1. TOLERANCE& AUTOIMMUNITY

2. Topic Overview Concept and significance of tolerance
Factors which determine induction of tolerance
Mechanism of tolerance induction
Concept of autoimmunity and disease
Features of major autoimmune diseases
Examples of autoimmune diseases.
Theories on aetiology of autoimmune diseases

3. Definition
Autoimmunity is a state in which the body’s immune system fails to distinguish between self and non self by formation of auto antibodies against one’s own tissues
A condition that occurs when the immune system mistakenly attacks and destroys healthy body tissue
Loss of immunologic tolerance to one’s own tissue

4. autoimmunity

5. Immunological tolerance
Is a type of specific unresponsiveness to an antigen induced by the exposure of specific lymphocytes to that antigen, but respond to other antigens normally
It is a normal phenomenon present from fetal life of an individual to recognize self tissues and antigens
This protects ability of individual’ immune system to mount a response towards their own antigens, regarded as self.
By so doing the individual avoids attacking and destroying oneself

6. Aspect of immune tolerance
Natural or "self" tolerance.
This is the failure to attack the body's own proteins and other antigens.
This protect the body from developing autoimmune diseases.
Induced tolerance.
This involves tolerance to external antigens.
It is created by manipulating the immune system.
This provide protection from allergic reactions acquired from food (e.g. peanuts), insect stings, or grass pollen (hay fever).

7. Tolerance Mechanisms
The mechanisms the immune system uses to ensure the absence of self-reactivity (autoimmunity) include:
Central Tolerance - this occurs during lymphocyte development.
Peripheral Tolerance - occurs after lymphocytes leave the primary lymphoid organs.

8. Central Tolerance Operates in the thymus and bone marrow.
Clonal deletion of T and B lymphocytes that recognize self antigens which occurs before they develop into fully immunocompetent cells in order to prevent autoimmunity.
This process is most active in fetal life
It may also continue throughout life as immature lymphocytes are generated.

9. Central Tolerance

10. Peripheral Tolerance
This is deletion of those self-reactive T&B cells that escape central tolerance achieved by 3 mechanisms
-Clonal deletion
-Clonal anergy
-Peripheral suppression by T cells

11. Peripheral Tolerance

12. Tolerance When an antigen induces tolerance, it is termed tolerogen.
Tolerance is specific and like immunological memory, it can exist in T-cells, B cells or both
Like immunological memory, T cell tolerance is longer lasting than B cell tolerance.

13. Tolerance to tissues and cells
Tolerance to tissue and cell antigens can be induced by injection of hemopoietic (stem) cells in neonatal or severely immunocompromised (by lethal irradiation or drug treatment) animals.
Also, grafting of allogeneic bone marrow or thymus in early life results in tolerance to the donor type cells and tissues.
Such animals are known as chimeras. These findings are of significant practical application in bone marrow grafting.

14. Tolerance to soluble antigens
A state of tolerance to a variety of T-dependent and T-independent antigens has been achieved in various experimental models.
Based on these observations it is clear that a number of factors determine whether an antigen will stimulate an immune response or tolerance

15. Tolerance

16. Tolerance cont……..
Induction of tolerance in T cells is easier and requires relatively smaller amounts of tolerogen than tolerance in B cells.
Maintenance of immunological tolerance requires persistence of antigen.
Tolerance can be broken naturally (as in autoimmune diseases) or artificially (as shown in experimental animals, by x-irradiation, certain drug treatments and by exposure to cross reactive antigens).

17. Ignorance It is a passive form of immunological tolerance
It can be shown that there are T cells and B cells specific for auto-antigens present in circulation.
These cells are quite capable of making a response but are unaware of the presence of their auto-antigen.

18. Ignorance cont…. This arises for 2 reasons
The antigen may appear in a very low concentration.
Since all lymphocytes have a threshold for receptor occupancy which is required to trigger a response then very low concentrations of antigen will not be sensed.

19. Ignorance……
2. Some antigens are sequestered from the immune system in locations which are not freely exposed to surveillance, e.g. eye, CNS and testis.
Pathologically mediated disruption of these privileged sites may expose the sequestered antigens leading to an autoimmune response.

20. Mechanism of tolerance induction
Clonal deletion:
Functionally immature cells of a clone encountering antigen undergo a programmed cell death, as auto-reactive T-cells are eliminated in the thymus following interaction with self antigen during their differentiation

21. Mechanism of tolerance induction
Lymphocytes & many cells express Fas(CD95)
The ligand for Fas(Fas L) is expressed on activated T lymphocytes
The engagement of Fas by Fas L,coexpresed on activated T cells, dampens the immune response by inducing apoptosis of the activated T lymphocytes

22. Mechanism of tolerance induction
Clonal anergy:
Auto-reactive T cells, when exposed to antigenic peptides which do not possess co-stimulatory molecules, become anergic to the antigen
In addition, B cells when exposed to large amounts of soluble antigen down regulate their surface IgM and become anergic.

