immunology 1, 2, 3

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Understanding Immunology

Dr. Ahmed Elshebiny , MDDr. Ahmed Elshebiny , MDLecturer of Internal MedicineLecturer of Internal Medicine

Faculty of Medicine, Menoufyia UniversityFaculty of Medicine, Menoufyia University

Former Clinical Research FellowFormer Clinical Research Fellow,,Joslin Diabetes Center, Harvard UniversityJoslin Diabetes Center, Harvard University

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Immunology Course Basics:

Immune system and disease Diseases:

Immunopatholy Applications:

Therapeutic applications

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Immune system and disease Immunity Immune system Innate Immunity Adaptive Immunity Immune Recognition

Cells of the Immune system Complement Immunoglobulins Cytokines

Human disease & Immunity Immunopathology Diagnostics Therapeutic applications

Structure andFunction of The

System

Cells and Molecules of

Immunity

Introduction toClinical

Immunology

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Immunity

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Immunity is characterized by:1. Specificity – activated by and responds to a

specific antigen

2. Versatility – is ready to confront any antigen at any time

3. Memory – “remembers” any antigen it has encountered

4. Tolerance – responds to foreign substances but ignores normal tissues

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History of discovery of immunity “Immune” meaning Noticing immunity centuries ago Small pox Edward Jenner Recent developments

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1st Line defense: Physical and chemical barriers

Skin – acts as a barrier to invasion Sweat – has chemicals which can kill different

pathogens. Tears - have lysozyme which has powerful digestive

abilities that render antigens harmless. Saliva – also has lysozyme. Mucus - can trap pathogens, which are then sneezed,

coughed, washed away, or destroyed by chemicals. Stomach Acid – destroys pathogens

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Innate Adaptive

Immunity

Immunity

Cellular HumoralCellular Humoral

Let us see this video about immunity

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Inflammation

Inflammation is a nonspecific response of living tissue to localize and eliminate the injurious agent

Immune Response

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Inflammation The word inflammation means "setting on

fire" (16th century), and the process has been known since ancient Egyptian times (c. 2500 B.C)

The cardinal signs of redness, swelling, heat, and pain were described by Celsus (first-century A.D.), and loss of function was added by Galen (130-200 A.D)

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Acute phase changes characterized by pronounced behavioral,

physiologic, biochemical and nutritional changes

Acute phase reactants Acute phase proteins

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C-reactive protein named for its capacity to precipitate the

somatic C-polysaccharide of Streptococcus Pneumoniae.

Systemic marker of inflammation produced by hepatocytes, predominantly

under transcriptional control by the cytokine IL-6

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The Immune system The immune system

recognizes, attacks, destroys, and remembers each pathogen that enters the body.  

It does this by making specialized cells and antibodies that render the pathogens harmless.

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Questions? What Happens during an infection ?

How can immune cells distinguish foreign invaders from our own cells ?

How can we make 100,000,000 different antibodies with only 30,000 genes ?

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Cells of the immune system

T-cell development

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Cells of the immune system

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Polymorphonuclear cells1- Neutrophils

Stored in bone marrow Released in response to infection Have surface receptors for IgG,

IgA, complement Phagocytose and destroy bacteria Short lived Dead neutrophils make a part of

pus

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Polymorphonuclear cells2-Basophils and mast cells

Basophil circulate Mast cells are tissue bound Released in response to infection Have surface receptors for IgE, complement C3, C5 Produce histamine, prostaglandins, leukotrienes and

proteases Involved in immune response to parasites Involved in immediate hypersensitivity

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Polymorphonuclear cells3-Eosinophils

Allergy Have surface receptors for IgG, complement

C3, C5 Also binds to IgE but less than mast cells or

basophils Phagocytose antigen antibody complexes

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Macrophage In the tissues Long lived Initiate immune responses as they display antigens

from the pathogens to the lymphocytes.

