

IL-10 Th2,M, Treg Th1 and MF inhibition, B cell differentiation to plasma cell

IL-12 MF, DC, B Th1 differentiation, NK stimulation

TNF M, MF, NK Induction of local inflammation, endothelium activation, induction of apoptosis

TGFb T, MF, platelets The anti-inflammatory effect (control of lymphocyte proliferation, control of Ig production, control MF activity), stimulation of fibroblasts and osteoblasts, gain production of extracellular matrix

IFNa L, M, MF Inhibition of viral replication

IFNb Fibroblasts, epithelial cells

Inhibition of viral replication

IFNg Th1, NK MF activation, stimulation of MHC gp. expression, Th2 inhibition

MF – macrophages; M – monocytes; N – neutrophils; DC – dendritic cells; NK – natural killers; L – lymphocytes; B – B cell; T – T cell

Cytokine receptors Consisting of 2 or 3 subunits

One subunit binds cytokine, other are associated with cytoplasmic signaling molecules (protein kinases)

Signaling subunit is shared by several different cytokine receptors - called receptor family

Signaling through these receptors may lead to proliferation, differentiation, activation of effector mechanisms or blocking the cell cycle and induction of apoptosis

External regulation of immune response

Substitution treatment

treatment with intravenous immunoglobulin (derived from plasma of blood donors)

substitution of C1 inhibitor for hereditary angioedema

substitution of erythropoietin in patients with chronic renal failure

substitution of G-CSF in agranulocytosis

Immunomodulation= medical procedure to adjust the disrupted immune

function

Non-specific immunosuppressive therapy

nonspecific = affects not only autoreactive and aloreactive                        lymphocytes, but also other components of immunity (risk of reduction antiinfectious and anti- tumor immunity)

used for treatment of autoimmune diseases, severe allergic conditions and for organ transplantation

Non-specific immunosuppressive therapy corticosteroids - anti-inflammatory,

immunosuppressive effects                    - blocking the activity of transcription factors (AP-1, NFkB)                    - suppress the expression of genes (IL-2, IL-1, phospholipase A, MHC gp II, adhesion molecules)                   - inhibition of histamine release from basophils                    - higher concentrations induce apoptosis of lymfocytes

immunosuppressants affecting the metabolism of DNA - cyclophosphamide, azathioprine,methotrexate

immunosuppressant selectively inhibiting T lymphocytes - immunosuppressive ATB: cyclosporine A, tacrolimus, rapamycin (suppressing the expression of IL-2 and IL-2R in activated T lymphocytes)                 - monoclonal antibody anti-CD3 (Immunosuppression after transplantation, treatment of rejection crises)

immunoglobulins in the immunosuppressive indication                  - Polyspecific intravenous immunoglobulins                    (Inhibition of B lymphocytes, antiidiotype activity, inhibition of cytokines, neutralization of toxins, inhibition of complement activation ...)

Anti-inflammatory and antiallergic treatment

nonsteroidal anti-inflammatory drugs

antihistamines - blocking H1 receptor                          - reduce the expression of adhesion molecules                          - reduce the secretion of histamine ...

inhibitors of inflammatory cytokine - receptor antagonist for IL-1

                         - monoclonal antibodies against TNF                          - thalidomide (TNF inhibitor)

enzyme therapy - in the enzyme mixture has a major effect trypsin and bromelain                            - anti-inflammatory and immunomodulatory effects

Non-specific immunostimulant therapy synthetic immunomodulators

Methisoprinol (Isoprinosine) - used in viral infections with more severe or relapsing course

bacterial extracts and lysates Broncho-Vaxom - prevention of recurrent respiratory tract

infections Ribomunyl

products of the immune system IL-2 - renal adenocarcinoma IFNa, IFNb - viral hepatitis, some leukemia Erythropoietin – renal failure G-CSF, GM-CSF – neutropenia Transfer factor (blood donors leukocytes undergoing dialysis) Thymus hormones

              

Antigen-specific immunomodulatory therapy

specific immunomodulation = induce an

immune response or tolerance against a specific

antigen

a) active immunization

b) passive immunization

c) specific immunosuppression

d) vaccination against cancer

a) active immunization

= use of antigen to induce an immune response that can

later protect against a pathogen bearing the antigen

(or similar antigen)

immunization vaccines are made from inactivated or

attenuated microorganisms or their antigens

(polysaccharide capsule, toxins)

creates long-term immunity

activate cellular and antibody immunity

administration of antigen injectable, oral

prophylaxis

risk of causing infection or anaphylactic reactions

b) passive immunization

natural - transfer of maternal antibodies in fetal blood

therapeutically - the use of animal antibodies against various toxins (snake toxins, tetanus toxin, botulinum toxin)

prophylaxis - the human immunoglobulin from immunized individuals (hepatitis A, rabies, tetanus)                     - Anti-RhD antibodies - preventing maternal immunization with RhD+ fetus

provides a temporary (3 weeks) specific humoral immunity

the risk of induction anaphylactic reactions

c) specific immunosuppression

= induction of tolerance against a specific antigen

ongoing clinical studies

induction of tolerance by oral administration of antigen (treatment of certain autoimmune diseases)

