1. Disorder of immune system
Yeong-Wook Song, MD
Division of Rheumatology
Seoul National University

2. The Immune System Objectives
1 Define the terms infection, pathogen, and antigen, tolerance, autoimmunity, rheumatic disease.
2 List and describe mechanism of the nonspecific and specific body defense mechanisms.
3 Explain the signs and causes of inflammation.
Define B cells and T cells and describe their locations and functions.
Explain the importance of MHC proteins.

3. The Immune System Objectives (cont.)
6 List the different types of T cells and describe their functions.
7 List the different types of antibodies and explain how they differ and how they fight infection.
Define complement and give its functions.
Explain the difference between innate and adaptive immunity.
Describe the signs and symptoms of common immune disorders (rheumatoid arthritis, lupus, ankylosing spondylitis scleroderma, myositis).

4. What does the immune system do?
Normal (physiologic) functions:
Immunity = protection against infection
Defense against some tumors
Roles in disease:
Cause of many immunological diseases (allergies, autoimmune diseases)
Suspected role in many diseases thought to be non-immune (atherosclerosis, Alzheimer’s disease, type 2 diabetes)

5. Innate and adaptive immunity
Abbas, Lichtman and Pillai. Cellular and Molecular Immunology, 7th edition, 2011 c
Elsevier
Innate immunity: always present (ready to attack); many pathogenic
microbes have evolved to resist innate immunity
Adaptive immunity: stimulated by exposure to microbe; more potent

6. Cells of the immune system
Lymphocytes: the cells of adaptive immunity; recognize antigens and develop (differentiate) into cells that perform the defense functions
Antigen-presenting cells: cells that capture antigens and display them to lymphocytes
Effector cells: leukocytes (white blood cells) that eliminate microbes (the “effect” of the immune response); may be lymphocytes, but are often other leukocytes

7. Classes of lymphocytes
Excluding NK cells and other innate lymphoid cells
Abbas, Lichtman and Pillai. Cellular and Molecular Immunology, 7th edition, 2011 c
Elsevier

8. Lymphocyte diversity and clonal selection
precursor
Antigen X
Antigen Y
Anti-Y
antibody
Anti-X
Generation of mature lymphocytes with many different antigen receptors
Naïve lymphocytes circulate through lymphoid organs
Specific lymphocytes recognize antigens
Lymphocytes are activated to proliferate and to differentiate into effector cells
Lymphocytes with highly specific and diverse antigen receptors develop prior to exposure to antigens

9. Adaptive immune responses

10. Stages in the life history of lymphocytes
Proliferation: expands number of antigen-specific cells
Differentiation: converts lymphocytes into effective defenders

11. The immune system can cause disease
Excessive, uncontrolled responses against infectious pathogens (collateral damage)
Inappropriate responses against self antigens may cause injury to normal tissues, resulting in disease
Fundamental defect is failure of control mechanisms in the immune system

12. The significance of recent advances
Provides a solid foundation of basic principles
Improved understanding of disease mechanisms
Development of novel therapies
Appreciation of the role of the immune system in non-immune diseases

13. Inflammation Causes: Signs:
Injured or infected with a pathogen, inflammation can result
Signs:
Redness
Heat
Swelling
Pain

14. Major Immune System Disorders
Diseases and disorders that challenge the immune system: (the following are the most significant)
HIV/AIDS
Infections
Autoimmune disease
Cancer
Allergies

15. Acquired Immune Deficiency Syndrome (AIDS)
Caused by human immunodeficiency virus (HIV) infection
Most common routes of transmission are through sexual contact, blood, or from mother to child during pregnancy or breast-feeding.
Can have infection for years before developing any symptoms of this disease
Less common routes of transmission are through accidental needle sticks, artificial insemination, and organ transplants.

16. Acquired Immune Deficiency Syndrome (AIDS) (cont.)
AIDS virus affects the immune system
Counts of CD4 cells are used to diagnose the stage of HIV infection. If below 200 patient has AIDS
CD4 cells are types of T cells and are important for the functions of other components of the immune system.

17. Acquired Immune Deficiency Syndrome (AIDS) (cont.)
Signs and Symptoms of AIDS:
Low T cell counts
Fever
Profuse sweating
Weakness
Weight loss
Swollen glands
Frequent infections
Some rare forms of cancer
A common form of cancer is called “Kaposi’s” sarcoma.

