Principle, etiology,pathogenesis and diseases

2. •
1. Define and discuss autoimmunity
2. Use autoimmune diseases to illustrate
mechanisms of autoimmunity
3. Provide you with clinical correlations and
applications of the basic principles of immunology
4. To illustrate the spectrum of autoimmune
diseases
5. To define pathogenic aspects of autoimmune
diseases

3. • Definition :
Autoimmunity is a condition in which body’s own
immunologically competent cells or antibodies act
against self – antigens resulting in structural or
functional damage.
Hashimoto’s Thyroiditis
Systemic Lupus Erythematosus (SLE)

4. : 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.

5. • Normally immune system does not react to its own
antigens due to protective mechanism called
• Any breach in tolerance mechanism predispose to
several autoimmune diseases.

6. is a state in which an individual
is incapable of developing an immune response against
his/her own tissue antigens.
• Mediated by broad mechanisms :
1. Central Tolerance
2. Peripheral Tolerance

7. : Refers to the deletion of self reactive
T & B lymphocytes during their maturation in
central lymphoid organs ( i.e. in the thymus for T
cells & in the bone marrow for B cells).

8. During T cell development in thymus, if any
self antigens are encountered, they are processed &
presented by thymic antigen presenting cells (APCs) in
association with self MHC. Any developing T cell that
expresses a receptor for such self antigens are
negatively selected ( i.e. deleted by apoptosis). Thus the
resulting peripheral T cell pool is devoid of self reactive
cells.

9. Immature T-cells migrate from bone
marrow to thymus. Interact with self peptide-MHC
complexes on thymic epithelium. Double
positive(CD4+/CD8+)thymocytes develop T-cell
receptors (TCRs) –Only those with low affinity for self-
antigens persist (Positive Selection). Cells with
dysfunctional TCRs or with very high or no affinity for
MHC-self peptide complex undergo apoptosis (Negative
Selection).
• Positively selected cells then lose either CD4 or CD8 and
leave thymus to function in periphery as mature CD4+
or CD8+T-cells

10. When developing immature B cells in
the bone marrow encounter a self antigen during their
development, the tolerance is developed by –
Many B cells reactivate the
machinery of antigen receptor gene arrangement
( genes coding for light chain) so that a different (edited)
B cell receptor will be produced which no longer
recognizes the self antigen

11. When developing immature B cells in
the bone marrow encounter a self antigen during their
development, the tolerance is developed by –
After receptor editing, if the B cells
again recognize a self antigen, then they are destroyed
by subjecting them to apoptosis.

14. • Several back – up mechanisms occur in peripheral
tissues to counteract the self reactivity. It is provided by
many mechanisms-
Self reactive T cells might never encounter
the self antigens which they recognize & therefore may
remain in a state of ignorance.
Unresponsiveness to antigenic stimulus. The
self reactive T cells interact with the APCs presenting
the self antigen, but the co stimulatory signal is
blocked. The B7 molecules on T cells bind to CTLA – 4
molecules on T cells instead of CD28 molecules.

15. Self reactive T cells interacting
with APCs presented with self antigens, undergo full
activation, but might secrete nonpathogenic cytokines
& chemokine receptors profile & fail to induce
autoimmune response even though are activated.
Self
reactive T cells are activated on interaction with APCs
presented with self antigens. But activation of T cells
induces upregulation of Fas ligand which subsequently
interacts with the death receptor Fas leading to
apoptosis. = AICD.

16. They down regulate the
self reactive T cells through secreting cytokine IL – 10 &
transforming growth factor  (TGF - ) or killing by
direct cell to cell contact.
When immature & tolerogenic
dendritic cells capture self antigens for processing, they
down regulate the expression of molecules of co
stimulatory ligands such as B7 & CD40 molecules or
may indirectly induce Treg Cells.
Certain self antigens
can evade immune recognition by sequestration in
immunologically

17. Certain self antigens
can evade immune recognition by sequestration in
immunologically privileged sites e.g. corneal proteins,
testicular antigens & antigens from brain.

18. • When the mechanisms
controlling and
maintaining tolerance
function poorly or
breakdown,
autoimmunity and
autoimmune disease
can develop.

19. Normal cells that do not
usually express co stimulatory molecules(B7) are
induced to do so leading to tissue necrosis & local
inflammation. This mechanism postulated in Multiple
sclerosis, Rheumatoid arthritis, Psoriasis.
Failure of autoreactive T cells to
undergo activation induced cell death(AICD). i.e.
apoptosis via Fas – Fas ligand can lead to autoimmunity.
Seen in Systemic Lupus Erythematosus(SLE).
Autoimmunity can result from the
loss of T cell mediated suppression of self reactive
lymphocytes.