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Phagocytosis

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Lymphocytes B and T cells mature then

circulate in the blood and lymph

B-cells mature in bone marrow

T-cells mature in thymus

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B-Lymphocytes The huge variety is caused

by genes coding for abs changing slightly during development.

The number of plasma cells goes down after a few weeks

Antibodies stay in the blood longer but eventually their numbers go down too.

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T-Lymphocytes CD3 in all types CD4 in helper

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Natural killer cells Large granular lymphocytes Recognize and destroy cells bedaring viral or

tumor surface markers

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Complement Definition : series of heat-labile serum proteins

Site : serum and all tissue fluids except urine and CSF

Synthesis : in liver – appear in fetal circulation during 1st 13 W Function : Responsible for certain aspects of immune response and inflammatory response

Activation : antigen-antibody complex or endotoxin, capsule series of proteins activated sequentially

Inactivation: inhibitors in plasma (short lived)

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Complement system Plasma protein sequence cascade Triggered by

Classic pathway Alternative pathway Lectin binding

Complement

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Complement ActivationComplement ActivationClassical PathwayClassical Pathway CC11

CC4 4 CC22

CC3 3 Alternative pathwayAlternative pathway CC55

CC66

CC77

CC88

CC99

Membrane damageMembrane damage

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Classic And Alterenative pathwaysClassic And Alterenative pathways

Classic Pathway Alternative pathwayClassic Pathway Alternative pathway

* Specific acquired immunity * Non-specific innate immunity* Specific acquired immunity * Non-specific innate immunity

* Initiated by antibody * Bacterial endotoxin, capsule* Initiated by antibody * Bacterial endotoxin, capsule

* Interaction of all components * C1, C4, C2 are by-passed* Interaction of all components * C1, C4, C2 are by-passed

* Properdin system not involved * Properdin system is involved* Properdin system not involved * Properdin system is involved

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Complement and disease Complement difficiency Difficiency of classic pathway components C3 difficiency Terminal complement protein difficiencies Difficiency of regulatory proteins

Heriditary angioedema PNH Complement consumption as in SLE

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Functions of Complement Biologically active complement products

have 3 main functions Opsonisation …… C3b Chemotaxis and inflammation……C3a, C5a Cell lysis……….. C5,C6,C7,C8,C9

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Immunoglobulins

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Immunoglobulins & age

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Plasma protein electrophoresis

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Antigens Antigens are macromolecules that elicit an immune

response in the body. The most common antigens are proteins and polysaccharides.

Hapten: incomplete Ag which can be conjugated with a carrier protein to form a complete Ag.

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Cytokines hormone-like soluble low molecular weight

protein molecules that act, generally in a paracrine fashion, to regulate immune responses

They are secreted not only by lymphocytes and macrophages but also by endothelial cells, adipocytes, neurons, glial cells, and other types of cells

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Chemokines cytokines that regulate cell movement and

trafficking; they attract neutrophils and other white blood cells to areas of inflammation or immune response.

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Interferons are potent cytokines that possess antiviral,

immunomodulating, and antiproliferative activities Interferon-α, Interferon-β & Interferon-γ Recombinant, natural, and pegylated IFNs currently

are available for treatment of condyloma acuminatum, chronic HCV infection, chronic

HBV infection, Kaposi's sarcoma in HIV-infected patients, other malignancies, multiple sclerosis

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Tolerance It is a specific immunologic unresponsiveness Unresponsiveness to self antigens is known as

auto tolerance

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ToleranceB-cells become tolerant to self by two mechanisms: 1) Clonal deletion Probably while B-cell precursors are in bon marrow

2) Clonal anergy B cells in the periphery

Tolerance in B-cells is less complete than in T-cells

The most autoimmune diseases are mediated by antibodies

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Factors affecting induction of tolerance Maturity of the immune system Antigen complexity Antigen dose Continuous presence of antigen Immunosuppressive drugs

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Clinical importance of tolerance Organ transplantation Tumor development Autoimmune diseases