18. Allergies Allergic reaction is an immune response to a substance
Allergens - trigger of allergic responses
Anaphylaxis - blood vessels dilate quickly causing blood pressure to drop too quickly for organs to adjust. This condition is life threatening.

19. Allergies (cont.)
Allergic reactions involve IgE antibodies and mast cells.
IgE antibodies bind to allergens, they cause mast cells to release histamine and heparin
These chemicals trigger allergic reactions.
If a person is receiving allergy shots, he is being injected with tiny amounts of the allergen and reduces symptoms

20. Immunology in Rheumatic Diseases

21. Toll like receptors (TLRs)

22. Value of the Immune System
Macrophages & toll-like receptors (TLRs) different TLRs can (collectively) bind a wide range of pathogens Each macrophage has all of the set of TLRs
Toll-like receptors recognize a variety of PAMPs. Gene duplication of the TLR precursor and divergence of function has led to a family of molecules capable of recognizing different types of pathogen.

23. TLRs and Autoimmunity Clear evidence they play a role in SLE and RA
Clear evidence that intrinsic molecules trigger TLRs in RA and SLE
Targeted inhibitors of TLRs are in Phase II trials
Agonists of TLRs are being used as vaccine and tumor adjuvants

24. Antigen Presenting Cells
Unlike the other cells, TH cells only recognize antigen that is properly presented with MHC by other cells
These specialized cells are called antigen presenting cells
They include macrophages, B cells, fibroblasts & dendritic cells

25. Major Histocompatibility Complex (MHC)
Antigen is ingested by the antigen presenting cell then presented on its surface in molecules called major histocompatibility complex
MHC are also the molecules responsible for rejection in transplant organs

26. Major Histocompatibility Complex
MHC proteins =HLA(Human Leucocyte Antigen) in
humans
Molecules on cell surfaces which can display antigen
Products of a region of highly polymorphogenic genes on chromosome 6
2 types :
Class I &
Class II

27. Comparison of MHC Class I & II Molecules
Genes
HLA A/B/C
HLA D
Expressed on
All nucleated cells
APCs – B cells,
macrophages &
dendritic cells
Size
9 to 10 amino acids
(smaller)
12 to 28 amino acids
(larger)
Source of antigen
displayed
Intracellular eg viral
infections
Extracellular eg
bacterial infections
Antigen presented to
CD8+ T cells
CD4+ cells
( APC = Antigen presenting cell)

28. Activation of the Adaptive Immune System
Antigens that escape the innate immune system encounter the adaptive system
Adaptive immune system – powerful must be activated

29. Activation of the Adaptive Immune System
In this diagram, the macrophage represents the innate system
& the TH cell, the adaptive system
3. T cell recognizes
its cognate Ag
2. Ag presented
on cell surface
with MHC
4. 2nd signal required
= protein on APC +
a TH cell receptor
APC eg
Macrophage
ingests Ag
5. ACTIVATION
&
6. Cytokine production

30. Cytokines
Cells of the immune system communicate with each other using cytokines
Protein hormones
Mediate the effect of the innate &
specific immunity
Autocrine/ paracrine/endocrine
Effects include cell activation, division, apoptosis, movement

31. Cytokine types Interleukins –
produced by leucocytes & have effects mainly on WBC
Chemokines –
chemoattractants
Colony stimulating factors –
differentiation & proliferation of stem cells
Interferons –
interfere with viral replication
Eg.
Il-2 = a growth factor that stimulates CTLs & NK cells to proliferate
TNF activates primed macrophages & NK cells

32. Cells & cytokine production
Cells produce different subgroups of cytokines which will instruct the innate & adaptive systems to produce cells & antibodies against specific antigens.
Here is an example
Cells Cytokines Antigen
IL2
TH1 IFN  Viruses
(CD4) TNF Bacteria
TH0
IL 4
TH2 IL 5 Parasites
(CD4) IL10

33. T Cell Subsets – the Family Grows

39. CM: central memory (CD45RA-CCR7+) EM: effector memory (CD45RA-CCR7-) 10 2 3 4 5
< CD45RA>
< CCR7 > 44
28.2
4.73
23.1 CM
Naive EM
TEM
Naïve (CD45RA+CCR7+)
CM: central memory (CD45RA-CCR7+)
EM: effector memory (CD45RA-CCR7-)
TEM: terminal effector memory (CD45RA+CCR7-)

42. ■ CD4+ cells that secrete IL-21 a.k.a. Follicular helper T cell

53. IL-17A or IL-17F share the same receptor (IL-17 RA and IL-17RC heterodimer). IL-17A induces TNF RII expression and have synergistic effect on TNF response. Receptor of IL-25/IL-17E (endogenous blocker) is IL-17RA and IL-17RB.

