1. AUTOIMMUNITY

2. TEACHING OBJECTIVES
1. Understand the concept and significance of tolerance
2. Understand the concepts of autoimmunity and disease
3. Know the features of major autoimmune diseases
4. Know the theories on etiology of autoimmune diseases

3. Tolerance
The absence of specific immune response to a particular antigen in a fully immunocompetent person.
Tolerance is a mechanism which the immune system can learn
Unresponsiveness to self antigens is known as autotolerance.

4. Tolerance to self antigens
We normally do not mount a strong immune response against our own (self) antigens, a phenomenon called self-tolerance

5. Mechanisms of self-tolerance
Tolerance is generated at 2 levels :
Central tolerance which develops primarily in fetal life & occurs in primary lymphoid organs (the bone marrow & the thymus)
Peripheral tolerance which develop post-natally to deal with self-reactive cells in the periphery that have escaped central tolerance.

6. Central tolerance
During development in primary lymphoid organs , immature B & T lymphocytes that encounter , recognize and interact with high affinity with self antigens are deleted by apoptosis (clonal deletion).
This process is called negative selection and ensures that self reactive B & T cells are removed from the immune cell repertoire before entering the periphery.

7. p. 402
Ch. 16

8. Peripheral tolerance
Self reactive B & T lymphocytes that have escaped central tolerance encounter several checkpoints in the periphery to prevent their activation.
Several mechanisms are involved in this process :
1-Anergy : a state of metabolic arrest. It occurs when a lymphocytes recieves an antigenic signal in the absence of costimulation.

9. .
2-Ignorance : Tcells that escape deletion & migrate to the periphery ,may never encounter the appropriate Ag (sequestered Ag in inaccessible tissue).
3-Regulation : Subset of T cells(regulatory Tcells) inhibit the effector functions of other lymphocytes e.g.,self reactive cells.Suppression can occur through inhibitory cytokines (TGF-B , IL-10).

10. I 4-Homeostatic controlI
4-Homeostatic control
Due to Lack of T-cells help for autoreactive B cells. As a result , autoreactive B cells do not get stimulated.
If the immune system recognizes a self antigen and mounts a strong response against it, autoimmune disease develops.

11. Ch. 16

12. AUTOIMMUNITY
A condition in which structural or functional damage is produced by the action of
immunologically competent cells or
Abs against the normal components of the body.

13. Autoimmunity Origins
Horror autotoxicus: Literally, the horror of self-toxicity.
A term coined by the German immunologist Paul Ehrlich ( ) to describe the body's innate aversion to immunological self-destruction.

14. Features Of Autoimmune Diseases
An elevated level of Igs.
Deposition of Igs or their derivatives at particular sites like glomeruli.
Accumulation of lymphocytes & plasma cells at the site of lesion.
Benefit from corticosteroid or other immunosuppressive therapy.
Genetic predisposition.

15. Features Of Autoimmune Diseases
Occurrence of more than one type of autoimmune disorders in an individual.
Higher incidence among females.
Usually non-reversible (chronic)
Predisposing factors
Familial history.
Certain HLA haplotypes -
Rheumatoid Arthritis - HLA DR4

16. Mechanisms Of Autoimmunisation
Molecular mimicry - Cross reacting foreign Ags
Polyclonal B cell activation
Breakdown of immunological homeostasis (tolerance)
Sequestered Ags

17. 1 .Molecular Mimicry
Due to the presence of cross reacting Ags - Presence of epitopes with identical peptide sequences in some infecting micro-organisms & self Ags. e.g
* Following streptococcal infection – Streptococcal M proteins and the heart muscle.

18. Rheumatic fever is a classic example of molecular mimicry

19. 2. Polyclonal B-cell Activation
Non-specific activation of multiple B cell clones by certain stimuli like
* Chemicals - 2-mercaptoethanol
* Bacterial products – PPD(purified protein derivative, LPS(LIPOPOLYSACCHARIDE)
* Enzymes - trypsin
* Antibiotics - nystatin
* Micro-organisms - Mycoplasma, EBV,
malaria
Multiple non-specific Abs are formed during such conditions.

20. 3. Breakdown Of Immunological Homeostasis
Cessation of tolerance to self Ag.
Enhanced helper T-cell and decreased suppressor T-cell functions

21. 4. Release of Sequestered Ags
Sequestered Ags - Certain Ags are present in closed systems (compartments) and are not accessible to the immune apparatus. e.g
* Lens protein of the eye is enclosed in its
capsule & does not circulate.