20. Antibody response to self antigens
occurs only when potentially self
reactive B cells receive help from T
cells. Autoreactive B-cells -Efficient
antigen presenting cells (APCs). May
present antigen to non- autoreactive
T- cells. Part of the cross-reactive
antigen has an epitope that normal
(non-autoreactive) T cells recognize.
This processed antigen is now
capable of stimulating T-cells and
provides “help” for autoreactive B
cells

21. The sequestrated antigens
are viewed as foreign to the immune system as they are never
been exposed to the tolerance mechanisms during development
of immune system. Injury to the organs lead to release of such
sequestrated antigens which are capable of mounting immune
response. Spermatozoa & ocular antigens release can cause post
vasectomy orchitis & post traumatic uveitis.
The self peptides released due to persistent
inflammation induce tissue damage ( chronic infection) & are
processed & presented by APCs along with microbial peptides.
Non specific activation of bystander self
reactive TH1 cells leads to cytokine influx which causes an
increased infiltration of various non specific T cells at the site of
infection.

22. Some
microorganisms share antigenic
determinants with self antigens, & induce
an immune response against such
microbes would produce antibodies that
can crossreact with self antigens.
• Acute rheumatic fever results due to
antibodies formed against streptococcal
M protein cross react with cardiac
glycoproteins due to antigenic cross
reactivity.
• Molecular mimicry involving T cell
epitopes – Multiple sclerosis where T cell
clones reacting myelin basic protein
probably would have been induced by
reacting against peptides derived from
many microbes including viruses.

23. Several microorganisms &
their products are capable of causing polyclonal (i.e. antigen non
– specific) activation of T cells or B cells.
• Polyclonal T cell activation – Superantigens released from
microbes e.g. Staphylococcus aureus polyclonally activate the T
cells directly by binding to antigen on non specific V region of T
cell receptor.
• Polyclonal B cell activation – It can be induced by products of
various microbes such as Epstein Barr virus, HIV etc.

24. • During development of immune system, not all epitopes of an
antigen are effectively processed & presented to T cells. There
are some non dominant cryptic epitopes which remain
sequestrated. Hence T cell clones reacting against such epitopes
are not deleted.
• Such cryptic epitopes can be released secondary to inflammation
at the site of tissue injury, which can induce increased protease
production & differential processing of released self – epitopes
by APCs.

25. The administration of drugs or
defects in synthesis could result in the modification of a
previously tolerated epitope, rendering it antigenic
• Not commonly reported
• Autoimmune hemolytic anaemia following treatment with
methyldopa
• Isoniazid may produce arthritis, associated with production of
anti-nuclear antibodies.
• Procainamide induces anti-nuclear antibodies in a high
proportion of patients, with 40% showing clinical signs of SLE

26. Disease Self antigen present on Type of immune response & important
features
Autoimmune anemias
Autoimmune hemolytic
anemia.
RBC membrane protein Autoantibodies to RBC antigens trigger
compliment mediated lysis or antibody
mediated opsonization of the RBCs.
Drug induced hemolytic
anemia
Drugs alter the red cell
membrane antigens
Drugs such as penicillin or methyldopa
interact with RBCs so that cells become
antigenic.
Pernicious anemia Intrinsic factor( a membrane
bound protein on gastric parietal
cells)
Autoantibodies to intrinsic factor block the
uptake of vitamin B12 leads to
megaloblastic anemia.
Idiopathic
thrombocytopenic
purpura
Platelate membrane proteins
(glycoproteins II b – III a or I b –
IX)
Auto – antibodies against platelate
membrane antigens leads to  platelate
count.
Goodpasture syndrome Renal & lung basement
membranes
Auto- antibodies bind to basement
membrane antigens or kidney glomeruli &
the alveoli of the lungs followed by
complement mediated injury leads to
progressive kidney damage & pulmonary
hemorrhage.

27. Disease Self antigen present on Type of immune response & important
features
Myasthenia gravis Acetylcholine receptors Blocking type of antibody directed against
Ach receptors present on motor nerve
endings, leads to progressive weakening of
the skeletal muscle.
Grave’s disease Thyroid stimulating hormone
(TSH) receptor
Anti – TSH auto- antibody (stimulates
thyroid follicles, leads to hyperthyroid
state)
Hashimoto’s thyroiditis Thyroid proteins & cells Auto- antibodies & TDTH cells targeted
against thyroid antigen leads to
suppression of thyroid gland
• Seen in middle aged females
• Hypothyroid state is produced(
production of thyroid hormone).
Post – Streptococcal
glomerulonephritis
Kidney Streptococcal antigen – antibody
complexes are deposited in glomerular
basement membrane.

