Autoimmunity and

Autoimmune diseases
Emmanuel Mang’ombe
UDOM
 Introduction
• Immune system normally responds only to
foreign antigens
• Immune system exhibit “tolerance” to self
antigen
• The mechanism of self-tolerance prevents
immune system responding to self antigen
• Failure of the immune system to “tolerate”
self antigens may result in the development of
pathological processes known as autoimmune
diseases
 Immunological tolerance
• Definition:
– specific immunological unresponsiveness to an
antigen that is induced by exposure of
lymphocytes to that antigen ie immune response to
certain antigen doesn’t occur
• Significance:
– All individuals are tolerant of their own antigens
(self-tolerance); breakdown of self-tolerance
results in autoimmunity
– Therapeutic potential: Inducing tolerance may be
exploited to prevent graft rejection, treat
autoimmune and allergic diseases, and prevent
immune responses in gene therapy, perhaps stem
cell transplantation
 Mechanisms of self tolerance

• Central tolerance: Immature self-reactive

lymphocytes that recognize self antigens in
generative (“central”) lymphoid organs die by
apoptosis

• Peripheral tolerance: Mature self-reactive

lymphocytes that recognize self antigens in
peripheral tissues are inactivated (anergy), killed
(deletion) or suppressed by regulatory T cells
producing cytokines
 Autoimmunity
• Definition: immune response against self (auto-)
antigen, by implication pathologic
• Many Autoimmune diseases are characterized by
tissue destruction
• Either specific or involving large number of tissue
• Result from loss of tolerance
• The most important step in autoimmunity is activation
of self-reactive helper (CD4) T cells
• Self-reactive Th-1 or Th-2 can induce either cell-
mediated or antibody-mediated autoimmune reactions
• Most autoimmune diseases are antibody mediated
 General principles:
• Pathogenesis: The development of
autoimmunity reflects a combination of
susceptibility genes (genetic
predisposition) and environmental
triggers (usually infections)
• Different autoimmune diseases may be
systemic or organ-specific; may be
caused by different types of immune
reactions (antibody- or T cell-
mediated)
 Genetic factors - 1
• Many autoimmune diseases exhibit marked
familial tendency, suggesting genetic
predisposition
– Increased incidence in twins ( more in rates
monozygotic twins than dizygotic)
• Strong association of some diseases with
certain HLA specificities, esp the class II
genes
– In general, class II MHC-related diseases, occur
more commonly in women
– class I MHC-related diseases,occur more
commonly in men
 Hormonal Factors on
Autoimmunity - 2
• Approximately 90% of all autoimmune
diseases occur in women
• Evidence from animal models that
estrogen can alter the B-cell repertoire
and enhance the formation of antibody
to DNA
• Clinically, the observation that SLE
either appears or exacerbates during
pregnancy
 Environmental Factors -
• Environmental agents trigger autoimmune
diseases, e.g bacteria or viruses
• Pharyngitis caused by Streptococcus pyogenes
predisposes to rheumatic fever
• Coxsackie virus infection in mice causes type I
diabetes
• Mechanisms:
• Infectious agents possess antigens that elicit an
immune response that cross-reacts with
components of human cells.
 Environmental Factors -2
• Mechanisms:
• The other is that tissue injury releases
intracellular (sequestered) antigens that elicit
an immune response
 Mechanism for autoimmune
diseases

Autoimmune diseases

Alteration Release of Failure of

Molecular of normal sequestered Epitope
mimicry regulatory T
protein protein spreading
cell
 1. Molecular mimicry --1
• Viruses and bacteria have shown to
possess antigenic determinants that are
identical or similar to normal host-cell
components

• Exposure to these agents triggers a

cross-reacting immune response against
some component of normal tissue
 Molecular mimicry --1
Example:
– M protein of S. pyogenes resembles the
myosin of cardiac muscle
– Antibodies against certain M proteins
cross-react with cardiac myosin, leading to
rheumatic fever

•Reiter's syndrome occurs following

infections with Shigella or Chlamydia
 2. Alteration of Normal
Proteins
• Normal proteins may be altered or
modified by
– physical (irradiation)
– chemical (drugs)
– microbial agents (intracellular viruses) make
them immunogenic.
• E.g Procainamide-induced SLE is an
example of this mechanism
 3. Release of Sequestered
Antigens
• Antigen are sequestered in places ie not
accessible to immune system (known as
immunologically privileged sites)
– e.g., sperm, central nervous system, and the
lens and uveal tract of the eye
• When such antigens enter the
circulation accidentally, e.g., after
damage, they elicit both humoral and
cellular responses
 4. Epitope Spreading
• Is the term used to describe the new
exposure of sequestered auto-antigens
as a result of damage to cells caused by
viral infection.
• These newly exposed stimulate auto-
reactive T cells, and autoimmune disease
results
 5. Failure of Regulatory T
Cells
• Suppress the proinflammatory effects
of other T cells.
• An important function of TR cells is to
produce IL-10, which inhibits
proinflammatory Th-1 cells
• If TR cells fail, then autoimmune
diseases characterized by inflammation
such as systemic lupus erythematous,
can occur.
 Autoimmune diseases
• Can be divided into two broad
categories:
• Organ-specific
– Addison’s disease
– Graves’ disease
– Poststreptococcal glomerulonephritis
– Autoimmune hemolytic anemia
– Insulin-dependent diabetes mellitus

