Transcript Environmental factors in the pathogenesis of autoimmunity

Rupture of self-tolerance.
Autoimmunity
Jan Novák
Autoimmunity
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Pathologic reaction of the immune
system against self antigens
Key players of the
autoimmune reaction
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Autoantigen
Autoreactive T and B cells
Autoantigens
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Organ specific (insulin, thyreoglobulin,
myelin basic protein)
Systemic (DNA, histones, ribosomes,
IgG)
How autoreactive lymphocytes
are created?
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Random rearrangement –
generation of T and B cells
with infinite variability and
specifity, capable to
recognize infinite diversity
of antigens
Generation of T and B cells
recognizing self antigens –
autoreactive
How autoreactive T and B cells are
deleted in normal body?
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Central (thymic/bone marrow) deletion
Peripheral passive mechanisms
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Ignorance
Anergy
Phenotype skewing
Peripheral deletion
Peripheral active mechanisms
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Tolerogenic dendritic cells
Regulatory T cells
Central education/deletion
Peripheral passive
mechanisms of tolerance
Peripheral active mechanisms
of tolerance
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Regulatory T cells
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CD4+CD25+ T cells
NKT cells
 T cells
CD8+CD25+ T cells
Tolerogenic dendritic cells (DC)
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Antigen presentation by immature DC
Antigen presentation by plasmocytoid DC
How tolerance is kept conclusion
Why tolerance is broken?
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Genetic factors
Environmental factors
Genetics of autoimmunity
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MHC molecules
Non MHC genes
MHC genes
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Confer both
susceptibility and
protection
MHC class II and I
alleles
HLA DR3/DR4,
HLA B27
Capacity to present
antigens and to
induce central and
peripheral deletion
Disease
Risk HLA
allele
Ankylosing spondylitis
B27
Acute anterior uveitis
B27
Goodpasture's
syndrome
DR2
Multiple sclerosis
DR2
Graves disease
DR3
Myasthenia gravis
DR3
SLE
DR3
T1DM
DR3/DR4
Rheumatoid arthritis
DR4
Pemphigus vulgaris
DR4
Hyshimoto's thyroiditis
DR5
Non MHC risk genes in
autoimmunity
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Genes associated with thymic antigen
presentation (AIRE, VNTR)
Genes assiciated with antigen
clearance (complement proteins)
Genes associated with tolerance
induction (CTLA-4, Fas-FasL)
Environmental factors in the
pathogenesis of autoimmunity
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Studies on monozygotic twins
Epidemiological, migration studies
Environmental factors in the
pathogenesis of autoimmunity
Infection in the pathogenesis
of autoimmunity
Infection can protect against
autoimmunity
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Infection with parazites induce Th2
schift and can protect against Th1
mediated autoimmune diseases
Some autoimmune mouse strains
develop autoimmunity strictly in
pathogen free conditions
Environmental factors in the
pathogenesis of autoimmunity
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Food (milk)
Drugs (AIHA)
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Hapten
Imunocomplex
Neoantigens
Mollecular mimicry
How the tissues are
destroyed?
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Participation of both innate and
adaptive immune responses.
T cells, cytokines, B cells, antibodies,
immunocomplexes
Macrophages, complement
Types II-V of immunopathologic
reactions
Mechanisms of tissue
destruction
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Cytotoxic reaction (type 2)
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IgG
IgM
Type 3 immunopathologic reaction
(immunocomplexes – type 3)
Immunopathologic reaction od delayed
hypersensitivity (type 4.)
Autoantigens
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Organ specific (insulin, thyreoglobulin,
myelin basic protein)
Systemic (DNA, histones, ribosomes,
IgG)
Autoimmune diseases
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Organ specific
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Systemic
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T1DM
Goodpasture‘s
syndrome
Multiple sclerosis
Graves disease
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Rheumatoid
arthritis
Scleroderma
Systemic lupus
erythematosus
Polymyositis
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