Autoimmune

Objective
By the end of this lecture, the student
should be able to:
 Define and discuss autoimmunity.
 Describe the term "autoimmune", indicate if it is either
cellular or humeral or both, and incident of occurrence
in males and females providing an examples of some
common autoimmune diseases.
 Define the term "autoantibodies".
 Determine if the autoantibodies either pathogenic or
not.
 Determine if autoimmune diseases are organ specific
or systemic.
 Autoimmune

ORGAN-SPECIFIC AUTOIMMUNITY:
Autoimmunity limited to a single organ/gland
e.g. thyroid, adrenal, pancreas, stomach.

NON -ORGAN SPECIFIC AUTOIMMUNITY:

 Broad range of target Ag involving a number of
organs and tissues e.g. skin, joints, kidney, liver
Mechanisms of pathology of
Autoimmune Diseases

Pathological changes in auto-immune diseases

can be mediated by variable immune responses
Mechanisms of pathology of
Autoimmune Diseases
Pathological changes in auto-immune
diseases can be mediated by variable
immune responses
1. Antibody-Mediated
Autoimmune Diseases :
Diseases in which Antibodies play
the predominant role in mediating
organ Damage in three mechanisms:

 - opsonization (Hemolytic anemia)

 - deposition as in (glomerulonephritis)
- interference with the function of some
receptors:

 - Stimulating AutoAntibody
 - Blocking AutoAntibody
Stimulating AutoAntibody
Some AutoAntibody bind to hormone receptor
and stimulate inappropriate activity

e.g .Grave’s disease-

 AutoAntibody to receptor for TSH.
Overproduction of thyroid hormones
Hyperthyroidism (hyperactive gland)
Complement-mediated damage
 In Graves’ disease,
binding of auto-
antibodies to the receptor
for thyroid-stimulating
hormone (TSH) induces
unregulated activation of
the thyroid, leading to
overproduction of the
thyroid hormones
( hyperthyroidism)
Grave’s disease
 Blocking AutoAntibody
Some AutoAntibody bind to hormone
receptors and prevent hormone from binding to
receptor

e.g .Myasthenia gravis-

AutoAntibody bind to Acetylcholine receptor

on muscles

No activation of muscles

 myasthenia gravis, binding of auto-
antibodies to the acetylcholine receptor
(right) blocks the normal binding of
acetylcholine and subsequent inhibit the
nerve impulse across the neuromuscular
junction, result in sever muscle weakness .

 Inaddition, auto-antibody activates

complement, which damages the muscle
endplate; the number of acetylcholine
receptors declines as the disease progresses.
Myasthenia gravis
the mechanism
 2. T cell-Mediated Autoimmune
diseases
Cellular damage by inflammation
e.g. Hashimoto’s thyroditis-
Infiltration of the thyroid by lymphocytes, MQ,
APC
 AutoAntibody are also
detected leads to Hypothyroidism
e.g .Insulin-dependent-diabetes mellitus (IDDM)
 Infiltration of the pancreas by
lymphocytes and AFC
 b cells are destroyed
Hashimoto’s Thyroiditis
most frequently seen in middle-aged women, The
DTH response is characterized by an intense
infiltration of the thyroid gland by lymphocytes,macrophages
and plasma cells , which form lymphocytic follicles
and germinal centers. The inflammatory response
causes a goiter, or visible enlargement of the
thyroid gland .
auto- Antibodies may contribute to a number of thyroid proteins
, including thyroglobulin and thyroid peroxidase
, both of which are involved in the uptake of iodine .
Binding of the auto-antibodies to these proteins
interfers with iodine uptake and leads to decreased
production of thyroid hormones (hypothyroidism ) .
Multiple sclerosis (MS)
 Autoimmune disease of the central
nervous system in which self-reactive
CD4+ T cells of the TH1 subset react
against self myelin antigens. Direct
killing occur by CD8 cells.
 Insulin-Dependent Diabetes
Mellitus
IDDMs are primarily due to the action of
T cells, and there is molecular mimicry
between coxsackie virus Antigen and
peptide of glutamic acid decarboxylase of
b island cells.

About 50% of IDDM patients are HLA-

DR3/ DR4 heterozygotes.
Murine model of MS
3. Immune-Complex-Mediated
Autoimmune diseases
Widespread tissue damage due to the formation
of AutoAntibody and the deposition of immune
complexes
e.g. Systemic Lupus Erythematosus (SLE)
AutoAntibody to nuclei, DNA, RBCs, leukocytes
Immune complex deposition in blood vessels,
Activation of Complement, chemotaxis of
neutrophils
Joint pain, Hemolytic anemia, Kidney
dysfunction
 Systemic lupus erythematosus
is a chronic, multisystem autoimmune
disease that affects predominantly women,
with an incidence of 1 in 700 among women
between the ages of 20 and 60 years.

Trigger unknown
The clinical manifestations are rashes,
arthritis, and glomerulonephritis, but
hemolytic anemia, thrombocytopenia, and
central nervous system involvement are
also common.
Pernicious anemia
the mechanism
4. Immune-complexes & T cell-
Mediated Autoimmune
Diseases
 Widespread tissue damage due
to hyperactive T & B cells
 e.g. Rheumatoid arthritis
 Rheumatoid factor-AutoAntibody to
Fc region of IgG
 Immune complex deposition in joints
 Chronic inflammation of joints
Many autoimmune diseases are
characterized by tissue destruction
mediated directly by T cells.
Examples
•Rheumatoid arthritis is a systemic disease
affecting the small joints and many other
tissues, in which self-reactiveT cells attack the
tissue in joints due the release of cytokines IL-
1,and TNF- a causing an inflammatory response
that results in swelling and tissue destruction.
Characterized by the presence of rheumatoid
factor (antibodies IgM against Fc portion of
IgG). Susceptibility to rheumatoid arthritis is
linked to the HLA-DR4 haplotype and less to
DR1 and DRW1D.
> 30% of cases doesn’t have
rheumatoid factor
Antagonists against the inflammatory cytokine such
asTNFa have a beneficial effect in rheumatoid
arthritis.
Diagnostic and Prognostic value of auto-
antibodies

The use of auto-Ab as diagnostic markers

e.g.

1. anti -acetylcholine receptor Ab MG

2. anti-nuclear Ab (ANA) SLE

3. Rheuamtoid factor (RF) RA

 Treatment
1. Metabolic control
Thyroxine Hypothyroidism

2. Anti-inflammatory RA

3 . Immunosuppression
antimitotic drugs SLE

4 . Plasmapheresis Organ-specific
diseases
Therapeutic Approaches for Immunologic Diseases
Antagonists of proinflammatory cytokines, such as IL-1 and TNF, and agents that block
leukocyte emigration into tissues, such as antibodies against integrins, are also being
tested for their anti-inflammatory effects. A soluble form of the TNF receptor and an
anti-TNF antibody that bind to and neutralize TNF are now approved for treatment of
rheumatoid arthritis. Other approaches to inhibit pathologic immune reactions include
antagonists against costimulators. and against T cell effector molecules, such as
CD40 ligand
 Therapeutic Approaches
for Immunologic Diseases
- anti-inflammatory
drug corticosteroid
-antagonists of proinflammatory
cytokines and agents that block
WBC migration
-inhibit pathologic reactions
antagonist vs costimulators
or T cell effector molecules
-induce T cell tolerance
Altered peptide ligand
 Future directions
-develop animal model of various
autoimmune diseases -identify
genes that may predispose to
autoimmunity
-identify eitiology of most
human autoimmune diseases
-drug discovery and specific
therapeutic approaches