54. ■ Ankylosing Spondylitis

56. Signal Signal IL-12 IL-23 p40 p35 p19 p40 IL-12Rβ1 IL-12Rβ2 IL-12Rβ1
NK or T cell
membrane
Signal
Signal
IL-1
IL-6
INF
IL-22
Th1 cell proliferation
Th17 cell proliferation

58. TFH – produce IL-21
CXCR5, PD1, CXCR3(-) T-B interaction
Transcription factor – Bcl 6

60. Success story
Anti TNF, anti-IL-6R, anti-CD20 : rheumatoid arthritis Anti-IL-12/IL-23 (Ustekinumab, Stellara) 45 mg SC q 4 wk X 2 → q 12 wk Psoriasis, Psoriatic Arthritis Anti-IL-17 (Secukinumab, Cosentyx) 150 mg SC Psoriasis, Psoriatic Arthritis, Ankylosing Spondylitis Anti-PD-1, anti-PDL-1 : malignancy Car T cell : leukemia

61. 2. Tolerance Is…………….
the immunologic unresponsiveness to self antigens
It allows the immune system to protect the body without turning against itself
The focus is on the adaptive immune system
T & B cells must be able to discriminate self from non self
This occurs centrally & peripherally

62. Central T Cell Tolerance
T cells are produced in the bone marrow & migrate to the thymus.
Here they go through a rigorous selections
process.
Only T cells that react to antigen but not self exit.
The rest die by apoptosis.
NEJM 2001;344(9): 655 – 664.

63. Peripheral T Cell Tolerance
If autoreactive T cells enter the circulation,
there are several mechanisms that can prevent an autoimmune reaction.
NEJM 2001;344(9): 655 – 664.

64. B Cell Tolerance PERIPHERAL CENTRAL
Clonal deletion of autoreactive B cells in the bone marrow, spleen & lymph nodes.
PERIPHERAL
Lack of help from T cells is the predominant factor.

65. Breakdown in peripheral tolerance

66. 3. Autoimmunity Breakdown in mechanisms preserving tolerance to self
Severe enough to cause a pathological condition

67. Autoimmune diseases Organ specific e.g. Multisystem e.g.
Insulin dependant diabetes
Myasthenia gravis
Multisystem e.g.
Rheumatoid arthritis
SLE

68. Mechanisms ENVIRONMENTAL FACTORS GENETIC FACTORS AUTOIMMUNE DISEASE
Infectious/ noninfectious triggers
Hypothesis : Molecular mimicry
GENETIC FACTORS
Aberant MHC/HLA - present self peptide
Autoreactive T & B cells
AUTOIMMUNE DISEASE
Molecular mimicry :
The antigen looks similar to a self-peptide. As a result, the body produces an immune response to the trigger factor as well as to self.

69. The Major Theories in the Development of Autoimmune Diseases
Release of the normally sequestered antigens
Increased expression of autoantigen/cryptic epitope/MHC II
Molecular mimicry, Epitope spreading
Defects in apoptosis
Decreased cell numbers or function of suppressor and/or regulatory cells
Altered Th1 and Th2 cytokine pattern
Increased expression of costimulatory molecules
Release of inflammatory mediators

70. Autoantibodies in Connective Tissue Diseases
Produced by B cells
May be pathogenic eg.
Form immune complexes in lupus nephritis
Markers of certain diseases
May not be diagnostic
Apart from rheumatic disorders, they may be found in normal population & with other conditions
Therefore only test when clinically indicated.

