Antiinfection immunity

Relationship between host and microorganism

microorganisms - commensal                             - potential pathogens                             - pathogenic microorganisms

- microorganisms can cause damage to the body by direct mechanisms (toxins, cytopathic effect), or indirect, which initiate harmful immune reactions

      In defense against various microorganisms are, despite a predominant type of immune response, involved all elements of nonspecific and specific immunity.

Use of receptors on host cells as a gateway of infection

CD4 - HIV, herpesvirus7

CD21 (CR2) - EBV

CD71 - hepatitis B virus

CD81 - hepatitis C virus

1 integrins - Yersinia, pathogenic E. coli

3 integrins - Borrelia

Mechanisms of microorganisms escape before defense system

- conceal the cells, integration into the genome and the persistence in the latent form (herpes viruses, retroviruses)

- variability of surface molecules (influenza, HIV ...)

- suppression of MHC gp expression in infected cells (adenoviruses, herpes viruses)

- suppression of Ag presentation (blocking cleavage antigen)

- suppression of inflammatory response by production of virus analogues of cytokines or their inhibitors

- inhibition of complement by production of protective proteins (herpes), secretion of proteases, which inactivate C3a and C5a, cell wall protects against membranolytic effect of complement

- cleavage of blocking sIgA antibodies

- the use of cytokines produced by the host to create an optimal environment (TNF stimulates HIV replication)

- integration of the host's own molecules into the microbial wall (borrelia burgdorferi)

- antigenic mimicry - surface structure mimic the structure of the host organism cells

- inhibition of phagocytosis, inhibition of fusion phagosome with lysosomes; escape from phagosome to the cytoplasm, inhibition of acid pH inside phagolysosome

- production of antagonistic peptides (hepatitis B virus, HIV)

Defense against extracellular bacteria

- gram-negative, gram-positive cocci, bacilli

- for their elimination is necessary opsonization (C3b, lectins, antibodies ...)

- neutrophilic granulocytes are chemotactic attracting to the site of the infection (C5a, C3a and chemotactic products of bacteria)

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

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

- 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 bacteria and molds

- intracellular parasitism is given by the ability of microorganisms to escape microbicidal mechanisms of phagocytes

- mycobacteria, some yeasts and molds

- macrophages, which absorbed them, produce IL-12 → TH1 differentiation, production of IFN and membrane TNF → activation of macrophages and induction of iNOS

- plasma cells under the influence of IFN produce IgG2, immune complexes containing IgG2 bind to Fc receptors on macrophages and thus stimulate

- 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 viruses

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

- 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)

- 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

- 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.

Defense against protozoa parasites

- defense against protozoa parasites is similar to bacteria

- extracellular parasites - antibodies

- intracellular parasites - TH1 lymphocytes and activated macrophages

Defense against multicelular parasites

- contact of mast cells, basophils and eosinophils with parasite antigens

- 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 in IgE

- IgE bind to FcRI 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

- start of production of cytokines (TNF, TGF, IL-4, 5,6 ...) by mast

- 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)

Possibilities of the therapeutic effect on the immune system

Causal treatment

a) stem cell transplantation

    - for serious congenital disorders of the immune system (some lymphoproliferative and myeloproliferative disorders)

    - complications: infectious complications                              Graft-versus-host

    - obtaining stem cells - the collection from shovel hip bone                                        - from umbilical cord blood                                        - from peripheral blood after stimulation with GM-CSF

b) gene therapy

    - with a suitable expression vector is introduced functional gene (to replace dysfunctional gen) into the lymphocytes or stem cells

    - used as a treatment for some cases 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

Non-specific immunomodulation therapy

Immunomodulation = medical procedure to adjust the disrupted immune function

a) 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

corticosteroids - anti-inflammatory, immunosuppressive effects                    - blocking the activity of transcription factors (AP-1, NFB)                    - suppress the expression of genes (IL-2, IL-1, phospholipase A, MHCgpII, adhesion molecules)                    - inhibition of histamine release from basophil                    - higher concentrations induce apoptosis

immunosuppressants affecting the metabolism of DNA

- cyclophosphamide                                                                                - methotrexate

immunosuppressant selectively inhibiting T lymphocyte                               - cyclosporin A (inhibits the expression of IL-2 and IL-2R in activated T lymphocytes)

                              - monoclonal antibody anti-CD3 (immunosuppression after transplantation, treatment of rejection crises)

b) 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)

c) non-specific immunostimulant therapy

imunostimulancia - stimulate the immune system

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                                                      - G-CSF, GM-CSF - neutropenia               

Antigen-specific immunomodulatory therapy

       specific immunomodulation = induce an immune response or tolerance against a specific antigen

a) active immunization       = use of antigen to induce an immune response that can later protect against a pathogen bearing the antigen (or antigen like him)

- immunization vaccines 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

Active immunization

DTP (diphtheria, tetanus, Pertussis)

Haemophilus influenzae

Neisseria meningitidis

Pneumococci

BCG (Bacillus Calmette-Guérin)

MMR (measles, mumps, rubella)

Poliomyelitis

Hepatitis A, B

• experimentally implementing specific vaccination against cancer

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 inducing anaphylactic reactions

c) specific immunosuppression

= induction of tolerance against a specific antigen

the clinical studies:

- induction of tolerance by oral administration of antigen

- allergen immunotherapy (pollen, insect poisons)

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