Physiological mechanisms of regulation of the immune system

Physiological

mechanisms of

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 FcR

on B cells, resulting in blocking activation of B

lymphocytes

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

Regulation by cytokines and cellular

contact

Interaction between APC and T cell

T cell:TCR - antigen-specific receptor

CD4 or CD8 - coreceptor (MHCgp

binding)

CD 28 - costimulatory receptor

(binds CD 80, CD 86)

CTLA-4 - inhibitory receptor (binds

CD 80, CD 86)

Regulation by cytokines and cellular

contact

Interaction between TH1 and TH2 cells

Negative regulation of effector cells

CTLA-4 - T cell inhibitory receptor, binds ligands

CD80 and CD86

Self-destruction interaction of the apoptotic

receptor Fas with ligand FasL on the surface of

activated T lymphocytes

Inhibitory receptors of NK cells

Suppression mediated by T lymphocytes

Mutual negative interaction TH1 and TH2 cytokine-

mediated

Clonal elimination or anergy of T lymphocytes after contact

with antigen on the surface of other cells than APC

Regulatory T cells (Treg, Tr1, Th3 - CD 4+) help to

maintain tolerance to autoantigens; produce TGF, IL-10

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 also outside the immune system

(angiogenesis, tissue regeneration, carcinogenesis, treatment of

many brain functions, embryonic development ...)

Cytokines - secreted

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

Cytokines

Pleiotropic effect

Operates in a cascade

Cytokine network

Cytokine system is redundant

Effects of cytokines- autocrine

- paracrine

- endocrine

Are known as interleukins (IL-1…IL-38)

(except: TNF, lymphotoxin, TGF, interferons, CSF and growth factors)

B cells communicate via cytokines with other cells, such as T cells and macrophages

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

TGF 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

IFN L, M, MF Inhibition of viral replication

IFN Fibroblasts, epithelial cells

Inhibition of viral replication

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

Clasification of cytokines by functions

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

Antiinflammatory cytokines (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-viral effect (IFN-, IFN-, IFN- )

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

Possibilities of therapeutic affecting of

the immune system

Causal treatmenta) Stem cell transplantation

treatment of severe congenital disorders of the immune system and

some

lymphoproliferative and myeloproliferative disorders

complications: infectious complications

Graft-versus-host disease

obtaining stem cells - from bone marrow

- from umbilical cord blood

- from peripheral blood

Causal treatment

b) Gene therapy

transduction of the missing gene to hematopoietic stem

cells using viral vectors

used as a treatment for 2 forms of SCID

Substitution treatment autologous stem cell transplantation

(following chemotherapy and radiotherapy)

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 immunosuppression

nonspecific = affects not only autoreactive and aloreactive

lymphocytes, but also other components of

immunity (risk of reduction antiinfectious and

antitumor immunity)

used for treatment of autoimmune diseases, for organ

transplantation and severe allergic conditions


Corticosteroids

• anti-inflammatory, immunosuppressive effects

• suppress the expression of some 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 (cytostatics)

• cyclophosphamide (alkylating agent)

• methotrexate (antimetabolite)

• azathioprine (purine analogue)


Immunosuppressant selectively inhibiting T

cells

• immunosuppressive ATB: cyclosporine A, tacrolimus,

rapamycin

(suppressing the expression of IL-2 and IL-2R in activated T

lymphocytes)

• anti-CD3 monoclonal antibody (imunosuppression

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 molekules

- reduce the secretion of histamine ...

• inhibitors of inflammatory cytokine

- monoclonal antibodies against TNF

- thalidomide (TNF inhibitor)

• Anti IgE antibodies (omalizumab) - severe allergic astma

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 IFN, IFN - viral hepatitis, some leukemia Erythropoietin – renal failure G-CSF, GM-CSF – neutropenia Transfer factor (blood donors leukocytes undergoing dialysis) Thymus hormones

Antigen-specific immunomodulation

specific immunomodulation = induce of an immune response or tolerance to a specific

antigen

• active immunization

• passive immunization

• specific immunosuppression


Active immunization (vaccination)

= the induction of immunity

after exposure to an antigen

• activates specific cellular and humoral immunity

• creates long-term immunity (memory cells)