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Autoimmune Diseases Autoimmune diseases occur due to breakdown of

the mechanisms that maintain auto tolerance

Auto-antibodies and self reactive T-cells are produced, resulting in tissue damage by several mechanisms

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References Lecture notes: Immunology 2010 Essential revision notes for MRCP 2009 Merck manual : online textbook Kumar & Klark : Clinical Medicine 2009 Other Web Resources & books

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Understanding Immunology(2)

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Immunodeficiency

Immunopathology

Immunopathology

Autoimmunity

Hypersensitivity

LymphoproliferativeDiseases

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Immunodeficiency

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Acquired Immunodeficiency Infections Drugs and toxins Radiation Malignancy Malnutrition , Diabetes & Renal failure Splenectomy & Thymectomy Aging Stress

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HIV/AIDS Infects T-helper cells Progressive decline in CD4 counts Impaired cell mediated immunity Associated polyclonal activation of B-cells

and hypergamaglobulinemia

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Immune response to HIV

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CD4 depletion along the course of HIV

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Primary immunodeficiency Immune system not fully developed until at

least two years of age. Immuno-competent kids may have up to six

URIs per year. Ten URIs per year if they attend daycare.

Risk Factors for Frequent Infections When to suspect?

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Complementdeficiencies

Immunodeficiency

Immunodeficiency

B-cell disorders

Neutrophil Disorders

T-cell disorders

Combined B and T-cell disorders

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Neutrophil disorders Chronic granulomatous disease Chediak-Higashi disease Hyper Ig-E syndrome Myeloperoxidase deficiency Lazy Leukocyte Syndrome Leukocyte adhesion deficiency

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Lymphocyte disorders

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B-cell disorders IgA deficiency Common variable immunodeficiency Bruton’s X-linked agamaglobulinemia( no

circulating B-cells)

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T-cell disorders Digeorge syndrome Nezelof syndrome Purine nucleoside phosphorylase deficiency

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Combined B- and T-cell disorders Severe combined immunodeficiency Reticular dysgenesis Ataxia telangiectasia Wiskott-Aldrich syndrome

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Diagnosis of primary immunodeficiency History Examination Investigations of the immune system

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Clinical history

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Disease Specific Skin Findings Eczema and petechiae – Wiskott-Aldrich

Syndrome Telangiectasia – Ataxia-Telangiectasia Oculocutaneous albinism – Chediak-Higashi Dermatomyositis-like rash – XLA Chronic dermatitis – Hyper-IgE Generalized molluscum, extensive warts,

candidiasis – T-Cell defects

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2 -Autoimmunity

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Type-1 diabetes

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Etiology of autoimmune diseases Genetic predisposition Cross reactivity Alteration of self antigens Hormonal influences

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Mechanisms Of Disease Production in autoimmunity

1) Binding of an autoantibody to host cells result in complement fixation and tissue destruction

e.g. Haemolytic anemia (Type II hypersensitivity)2) Formation of immune complexes and their deposition in tissues, joints, kidney and skin The immune complexes fix complement resulting in tissue damage e.g. SLE and rheumatoid arthritis (Type III hyper.) 3) DTH reactions (Type IV)) due to auto reactive T-cells e.g. Ulcerative colitis, multiple sclerosis and type I diabetes

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Auto-antibodies ANA Anti-dsDNA Anti-smith RF Anti-Ro Anti-La ANCA ASMA Anti-mitochondrial

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Transplacental transfer

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3 -Allergy and Hypersensitivity Immune responses with undesirable

consequences 5 Types Type I: Anaphylactic or immediate Type II:Antibody dependant cytotoxcicity Type III:Immune complex mediated or Arthus TypeIV: Cell mediated or delayed Type V: Stimulatory

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4 -Malignancies of the immune system Lymphocytosis and lymphadenopathy Leukemias Lymphomas Mylomas and monoclonal gammopathies

