mucosa and skin associated immune system immunological...

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