71. Autoantibodies associated with disease
AUTOANTIBODY
Rheumatoid Arthritis
Rheumatoid factor
SLE
ANA,dsDNA, Smith
Scleroderma
ANA,centromere,
topoisomerase
Antiphospholipid
Syndrome
Anticardiolipin (ACLA)
Sjogren’s syndrome
Ro, La
Polymyositis
Jo-1
Dermatomyositis
Mi-2
Wegener’s granulomatosis
c-ANCA

72. Cellular Targets for autoantibodies
Ab to intracellular proteins
-proteinase 3
cANCA
Ab to cell membrane
Proteins
ACLA
Ab to IgG
Rheumatoid factor
Antinuclear antibodies (ANA)
dsDNA
ENA – Smith, Ro , La, RNP
Centromere, topoisomerase
Ribosomal &
lysosomal components
-t RNA synthetase
AntiJo 1
This diagram depicts the autoantibodies & their respective target antigens

73. 4. Rheumatologic conditions
Immune Mechanisms
Tolerance
Autoimmunity
4. Rheumatologic conditions
Rheumatoid arthritis
Systemic Lupus Erythematosis
Spondarthropathies
Inflammatory myopathies
Systemic sclerosis
The above disease will be used to highlight some of the concepts of Immunology in Rheumatology.
Note that the details of each pathway does NOT have to be memorized.

74. Rheumatoid Arthritis Chronic autoimmune disorder
Affects 1% of population
A symmetrical peripheral polyarthritis of unknown etiology that leads to joint deformity & destruction due to erosion of cartilage & bone

75. Inflammation Drives Arthritis
The inflammatory process results in damage to cartilage & bone
NEJM 2001; 344 (12): 907 – 916.

76. Rheumatoid Factor Rheumatoid Factor is an autoantibody produced in RA
It is however produced in several other conditions
 Clinical features are important in making the diagnosis
Anti-CCP Ab

77. Rheumatoid Arthritis Current therapies
Nonsteroidal anti-inflammatory drugs (NSAIDs)
Oral corticosteroids
Disease-modifying antirheumatic drugs (DMARDs)
D-penicillamine, auranofin, hydroxychloroquine, azathioprine, MTX
MTX has the most rapid onset of action and is well tolerated with long-term use
Many patients receiving DMARD therapy show only partial symptom relief and still exhibit features of active disease

78. New Agents for the Treatment of RA
Cytokine inhibitors
Human monoclonal Ab to TNFα
PEGylated anti-TNFα
Monoclonal antibody to IL-6 receptor
JAK3 inhibition
Co-stimulatory molecule blockers-abatacept
Targeted B-cell therapy- anti-CD20
Other unique mechanisms of action

79. Systemic Lupus Erythematosus
A generalized connective tissue disorder affecting many organs and characterized by the production of many autoantibodies
Signs:
Arthritis
“Butterfly” rash on face
Sensitivity to sunlight
Renal failure
Headaches
Mental disorders

80. Systemic lupus erythematosus classification criteria (SOAP BRAIN MD)
5. Blood/Hematologic disorder: (a) hemolytic anemia or (b) leukopenia of < 4.0 x (c) lymphopenia of < 1.5 x (d) thrombocytopenia < 100 X 109
6. Renal disorder: (a) proteinuria > 0.5 gm/24 h or 3+ dipstick or (b) cellular casts
7. Antinuclear antibody (positive ANA)
8. Immunologic disorders: (a) raised anti-native DNA antibody binding or (b) anti-Sm antibody or (c) positive anti-phospholipid antibody work-up
9. Neurological disorder: (a) seizures or (b) psychosis
1. Serositis: (a) pleuritis, or (b) pericarditis
2. Oral ulcers
3. Arthritis
4. Photosensitivity
10. Malar rash
11. Discoid rash
". ..A person shall be said to have SLE if four or more of the 11 criteria are present, serially or simultaneously, during any interval of observation."

81. Lupus Nephritis
The kidney biopsy on the right is from a patient with diffuse proliferative lupus nephritis shows massive deposits of IgG on immunofluorescence

82. Ankylosing Spondylitis
AS is a chronic inflammatory disease of the axial skeleton manifested by back pain & progressive stiffness of the spine

83. Ankylosing Spondylitis
The prevalence of the MHC,HLA-B27 is high in
Caucasians
but rare in Black
populations with Ankylosing Spondylitis

84. Dermatomyositis An idiopathic inflammatory myopathy associated
with certain characteristic cutaneous manifestations

85. Note: the inflammatory infiltrate in the muscle
biopsy of this patient with Dermatomyositis

86. Scleroderma The term encompasses a heterogeneous group of
conditions linked by the presence of thickened
sclerotic skin lesions

87. The inflammatory process in Scleroderma results a marked fibrotic precess responsible for many of the clinical features

88. Scleroderma Lung Disease
2 important lung diseases which occur due to the inflammatory process in Scleroderma

89. Summary Medical Assistant
Knowledge of the immune system forms the basis of understanding many of the diseases and disorders of the immune system and has become the focus of many exciting new treatment strategies.
You must have knowledge of this system when assisting the physician during the examination of a patient who is having problems with their immune system.

