Auto Immune Disorder

Sry Suryani W
Biochemistry Department
FK USU
 Autoimmunity Origins
Horror autotoxicus:
Literally, the horror of
self-toxicity.

A term coined by the

German immunologist
Paul Ehrlich (1854-1915)
to describe the body's
innate aversion to
immunological self-
destruction.
The immunological equilibrium: balancing
lymphocyte activation and control
Activation Tolerance
Effector T cells Regulatory T cells

Normal: reactions against pathogens No response to self

Pathologic: inflammatory Controlled response to pathogens
disease, e.g. caused by reactions
against self
 Autoimmunity

Basically means
immunity to self

A condition that
occurs when the
immune system
mistakenly attacks and
destroys healthy body
tissue.
The Immunology Definition

Failure of immune
tolerance
 When the immune system recognizes a self
antigen and mounts a strong response against
it, autoimmune disease develops.
Nonetheless, the immune system has to
recognize self-MHC to mount a response
against a foreign antigen. Thus, the immune
system is constantly challenged to
discriminate self vs non-self and mediate the
right response.
Cells of the Immune System

Source: http://www.biologymad.com/
 Lymphocyte
Maturation

Antibody Mediated Cell Mediated

Immunity Immunity

Stem Cells
B Cells Mature T Cells Mature
of the Bone
in Marrow in Thymus
Marrow

Released into Macrophages

Identify
blood, spleen, carry foreign
Antigens
lymph cells to T
Helper cells

B Cells Replicate T Helper cells (Th)

to form produce proteins
Plasma cells

B Memory Release Secrete Secrete

Cells Antibodies Interleukins lymphokines

Replicate Stimulates
Cytotoxic (killer) Phagocytosis
T (Tc) Cells

Effector Tc Tm Memory
Cells Cells
What happens when the bodys
lymphocytes fail to recognize its own
cells and tissues as such?
 Autoimmune Diseases
Failure of autoantibodies and T cells to
recognize own cells

Autoantibodies and T cells launch attack

against own cells

Perhaps due to overactive or an

overabundance of helper T lymphocytes
Pathogenesis of organ-specific autoimmunity

Abbas, Lichtman and Pillai. Cellular and Molecular Immunology, 7th edition, 2011 c Elsevier
Infections and autoimmunity

Infections trigger autoimmune reactions

Clinical prodromes, animal models
Autoimmunity may develop after infection is eradicated (i.e. the
autoimmune disease is precipitated by infection but is not directly
caused by the infection)
Some autoimmune diseases are prevented by infections (type 1
diabetes, multiple sclerosis, others? -- increasing incidence in
developed countries): mechanism unknown; similar protection
suggested for asthma
The hygiene hypothesis
Mechanisms by which infections may promote autoimmunity
Pathogenesis of autoimmunity
Immune-mediated inflammatory
diseases
Chronic diseases in which inflammation is a
prominent component and the immune system
reacts excessively against one or more
tissues

Immune-mediated inflammatory diseases

develop because the normal controls on
immune responses fail; typically due to
autoimmunity but may be excessive reactions
to microbes
MS, type 1 diabetes, RA: autoimmunity
Crohns: reaction against gut microbes?
 Diagnosis: Autoimmune Disease
Genetic predisposition
coding for the variety of MHC molecules
Demographics
most common among middle aged women
Additional viral infections
Disease specific environmental factors
Aging, stress, hormones, pregnancy
 Possible Causes:
Inefficient lymphocyte
programming
Self proteins circulate
without having been exposed
to system
(ex: sperm, eye lens, thyroid)
Reactions between self-
antigens and antibody
production against foreign
antigens
Potential Treatments:
Control inflammation
(ex: diabetes mellitus)
Immunosuppressive Medication
(ex: corticosteriods,
cyclosporin, methotrexate)
Therapeutic Antibodies against
specific T cell molecules
(with fewer side effects)
 Examples of Autoimmune Diseases

Multiple sclerosis
Myasthenia gravis
Crohns disease
Graves disease
Type 1 Diabetes mellitus
Rheumatoid arthritis
Psoriasis
Scleroderma
Systemic lupus erythematosus
EXAMPLES 0F ORGAN-SPECIFIC AND NON
ORGAN-SPECIFIC (SYSTEMIC)
AUTOIMMUNE DISEASES

Organ-specific Non organ-specific

Hashimoto Systemic lupus (SLE)
thyroiditis Rheumatoid arthritis
Thyrotoxicosis (RA)
Scleroderma
Addisons disease
Dermatomyositis
Atrophic gastritis Mixed connective
Juvenile diabetes tissue disease
mellitus (MCTD)
Multiple sclerosis Sjgrens syndrome
 ORGAN-SPECIFIC AND NON ORGAN-
SPECIFIC AUTOIMMUNE DISEASES
Organ-specific
Non organ- specific
Autoimmune attack vs. (systemic)
self-antigens of given Widespread self-anti-
organ gens are targets for
It results in a damage of autoimmune attack
organ structure and Damage affects such
function structures as blood
Treatment is focused on vessels, cell nuclei etc.
the replacement of organ Treatment is aimed to
function inhibit excessive
activation of the immune
system
 DIAGNOSIS
symptoms and detection of antibodies (and/or
very early T cells) reactive against antigens of
tissues and cells involved.
Antibodies against cell/tissue associated antigens
are detected by immunofluorescence.
Antibodies against soluble antigens are normally
detected ELISA or radioimmunoassay anemia).
 DIAGNOSTIC STEPS IN SYSTEMIC LUPUS