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Hodgkin's disease

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Immunity and cancer Tumor immunology Tumor antigens Immune surveillance system Tumor escape from immune surveillance

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Tumor MarkersTumor Markers

* Tumor markers :* Tumor markers :

Tumor antigensTumor antigens

* They are either or* They are either or

Tumor products Tumor products

(enzymes and hormones)(enzymes and hormones)

* Tumor products are released in the serum of patients* Tumor products are released in the serum of patients

* They are used to * They are used to confirm diagnosisconfirm diagnosis and and follow upfollow up the the response to response to therapytherapy

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Tumor AntigensTumor Antigens

1) Alpha fetoprotein antigen (AFP)1) Alpha fetoprotein antigen (AFP) in cases of hepatoma in cases of hepatoma

2) Carcinoembryoinic antigen (CEA)2) Carcinoembryoinic antigen (CEA) in gastrointestinal in gastrointestinal tumors, tumors of biliary system and cancer breasttumors, tumors of biliary system and cancer breast

3) Cancer antigen 1253) Cancer antigen 125 (CA 125)(CA 125) in ovarian carcinoma in ovarian carcinoma

4) Cancer antigen 15-3 (CA15-3)4) Cancer antigen 15-3 (CA15-3) in breast cancer in breast cancer

5) Cancer antigen 19-95) Cancer antigen 19-9 in colon and pancreatic tumor in colon and pancreatic tumor

6) Prostatic specific antigen (PSA)6) Prostatic specific antigen (PSA) in prostatic tumors in prostatic tumors

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Tumor ProductsTumor Products

a) Hormones :a) Hormones :

-- Human chorionic gonadotrophins (HCG)Human chorionic gonadotrophins (HCG) are secreted are secreted

in cases of choriocarcinomain cases of choriocarcinoma

- Thyroxin (T3 & T4)- Thyroxin (T3 & T4) is secreted in cases of cancer is secreted in cases of cancer

of thyroid glandof thyroid gland

b) Enzymes :b) Enzymes :

- Acid phosphatase- Acid phosphatase enzymes in cases of cancer prostae enzymes in cases of cancer prostae

- Alkaline phosphatese, lipase and amylase- Alkaline phosphatese, lipase and amylase enzymes in enzymes in cases of cancer pancreascases of cancer pancreas

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References Lecture notes: Immunology 2010 Essential revision notes for MRCP 2009 Merck manual : online textbook Kumar & Klark : Clinical Medicine 2009 Other Web Resources & books

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Understanding Immunology

(3)

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Immunization

Therapeutic applications of Immunology

Therapeutic applications of Immunology

Immunomodulation

Transplantation

Immunosupression

Anti-allergic

Replacement

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Immunization Passive immunization Active immunization

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History of immunization 1721---------Variolation 1796---------vaccination 1885--------- Rabies 1925--------- Toxoids 1954---------Salk 1956---------Sabin 1975--------- hepatitis B 1995--------- hepatitis A 2007---------- HPV

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Types of vaccines Killed vaccines

Salk , pertussis, typhoid, rabies

Live attenuated vaccines BCG, sabin, rubella, measles, mumps

Subunit vaccines Hepatitis B, H influenza, strept pneumonia

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No satisfactory vaccine for HIV, HCV Herpes viruses Rhinoviruses T.B Leprosy Cholera Parasites

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Pneumococcal vaccination INDICATIONS:

Primary vaccination (conjugate vaccine) children 2 yr. or older with

Anatomical or functional asplenia Sickle cell disease Nephrotic syndrome Immunosuppression

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Contraindications of vaccines Moderate or severe illness with or without fever Anaphylactic reaction to vaccine or vaccine

constituent Live attenuated vaccines

Pregnant women Immunocompromised / Immunosuppressed

children within 3-11 months of immunoglobulin

administration

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Invalid contraindications to vaccines Mild to moderate local reaction Mild acute illness with or without low grade fever Current antimicrobial therapy Convalescent phase of illnesses Prematurity and low birth weight History of penicillin or other nonspecific allergies Malnutrition