90. Apply Your Knowledge
Your 18-year-old patient states that he thinks his right big toe is inflamed. What symptoms would you expect to see?

91. Apply Your Knowledge - Answer
Your 18-year-old patient states that he thinks his right big toe is inflamed. What symptoms would you expect to see?
Redness, heat, swelling, and pain

92. Apply Your Knowledge
How can a patient contract HIV?

93. Apply Your Knowledge -Answer
How can a patient contract HIV?
Most common routes of transmission are through sexual contact, blood, or from mother to child during pregnancy or breast-feeding

94. Apply Your Knowledge
As you are taking your patient to the exam room, you notice that she has “Butterfly” rash on her face. What disorder exhibits this sign?

95. Apply Your Knowledge -Answer
As you are taking your patient to the exam room, you notice that she has “Butterfly” rash on her face. What disorder exhibits this sign?
Lupus

96. References
Sompayrac L. How the Immune System works. Blackwell Science, Inc. 1999
Roitt IM. Roitt’s Essential Immunology 10th ed. Blackwell Science 2001
Hochburg et al. Rheumatology 3rd ed. Mosby 2003
UpToDate 12.3
Kalla AA. Rheumatology Handbook. Rheumatic Diseases Unit Univrersity of Cape Town. 2003

97. References (cont)
Parkin J, Cohen B. An overview of the immune system. Lancet 2001;357:
Mackay IR, Rosen FS. Tolerance and Autoimmunity. NEJM 2001;344(9): 655 – 664.
Mackay IR, Rosen FS. Autoimmune diseases. NEJM 2001; 345(5):
Epstein FH. Cytokine pathway and Joint Inflammation in Rheumatoid Arthritis. NEJM 2001; 344 (12): 907 – 916.
Yuan G et al. Immunologic Intervention in the Pathogenesis of Osteoarthritis. Arthritis & Rheumatism 2003; 48(3)

98. 감사합니다

99. Introduction Immune system - protects the body against Bacteria
Viruses
Fungi
Toxins
Parasites
Cancer

100. Defenses Against Disease
Nonspecific Defenses
Species Resistance
Mechanical Barriers
Chemical Barriers
Fever
Inflammation
Phagocytosis
Nonspecific defenses - mechanisms to protect us against pathogens in general

101. Specific Defenses Against Disease
Specific defenses are called immunities and protect the body against very specific pathogens
Lymphocytes and macrophages are the major white blood cells involved in specific defenses.
Antibodies and complement are the major proteins involved in specific defenses

102. Immunity Can Be Divided Into 2 Main Components:
Innate immunity
Rapid acting, nonspecific
Specific or adaptive immunity
Slower onset of action
Targets pathogens that escape the innate immune system
Activated by the innate immune system

103. Physical barrier Complement
Innate NK cells
Phagocytic cells
- neutrophils
- macrophages
IMMUNITY Eosinophils
Mast Cells
Humoral ( B cells)
Specific
CMI ( T cells)

104. Two major types of lymphocytes
B Cells & T Cells
Two major types of lymphocytes
B Cells and T Cells
Recognize antigens in the body
B cells
Respond to antigens by becoming plasma cell - make antibodies against the specific antigen
T Cells
Cell-mediated
bind to antigens on cells and attack them directly

105. T Cells
Helper T cells
increase antibody formation, memory cell formation, B cell formation, and phagocytosis
Memory T cells
memory cells “remember” the pathogen that activated the original T cell
person is later exposed to the same pathogen, memory cells trigger an immune response that is more effective than the first immune response

106. Antibodies
IgG - recognizes bacteria, viruses, and toxins. It can also activate complement.
IgA - found in secretions of the body such as breast milk, sweat, tears, saliva, and mucus-prevents pathogens from entering the body.
IgM - very large - primarily binds to antigens on food, bacteria, or incompatible blood cells- activates complement.
IgE - found wherever IgA is located- involved in triggering allergic reactions.