Ig level (60%)
Anti-nuclear antibodies(ANA)(1:80< 95%)
Anti-ds DNA Ab (90-95%)
Rheumatoid factor (30%)
Immune complex deposits in the skin(60%)
in kidney
(90Immunoglobulin level ( >90%)
Complement components %)
 Full Blood Count
Anemia - normochromic
normocytic, microcytic,
macrocytic ?
chronic inflammation or illness
blood loss e.g. NSAIDs,
pulmonary haemorrhage
Hemolysis
Leucocytosis
infection
Leucopenia
* SLE (lymphopenia <1500/mm3)
* Sjogrens syndrome
* side effect of medications
Thrombocytosis
* blood loss e.g. GI, lung
* other inflammatory arthritis or
systemic vasculitis
Thrombocytopenia
* SLE
* anti-phospholipid syndrome
* side effect of therapy
 Urine and protein
Active urinary sediments always indicate
active SLE rbc, granular or rbc casts.
Proteinuria indicates renal involvement but
not necessarily active renal disease.
Proteinuria may be due to other causes such
as renal vein thrombosis from secondary APS.
 Role of the ANA test in diagnosis of SLE
Highly sensitive for SLE.
ANA is present in 95-99% of SLE population.
A negative test argues strongly against a
diagnosis of SLE.
Lacks specificity: should only be ordered if the
pre-test probability of SLE is high.
 Value of ANA test titer
Presence of very high concentrations of antibody (titer
>1:640) should arouse suspicion of an autoimmune
disorder. However, its presence alone is not diagnostic of
disease. If no initial diagnosis can be made, watch the
patient carefully over time to exclude ANA associated
diseases.
The combination of very low titers of antibody (1:80 or
lower) and no signs or symptoms of disease suggest a much
less ominous prognosis. Need reevaluation far less
frequently than those with extremely high antibody titers.
 Anti-double stranded DNA (dsDNA)
Is relatively specific (97%) for SLE.
Helps in diagnosis but not useful as screening test for SLE since positive in
only about 60% of SLE patients.
Often used to monitor response to therapy of lupus.
Some patients have elevated titers of anti-dsDNA antibodies in the
setting of inactive or minimally active lupus.
Found at low frequency (generally less than 5%), and usually in low titer
and with low avidity, in patients with rheumatoid arthritis, Sjgren's
syndrome, scleroderma, Raynaud phenomenon, mixed connective tissue
disease, discoid lupus, myositis, uveitis, juvenile arthritis,
antiphospholipid syndrome, Grave's disease, Alzheimer's disease, and in
autoimmune hepatitis.
Has also been reported in patients receiving minocycline, etanercept,
infliximab and penicillamine.
 Antibody Findings

Disease ANA RF dsDNA Sm Scl-70 RNP

SLE 95-99 20 50-70 30 0 30-50

RA 15-35 85 <5 0 0 10

Diffuse >90 30 0 0 40 30
SSc
MCTD 95-99 50 0 <5 0 100
 Autoantibodies in SLE2
Autoantibody Frequency Clinical Associations
Anti - Sm 30%; very specific for SLE Lupus nephritis
Anti Ro 15-35% - Sjgrens/SLE overlap
Anti - La Anti Ro in ANA Neonatal lupus
Photosensitivity
Subacute cutaneous
lupus
Anti-U1-RNP 40% MCTD;Raynauds
Tend not to have
nephritis
Anti-histone Drug-induced lupus (DLE), Mild arthritis and
SLE serositis

Sabatine, S Marc : Pocket Medicine Second Edition ; 2004

 Indications for ordering anti-Ro/SSA
Women with SLE planning to or who have
become pregnant.
Women who have a history of giving birth to
a child with heart block or myocarditis.
Patients with a history of unexplained
photosensitive skin eruptions.
Patients suspected of having a systemic
connective tissue disease in whom the
screening ANA test is negative.
Patients with symptoms of xerostomia,
keratoconjunctivitis sicca and/or salivary and
lacrimal gland enlargement.
Patients with unexplained small vessel
vasculitis or atypical multiple sclerosis.
A Practical Guide to Interpretation of The ANA Test

ANA Negative
If the ANA is negative, but disease is suspected, test for specific
antibodies

Positive Negative

Ro aCL, LA,
Jo-1, PL-7 2GPI
PL-12, EJ,
OJ, KS

Clinical
SS PM/DM APS
Diagnose
CONTOH ANA
& PROFIL ANA
 Nucleolar proteins
Ro

La
dsDNA
Smith

Proteins that have

RNP
been synthesized in
the nucleus and Jo-1

thereafter where Scl-70

distributed to their Ro
respective sites in the
cell Nucleosomes
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