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Principles of immune defense
Toxicology Course Vienna
MODULE 12 Immunotoxicology, Allergy
July 2, 2008
Adaptive immunity
Prof. Erika Jensen-Jarolim, MD
Dept. of Pathophysiology
Medical University Vienna
Gastrointestinaltrakt: Mukosale Pathophysiologie und Immunologie
Jensen-Jarolim, Schöll, Szalai. Springer 2006
Wörterbuch Allergologie und Immunologie, Ferencik, Jensen-Jarolim et al, Springer 2004
Innate immunity
Adaptive immunity
Immunologie (Charles A. Janeway and P. Travers)
Adaptive immunity
Adaptive Immunity
• available with delay
against extracellular or intracellular pathogens
• highly specific antigen recognition
• huge repertoire
• improvable
• memory
B-lymphocytes:
T-lymphocytes:
•Soluble B-cell receptors are
immunoglobulins
•No solubleT-cell receptors
•Recognize antigen directly
Primary immune organs:
•Recognize digested
and presented antigens
Primary immune organ:
Bone marrow
Building and maturation of
immune cells and receptors
Bone marrow, thymus
Secondary immune organs: antigen
contact sites
Lymph nodes, spleen,
peyer´s patches, appendix
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The generation of antigen receptors & repertoire
The T-lymphocyte receptor
Combinatorial diversity: 5,2 x 10^15
Danger of autoreactivity mimimized:
negative selection and deletion in thymus
Primary immune organs:
Building and maturation of immune
cells and receptors
Cortex:
positive selection
for HLA-reactive T-cells
Bone marrow, thymus
Secondary immune organs:
antigen contact sites
APCs
Lymph nodes, spleen,
peyer´s patches, appendix
Medulla:
negative selection for autoreactivity
medulla thymus epithelial cells (mTEC):
AIRE gene expressed
Negative selection — clearing out the
bad apples from the T-cell repertoire. Ed Palmer
Nature Reviews Immunology 3, 383-391 (May 2003)
Cooperation with APCs: antigen focussing and transport
Dendritic cells, macrophages, Langerhans cells present
• intact antigen on surface for B-cells
• digested antigen with HLA II. for T-cells
no costimulation
Within 2 days all naive lymphocytes of a certain specificity
trapped in secondary lymph organs.
Emigration of effector cells within 5 days
Develop into dendritic cells - costimulation
Clonal expansion
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Proliferation in germinal centers and expansion
of specific effector B- and T-lymphocytes
The clonal selection theory by McBurney.
From the following article:
The double helix and immunology
Gustav J. V. Nossal
Nature 421, 440-444(23 January 2003)
SLAM receptors and SAP influence lymphocyte interactions, development and function
Pamela L. Schwartzberg, Kristen L. Mueller, Hai Qi & Jennifer L. Cannons
Nature Reviews Immunology 9, 39-46 (January 2009)
The building of an immunoglobuline
Idiotype
Secondary immune organs:
antigen contact sites:
• Expansion
• Adaption
• Improvement
Isotype:
receptor binding
How can a B-cell switch immunoglobulin isotype?
The functions of immunoglobulins
• Membrane bound: BCR
B-cell
IgD
IgM
• Secreted:
IgM: neutralization, complement activ.
IgA: neutralization, binds FcaR
IgG: neutralization, complement act., binds FcgR
IgE: cytophilic through FceR, needs crosslink
IgE
IgG
IgA
Linking class-switch recombination with somatic hypermutation
Kazuo Kinoshita & Tasuku Honjo
Nature Reviews Molecular Cell Biology 2, 493-503 (July 2001)
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Specific in fluid phase: IgG, IgM, IgA
In tissues: IgG, IgE
• IgG: predominant isotype in serum, IgA: in mucosa
Specific Defense in serum: IgG and IgM
• Aggregation, Agglutination
• Most produced Ig-class sIgA, main source bone marrow
Production (mg/day)
IgA
IgG
Circulation
2100
2100
Saliva
200
2
Tears
5
?
