1. دكتر وجگاني گروه ايمونولو‍‍ژي دانشگاه علوم پزشكي تهران
بسم الله الرحمن الرحيم
Autoimmunity
دكتر وجگاني
گروه ايمونولو‍‍ژي
دانشگاه علوم پزشكي تهران

2. Autoimmunity Origins Horror autotoxicus: the horror of self-toxicity.
A term coined by the German immunologist Paul Ehrlich (1900) to describe the body's innate aversion to immunological self-destruction.

5. Immunity against self antigens (autoantigens) is called autoimmunity
Autoimmunity results from a
“loss of self tolerance”
Approximately 3–4% of the population in industrialized countries suffers from autoimmune diseases

6. Autoimmunity Lack of immune unresponsiveness to an individual’s own tissue antigens

7. Examples of Autoimmune Diseases
Multiple sclerosis
Myasthenia gravis
Crohn’s disease
Grave’s disease
Type 1 Diabetes mellitus
Rheumatoid arthritis
Psoriasis
Scleroderma
Systemic lupus erythematosus

8. Lupus “Butterfly Rash”
Acute and chronic inflammation of various tissues of the body

11. Multiple sclerosis
Myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination

12. Multiple Sclerosis

14. Rheumatoid Artheritis

16. Self -Tolerance

17. Peripheral T Cell Tolerance
THYMUS
Escape from Clonal Deletion
Autoreactive T cell
(Naïve)
Suppression by
Regulatory T Cells
Repeated stimulation
MHC/Ag
No Costim.
Antigen Sequestered
Clonal Ignorance
AICD
Clonal Anergy
Escape from peripheral tolerance
Autoimmunity

18. What Causes Autoimmunity?

19. Mechanisms proposed for induction of Autoimmunity
Release of “sequestered antigens”

21. sympathetic ophthalmia

22. is sequestered in the CNS
Transgenic Mouse
TCR specific to Myelin
Basic protein (MBP)
T cells carry
the autoreactive TCR
Brain autoantigen, MBP
is sequestered in the CNS
Inject MBP With adjuvant
No Autoimmune Disease
Activation of Autoreactive
T Cells
Immunological Ignorance
Migrate to tissues
Including CNS
Encephalitis and Death
Activated T cells cross BBB and cause CNS disease

23. Mechanisms proposed for induction of Autoimmunity
Release of “sequestered antigens”
Abnormal immunoregulation

26. Immuno-regulatory T cells

29. Autoimmunity: a question of balance
Activating signals
MHC-II peptide
Cytokines (IFN-g)
CD40/CD40L
CD28/CD80,86
Downregulating signals
Cytokines (IL-10,TGFβ)
CD80,86/CTLA-4

31. Importance of T regulatory?
Genetic mutations in Foxp3 in humans leads to development of a severe and rapidly fatal autoimmune disorder known as
Immune dysregulation, Polyendocrinopathy, Enteropathy,X-linked (IPEX) syndrome.
Foxp3 mutations lead to massive
Lymphoproliferation,
Diabetes,
Dermatitis,
Thyroiditis

32. Mechanisms proposed for induction of Autoimmunity
Release of “sequestered antigens”
Abnormal immunoregulation
Bypass of helper T-cell tolerance

33. Bypass of helper T-Cell Tolerance
1) Modification of antigen (via drugs, microorganisms)
Foreign Th epitope/self B-cell epitope
Me-Dopa  altered synth. of Rh Ag  AIHA
Procainamide SLE
over 90% of patients undergoing treatment with procainamide for 1 to 2 years mount antinuclear antibodies and
20% of them develop lupus-like symptoms

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

37. 3- Shared Epitopes
Rheumatic fever is a classic example of molecular mimicry

39. 4- Bystander Activation

41. Recruit leukocytes into the tissues
4) Bystander activation
Infections of particular tissues may induce local innate immune responses
Recruit leukocytes into the tissues
Result in the expression of co-stimulators on tissue APCs
The breakdown of T cell tolerance to self antigens
Infection results in the activation of T cells that are not specific for the infectious pathogen

42. Mechanisms proposed for induction of Autoimmunity
Release of “sequestered antigens”
Abnormal immunoregulation
Bypass of helper T-cell tolerance
Polyclonal lymphocyte activation

43. Polyclonal Lymphocyte Activation
Endotoxins cause such activation independent of specific antigens
Super antigens? TCR (V), MHC-II
Mitogens?
Con A - T cell mitogen PHA - T cell mitogen PWM - T and B cell mitogen
LPS, EBV - B cells mitogen

45. Mechanisms proposed for induction of Autoimmunity
Release of “sequestered antigens”
Abnormal immunoregulation
Bypass of helper T-cell tolerance
Polyclonal lymphocyte activation
Somatic hypermutation

47. Mechanisms proposed for induction of Autoimmunity
Release of “sequestered antigens”
Abnormal immunoregulation
Bypass of helper T-cell tolerance
Polyclonal lymphocyte activation
Genetic Defects

48. MHC Association with Autoimmune Disease
Many autoimmune diseases show association with specific MHC genes
The number of autoimmune patients carrying a HLA allele compared with the prevalence of that allele in the general population

49. 87 times more likely to develop AS than the non-B27
Figure 13-20
87 times more likely to develop AS than the non-B27

50. Relative Risk? or risk ratio
TOTAL
No AS AS
100 30 70
HLA-B27+ 90 10
HLA-B27-
RR=70/100 ÷10/100

51. Genes and Autoimmunity
The concept that a single gene mutation leads to a single autoimmune disease is the EXCEPTION not the rule.
Because of this autoimmune diseases are generally classified as complex diseases as there is not a single “pinpoint-able” gene

