Basic Immunology Lecture 19th - 20th
Systemic and local immunity Mucosa and skin associated immune
system Immunological tolerance
Cellular and molecular mechanisms of the immunological tolerance
Central immune system: bone marrow thymus spleen lymph nodes
Local immune system: SALT MALT
In the cases of local immune responses the immune reaction develops in the place of the antigen administration (in the external and/or internal body surface) and remains locally. Different connections are existing between the systemic and local immunity.
External skin surface (“dry body surface” is apr. 1.7 - 1.8 m2) and the internal mucosal surface, (“wet body surface” is apr. 400 m2).
Local immunity
• Skin Associated Lymphatic Tissue (SALT)
• Mucosa Associated Lymphatic Tissue (MALT, BALT, GALT)
Two types of body surfaces
Skin associated immune system (SIS or SALT)
Special structural elements: • Antigen presenting cells (Langerhans cells,
veiled cells, monocytes, tissue macrophages) • Effector cells (gamma-delta T cells, alpha-beta
T cells, B cells, NK cells, granulocytes, mast cells),
• Keratinocytes (cytokine production).
The co-operation between keratinocytes and T cells is similar to the thymus epithelia and thymocyte co-operations.
L: Langerhans cell
m: melanocyte
M: Merkel cell
Cytokines produced by human keratinocytes
Interleukines IL-1α, IL-1β, IL-6, IL-8
Colony stimulating factors
IL-3, GM-CSF, G-CSF, M-CSF
Interferons IFN-α, IFN-β
Cytotoxic cytokines TNF-α
Transforming growth factors
TGF-α, TGF-β
Growth factors PDGF, fibroblast GF
Mucosal immunity (MIS or MALT)
Special structures • M cells • Migrating antigen presenting cells • Peyer paches • Mesenterial lymph nodes • IgA1 and IgA2 • Effector cells (T cells, macrophages, NK
cells, eosinophils, mast cells, granulocytes)
Gut associated lymphatic tissue
M cell region
Peyer’s patches
M cell
Dichotomy of immune systems
Immunological Yin-Yang
The cytokines IL-12 and TGF beta 1 are predominant influences in "peripheral" and "mucosal" lymphatic tissues. Thus vectorial expression of these cytokines affect T cells and B cells in such a way that proliferating B cells become committed to secrete "peripheral" IgG or "mucosal" IgA, respectively.
IgA secretion and transport in GALT
Transport of IgA through mucous membrane epithelial cells
Three types of tonsils
Normal and inflamed tonsils
Secretory immune system
A new-generation single-dose, live-attenuated, oral vaccine for cholera. It contains a live recombinant strain of Vibrio cholerae
Immunological tolerance
Cellular and molecular mechanisms of the immunological tolerance
Tolerated skin grafts on MHC (H2) identical mice
TOLERANCE & AUTOIMMUNITY • Upon encountering an antigen, the immune system
can either develop an immune response or enter a state of unresponsiveness called tolerance.
• Immunological tolerance is thus the lack of ability to mount an immune response to epitopes to which an individual has the potential to respond.
• Targeting type and tolerating type immune responses composed by the same cellular and molecular components, the differences are in the effector phase only.
• Targeting type immune response or tolerance needs to be carefully regulated since an inappropriate response – whether it be autoimmune reaction to self-antigens or tolerance to a potential pathogen – can have serious and possibly life-threatening consequences.
TOLERANCE - PASSIVE - ACTIVE
AUTOIMMUNITY - PHYSIOLOGIC REGULATION - AUTOIMMUNE DISEASES
Passive tolerance
Unresponsiveness: no MHC recognition or inhibited cellular differentiation. • Tolerance induced by the nature
of the antigen
• Tolerance induced by the body
Passive tolerance induced by the nature of the antigen
• chemical nature • dose of the antigen
- low dose tolerance (T cell mediated, long ranging) - high dose tolerance (B cell mediated, short ranging)
• mode of the administration
T-cell tolerance
– Central tolerance (selection in the Thymus and thymus equivalent tissues)
– Peripheral tolerance
• Lack of co-stimulation • Failure to encounter self antigens • Receipt of death signal • Control by regulatory T cells
Failed co-stimulation results low dose tolerance
B-cell Tolerance - Central tolerance - Peripheral tolerance
Tolerance induced by the body
• sequestered antigens no MHC recognition no antigen presentation no systemic response
• heredited or acquired immunodeficiency • clonal anergies • tolerance induction
ACTIVE TOLERANCE Anti-idiotype network • Anti-idiotype antibodies against T cell and B cell
receptors and immunoglobulins • Antigen-specific inhibition and induction of
memory • Learned and adaptive function
“Immunological homunculus” • Low affinity IgM natural autoantibodies produced
by CD5+ B cells • γ/δ T cells • Innate-like function
Anti-idiotype antibodies
Anti-idiotype network (N. K. Jerne)
idiotípus
paratop
anti- idiotípus 2(idiotop-specifikus)
anti -idiotípus 1(paratop-specifikus)
anti-anti-idiot ípus 1 anti-anti-idiotípus 2 anti-anti-idiot ípus 1 anti-anti-id iotípus 2
idiotopantigén • T- & B-cell suppression • Memory formation; • Biological mimicri (insulin
– anti-insulin – anti-anti-insulin ~ insulin)
Genetically well conserved antigens recognized by natural (auto)antibodies
Heatshock proteins
hsp65, hsp70, hsp90, ubiquitin
Enzymes aldolase, citockrom c, SOD, NAPDH, citrate synthase, DNA-topoisomerase I
Cell membrane components
β2-microglobulin, spectrin, acetylcholin receptor
Cytoplasmic components
actin, myosin, tubulin, myoglobin, myelin basic protein
Nuclear components
DNS, histones
Plasma proteins albumin, IgG, transferrin Cytokines, hormones
IL-1, TNF, IFN, insulin, thyreoglobin