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Types of grafts Autografts Isografts Allografts (homograft): Xenograft (heterograft):

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Major Histocompatibility Complex (MHC)

The MHC is a closely linked complex of genes that govern production of the major histocompatibility

In humans, MHC resides on the short arm of chromosome 6

Three genes (HLA-A, HLA-B, HLA-C) code for the class I MHC proteins

Several HLA-D loci determine the class II MHC proteins i.e. DP, DQ and DR

HLA genes are very diverse (polymorphic)i.e. there are many alleles of the class I and II genes

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Class III MHC Between the class I and class II gene loci, there is a

third locus (Class III)

This locus contains genes encoding tumor necrosis factor, lymphotoxin and two complement components (C2 and C4)

Class III antigens do not participate in MHC restriction or graft rejection

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MHC I & II

MHC Class I MHC Class II

Nomenclature HLA-A, HLA-B, HLA-C HLA-DP, HLA-DQ ,

HLA-DR

Found on All nucleated somatic cells Macrophages, B-cells, Dentritic cells, langerhans

cells of skin and activated T cells

Recognized by CD8 TC cells CD4 TH cells

Functions Presentation of Ag to TC cells leading to elimination of tumor or infected host

cell

Presentation of Ag to TH cells which secrete

cytokines

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MHC and antigen presentation T-cells are only activated when they

recognize both antigen and class I MHC molecules in association

Helper T-cells recognize antigens on antigen-presenting cells only when the antigens are presented on the surface of cells in association with class II MHC

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Matching with donors HLA DR and HLA B in the kidney Heart and liver survive well with

immunosupression

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Types of rejection Hyperacute rejection Acute Rejection Acute late Chronic or late rejection

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Graft Versus Host reaction (GVH) An immunologically competent graft is transplanted

into an immunologically suppressed recipient (host)

The grafted cells survive and react against the host cells i.e instead of reaction of host against the graft, the reverse occurs

GVH reaction is characterized by fever, pancytopenia, weight loss, rash , diarrhea, hepatsplenomegaly and death

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Immunosupression Calcineurin inhibitors Azathioprin Methotrexate Cyclophosphamide

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Replacement therapy IV IG C1 estrase

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IG therapy IV SC Indications Side effects

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Antibodies as drugs Infliximab Etanercept Anakinra Rutiximab Abciximab Digibind Natalizumab

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Nomenclature of monoclonal absPrefix Target Source Suffix

variable

-o(s)- bone -u- human

-mab

-vi(r)- viral -o- mouse

-ba(c)- bacterial -a- rat

-li(m)- immune -e- hamster

-le(s)- infectious lesions -i- primate

-ci(r)- cardiovascular -xi- chimeric

-mu(l)- musculoskeletal -zu- humanized

-ki(n)- interleukin -axo- rat/murine hybrid

-co(l)- colonic tumor

-me(l)- melanoma

-ma(r)- mammary tumor

-go(t)- testicular tumor

-go(v)- ovarian tumor

-pr(o)- prostate tumor

-tu(m)- miscellaneous tumor

-neu(r)- nervous system

-tox(a)- toxin as target

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Rutiximab( anti CD-20) Rituxan® by Genentech Anti-B cell (CD20) antibody First approved in 1997 for use in B-cell lymphoma Given in combination with Methotrexate Directed for patients who do not respond to Anti-

TNF treatments Indicates the rheumatoid arthritis has a B cell

component to its pathology

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Desensitization In ttt of allergic conditions

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Anti-allergic drugs Antihistamines Mast cell stabilizers others

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Immunotherapy for cancer Pathogen vaccines Tumor vaccines others

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References Lecture notes: Immunology 2010 Essential revision notes for MRCP 2009 Merck manual : online textbook Kumar & Klark : Clinical Medicine 2009 Other Web Resources & books

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