allergen immunotherapy (pollen, insect poisons)

d) vaccination against cancer

s a promising approach appears to immunization dendritic cells

Defense against

extracellular pathogens

Defence against extracellular pathogens

bacteria (gram-negative, gram-positive cocci, bacilli), unicellular parasites

complement activation stimulated by bacterial cell wall

phagocytosis by neutrophil granulocytes

opsonization (C3b, lectins, antibodies ...) enhance phagocytosis

Opsonisation

Phagocytes are attracted to the site of infection by chemotactic substances (C5a, C3a and chemotactic products of bacteria)

absorbed bacteria are destroyed by the microbicidal systems (products of NADP-H oxidase, hydrolytic enzymes and bactericidal substances in lysosomes)

phagocytes produce proinflammatory cytokines (IL-1, IL-6, TNF) that induce an increase in temperature, metabolic response of the organism and synthesis of acute phase proteins

Phagocytosis

in later stages of infection are stimulated antigen-specific mechanisms

plasma cells initially produce IgM isotype after isotype switching produce IgG1 and IgA (opsonization)

sIgA protect against intestinal and respiratory infections by bacteria

bacteria with a polysaccharide capsule may cause T-independent IgM antibody production (after the establishment to the bacteria activate the classical complement path)

after infection persist IgG, IgA (protective effect) and memory T and B lymphocytes

in the defense against bacterial toxins apply neutralizing antibodies (Clostridium tetani and botulinum ...)

"indirect toxins - bacterial Lipopolysaccharide (LPS) stimulates big number of monocytes to release TNF, which can cause septic shock

extracellular bacterial infections are especially at risk individuals with disorders in the function of phagocytes, complement and antibody production

Defense against

intracellular pathogens

Defense against intracellular pathogens

bacteria, fungi and unicellular parasites

intracellular parasites are resistant to the microbicidal mechanisms of phagocytes

macrophages, which absorbed them, produce IL-12 →

TH1 differentiation, production of IFNg and membrane

TNF → activation of macrophages and induction of iNOS

Obrana proti intracelulárním patogenům

in the defense against intracelular parasites, which escape from phagolysosomes apply TC lymphocytes

intracellular microorganisms infections are at risk individuals with certain disorders of phagocytes and defects of T lymphocytes

Defense against intracellular pathogens

Anti-viral defense

Anti-viral defence

interferons - in infected cells is induced production of IFNa and IFNb (prevents viral replication and in uninfected cells cause the anti-virus status); IFNg stimulates the conversion to activated macrophages (iNOS)

IFNa and IFN b induce proliferation of NK cells

Anti-viral defence - interferons

NK cells - ADCC (Antibody-dependent cell-mediated cytotoxicity) = cytotoxic reaction depends on the antibodies; the NK-lymphocyte recognizes cell opsonized with IgG by stimulation Fc receptor CD16 and then activate cytotoxic mechanisms (degranulation)

infected macrophages produce IL-12 (a strong activator of NK cells)

NK cell activation

in the defense against cytopathic viruses mostly applied antibodies:

sIgA inhibit mucosal adhesion of viruses (defense against respiratory viruses and enteroviruses)

neutralizing IgG and IgM antibodies activate the classical way of complement, which is capable of some viruses lysis

IgA and IgG derived in viral infection have a preventive effect in secondary infection

Anti-viral defence - antibodies

effector TC lymphocytes destroy infected cells in direct contact (granzym/perforin; FasL) and by produced cytokines (lymfotoxin)

some viruses after infection integrate into the host genome, where persist for years (varicella zoster, EBV, papillomavirus)

by these infections are at risk individuals with T lymphocyte immunodeficiency and with combined immune disorders

increased susceptibility to herpes infections in individuals with dysfunction of NK cells

Anti-viral defence – NK cells and Tc lymphocytes

Defense against

multicellular parasites

Defense against multicellular parasites

IgE, mast cells, basophils and eosinophils

TH2 stimulation under the influence of IL-4 (mast cells and other APC stimulated by parasite)

TH2 stimulate B cells with BCR-specific parasite antigens

isotype switching under the influence of IL-4 to IgE

IgE bind to FceRI on mast cells and basophils („antigen-specific receptors“)

establish of multivalent antigen (multicellular parasite) using the IgE to highafinity Fc receptor for IgE (FcRI) aggregation of several molecules FcRI

initiate mast cell degranulation (cytoplasmic granules mergers with the surface membrane and release their contents)

activation of arachidonic acid metabolism (leukotriene C4, prostaglandin PGD2) - amplification of inflammatory responses

cytokine production by mast cell (TNF, TGF, IL-4, 5,6 ...)

Mast cell activation

Activation of mast cell

in later stages are activated TH1 and are produced antibodies of other classes

eosinophils fagocyte complexes of parasitic

particles with IgE via their receptors for IgE

eosinophils use against parasites extracellular bactericidal substances released from granules (eosinophil cationic protein, protease)

Defense against multicellular parasites - eosinophils

Thank you for your attention