AUTOIMMUNITY AND

TOLERANCE
DR RICHARD
 Outline
• Define tolerance
• Mechanisms of development of tolerance
• Clinical importance of tolerance
• Understand concept of autoimmunity & auto
immune diseases
• List some of the commonly occurring auto
immune diseases
• Diagnosis and management of auto immune
diseases
 Definition
• Immunologic tolerance – specific
immunologic non -
reactivity/responsiveness to either
self(natural tolerance during fetal{immune
sys},dev’t ) or other antigens resulting from
previous exposure to the same
antigen(acquired tolerance, a potential
immunogen induces a state of
unresponsiveness to itself)
 Continued
• Tolerogen antigen that induces torelance
• Immunologic features of tolerance
1.Unlike
immunosuppresion/immunodeficiency,
tolerance is an antigen – dependent
process, specific & both T(>) & B cells
immunological memory
 continued
2. Tolerance broken naturally(autoimmune
diseases) or artificially(x- irradiation, drug
treatments, exposure to cross reactive antigens
(immunization)
3. Mechanisms of tolerance
i. Clonal deletion –immature cells of a clone
undergo a programmed cell death e.g. during
differentiation of auto reactive cells of the
thymus( interaction with self antigen(negative
selection)
 Continued
ii. Clonal anergy - auto reactive T cells,
exposed to antigenic peptides without co-
stimulatory molecules (B7-1 or B7-2), thus
becoming anergic to the antigen.
B cells exposed to large amounts of
soluble antigen down regulate their
surface IgM → anergy, also up regulate
the fas molecules hence forming B cells +
fas- ligand bearing cells thus apoptosis
 continued
• Clonal ignorance- T cells reactive to self
antigen may not be presented to the
thymus, mature & migrate to e periphery,
sequestrated in innaccesible tissues
→cells death due to lack of stimulation,
Bcells escape deletion,may not find
antigen/ specific helper T cells, not
activated & die out
 continued
• Receptor editing-B cells which encounter large
amounts of soluble & then bind to this antigen with
very low affinity, activated to re-express their RAG 1
& RAG 2 genes, resulting in their DNA recombination
& change their specificity
• Anti idiotype Ab- prdced experimentally inhibit
immune response to specific antigens, by preventing
receptor- antigen combination
• Suppressor cells- both low/high doses of antigen may
induce suppressor T cells, suppressing immune
response (B & T cells),directly/cytokine prdn (TGF ᵦ
&IL 10)
 Continued
• Termination of tolerance- experimentally induced
tolerance, stopped by prolonged absence of
exposure to toleragen, treatments( x-irradiation)/
immunization with cross reactive antigens
• Clinically tolerance –
1. auto immmune disorders mgmt
2.Foreign tissue grafts
3.Control of hypersensitivity reactions
4.Limit growth of tumour cells
 Autoimmunity
• Breakdown in the mechanisms responsible
for self tolerance & induction of immune
response against components of the self
( harmless{anti-idiotype antibodies}or
harmful resulting into autoimmune disease
• Both antibodies & effector T cells can be
damaged
• Auto immune diseases, classified a per
organ / tissuess involved
 Continued
• Organ specific- immune system is directed
against antigens associated with target
organ being damaged e.g.
• Non organ specific- antibody is directed
against antigens not associated with the
target organ e.g.
• Name of the disease depicts the antigen
involved in most of the auto immune.
 Genetic predisposition &
aetiology
• Studies in mice & humans suggest a genetic
predisposition e.g. association btn (HLA,B8,
B27,DR2, DR3, DR4 & DR5) & autoimmune
diseases
• Exact cause not known h’ver various theories
explain some occurrences
a.Cross reactive antigens- on certain pathogens
may have determinant which cross react with self
antigens→immune response(effector cells/
antibodies against tissue antigens.
 Continued
b. Escape of auto reactive clones – apart from
negative selection, some antigens may not be
properly processed & presented
c. Sequestered antigen – lymphoid cells may not
be exposed to some self antigens during their
differentiation (late developing antigen/confined
to specialized organs i.e.testes, brain &
eye,hence in trauma(accidetal injury/surgey),
immune response is stimulated thus initiating
an a.i.d
 continued
• Familial- incidences of auto immune
disease runs in certain families as
evidenced with the study of both identical/
non identical twins, assns of thyroid auto
antibodies with abnormalities with x-
xsome
• Loss of suppressor cells
• Spontaneous auto immunity
Table of auto immune diseases,
target organs, lesions & tests
Disease target/ Antibody to Diagnostic
affected test
organ
Hashimito’s thyroid Thyroglobulin, RIA,
thyroiditis Thyroid Hemagglutina
peroxidase tion
Primary thyroid Cytoplamic immunofloure
myxoedema TSH receptor scence
Graves d’se Thyroid Thyroid Bioasay,
(diffuse toxic stimulating competition
goitre immunoglobul for TSH
in receptor
Pernicious Red blood Gastric Radioimmuno
aneamia cells parietal cells assay,
+ vit B12 immunofloure
binding site of scence
intrinsic factor
 Table continued
Addison’ s Adrenals Adrenal cells immunoflouresc
ence
Myasthenia gravis Muscle Acetyl choline Immunoflourescen
receptor ce/ competing for
receptor
Osteosclerosis & Anti collagen type RIA
meniere’ s II antibodies
disease
Idiopathatic platelets platelets Immuno
thrombocytopenia flourescence
purpura assay
Juvenile Insulin Pancrease Islets ᵦ cells, Anti Immuno
Depenaent – insulin Abs flourescence
Diabetes assay, competitive
inhibition of insulin
binding,
stimulation of
 Non organ specific/systemic
disease
Disease Target organ Antibodies to Diagnostic test
Good pasture’ s systemic Basement Immunoflourescen
syndrome membranes ce assy,
radioimmunoassa
y
Rheumatoid Skin, joints, Anti – Ƴ globulin IFA, RIA,
arthritis kidney etc anti bodies Immunodiffusion
Systemic lupus joints DNA, RNA, RNA,DNA-latex
erythematosus nucleoproteins agglutination,
IF(granular in
kidney)
sjÖgren’s Secretory glands Duct mitochondria Immunoflourescen
syndrome ce
Scleroderma Skin, mucosa, Topoisomerase I, ELISA, IFA, gel
electrophoresis,
immunodiffusion
 Diagnosis
• Based on symptoms
• Auto-antibodies reactive against antigens
of tissues & cells e.g.
immunoflourescence, ELISA/RIA
(antibodies against soluble antigens),
biological/biochemical assay( Graves
disease & pernicious anaemia)
• Others
 Treatment
• Depends on the cause & nature of lesion
• Immunosuppressives ( cyclosporin A)
• Anti inflammatory
• Corticosteroids
• Use of specific antibodies( anti- IL2 antibodies)
• Metabolic control e.g. thyroxine admn in
hypothyroidism, i/m vit B12 in pernicious
anaemia
 References
• Immunology by donald weir & stuart 7th
edition
• Immunology by Ivan Roitt & D. Male 6th
edition
• Basic & clinical immunology by Daniel
Stites 1987 6th edition
• On line microbiology by Abdul Ghaffar of
the university of south carolina