Defense against pathogens, possibilities of therapeutic

affecting of the immune system

Martin Liška

Extracellular microorganisms

• Typically bacteria or parasites

• For defense against extracellular microbes and their toxins, specific humoral immune response is important

Humoral immune response

• Recognition of antigen by specific Ig, bound i cell membrane of naive B lymphocyte

• The binding of antigen cross-links Ig receptors of specific B cells and then biochemical signal is delivered to the inside B cell; a breakdown product of the complement protein C3 provides necessary „second signal“

• Clonal expansion of B cell and secretion of low levels of IgM

Humoral immune response

• Protein antigens activate CD4+ T helper cells after presentation of specific antigen

• T helper cells exprime CD40L on their surface and secrete cytokines → proliferation and differentiation of antigen-specific B cells, isotype switching, affinity maturation

Phases of humoral immune response

Effector functions of antibodies

• Neutralization of microbes (incl.viruses) and their toxins

• Opsonization of microbec (binding to Fc receptors on phagocytes; at the same time, stimulation of microbicidal activities of phagocytes)

• ADCC (Antibody-dependent cell-mediated cytotoxicity) – IgG opsonized microb is destroyed by NK cells after its binding to IC

• Activation of the complement system (classical pathway)

Defense against extracellular pathogens (bacteria and unicellular parasites)

a/ non-specific (innate) immune system

- monocytes/macrophages, neutrophils, complement system, acute phase proteins (e.g.CRP)

b/ specific (adaptive) immune system

- antibodies (opsonization, neutralization)

Defense against multicellular parasites

• Production of IgE → coating and opsonization of parasites

• Activation of eosinophils - they recognize Fc regions of the bound IgE, then they are activated and release their granule contents, which kill the parasites

• Th2-lymphocytes support this type of immune response

Intracellular microorganisms

• Initially: non-specific immune response (ingestion by phagocytes)

• Some microorganisms are able to survive inside phagocytes (e.g. some bacteria, fungi, unicellular parasites, viruses) – they survive inside phagosomes or enter the cytoplasm and multiply in this compartment

• The elimination of these microorganisms is the main function of T cells (specific cell-mediated response)

Processing and presentation of antigen

• Professional antigen-presenting cells: macrophages, dendritic cells, B lymphocytes (they express constitutionally class II MHC)

a/ exogenous antigens – e.g. bacterial,

parasitic, viral (if they are ingested in IC or

during the processing of infected cells)- hydrolysed in endosomes to linear peptides →

presentation on the cell surface together with class II

MHC to CD4+ T lymphocytes

Processing and presentation of antigen

b/ endogenous antigens – e.g. autoantigens, foreign antigens from i.c. parasites or tumorous antigens- hydrolysed to peptides → transportation

into ER → in Golgi complex they are associated with class I MHC → presentation on the cell surface to CD8+ T lymphocytes

T cell-mediated immune response

• Presentation of peptides to naive T lymphocytes in peripheral lymphoid organs → recognition of antigen by naive T lymphocytes

• At the same time, T lymphocytes receive additional signals from microbe or from innate immune reactions → production of cytokines → clonal expansion → differentiation → effector & memory cells → effector cells die after elimination of infection

T cell-mediated immune response

• TCR (T cell receptor) – T cell antigen-specific receptor

- TCR recognizes (together with co-receptors - CD4 or CD8) the complex of antigen and MHC

- a signal is delivered into the cell through molecules associated with TCR and co-receptors (CD4 or CD8) after antigen recognition

T cell-mediated immune response

• APC exposed to microbes or to cytokines produced as part of innate immune reactions to microbes express costimulators that are recognized by receptors on T cells and delivered necessary „second signals“ for T cell activation

• Activated macrophages kill ingested bacteria by reactive oxygen intermediates, NO and lysosomal enzymes

T cell-mediated immune response

• Naive CD4+ T (helper) cells → effector cells (activation of macrophages for killing of ingested microbes, activation of B cells for production of antibodie, activation of other cells)

- Th1 lymphocytes: production of IFN-, activation of phagocytes, stimulation of production of opsonizing a complement binding antibodies; support defense against i.c. microbes

T cell-mediated immune response

- Th2 lymphocytes: production of IL-4 and IL-5, stimulation of IgE production, activation of eosinophils (= defense against multicellular parasites); they suppress defense reactions against i.c. microbes

T cell-mediated immune response

• Naive CD8+ T (cytotoxic) lymphocytes → effector cells (killing of target cells, activation of macrophages)

- differentiation into CTL – their function is killing of cells producing cytoplasmic microbial antigens

- Killing the cells mainly by induction of DNA fragmentation and induction of apoptosis

Mechanisms of resistance of intracellular microbes to cell-mediated

immune response• Inhibiting phagolysosome fusion

• Escaping from the vesicles of phagocytes

• Inhibiting the assembly of class I MHC-peptide complexes

• Production of inhibitory cytokines

• Production of decoy cytokine receptors

Defense against intracellular pathogens (bacteria and unicellular

parasites) • Intracellular bacteria (Mycobacteria,

Listeria monocytogenes, Legionella pneumophila), parasites (Cryptococcus neoformans, Plasmodium falciparum), fungi (Leishmania, Trypanosoma cruzei)

• Specific immune response is necessary

Anti-viral defense

• Viruses may bind to receptors on a wide variety of cells and are able to infect and replicate in the cytoplasm of these cells, which do not possess intrinsic mechanisms for destroying the viruses

• Some viruses can integrate viral DNA into host genome and viral proteins are produced in the infected cells (e.g. Retroviruses)

Possibilities of therapeutic affecting of the immune system • Immunomodulation = therapeutic approach to

modulation of affected immune function• Based on their effect, we can distinguish following

immunomodulators:- immunostimulants- immunosuppressives - immunomodulators with the complex effect

Immunostimulants

• They stimulate the immune system

• Methisoprinol (Isoprinosine) – used for the treatment of severe or recurrent viral infections

• Cytokines – IL-2 (anti-tumour therapy), colony-stimulating factors (e.g. treatment of severe granulocytopenia)

Immunosuppressives

• They are used for the treatment of autoimmune or allergic diseases, in transplantology

• Corticosteroids – anti-inflammatory, immunosuppressive effect

• Cytostatics, antimetabolites (cyclofosfamide, methotrexate, cyclosporine A) – lymfocytotoxic effect

• Monoclonal antibodies – antiCD3

Immunomodulator with the complex effect

• Bacterial lysates (Broncho-Vaxom, Ribomunyl)

• Transferfactor

• Antihistamines – esp. 3rd generation

Substitution

• Typically substitution therapy with intravenous Ig (IVIG) in primary or secondary hypo- or agamaglobulinemia

• Life-long substitution

• IVIG 200-300 mg/kg every 3 weeks

Active and passive immunization

a/ active immunization- immunization with vaccines made from killed or

attenuated microorganisms or their products- the immunity is long-lasting- both B cell and T cell based immunity are

activated- injective, oral administration- prophylactic procedure

Active immunization

• DTP (diphtheria, pertussis, tetanus)• H.influenzae• N.meningitidis • Pneumococci• BCG• MMR (measles, mumps, rubella)• Poliomyelitis• Hepatitis A,B

Active and passive immunization

b/ passive immunization

- provides humoral temporary (approximately 3 weeks)

- prophylactic or therapeutic