52. Exceptions to the Rule – Simple Genetic Autoimmune Illnesses
Disease
Gene
Mechanism
APS-1
(Autoimmune polyglandular syndrome type 1)
AIRE
Decreased expression of self-antigens in the thymus, resulting is a defect in negative selection
IPEX
(Immunodysregulation, polyendocrinopathy, enteropathy,
X-linked)
FOXP3
Decreased generation of Tregs
ALPS
(autoimmune lymphoproliferative syndrome )
FAS, FASL
Failure of apoptotic death of self reactive T or B cells

53. Other Genetic Factors Genetic defects in: Signaling (TCRζ)
Co-stimulatory molecules (CTLA-4)
Apoptosis (Fas & FasL)
Cytokines (IL-2)

54. Mechanisms proposed for induction of Autoimmunity
Release of “sequestered antigens”
Abnormal immunoregulation
Bypass of helper T-cell tolerance
Polyclonal lymphocyte activation
Somatic hypermutation
Genetic Defects
Danger theory

55. Danger theory Proposes anti-self B & T-cells are always present
AIR is due to release of “danger signals”
Response to tissue damage, necrosis or cell distress,
( infection or injury)
Inflammation response to danger signals are mediated by effector molecules ( cytokines)

58. Mechanisms proposed for induction of Autoimmunity
Release of “sequestered antigens”
Abnormal immunoregulation
Bypass of helper T-cell tolerance
Polyclonal lymphocyte activation
Somatic hypermutation
Genetic Factors
Danger theory
Hormonal status

59. Hypothesis: estrogen response elements (EREs) in several genes
Hormones
Females are much more likely to develop autoimmune illness
Rise in hormones associated with pregnancy may even cause abortion of the fetus (RSA)
Hypothesis: estrogen response elements (EREs) in several genes

60. Hormones
Females are much more likely to develop autoimmune illness

61. Environment
Pathogens, drugs, hormones, and toxins are just a few ways that the environment can trigger autoimmunity

62. Sex-based Differences in Autoimmunity
Differences can be traced to sex hormones
- hormones circulate throughout the body and alter immune response by influencing gene expression
- (in general) estrogen can trigger autoimmunity
- androgens (such as testosterone) and progesterone can protect against it
Difference in immune response:
- ♀ mount more vigorous immune responses than ♂
- ♀ have higher serum antibody concentrations, numbers of CD4+ T cells and CD4/CD8 ratios in blood

63. Autoimmunity Classification
Can be classified into clusters that are either organ-specific or systemic

64. Examples of Organ Specific
Lungs of a patient with Goodpasture’s
Hashimoto’s disease
(thyroiditis)
Vitiligo

65. Mechanisms of Autoimmune Damage

66. Mechanisms of Autoimmune Damage
Autoimmunity is initiated in the same way as adaptive immune responses
The mechanism of tissue damage is classified by the scheme adopted for hypersensitivity reactions
More than one type of hypersensitivity may be involved
Tissue injury is caused by a response to self Ag (Chronic diseases)
The Ag cannot be removed so the response persists
Epitope spreading Progressive diseases

67. Figure 13-7
Epitope spreading

68. Autoimmune responses resemble hypersensitivity reactions
Type II: Antibodies (Abs) against cell
surfaces/extracellular matrix
Type III: Soluble immune complexes
deposited in tissues
Type IV: Effector T cells

70. Type II Hypersensitivity
Autoimmunity

73. Graves’ Disease

74. Abs against the TSH receptor mimic the natural ligand
leads to chronic overproduction of T3/T4 insensitive to regulation
•Results in hyperthyroidism
•Individuals suffer from heat intolerance,nervousness, weight loss, outwardly bulging eyes

75. Myasthenia Gravis

76. Abs bind to the Ach receptor on muscle cells, resulting in their endocytosis and degradation
Results in loss of muscle sensitivity to neuronal stimulation, progressive muscle weakness
• Often characterized by droopy eyelids, double vision

77. Pernicious Anemia

78. Type III Hypersensitivity
Autoimmunity

79. Type IV Hypersensitivity

81. Multiple Sclerosis
MS patients can have autoantibodies and/or self reactive T cells which are responsible for the demyelination

82. Rheumatoid arthritis
Non-suppurative proliferative synovitis which leads
to descruction of articular cartilage and progressive disabling arthritis
3-5X more common in women than in men
Initiated by activation of T-helper cells which produce cytokines and activate B cells to produce antibodies
80% of patients with rhematoid factors (antibodies against Fc portion of IgG)
precise trigger which initates destructive immune response is not known

83. Systemic Lupus Erythematosus (SLE)
Multisystem autoimmune disease
Abs against DNA, histones, ribosomes form immune complexes with Ags released from damaged cells
B-cell hyper-reactivity is a feature of SLE, caused by
excess T-helper activity
Affects skin, kidneys, serosal surfaces, joints,
CNS and heart (deposition of Immune complex)

84. Insulin-dependent diabetes mellitus
(IDDM)
Selective destruction of insulin-producing β cells
located within the islets of Langerhans by T cells
Several autoantigens are recognized by both Abs
and T cells, including insulin and glutamic acid
decarboxylase (GAD)

85. Diabetes
Disease in which the body does not produce or properly use insulin “ T cell” Disease T cells attack and destroy pancreatic beta cells

86. Susceptibility loci for autoimmune diseases