28. Disease Self antigen present on Type of immune response & important
features
Systemic lupus
Erythematosus (SLE)
Autoantibodies are produced
against various tissue antigens
such as DNA, nucleus protein,
RBC & platelate membranes.
• Age & sex – Women (20 – 40 yrs) are
commonly affected female to male ratio
10 :1
• Immune complexes – (self Ag - auto Ab)
are formed which are deposited in various
organs
•Major symptoms Fever, butterfly rash
over the cheeks, arthritis, pleurisy, &
kidney dysfunction.
Rheumatoid arthritis Here a group of auto –
antibodies against the host IgG
antibodies are produced called
RA factor. It is an IgM antibody
against the Fc region of IgG
Anticitrulinated peptide
antibodies (ACPA) are also
produced
•Age & sex : Women(40 – 60 yrs) affected.
• Autoantibodies bind to circulating IgG,
forming IgM – IgG complexes that are
deposited in the joints & can activate the
complement cascade.
• Major symptoms – Arthritis( chronic
inflammation of joints, begins at
synovium, common joints – small joints of
hands, feet & cervical spine.
• Other features – Hematologic, CVS & RS
also frequently affected.

29. Disease Self antigen present on Type of immune response & important
features
Sjogren syndrome Ribonucleoprotein (RNP)
antigens SS – A (Ro) & SS – B
(La) present on salivary gland,
lacrimal gland, liver, kidney,
thyroid.
• Autoantibodies to the RNP antigens SS –
A (Ro) & SS – B (La) ; leads to immune
mediated destruction of the lacrimal &
salivary glands resulting in dry eyes
(Keratoconjunctivitis) & dry mouth
(xerostomia).
Scleroderma (systemic
sclerosis)
Nuclear antigens such as DNA
topoisomerase & centromere
present in heart, lungs, GIT,
Kidney etc.
Helper T cells (mainly) & autoantibody
mediated. Excessive fibrosis of the skin,
throughout the body.
Two types:
• Diffuse scleroderma – Autoantibodies
against DNA topoisomerase I (anti Scl 70)
is elevated.
• Limited scleroderma -  Anticentromere
antibody, characterized by CREST
syndrome - calcinosis, Raynaud
phenomenon, esophageal dysmotility,
sclerodactyly, & telangiectasia.

30. Disease Self antigen present on Type of immune response & important
features
Seronegative
Spondyloarthropathies
Sacroiliac joints & other
vertebrae. Several types-
• Ankylosing spondylitis
• Reiter Syndrome
• Psoriatic Arthritis
•Spondylitis with inflammatory
Bowel Disease
•Reactive arthritis.
Common Characteristics: They present as
rheumatoid arthritis like features, but
differ from it by:
• Association with HLA – B 27
• Pathologic changes begin in ligamentous
attachments to the bone rather than in
the synovium.
• Involvement of the sacroiliac joints
and/or arthritis in other peripheral joints.
• Absence of RA( hence the name
seronegative).
• Auto – Ab & immune complex mediated.
Multiple sclerosis Brain (white matter) Self reactive T cells produce characteristic
inflammatory lesions in brain that
destroys the myelin sheath of the nerve
fibers; leads to numerous neurologic
dysfunctions.

31. Diagnosed by Coombs test, in
which the red cells are incubated with an anti – human IgG
antiserum. If IgG autoantibodies are present on the red cells, the
cells are agglutinated by the antiserum.
Biopsies from the patients are stained
with fluorescent – labeled anti – IgG & anti – C3b reveal linear
deposits of IgG & C3b along the basement membranes.

32. is diagnosed by :
1. Detection of autoantibodies against various nuclear
antigens by indirect immunofluorescence assay & ELISA
based techniques
2. Antinuclear antibody (ANA) : Positive in >90% of cases
used as screening method
3. Anti – double stranded DNA (dsDNA): Highly specific, used
for confirmation of cases.
4. Anti – Sm antibodies.
5. Lupus band test: It is a direct immunofluorescence test,
can detect deposits of immunoglobulins & complement
proteins in the patient’s skin.
6. LE cell test: Lupus erythematosus (LE) cell test was
commonly used for diagnosis .

33. Anti Scl 70 antibody is raised, detected by indirect
immunofluorescence assay.
Is diagnosed by detection of SS- A (or anti
Ro) and SS – B (or anti La) antibodies by indirect
immunofluorescence assay.