• protect against a pathogen bearing this antigen or similar

antigen (prophylaxis)


active immunization (vaccination)

• vaccines are made from inactivated or attenuated

microorganisms or their antigens (polysaccharide capsule, toxins)

• attenuated vaccines cannot be used by

immunocompromised individuals

• risk of infection or anaphylactic reactions


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 – prevent immunization of mother with RhD+ fetus erythrocytes

• provides a temporary (3 weeks) specific humoral immunity

• the risk anaphylactic reactions


Specific immunosuppression

= induction of tolerance to a specific antigen

• induction of tolerance by oral administration of antigen

(treatment of certain autoimmune diseases)

• allergen immunotherapy (pollen, insect poisons)

Vaccination against cancer

• immunization by dendritic cells

Antiinfection immunity

Defence against extracellular pathogens

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

pathogens induce inflammation

removed by phagocytosis - neutrophil granulocytes

opsonization (IgG and IgA antibodies, C3b, lectins, CRP...)

Defence against extracellular

pathogens

Opsonisation and phagocytosis


Phagocytes are attracted to the site of infection by

chemotactic substances (C5a, C3a and chemotactic

products of bacteria…)

ingested 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)


IgM - complement activation

IgG - complement activation, opsonization

IgA - opsonization

sIgA prevents against infection by intestinal and respiratory bacteria

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

individuals with immunodeficiency of phagocytes,

complement and antibodies production are

especially

at risk of infections with extracellular bacterial

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 IFN and membrane

TNF → activation of macrophages and production of NO


TC lymphocytes apply in the defense against

intracelular parasites, which escape from

phagolysosomes

individuals with certain disorders of phagocytes

and defects of T lymphocytes are at risk of

infections with intracellular microorganisms



Anti-viral defense

Anti-viral defence

interferons - production of IFN and IFN is

induced in infected cells; IFN activates

macrophages (iNOS)

IFN and IFN prevents viral replication

induce proliferation ofNK

cells

increase the expression of

HLA-I

Anti-viral defence - interferons

Anti-viral defence

NK cells - ADCC (Antibody-dependent cell-

mediated cytotoxicity); NK cell bind with CD16

(Fcreceptor) to IgG which has bound to the surface of

infected cell and then NK cell release perforins and

granzymes (degranulation)

infected macrophages produce IL-12 (a strong

activator of NK cells)

Anti-viral defence - NK cell activation

ADCCADCC

Anti-viral defence

in the defense against cytopathic viruses applied antibodies:

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

neutralizing IgG and IgM antibodies activate the classical pathway of complement, that is able to lyse certain viruses

opsonized viral particles are phagocytosed

IgA and IgG have preventive effect in secondary viral infection

Anti-viral defence - antibodies

Anti-viral defence

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)

individuals with T lymphocyte immunodeficiency and with combined

immune disorders are at risk by viral infections

increased susceptibility to herpes infections in individuals with

dysfunction of NK cells

Anti-viral defence – NK cells and Tc lymphocytes

Defense against protozoa parasites

Defense against protozoa parasites

Toxoplasma gondii, Leishmania, Trypanosoma

defense against protozoa parasites is similar to bacteria

extracellular parasites - antibodies

intracellular parasites - TH1 lymphocytes and activated macrophages

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 FcRI on mast cells and basophils


multicellular parasite binds to IgE on mast cell→ cross-linking of several molecules FcRI

initiate mast cell degranulation (release of histamin, tryptase, serotonin…)

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

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


Histamine

vasodilatation, increase vascular permeability (erythema,

edema, itching)

bronchoconstriction (cough)

increases intestinal peristalsis (diarrhea)

increased mucus secretion

This helps eliminate the parasite.

Mast cell activation


eosinophils fagocyte complexes of parasitic

particles with IgE via their receptors for IgE

eosinophils use against parasites extracellular

bactericidal substances released from granules

(ECP- eosinophil cationic protein, MBP-major basic

protein…)

Defense against multicellular parasites - eosinophils

Thank you for your attention

• Phagocytosishttps://www.youtube.com/watch?v=7VQU28itVVw

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Physiological mechanisms of regulation of the immune system