23. Mechanism of tolerance induction
These cells also up-regulate the Fas molecules on their surface.
An interaction of these B cells with Fas-ligand-bearing cells results in their death via apoptosis.

24. Mechanism of tolerance induction
Receptor editing:
B cells which encounter large amounts of soluble antigen, as they do in the body, and bind to this antigen with very low affinity become activated to re-express their RAG-1 and RAG-2 genes.
These genes cause them to undergo DNA recombination and change their antigen specificity.

25. Mechanism of tolerance induction
Anti-idiotype antibody:
Anti-idiotype antibodies produced experimentally
Have been demonstrated to inhibit immune response to specific antigens.
They are produced during the process of tolerization.
May respond to the unique receptors of other lymphocytes and serve to shut off antigen specific responses.
Therefore, they prevent the receptor from combining with antigen.

26. Mechanism of tolerance induction
Termination of tolerance
Experimentally induced tolerance can be terminated by prolonged absence of exposure to the tolerogen, by treatments which severely damage the immune system (x-irradiation) or by immunization with cross reactive antigens.
These observations are of significance in the conceptualization of autoimmune diseases.

27. Mechanism of tolerance induction
Suppressor cells:
Both low and high doses of antigen may induce suppressor T cells (Regulatory T cells) which can specifically suppress immune responses of both B and T cells, either directly or by production of cytokines, most importantly, TGF-b and IL-10.

28. Regulatory T cells
CD4+ T lymphocytes that express high levels of IL-2r a chain (CD25) but not other markers of activation.
Regulatory T cells may be generated by self antigen recognition in the thymus or in the periphery.

29. AUTOIMMUNE DISEASES Defination:
Autoimmune diseases are disorders in which the body's immune system reacts against some (or all) of its own tissue and produces antibodies to attack itself

30. Causes of Autoimmunity

31. Epidemiology
About 3% of US population is affected by autoimmune disorders
Women are most frequently affected e.g. 85% of SLE, Scleroderma and thyroiditis are women.
Higher Mortality and morbidity is reported among the young and middle aged.
Twin studies have been widely used in studies of familial tendencies of AID’s

32. Pathogenesis The exact etiology of autoimmune disease is not known
However the pathogenesis of autoimmunity appears to involve immunologic, genetic and microbial factors interacting through several mechanisms
Mechanisms leading to failure of peripheral tolerance contributes to the pathogenesis of autoimmune diseases.

33. Immunological
This involves failure of immunological mechanism of tolerance e.g.
Polyclonal activation of B-cells
Escape of auto reactive clones
Failure of Apoptosis of auto reactive T cells

34. Genetic factors Evidenced by:
increased expression of class II HLA antigens on tissues involved in autoimmunity
Increased familial incidence of some of the autoimmune disorders

35. Microbial factors
Infections with organisms, particularly viruses eg ( EBV infection), Bacterial (streptococci, Klebsiella and mycoplasma has been implicated in the pathogenesis of auto immune diseases

36. Autoimmunity Classification
Autoimmunity can affect ANY organ/organ system in the human body
Classified into 2 groups depending on the type of auto antibody formation.
Organ specific diseases
Non organ specific (systemic) diseases
Both – can get overlap

38. Organ specific
Organ specific means the auto-immunity is directed against a component of one particular type of organ.

39. Examples of organ specific auto. diseases
Vitiligo
Lungs of a patient with Goodpasture’s
Hashimoto’s disease
(thyroiditis

41. Hashimoto's Thyroiditis
Hashimoto's Thyroiditis is a type of autoimmune thyroid disease in which the immune system attacks and destroys the thyroid gland.
The thyroid helps set the rate of metabolism - the rate at which the body uses energy.
Hashimoto’s prevents the gland from producing enough thyroid hormones for the body to work correctly.
It is the most common form of Hypothyroidism (underactive thyroid).

42. Hashimoto’s Thyroiditis cont…
Organ specific disease affecting the thyroid gland.
Most often seen in women 30 to 40 years old, may be genetic predisposition.
Causes diffuse hyperplasia in the gland resulting in development of a goiter.
Thyroid autoantibodies are formed.

43. Symptoms The most common symptoms includes:
Goiter (enlarged thyroid gland which may cause a bulge in the neck)
Other endocrine disorders such as diabetes, an underactive adrenal gland, underactive parathyroid glands, and other autoimmune disorders
Fatigue
Muscle weakness
Weight gain
However, each individual may experience symptoms differently:

44. Thyroid hormones are produced by the thyroid gland
Thyroid hormones are produced by the thyroid gland. This gland is located in the lower part of the neck, below the Adam's apple.
The gland wraps around the windpipe (trachea) and has a shape that is similar to a butterfly - formed by two wings (lobes) and attached by a middle part (isthmus).

45. Goiter
This enlargement is due to the inflammatory cells which destroy thyroid cells, resulting in long term scarring. When the cells are damaged they cease thyroid hormone production, resulting in hypothyroidism
A goiter only needs to be treated if it is causing symptoms.

