Autoimmune disease

1. DR MEGHANA B S
MBBS, MD, DNB GENERAL MEDICINE
Autoimmune disease

2. Topics:
 IM 7.1: Describe the pathophysiology of autoimmune
disease
 IM 7.3 : Classify causes of joint pain based on the
pathophysiology

3. Pathophysiology of autoimmune diseases:
Objectives:
1) Autoimmunity results from activation of immune response
against self antigens.
2) To learn how immunological tolerance (central and
peripheral) is induced against self antigens for maintaining
normal health.
3) To gain understanding of various factors contributing to the
breakdown of immunological tolerance and development of
autoimmunity.
4) Gender predilection in autoimmunity is a well known
phenomenon and is briefly described.

4. Immune tolerance:
 Tolerance : It is a state of unresponsiveness in which
the lymphocytes remain alive but cannot exert
effector functions against a particular antigen
 2 Types:
1. Central Tolerance
2. Peripheral Tolerance

6. Central Tolerance
 Lymphocytes with receptors specific for self-antigens are deleted at
an early stage in lymphoid cell development. This process is
called central tolerance and allows self-reactive B and T cells to
be removed.
 Lymphocytes that do not receive survival signals undergo apoptosis.
 The subset of T cell receptors that receive the correct antigen signals
will leave the thymus and circulate in the periphery.
 Some CD4+ T cells receive signals in the thymus that select them to
differentiate into "natural" T regulatory cells (nTregs), which
express the FoxP3 transcription factor and suppress the
immune response by both direct and indirect mechanisms.

8. Peripheral Tolerance
 When self-reactive T cells escape into the periphery,
peripheral tolerance ensures that they are deleted or
become anergic (functionally unresponsive to
antigen).
 Peripheral tolerance can occur through 2
mechanisms:
1) Deletion (clonal deletion) OR
2) Functional inactivation (clonal anergy) of
developing lymphocytes that possess antigenic
receptors with high affinity for self-antigens.

10. Failure of immune tolerance
( Development of autoimmunity)

11. Induction of Autoimmunity
“Proposed Mechanisms!”
1) Sequestered antigens
2) Molecular mimicry
3) Inappropriate class II MHC expression on non-
antigen presenting cells
4) Polyclonal B cell activation

12. 1. Sequestered antigens
 Some self-antigens are sequestered (hidden) in
specialized tissues.
 These are not seen by the developing immune
system-will not induce self-tolerance.
 Exposure of T cells to these normally sequestered/
tissue-specific self-antigens in the periphery
results in their activation.

13. Examples of Sequestered Antigens
 Myelin basic protein (MBP), associated with
Multiple sclerosis (MS)
 Sperm-associated antigens in some individuals
following vasectomy
 Lens and corneal proteins of the eye following
infection or trauma
 Heart muscle antigens following myocardial
infarction

15. 2. Molecular Mimicry
(Cross-reacting Antigens)
Virus and bacteria possess antigenic determinants that are
very similar, or even identical, to the normal host cell
components.
This phenomenon, known as molecular mimicry, occurs in
wide variety of organisms.
Molecular mimicry may be the initiating step in a variety
of autoimmune diseases.

17. 3. Inappropriate Expression of Class II MHC
Molecules
 Class II MHC ordinarily expressed on antigens
presenting cells, such as macrophages, dendritic cells
and B cells.
 Abnormal expression of MHC determinants allows
the recognition of these auto-antigens by self-
reactive T cells.

18. Inappropriate Expression of Class II MHC
Molecules
 This may occur due to the local production of INF-ᵞ,
which is known to increase class II MHC expression
on a variety of cells.
 The inducer of IFN- ᵞ under these circumstances
could be a viral infection.

21. 4. Polyclonal B Cell Activation
Viruses and bacteria can induce nonspecific polyclonal
B cell activation, including:
 Certain gram negative bacteria
 Herpes simplex virus
 Cytomegalovirus
 Epstein Barr Virus
 Human immunodefiency virus (HIV)

22.  These viruses induce the proliferation of numerous
clones of B cells to secrete IgM in the absence of a
requirement for CD4 T cell help.
 Polyclonal activation leads to the activation of self-
reactive B cells and autoantibody production.
 Patients with infectious mononucleosis ( caused by
EBV) and AIDS (HIV) have a variety of auto-
antibodies.