Bile
400
160
Small intestines
5200
600
Large intestines
1200
140
Nasopharynx
45
15
Urine
3
3
Total
9200
3000
• Opsonisation
• Neutralization
MDCK cells
(no CPE)
H5N1 virus infection protected from H5N1
by anti-H5N1 F(ab')2.
after 72h (CPE)
Mestecky 1986; Clin Immunol Immunopathol.
Somatic hypermutation: Improvement of antigen binding
Secondary immune organs:
antigen contact sites:
• Expansion
• Adaption
• Improvement
Affinity: Binding strength to a single antigenic determinant
Avidity: Sum of binding strengths to antigenic determinants
Nature Medicine 9, 164 - 166 (2003)
B cell memory: Sapping the T cell
Raymond M. Welsh, Susan E. Stepp & Eva Szomolanyi-Tsuda
Adaptive immunity
Boost injections in vaccination
induce and improve immunity
and memory
against extracellular or intracellular pathogens
B-lymphocytes:
T-lymphocytes:
•Soluble B-cell receptors are
immunoglobulins
•No solubleT-cell receptors
•Recognize antigen directly
•Recognize digested
and presented antigens
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Proper stimulation of T-lymphocytes
involves cell-cell interactions
Helper &
regulatory T-cells
HLA II.
HLA I.
Cytotoxic
T-lymphocytes
Cytotoxic
Helper & regulatory
The many important facets of T-cell repertoire diversity
Janko Nikolichugich, Mark K. Slifka and Ilhem Messaoudi
Nature Reviews Immunology 4, 123-132 (February 2004)
The many important facets of T-cell repertoire diversity
Janko Nikolichugich, Mark K. Slifka and Ilhem Messaoudi
Nature Reviews Immunology 4, 123-132 (February 2004)
Antigen digestion by
antigen present.cells & HLA
All APCs
HLA typing: Forensic medicine and transplantation
All cells
with nuclei
Polymorphism
HLA = MHC
Cytotoxic T-lymphocytes: CD8+
Helper T-lymphocytes: CD4+
need HLA I. presentation
Th1
need HLA II. presentation
NK
Viral infections, aberrant cells, high HLA I.
IL-12
Tu
IL-4
Inflammation, IgG1, 2, 3
Th2
IgG4, IgE
IL-23
Target cell recognition: specific
Tu
• HLA I expression and viral peptides
Th17
Lysis program and target cell death
Inflammation
NK
NK cell lyses
tumor cell
Diversification of T-helper-cell lineages: finding the family root of IL-17-producing cells
Chen Dong, Nature Reviews Immunology 6, 329-334 (April 2006)
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Regulatory T-cells modulate immune responses
• Activation of Tregs
Th-cells help B-cells for isotype switch
Th17
IgA
Clark & Cupper, JID 2005:
„Immature dendritic cells are polarized by the binding of type 1, type 2, or regulatory PAMP and
differentiate
into mature
dendritic
that induce the
formation of Th1, Th2, or T regulatory T cells,
DCs decide
on
typecells
of immune
response
respectively. In general, viral-associated PAMP give rise to Th1 responses, and PAMP from
parasitic organisms favor Th2 responses….“
Synthesized cytokines induce isotype switch
Costimulation decides T-cell activation
How to activate a T-cell ?
Costimulation by
professional APC –
Immunity
Signal 1: Specific interaction
MHC/TCR
Signal 2: DANGER !
costimulation
B7/CD28
without costimulation –
Tolerance via Anergy
Then proliferation, and
cytokine synthesis occur
Toxicology Course Vienna
MODULE 12 Immunotoxicology, Allergy
July 2, 2008
Adaptive immunity
Prof. Erika Jensen-Jarolim, MD
Dept. of Pathophysiology
Medical University Vienna
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