Transcript Kuby Immunology 6/e - Dr. Jennifer Capers, PhD

Chapter 16
Tolerance and Autoimmunity
Dr. Capers
Kindt • Goldsby • Osborne
Kuby IMMUNOLOGY
Sixth Edition
Chapter 16
Tolerance and Autoimmunity
Copyright © 2007 by W. H. Freeman and Company
“Horror Autotoxicus”

Failure of host’s humoral and cellular
immune systems to distinguish self from
non-self
 Autoimmunity
 Can result in tissue and organ damage, can
be fatal
Tolerance

# of mechanisms are in place to protect
individual from self-reactive lymphocytes
 Central tolerance – deleting T or B clones
before maturity if they have receptors that
recognize self-antigens with great affinity
 Peripheral tolerance – kills lymphocytes in
secondary lymphoid tissue
○ Also, life span of lymphocytes regulated by
apoptosis

Some antigens can produce tolerance
 Termed tolerogens rather than immunogens
○ High dosages of antigen
○ Persistance of antigen in host
○ IV or oral introduction
○ Absence of adjuvants
○ Low levels of costimulators
 CD28 will bind to B7 and provide activating signals;
however, it was discovered that another receptor,
CTLA-4 will bind to B7 and inhibit

Anergy
 Unresponsiveness to antigenic stimulus
The F1 mouse does not have any B cells that
Express anti-HEL antibodies

Peripheral Tolerance
 May be induced by
Treg cells
○ Unique group of
CD4+ T cells
○ Recognize selfantigens on immune
system cells and
seem to be able to
suppress immune
system
○ Induce cell death in
some immune cells
Organ-specific autoimmune
diseases

Target antigen specific to organ or gland

Cellular lysis and chronic inflammation
that can damage organ

Hashimoto’s Thyroiditis
 Mainly middle-aged women
 Target is thyroid antigens
 Goiter can form
 Hypothyroidism - decrease

Autoimmune anemias
 Pernicious anemia
○ Ab against membrane bound intestinal protein
that uptakes B12 - needed for hematopoiesis
 Hemolytic anemia
○ Abs to red-blood cell antigens
 Drug-induced anemia

Goodpasture’s syndrome
 Abs against basement membranes in
glomeruli and aveoli
 Leads to kidney damage and pulmonary
hemmorhage

Insulin-Dependent Diabetes Mellitus
 Abs against beta cells that produce insulin
 Insulin is needed by cells to uptake glucose
needed for cellular respiration

In some autoimmune diseases,
antibodies act as agonists
 Bind inappropriately to receptors, resulting in
overproduction
○ For example, up-regulating a hormonal
response without the presence of that
hormone
○ Grave’s Disease – auto-Ab binds to receptor
for thyroid stimulating hormone resulting in
over-stimulation of thyroid
○ Myasthenia gravis
 Auto-Abs bind acetylcholine receptors on motor end
plate of muscles – progressively weakened skeletal
muscles
Systemic Autoimmune Diseases

Response is directed toward wide range
of target antigens

Systemic Lupus Erythematosus
 Typically middle-aged women
 Fever, weakness, arthritis, skin rash, kidney
problems
 Produce auto-Abs to DNA, histones,
platelets, leukocytes, clotting factors
 Excessive complement activation

Multiple sclerosis
 Numbness, paralysis, vision loss
 Inflammatory lesions in myelin sheath
caused by T cells
 Epidemiology
○ Frequent in African American and Hispanic
women
○ More common in Northern Hemisphere, more
common north of 37th parallel
○ Environmental components as well as genetic
components

Rheumatoid Arthritis
 Chronic inflammation of joints
 Produce auto-Abs that bind Fc portion of
IgG circulating in blood that creates immune
complexes
Animal Models

Autoimmunity develops spontaneously
in some lab animals and can be induced
with manipulation
 Rabbits injected with acetylcholine receptors
from eels
○ Soon developed muscular weakness as seen
with Myasthenia gravis

Animal models have implicated CD4+ T
cells to be primary mediator of some
autoimmune responses
 Treatment with anti-CD4 antibodies can help

Some studies have shown association
between expressing particular MHC
allele and susceptibility to autoimmunity
 Individuals that express HLA-B27 have 90
times greater chance of having ankylosing
spondylitis (spine inflammation)
○ Interestingly, most of those are male even
though women are more likely to suffer from
autoimmune disease

Proposed mechanisms for induction of
autoimmunity
 Release of sequestered antigens
○ Blood-brain barrier, sperm released into
tissues during vasectomy
 Molecular mimicry
 Inappropriate expression of Class II MHC
○ Non-antigen presenting cells will for some
reason express Class II MHC
- Can be caused by viral infection
○ This allows them to present self antigen to T
helper cells – leads to inappropriate reaction
Treatment
Immunosuppressive drugs
 Removal of thymus (for example, with
myasthenia gravis)
 Plasmapheresis – removing plasma and
then returning RBCs (removes extra
immune complexes)
 Treating the inflammation
 Antigen given orally can induce
tolerance