22. Dr Ekta, Microbiology

23. Localised Autoimmune Diseases
AUTOIMMUNE DISEASES OF THE THYROID GLAND
A. Hashimoto’s
thyroiditis.

24. Localised Autoimmune Diseases
AUTOIMMUNE DISEASES OF THE THYROID GLAND
B. Thyrotoxicosis
(Grave’s disease)
- Abs against
thyroglobulin

25. Localised Autoimmune Diseases
ADDISONS’S DISEASE
* antibodies to the cells of Zona Glomerulosa layer of adrenal glands
Dr Ekta, Microbiology

26. Localised Autoimmune Diseases
PERNICIOUS ANAEMIA
2 types of auto-antibodies are present -
* against the parietal cells of the gastric
mucosa - Atrophic gastritis, Achlorhydria.
* Ab against the intrinsic factor – prevents
Vit.B12 absorption.

27. Diabetes mellitus type-1
Localised Autoimmune
Diseases
Diabetes mellitus type-1 -
Also called Insulin dependent diabetes or Juvenile diabetes.
-Autoimmune destruction of insulin-producing (beta cells) of the pancreas
-Results in total insulin deficiency.
-Affects 1 in 300 children and more adults. 4

28. Pathophysiology: Triggers
Molecular mimicry: similar epitopes between pathogen and host.
-Viruses can produce proteins similar to those of the host.
-Immune cells present viral protein homologous to self protein.
Failure of tolerance and autoimmunity.
Injury to Islet cells: macrophages provoke insulitis by release of interleukin. -
HGAD65: auto antigen
Coxsackie & hCMV: Viral peptides 3 3

29. Localised Autoimmune Diseases
AUTOIMMUNE DISEASES OF THE SKIN
* Pemphigus vulgaris
– blistering disease of the skin
- Abs to desmosomes, results in breakdown of epithelial cells
AUTOIMMUNE ORCHITIS
* Lymphocytic infiltration of testes and circulating Abs to the sperms & germinal cells
* Follows mumps orchitis

30. Systemic Autoimmune Diseases
Immune response to a variety of self-Ags
Damage to several organs & tissue systems.
Includes –
SLE (systemic lupus erythematosus)
RA (rheumatoid arthritis)
Polyarteritis nodosa
Sjogren’s syndrome

31. SLE Chronic , multisystem disease
Auto-antibodies against cell nuclei, intra-cytoplasmic constituents, Igs & other organ-specific Ags.
Extensive immune complex-mediated inflammatory lesions affecting Kidneys, Joints, Skin, Serous membrane and Lungs
Women are more affected (80%), usually those of childbearing age
HLA-DR2 or DR3 are predisposed to SLE
Diagnosis: Antinuclear Ab - immunofluorescence
Anti-DNA Ab (RIA/ ELISA)

32. Rheumatoid Arthritis (RA)
Symmetric polyarthritis with muscle wasting and subcutaneous nodules.
Associated with myocarditis, vasculitis & other disseminated lesions.
Presence of a circulating auto Ab called Rheumatoid Factor (RF)
RF- IgM directed against one’s own IgG
Diagnosis : Latex agglutination test ( RF,CRP),ANTI-CCP(Anti-cyclic citrullinated peptide)

33. Sjogren’s Syndrome
Triad of conjunctivitis sicca, dryness of the mouth with or without salivary gland enlargement,
May occur along with other collagen diseases.

34. Diagnosis
Diagnosis of autoimmune diseases is based on symptoms and detection of antibodies (and/or very early T cells) reactive against antigens of tissues and cells involved

35. Diagnosis………
Antibodies against cell/tissue associated antigens are detected by immunofluorescence
Antibodies against soluble antigens are normally detected ELISA or radioimmunoassay

36. Treatment
The goals of treatment of autoimmune disorders are to reduce symptoms and control the autoimmune response while maintaining the body's ability to fight infections. Treatments vary widely and depend on the specific disease and symptoms

37. Treatment………
Anti-inflammatory (corticosteroid) and immunosuppressive drug therapy (such as cyclophosphamide, azathioprine, cyclosporine ) is the present method of treating autoimmune diseases.

38. Treatment……..
Extensive research is being carried out to develop innovative treatments which include: anti-TNF alpha therapy against arthritis, feeding antigen orally to trigger tolerance, anti-idiotype antibodies,, anti-IL2 receptor antibodies, anti-CD4 antibodies, anti-TCR antibodies, etc.