• Systemic autoimmune disease

• Multiple sclerosis, SLE , Rheumatoid arthritis
 Organ-specific

• Immune response is directed to a target

antigen unique to a single organ or gland

• Manifestations are largely limited to

that organ
 1. Autoimmune anemia
• Include:
• pernicious anemia
• autoimmune hemolytic anemia
• drug-induced hemolytic anemia
• Pernicious anemia – auto-antibodies to
intrinsic factor
• Autoimmune hemolytic anemia - auto-
antibody to RBC antigens, triggering
complement mediated lysis or antibody-
mediated opsonization and phagocytosis of
the red blood cells
 2. Thrombocytopenias
• Antibodies directed against platelets
• Platelets coated with antibody are
either destroyed in the spleen or lysed
by the membrane attack complex of
complement
• Several drugs, acting as haptens, bind
to the platelet membrane and form a
"neoantigen" that induces the cytotoxic
antibody that results in platelet
destruction
 3. Grave’s (anti-thyroid
stimulating hormone; anti-TSH)
 3. Thyrotoxicosis (grave’s d’se)
• Production of THs is regulated by TSH
produced pituitary gland
• Binding of TSH to receptor on thyroid
cells stimulates the synthesis of
thyroxine and triiodothyronine
• Graves’ disease - auto-antibodies bind
the receptor for TSH and mimic the
normal action of TSH
• Autoantibodies are not regulated, and
consequently they overstimulate the
thyroid
4. Insulin-Dependent diabetes
Mellitus
• Auto-reactive T cells destroy the islet
cells of the pancreas (Insulin producing
cells)
• Resulting in decreased production of
insulin and consequently increased levels
of blood glucose
• Infection with Coxsackie virus B4 has
been shown to be a trigger of IDDM in
mice
 5. MYASTHENIA GRAVIS
• Auto-antibodies bind the acetylcholine
receptors on the motor end-plates of
muscles
• Blocking the normal binding of
acetylcholine and also inducing
complement mediated lysis of the cells
• The result is a progressive weakening
of the skeletal muscles
 Systemic autoimmune disease
• The response is directed toward a broad
range of target antigens and involves a
number of organs and tissues
• Reflect a general defect in immune
regulation resulting in hyperactive T cells
and B cells
• Tissue damage is widespread, both from
cell mediated immune responses and from
direct cellular damage caused by auto-
antibodies or by accumulation of immune
complexes.
 SLE --1
• Autoantibodies are formed against
DNA, histones, nucleolar proteins, and
other components of the cell nucleus
• Primarily women btn the ages of 20 and
60 years
• Characterized by fever, weakness,
arthritis, skin rashes, pleurisy, and
kidney dysfunction
 SLE --1
• Individuals with HLA-DR2 or -DR3
genes are predisposed to SLE
• Most of the clinical findings are caused
by immune complexes that activate
complement and, as a consequence,
damage tissue
 Multiple sclerosis (MS) --1
• Auto-reactive T cells and activated
macrophages cause demyelination of the
white matter of the brain
• The trigger that stimulates the auto-
reactive T cells is thought to be a viral
infection
• Evidence polymerase of Epstein-Barr
virus may be the trigger
 Multiple sclerosis (MS)--2
• Certain alleles in the HLA-DR region
have an increased risk
• The symptoms may be mild, such as
numbness in the limbs, or severe, such
as paralysis or loss of vision
• Diagnosed between the ages of 20 and
40
 Rheumatoid Arthritis--1
• Autoantibodies are formed against IgG
• Autoantibodies are called rheumatoid
factors and are of the IgM class
• Auto-antibodies bind to normal circulating
IgG, forming IgM-IgG complexes that are
deposited in the joints
• Most of the clinical findings are caused by
immune complexes that activate complement
and, as a consequence, damage tissue
 Rheumatoid Arthritis--2
• The major symptom is chronic
inflammation of the joints, although the
hematologic, cardiovascular, and
respiratory systems are also frequently
affected
• Primarily women between the ages of 30
and 50 years
 Diagnosis of Auto immune
disease
• Diagnosed by clinical symptoms.
• Confirmed by detecting the auto Ab in
the serum of the patients.
• Autoantibodies are demonstrated by
• Immunoflurescent Ab test
• Haemagglutination
• Complement fixation
• Immunodiffusion
• Radio immuno assay, etc.
 Treatment
• Ideally, treatment for autoimmune
diseases should be aimed at reducing
only the autoimmune response
• Current therapies for autoimmune
diseases are not cures but merely
palliatives, aimed at reducing symptoms
 Treatment
• Corticosteroids, such as prednisolone,
are the mainstay of treatment
• Antimetabolites, such as azathioprine
and methotrexate, can be added
• The general reduction in immune
responsiveness, however, puts the
patient at greater risk for infection or
the development of cancer
 Treatment
• Immunosuppressive therapy must be
given cautiously because of the risk of
opportunistic infections
 Other autoimmune diseases
• Rheumatic fever/acute
glomerulonephretis
• Goodpasture’s syndrome
• Hashimoto thyroiditis
• Addison disease
• Guillain Barre syndrome
• Inflammatory disease of the bowel