46. Laboratory diagnosis
Hashimoto's thyroiditis is simply diagnosed by two blood tests.
Routine thyroid function tests to confirm that a patient has an underactive thyroid gland.
Anti-microsomal and anti-thyroglobulin antibodies are immune cells which the body produces to attack specific portions of the thyroid cells which pinpoint Hashimoto's thyroiditis as the cause of the hypothyroidism.

47. Lab. Diagnosis cont..
The anti-microsomal antibody test is much more sensitive than the anti-thyroglobulin, therefore some doctors use only the former blood test.
These thyroid auto-antibodies blood tests are high in about 95% of patients with Hashimoto's thyroiditis, but are not diagnostic.

48. Treatment Thyroid hormone replacement.
Spontaneous remissions have occurred.
The enlarged thyroid can be treated with radioactive iodine to shrink the gland or with surgical removal of part or all of the gland (thyroidectomy).
Small doses of iodine (Lugol's or potassium iodine solution) may help when the goiter is due to iodine deficiency.

49. Non organ specific (systemic) autoimmune diseases
Systemic autoimmunity is directed against an antigen that is present at many different sites and can involve several organs

50. Examples of systemic autoimmune

51. Systemic Lupus Erythematosus (SLE)
Chronic, systemic inflammatory disease caused by immune complex formation.
The word "systemic" means the disease can affect many parts of the body.
Pathophysiology associated with clinical features secondary to immune complexes depositing in tissues resulting in inflammation.
Parts of the body affected include: the joints, skin, kidneys, heart, lungs, blood vessels, and brain.

52. SLE cont… Peak age of onset is 20 to 40 years of age.
Found more frequently in women.
Has both genetic and environmental factors.

53. SLE clinical signs Extremely diverse and nonspecific.
Joint involvement most frequent sign: polyarthralgia and arthritis occur in 90% of patients.
Skin manifestations next most common.
Erythematosus rash may appear.
Most classic is butterfly rash.

54. SLE clinical signs cont…
Renal involvement very common.
Caused by deposition of immune complexes in kidney tissue.
Leads to renal failure, most common cause of death.
Other systemic effects:
Cardiac
Central nervous system.
Hematologic abnormalities.

55. SLE Laboratory diagnosis
Screening test for anti-nuclear antibodies (ANA)
Antibodies directed against nuclear material of cells.
Flourescent anti-nuclear antibody (FANA) most widely used, extremely sensitive, low diagnostic specificity.
Animal or human cells fixed to slide.
Add patient serum and incubate.
Wash to remove un-reacted antibody.
Add anti-human globulin labeled with fluorescent tag or enzyme.

56. Antinuclear Antibody Test
Antinuclear antibodies (ANA) are autoantibodies against various cell nucleus antigens and are found in patients with autoimmune diseases such as SLE.
Some of ANA are considered to be useful for diagnosis of autoimmune diseases.

57. Treatment Aspirin and anti-inflammatories for fever and arthritis.
Skin manifestations-anti-malarials or topical steroids.
Systemic corticosteroids for acute fulminant lupus, lupus nephritis or central nervous system complications.
Five year survival rate is 80 to 90%.

58. Rheumatoid Arthritis
Chronic inflammatory disease primarily affecting joints, but can affect heart, lung and blood vessels.
Women three more times as likely as men to have it.
Typically strikes at ages between 20 and 40, but can occur at any age.
Involves joint pain, inflammation, and stiffness.

59. Clinical Signs Morning stiffness lasting 1 hour.
Swelling of soft tissue around 3 or more joints.
Swelling of hand/wrist joints.
Symmetric arthritis.Subcutaneous nodules
Positive test for rheumatoid factor.
Xray evidence of joint erosion.

60. Immunologic Findings
Rheumatoid Factor (RF) is an IgM antibody directed against the Fc portion of the IgG molecule, it is an anti-antibody.
Not specific for RA, found in other diseases.
Immune complexes form and activate complement and the inflammatory response.
Enzymatic destruction of cartilage is followed by abnormal growth of synovial cells

61. Rheumatoid Arthritis

62. Diagnosis Diagnosis is based on:
Clinical findings.
Radiographic findings
Laboratory testing.
Laboratory tests involve testing patients serum with red blood cells or latex particles coated with IgG, agglutination is a positive result.
Nephelometry and ELISA techniques are available to quantitate the RF.
Erythrocyte Sedimentation Rate (ESR) used to monitor inflammation.
C-Reactive protein (CRP) is utilized to monitor inflammation

63. Rest and nonsteroidal anti-inflammatory drugs control swelling and pain.
Substantial functional loss seen in 50% of patients within 5 years.
Slow acting antirheumatic drugs are coming into use but have side affects.
Joint replacement.
Treatment Treatments of RA include: NSAIDs, glucocorticoids, DMARDs, and biological agents. of the pathophysiology of RA