23. Drug induced Lupus Erythematosus
Lupus erythematosus like syndrome develops in patients receiving
a variety of drugs such as
- Hydralazine
- Procainamide
- Isoniazid
- Penicillin
 Many are associated with the development of anti-nuclear
antibodies (ANAs)
 Renal and CNS involvement is uncommon
 Anti-histone antibodies are frequently present

24. Take home message
• Normal healthy state is maintained by immunological
tolerance against self antigens at central and peripheral
levels
• Autoimmune diseases result from the breakdown of
immunological tolerance to self antigens
• Certain autoimmune diseases exhibit strong association
with female gender

26. Topic: Arthralgia
7.3 Classify cause of joint pain based on the
pathophysiology

28. STRUCTURE OF A JOINT

29. Pain sensitive structures in joint
 Innervated structures in the joint include synovium,
ligaments, joint capsule, muscles, and subchondral
bone.
 Cartilage is aneural structure

32. Pathogenesis.
Although a large number of cytokines can be isolated from inflamed
joints, the most important ones include:
• IFN-γ from TH1 cells activates macrophages and resident synovial cells.
• IL-17 from TH17 cells recruits neutrophils and monocytes.
• TNF and IL-1 from macrophages stimulates resident synovial cells to
secrete proteases that destroy hyaline cartilage.
• RANKL expressed on activated T cells stimulates bone resorption.

33. Of these, TNF has been most firmly implicated in the pathogenesis of RA and
TNF antagonists have proved to be remarkable effective therapies for the
disease . The synovium of RA contains germinal centers with secondary follicles
and abundant plasma cells which produce antibodies, some of which are
against self-antigens. Many of the autoantibodies produced in lymphoid organs
and in the synovium are specific for citrullinated peptides (CCPs) in which
arginine residues are post-translationally converted to citrulline. In RA,
antigenantibody complexes containing citrullinated fibrinogen, type II collagen,
α-enolase and vimentin deposit in the joints. Antibodies against these peptides
are diagnostic markers for the disease and may mediate joint injury. Evidence
suggests that the raised levels of anti-CCP antibodies in combination with a T-
cell response to the citrullinated proteins contribute to the disease becoming
chronic. Additionally, about 80% of patients have serum IgM or IgA
autoantibodies that bind to the Fc portions of their own IgG. These
autoantibodies are called rheumatoid factor and may also deposit in joints as
immune complexes although they are not uniformly present in all patients with
RA and can be found in patients without the disease, so the link to
pathogenesis is questionable.

34. It is estimated that 50% of the risk of developing RA is related to inherited
genetic susceptibility. Specific HLA-DRB1 alleles are linked to rheumatoid
arthritis, and these alleles share a common sequence of amino acids in a
polymorphic region of the β chain, which is designated the shared epitope.
The shared epitope is located in the antigen-binding cleft of the DR molecule.
This location is presumably the specific binding site of the arthritogen(s) that
initiates the inflammatory synovitis. Linkage and genome wide association
studies have also implicated the PTPN22 gene. PTPN22 encodes a protein
tyrosine phosphatase that is postulated to inhibit T-cell activation. The
environmental arthritogen whose antigens initiate RA by activating T or B
cells remains uncertain. CCPs are produced during inflammation, so insults
such as infection and smoking may promote citrullination of self-proteins,
creating new epitopes that trigger autoimmune reactions. The robust immune
reaction to these autoantigens suggests that they may be important
arthritogenic agents.

39. ALGORITHM

40. ..CONTD

41. REFERENCES
• Harrison’s textbook of Internal medicine 20th
ed.
• Kelly’s textbook of Rheumatology 10th ed.
• Woolf AD, Akesson K. Primer: History and
examination in assessment of musculoskeletal
problems. Nat Cln Pract rheumatol.2008
Jan.4(1)26-33.